US20190054182A1

US20190054182A1 - Trispecific and/or trivalent binding proteins for prevention or treatment of hiv infection

Info

Publication number: US20190054182A1
Application number: US15/770,471
Authority: US
Inventors: Zhi-Yong Yang; Gary J. Nabel; Ling Xu; Ronnie Wei; Huawei Qiu; Jochen Beninga; Jochen Kruip; Ercole Rao; Wulf Dirk LEUSCHNER; Christian Beil; Christian Lange; Mark Connors; John R. Mascola; Richard A. Koup; Jinghe Huang; Nicole A. DORIA-ROSE; Tongqing Zhou; Peter D. Kwong; Young Do Kwon; Amarendra PEGU
Original assignee: Sanofi SA; US Department of Health and Human Services
Current assignee: Sanofi SA; US Department of Health and Human Services
Priority date: 2015-10-25
Filing date: 2016-10-24
Publication date: 2019-02-21
Also published as: US20250312475A1; IL301140A; NZ781602A; MY192278A; PE20181167A1; EP3365366A1; JP2023085476A; EA201891028A1; ES2894304T3; BR112018008011A2; JP2021072847A; WO2017074878A8; AU2016347058B2; AR106466A1; CN116789841A; NZ742825A; CN116675776A; IL258822A; MX2022014631A; TW201730210A

Abstract

Provided herein are compositions comprising trispecific and/or trivalent binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins or one or more T-cell receptors, where in a first pair of polypeptides forming the binding protein possess dual variable domains having a cross-over orientation and wherein a second pair of polypeptides forming the binding protein possess a single variable domain. Also provided herein are methods for making trispecific and/or trivalent binding proteins and uses of such binding proteins for the treatment and/or prevention of HIV/AIDS.

Description

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims the priority benefit of U.S. Provisional Application Ser. No. 62/246,113, filed Oct. 25, 2015, EP Application No. EP16305211.1, filed Feb. 24, 2016, U.S. Provisional Application Ser. No. 62/322,029, filed Apr. 13, 2016, and U.S. Provisional Application Ser. No. 62/331,169, filed May 3, 2016, which are incorporated herein by reference in their entirety.
This invention was created in the performance of a Cooperative Research and Development Agreement (NIAID #2014-0038) with the National Institutes of Health, an agency of the Department of Health and Human Services. The Government of the United States has certain rights in this invention.

SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE

The content of the following submission on ASCII text file is incorporated herein by reference in its entirety: a computer readable form (CRF) of the Sequence Listing (file name: 183952027041SEQLIST.txt, date recorded: Oct. 19, 2016, size: 1,064 KB).

FIELD OF THE INVENTION

The disclosure relates to trispecific and/or trivalent binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins, wherein a first pair of polypeptides forming the binding protein possess dual variable domains having a cross-over orientation and wherein a second pair of polypeptides forming the binding protein possess a single variable domain. The disclosure also relates to methods for making trispecific and/or trivalent binding proteins and uses of such binding proteins for treating and/or preventing HIV/AIDS.

BACKGROUND

One of the challenges in treating HIV/AIDS with neutralizing antibodies is potential breakthrough infection due to the high mutation rate of HIV-1 viruses. Additionally, virological events in the early weeks following HIV-1 transmission set the stage for lifelong chronic infection that remains incurable with currently available combination antiretroviral therapy (cART). This is due, at least in part, to the early establishment of viral reservoirs, including latently infected cells, which persist despite cART, leading to recrudescent infection when treatment is interrupted. Newly discovered anti-HIV-1 neutralizing antibodies with improved breadth and potency may provide more options for HIV/AIDS treatment and prevention; however, breakthrough infection remains a major issue in the field.

BRIEF SUMMARY

In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I];
a second polypeptide chain comprises a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1 [II];
a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1 [III];
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-C_L [IV];
wherein
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is an immunoglobulin C_H1heavy chain constant domain; and
L₁, L₂, L₃, and L₄are amino acid linkers;
and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
In some embodiments, the second polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains. In some embodiments, the third polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I];
and a second polypeptide chain comprises a structure represented by the formula:
V_H1-L₃-V_H2-L₄-hinge-C_H2-C_H3 [II];
and a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1-hinge-C_H2-C_H3 [III];
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-C_L [IV];
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is an immunoglobulin C_H1heavy chain constant domain;
C_H2is an immunoglobulin C_H2heavy chain constant domain;
C_H3is an immunoglobulin C_H3heavy chain constant domain;
hinge is an immunoglobulin hinge region connecting the C_H1and C_H2domains; and
L₁, L₂, L₃and L₄are amino acid linkers;
and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
In some embodiments, the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the C_H3domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
In some embodiments, the one or more HIV target protein is selected from the group consisting of glycoprotein 120, glycoprotein 41 and glycoprotein 160. In some embodiments, the binding protein is trispecific and capable of specifically binding three different epitopes on a single HIV target protein. In some embodiments, the binding protein is trispecific and capable of specifically binding two different epitopes on a first HIV target protein, and one epitope on a second HIV target protein, wherein the first and second HIV target proteins are different. In some embodiments, the binding protein is trispecific and capable of specifically binding three different antigen targets. In some embodiments, the binding protein is capable of inhibiting the function of one or more HIV target proteins. In some embodiments, V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively. In some embodiments, V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521. In some embodiments, V_L1comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521. In some embodiments, V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively, a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively, or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively. In some embodiments, V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521. In some embodiments, V_L2comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521. In some embodiments, V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively. In some embodiments, V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521. In some embodiments, V_L3comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521. In some embodiments, V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively. In some embodiments, V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508. In some embodiments, V_H1comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508. In some embodiments, V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively. In some embodiments, V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508. In some embodiments, V_H2comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508. In some embodiments, V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively. In some embodiments, V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508. In some embodiments, V_H3comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508. In some embodiments, V_L1comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; V_L2comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; V_L3comprises a CDR-L1 comprising the sequence of SEQ ID NO: 266, a CDR-L2 comprising the sequence of SEQ ID NO: 267, and a CDR-L3 comprising the sequence of SEQ ID NO: 268; V_H1comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; V_H2comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; and V_H3comprises a CDR-H1 comprising the sequence of SEQ ID NO: 248, a CDR-H2 comprising the sequence of SEQ ID NO: 497, and a CDR-H3 comprising the sequence of SEQ ID NO: 250. In some embodiments, V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 512; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; and V _H3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 502. In some embodiments, V_L1comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; V_L2comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; V_L3comprises a light chain variable domain comprising the sequence of SEQ ID NO: 512; V_H1comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; V_H2comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; and V _H3 comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 502. In some embodiments, V_L1comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; V_L2comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; V_L3comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; V_H1comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; V_H2comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; and V_H3comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253. In some embodiments, V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503. In some embodiments, V_LJ comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; V_L2comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; V_L3comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513, V_H1comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; V_H2comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; and V_H3comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503. In some embodiments, V_L1comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; V_L2comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; V_L3comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; V_H1comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; V_H2comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; and V_H3comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253. In some embodiments, V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503. In some embodiments, V_L1comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; V_L2comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; V_L3comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; V_H1comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; V_H2comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; and V_H3comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503. In some embodiments, at least one of L₁, L₂, L₃, or L₄is independently 0 amino acids in length. In some embodiments, L₁, L₂, L₃, or L₄are each independently at least one amino acid in length. In some embodiments, L₁comprises Asp-Lys-Thr-His-Thr (SEQ ID NO: 525).
In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain comprises a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1 [II]
and a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1 [III]
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-C_L [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain; and
L₁, L₂, L₃, and L₄are amino acid linkers;
wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;
wherein:
(a) V_L1, V_L2and V_L3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 2, 4, 10, 12, 18, 20, 26, 28, 34, 36, 42, 44, 50, 52, 58, 60, 66, 68, 74, 76, 82, 84, 90, 92, 98, 100, 106, 108, 114, 116, 122, 124, 130, 132, 138, 140, 146, 148, 154, 156, 162, 164, 170, 172, 178, 180, 186, 188, 194, 196, 202, 204, 210, 212, 218, 220, 226, 228, 233, 235, 241, 243; or
(b) V_L1, V_L2and V_L3each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs:266-283; and
wherein:
(a) V_H1, V_H2, and V_H3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 1, 3, 9, 11, 17, 10, 25, 27, 33, 35, 41, 43, 49, 51, 57, 59, 65, 67, 73, 75, 81, 83, 89, 91, 97, 99, 105, 107, 113, 115, 121, 123, 129, 131, 137, 139, 145, 147, 153, 155, 161, 163, 169, 171, 177, 179, 185, 187, 193, 195, 201, 203, 209, 211, 217, 219, 225, 227, 232, 234, 240, 242; or
(b) V_H1, V_H2, and V_H3each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-265.
In some embodiments, the second polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains. In some embodiments, the third polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain comprises a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1-hinge-C_H2-C_H3 [II]
and a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1-hinge-C_H2-C_H3 [III]
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-C_L [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain;
C_H2is an immunoglobulin C_H2heavy chain constant domain;
C_H3is an immunoglobulin C_H3heavy chain constant domain;
hinge is an immunoglobulin hinge region connecting the C_H1and C_H2domains; and
L₁, L₂, L₃, and L₄are amino acid linkers;
wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;
wherein:
(a) V_L1, V_L2and V_L3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 2, 4, 10, 12, 18, 20, 26, 28, 34, 36, 42, 44, 50, 52, 58, 60, 66, 68, 74, 76, 82, 84, 90, 92, 98, 100, 106, 108, 114, 116, 122, 124, 130, 132, 138, 140, 146, 148, 154, 156, 162, 164, 170, 172, 178, 180, 186, 188, 194, 196, 202, 204, 210, 212, 218, 220, 226, 228, 233, 235, 241, 243; or
(b) V_L1, V_L2and V_L3each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs:266-283; and
wherein:
(a) V_H1, V_H2, and V_H3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 1, 3, 9, 11, 17, 10, 25, 27, 33, 35, 41, 43, 49, 51, 57, 59, 65, 67, 73, 75, 81, 83, 89, 91, 97, 99, 105, 107, 113, 115, 121, 123, 129, 131, 137, 139, 145, 147, 153, 155, 161, 163, 169, 171, 177, 179, 185, 187, 193, 195, 201, 203, 209, 211, 217, 219, 225, 227, 232, 234, 240, 242; or
(b) V_H1, V_H2, and V_H3each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-265.
In some embodiments, the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the C_H3domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
In some embodiments, at least one of L₁, L₂, L₃, or L₄is independently 0 amino acids in length. In some embodiments, L₁, L₂, L₃, or L₄are each independently at least one amino acid in length. In some embodiments, L₁comprises Asp-Lys-Thr-His-Thr (SEQ ID NO: 525).
In one embodiment, the disclosure provides a trispecific and/or trivalent binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind three different HIV target proteins, wherein a first polypeptide chain has a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain has a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1 [II]
and a third polypeptide chain has a structure represented by the formula:
V_H3-C_H1 [III]
and a fourth polypeptide chain has a structure represented by the formula:
V_L3-C_L [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain; and
L₁, L₂, L₃and L₄are amino acid linkers;
and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain has a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain has a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1 [II]
and a third polypeptide chain has a structure represented by the formula:
V_H3-C_H1 [III]
and a fourth polypeptide chain has a structure represented by the formula:
V_L3-C_L [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain; and
L₁, L₂, L₃, and L₄are amino acid linkers;
wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;
wherein:
(a) V_L1, V_L2and V_L3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 2, 4, 10, 12, 18, 20, 26, 28, 34, 36, 42, 44, 50, 52, 58, 60, 66, 68, 74, 76, 82, 84, 90, 92, 98, 100, 106, 108, 114, 116, 122, 124, 130, 132, 138, 140, 146, 148, 154, 156, 162, 164, 170, 172, 178, 180, 186, 188, 194, 196, 202, 204, 210, 212, 218, 220, 226, 228, 233, 235, 241, 243; or
(b) V_L1, V_L2and V_L3each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs:266-283; and
wherein:
(a) V_H1, V_H2, and V_H3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 1, 3, 9, 11, 17, 10, 25, 27, 33, 35, 41, 43, 49, 51, 57, 59, 65, 67, 73, 75, 81, 83, 89, 91, 97, 99, 105, 107, 113, 115, 121, 123, 129, 131, 137, 139, 145, 147, 153, 155, 161, 163, 169, 171, 177, 179, 185, 187, 193, 195, 201, 203, 209, 211, 217, 219, 225, 227, 232, 234, 240, 242; or
(b) V_H1, V_H2, and V_H3each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-265.
In another embodiment, the disclosure provides a binding protein comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain wherein:
(a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 4; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2;
(b) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 12 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 12; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 11 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 11; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 9 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 9; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10;
(c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 20 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 20; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 19 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 17 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 17; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 18 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18;
(d) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 28 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 28; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 27 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 25 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 26 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 26;
(e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 36; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 35 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 35; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 33 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 33; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 34 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 34;
(f) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 44; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 43 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 43; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 41 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 41; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 42 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 42;
(g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 52 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 52; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 51 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 51; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 49 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 49; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 50 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 50;
(h) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 60 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 60; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 59 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 59; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 57; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 58 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 58;
(i) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 68; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 67; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 65 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 65; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 66 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 66;
(j) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 76; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 75; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 73; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 74 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 74;
(k) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 84 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 84; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 83 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 83; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 81 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 81; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 82 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 82;
(l) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 92 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:92; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 91 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 91; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 89 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 89; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 90 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 90;
(m) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 100 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 100; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 99 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 99; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 97 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 97; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 98 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 98;
(n) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 108 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 108; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 107 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 107; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 105 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 105; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 106 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 106;
(o) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 116 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 116; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 115 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 115; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 113 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 113; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 114;
(p) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 124 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 124; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 123 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 123; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 121 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 121; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 122 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 122;
(q) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 132 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 132; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 131; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 129 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 129; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 130 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 130;
(r) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 140 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 140; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 139 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 139; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 137 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 137; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 138;
(s) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 148 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 148; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 147 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 147; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 145 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 145; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 146 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 146;
(t) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 156 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 156; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 155 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 155; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 153 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 153; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 154 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 154;
(u) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 164 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 164; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 163 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 163; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 161 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 161; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 162 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 162;
(v) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 172 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 172; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 171 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 171; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 169 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 169; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 170 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 170;
(w) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 180 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 180; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 179; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 177 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 177; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 178 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 178;
(x) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 188 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 188; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 187 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 187; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 185 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 185; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 186 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 186;
(y) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 196 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 196; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 195 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 195; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 193 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 193; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 194 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 194;
(z) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 204 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 204; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 203 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 203; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 201 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 201; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 202 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 202;
(aa) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 212 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 212; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 211 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 211; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 209 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 209, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 210 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 210;
(bb) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 220 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 220; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 219 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 219; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 217 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 217; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 218 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 218;
(cc) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 228 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 228; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 227 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 227; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 225 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 225; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 226 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 226;
(dd) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 235 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 235; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 234 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 234; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 232 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 232; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 233 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 233; or
(ee) first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 243 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 243; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 242 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 242; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 240 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 240; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 241 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 241.
In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins and one or more T cell target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I];
a second polypeptide chain comprises a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1 [II];
a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1 [III];
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-C_L [IV];
wherein
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain:
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain; and
L₁, L₂, L₃, and L₄are amino acid linkers;
and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
In some embodiments, the second polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains. In some embodiments, the third polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins and one or more T cell target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I];
a second polypeptide chain comprises a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1-hinge-C_H2-C_H3 [II];
a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1-hinge-C_H2-CH₃ [III];
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-C_L [IV];
wherein
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain;
C_H2is an immunoglobulin C_H2heavy chain constant domain;
C_H3is an immunoglobulin C_H3heavy chain constant domain;
hinge is an immunoglobulin hinge region connecting the C_H1and C_H2domains; and
L₁, L₂, L₃, and L₄are amino acid linkers;
and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
In some embodiments, the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the C_H3domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
In some embodiments, the one or more HIV target proteins are selected from the group consisting of glycoprotein 120, glycoprotein 41 and glycoprotein 160. In some embodiments, the one or more T cell target proteins are CD3 or CD28. In some embodiments, the binding protein is trispecific and capable of specifically binding an HIV target protein and two different epitopes on a single T cell target protein. In some embodiments, the binding protein is trispecific and capable of specifically binding an HIV target protein and two different T cell target proteins. In some embodiments, the binding protein is trispecific and capable of specifically binding a T cell target protein and two different epitopes on a single HIV target protein. In some embodiments, the binding protein is trispecific and capable of specifically binding a T cell target protein and two different HIV target proteins. In some embodiments, the first and second polypeptide chains form two antigen binding sites that specifically target two T cell target proteins, and the third and fourth polypeptide chains form an antigen binding site that specifically binds an HIV target protein. In some embodiments, V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively. In some embodiments, V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524. In some embodiments, V_L1comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524. In some embodiments, V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively. In some embodiments, V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524. In some embodiments, V_L2comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524. In some embodiments, V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively. In some embodiments, V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524. In some embodiments, V_L3comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524. In some embodiments, V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively, a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively. In some embodiments, V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511. In some embodiments, V_H1comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511. In some embodiments, V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively. In some embodiments, V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511. In some embodiments. V_H2comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511. In some embodiments, V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively. In some embodiments, V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511. In some embodiments, V_H3comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511. In some embodiments, V_L1comprises a CDR-L1 comprising the sequence of SEQ ID NO: 488, a CDR-L2 comprising the sequence of SEQ ID NO: 489, and a CDR-L3 comprising the sequence of SEQ ID NO: 490; V_L2comprises a CDR-L1 comprising the sequence of SEQ ID NO: 494, a CDR-L2 comprising the sequence of SEQ ID NO: 495, and a CDR-L3 comprising the sequence of SEQ ID NO: 496; V_L3comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; V_H1comprises a CDR-H1 comprising the sequence of SEQ ID NO: 479, a CDR-H2 comprising the sequence of SEQ ID NO: 480, and a CDR-H3 comprising the sequence of SEQ ID NO: 481; V_H2comprises a CDR-H1 comprising the sequence of SEQ ID NO: 485, a CDR-H2 comprising the sequence of SEQ ID NO: 486, and a CDR-H3 comprising the sequence of SEQ ID NO: 487; and V_H3comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253. In some embodiments, V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 522; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 524; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 509; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 511; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503. In some embodiments, V_L1comprises a light chain variable domain comprising the sequence of SEQ ID NO: 522; V_L2comprises a light chain variable domain comprising the sequence of SEQ ID NO: 524; V_L3comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; V_H1comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 509; V_H2comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 511; and V_H3comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503. In some embodiments, V_L1comprises a CDR-L1 comprising the sequence of SEQ ID NO: 494, a CDR-L2 comprising the sequence of SEQ ID NO: 495, and a CDR-L3 comprising the sequence of SEQ ID NO: 496; V_L2comprises a CDR-L1 comprising the sequence of SEQ ID NO: 488, a CDR-L2 comprising the sequence of SEQ ID NO: 489, and a CDR-L3 comprising the sequence of SEQ ID NO: 490; V_L3comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; V_H1comprises a CDR-H1 comprising the sequence of SEQ ID NO: 485, a CDR-H2 comprising the sequence of SEQ ID NO: 486, and a CDR-H3 comprising the sequence of SEQ ID NO: 487; V_H2comprises a CDR-H1 comprising the sequence of SEQ ID NO: 479, a CDR-H2 comprising the sequence of SEQ ID NO: 480, and a CDR-H3 comprising the sequence of SEQ ID NO: 481; and V_H3comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253. In some embodiments, V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 524; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 522; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 511; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 509; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503. In some embodiments, V_L1comprises a light chain variable domain comprising the sequence of SEQ ID NO: 524; V_L2comprises a light chain variable domain comprising the sequence of SEQ ID NO: 522; V_L3comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513, V_H1comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 511; V_H2comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 509; and V_H3comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503. In some embodiments, at least one of L₁, L₂, L₃, or L₄is independently 0 amino acids in length. In some embodiments, L₁, L₂, L₃, or L₄are each independently at least one amino acid in length. In some embodiments, L₁is Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299).
In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain comprises a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1 [II]
and a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1 [III]
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-C_L [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain; and
L₁, L₂, L₃, and L₄are amino acid linkers;
wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;
wherein:
(a) V_L1, V_L2and V_L3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 303, 305, 311, 313, 319, 321, 327, 329, 335, 337, 343, 345, 351, 353, 359, 361, 367, 369, 375, 377, 383, 385, 391, 393, 399, 401, 407, 409, 415, 417, 423, 425, 431, 433, 439, 441, 447, 449, 455, 457, 463, 465, 471, 473; or
(b) V_L1, V_L2and V_L3each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 266-271, 275-277, 488-496; and
wherein:
(a) V_H1, V_H2, and V_H3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 302, 304, 310, 312, 318, 320, 326, 328, 334, 336, 342, 344, 350, 352, 358, 360, 366, 368, 374, 376, 382, 384, 390, 392, 398, 400, 406, 408, 414, 416, 422, 424, 430, 432, 438, 440, 446, 448, 454, 456, 462, 464, 470, 472; or
(b) V_H1, V_H2, and V_H3each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-253, 257-259, 479-487.
In some embodiments, the second polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains. In some embodiments, the third polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CHI, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain comprises a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1-hinge-C_H2-C_H3 [II]
and a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1-hinge-C_H2-C_H3 [III]
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-C_L [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain;
C_H2is an immunoglobulin C_H2heavy chain constant domain;
C_H3is an immunoglobulin C_H3heavy chain constant domain;
hinge is an immunoglobulin hinge region connecting the C_H1and C_H2domains; and
L₁, L₂, L₃, and L₄are amino acid linkers;
wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;
wherein:
(a) V_L1, V_L2and V_L3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 303, 305, 311, 313, 319, 321, 327, 329, 335, 337, 343, 345, 351, 353, 359, 361, 367, 369, 375, 377, 383, 385, 391, 393, 399, 401, 407, 409, 415, 417, 423, 425, 431, 433, 439, 441, 447, 449, 455, 457, 463, 465, 471, 473; or
(b) V_L1, V_L2and V_L3each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 266-271, 275-277, 488-496; and
wherein:
(a) V_H1, V_H2, and V_H3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 302, 304, 310, 312, 318, 320, 326, 328, 334, 336, 342, 344, 350, 352, 358, 360, 366, 368, 374, 376, 382, 384, 390, 392, 398, 400, 406, 408, 414, 416, 422, 424, 430, 432, 438, 440, 446, 448, 454, 456, 462, 464, 470, 472; or
(b) V_H1, V _H2, and V_H3each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-253, 257-259, 479-487.
In some embodiments, the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the C_H3domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
In some embodiments, at least one of L₁, L₂, L₃, or L₄is independently 0 amino acids in length. In some embodiments, L₁, L₂, L₃, or L₄are each independently at least one amino acid in length. In some embodiments, L₁is Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299).
In one embodiment, the disclosure provides a binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain has a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain has a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1 [II]
and a third polypeptide chain has a structure represented by the formula:
V_H3-C_H1 [III]
and a fourth polypeptide chain has a structure represented by the formula:
V_L3-C_L [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain; and
L₁, L₂, L₃, and L₄are amino acid linkers;
wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;
wherein:
(a) V_L1, V_L2and V_L3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 303, 305, 311, 313, 319, 321, 327, 329, 335, 337, 343, 345, 351, 353, 359, 361, 367, 369, 375, 377, 383, 385, 391, 393, 399, 401, 407, 409, 415, 417, 423, 425, 431, 433, 439, 441, 447, 449, 455, 457, 463, 465, 471, 473; or
(b) V_L1, V_L2and V_L3each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 266-271, 275-277, 488-496; and
wherein:
(a) V_H1, V_H2, and V_H3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 302, 304, 310, 312, 318, 320, 326, 328, 334, 336, 342, 344, 350, 352, 358, 360, 366, 368, 374, 376, 382, 384, 390, 392, 398, 400, 406, 408, 414, 416, 422, 424, 430, 432, 438, 440, 446, 448, 454, 456, 462, 464, 470, 472; or
(b) V_H1, V_H2, and V_H3each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-253, 257-259, 479-487.
In another embodiment, the disclosure provides a binding protein comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain wherein:
(a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 305 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 305; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 304 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 304; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 302 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 302; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 303 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 303;
(b) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 313 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 313; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 312 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 312; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 310 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 310; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 311 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 311;
(c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 321 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 321; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 320 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 320; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 318 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 318; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 319 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 319;
(d) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 329 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 329; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 328 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 328; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 326 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 326; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 327 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 327;
(e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 337 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 337; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 336 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 336; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 334 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 334; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 335 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 335;
(f) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 345 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 345; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 344 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 344; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 342 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 342; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 343 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 343;
(g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 353 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 353; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 352 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:352; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 350 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 350; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 351 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 351;
(h) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 361 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 361; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 360 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 360; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 358 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 358; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 359 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 359;
(i) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 369 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 369; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 368 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 368; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 366 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 366; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 367 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 367;
(j) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 377 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 377; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 376 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 376; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 374 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 374; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 375 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 375;
(k) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 385 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 385; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 384 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 384; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 382 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 382; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 383 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 383;
(l) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 393 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 393; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 392 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 392; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 390 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 390; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 391 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 391;
(m) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 401 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 401; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 400 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 400; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 398 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 398; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 399 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 399;
(n) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 409 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 409; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 408 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 408; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 406 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 406; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 407 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 407;
(p) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 417 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 417; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 416 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 416; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 414 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 414; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 415 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 415;
(q) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 425 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 425; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 424 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 424; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 422 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 422; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 423 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 423;
(r) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 433 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:433; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 432 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 432; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 430 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 430; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 431 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 431;
(s) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 441 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 441; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 440 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 440; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 438 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 438; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 439 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 439;
(t) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 449 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 449; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 448 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 448; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 446 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 446; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 447 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 447;
(u) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 457 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 457; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 456 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 456; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 454 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 454; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 455 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 455;
(v) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 465 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 465; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 464 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 464; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 462 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 462; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 463 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 463; or
(w) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 473 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 473; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 472 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 472; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 470 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 470; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 471 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 471.
In one embodiment, the disclosure provides an isolated nucleic acid molecule comprising a nucleotide sequence encoding the binding protein according to any of the above embodiments. In one embodiment, the disclosure provides an expression vector comprising the nucleic acid molecule according to any of the above embodiments. In one embodiment, the disclosure provides an isolated host cell comprising the nucleic acid molecule according to any of the above embodiments. In one embodiment, the disclosure provides an isolated host cell comprising the expression vector according to any of the above embodiments. In some embodiments, the isolated host cell is a mammalian cell or an insect cell. In one embodiment, the disclosure provides a vector system comprising one or more vectors encoding a first, second, third, and fourth polypeptide chain of a binding protein according to any of the above embodiments. In some embodiments, the vector system comprises a first vector encoding the first polypeptide chain of the binding protein, a second vector encoding the second polypeptide chain of the binding protein, a third vector encoding the third polypeptide chain of the binding protein, and a fourth vector encoding the fourth polypeptide chain of the binding protein. In some embodiments, the vector system comprises a first vector encoding the first and second polypeptide chains of the binding protein, and a second vector encoding the third and fourth polypeptide chains of the binding protein. In some embodiments, the one or more vectors are expression vectors. In one embodiment, the disclosure provides an isolated host cell comprising the vector system according to any of the above embodiments. In some embodiments, the isolated host cell is a mammalian cell or an insect cell. In one embodiment, the disclosure provides a method of producing a binding protein, the method comprising: a) culturing a host cell according to any of the above embodiments under conditions such that the host cell expresses the binding protein; and b) isolating the binding protein from the host cell.
In one embodiment, the disclosure provides a method of preventing and/or treating HIV infection in a patient comprising administering to the patient a therapeutically effective amount of at least one binding protein according to any of the above embodiments. In some embodiments, the binding protein is co-administered with standard anti-retroviral therapy. In some embodiments, administration of the at least one binding protein results in the neutralization of one or more HIV virions. In some embodiments, administration of the at least one binding protein results in the elimination of one or more latently and/or chronically HIV-infected cells in the patient. In some embodiments, the patient is a human.
In one embodiment, the disclosure provides a binding protein according to any of the above embodiments for the prevention or treatment of an HIV infection in a patient. In some embodiments, the binding protein is co-administered with standard anti-retroviral therapy. In some embodiments, the binding protein causes the neutralization of one or more HIV virions in the patient. In some embodiments, the binding protein causes the elimination of one or more latently and/or chronically HIV-infected cells in the patient. In some embodiments, the patient is a human.
Specific embodiments of the invention will become evident from the following more detailed description of certain embodiments and the claims.
It is to be understood that one, some, or all of the properties of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the invention will become apparent to one of skill in the art.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-D show schematic representations of trispecific binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind three different epitopes on one or more antigens, wherein a first pair of polypeptides possess dual variable domains having a cross-over orientation forming two antigen binding sites (comprising V_H1-V_L1and V_H2-V_L2) and wherein a second pair of polypeptides possess a single antigen binding site (comprising V_H3-V_L3), in accordance with some embodiments. FIG. 1A shows a trispecific binding protein comprising a “knobs-into-holes” modification, wherein the knob is on the first pair of polypeptides. FIG. 1B shows a trispecific binding protein comprising a “knobs-into-holes” modification, wherein the knob is on the second pair of polypeptides. FIG. 1C shows the orientation of variable domains on the polypeptide chains, and the knob/hole orientation for binding proteins 1-31 shown in Tables 1 and 2. “Heavy chain A” (e.g., a third polypeptide chain of the present disclosure) indicates the variable domain of heavy chain A. “Light chain A” (e.g., a fourth polypeptide chain of the present disclosure) indicates the variable domain of light chain A. “Heavy chain B” (e.g., a second polypeptide chain of the present disclosure) indicates variable domain 1 and variable domain 2 of heavy chain B. “Light chain B” (e.g., a first polypeptide chain of the present disclosure) indicates variable domain 1 and variable domain 2 of light chain B. FIG. 1D shows the orientation of variable domains on the polypeptide chains, and the knob/hole orientation for binding proteins 32-53 shown in Tables 1 and 2. “Heavy chain A” (e.g., a third polypeptide chain of the present disclosure) indicates the variable domain of heavy chain A. “Light chain A” (e.g., a fourth polypeptide chain of the present disclosure) indicates the variable domain of light chain A. “Heavy chain B” (e.g., a second polypeptide chain of the present disclosure) indicates variable domain 1 and variable domain 2 of heavy chain B. “Light chain B” (e.g., a first polypeptide chain of the present disclosure) indicates variable domain 1 and variable domain 2 of light chain B.

FIGS. 2A-B show purification of three trispecific binding proteins first using affinity chromatography, and then using preparative size exclusion chromatography. FIG. 2A shows the elution profile of the trispecific binding proteins during purification using protein A affinity chromatography. FIG. 2B shows purification of monomeric proteins by Superdex200 size exclusion chromatography.

FIGS. 3A-B show purification of the MPER Ab, CD4BS Ab “b”, and V1/V2 directed Ab “a” parental antibodies first using affinity chromatography, and then using preparative size exclusion chromatography. FIG. 3A shows the elution profile of the parental antibodies during purification using protein A affinity chromatography. FIG. 3B shows purification of monomeric proteins by Superdex200 size exclusion chromatography.

FIGS. 4A-B show the size exclusion chromatography profiles of bispecific and trispecific binding proteins. FIG. 4A shows the size exclusion chromatography profiles of the bispecific binding proteins. FIG. 4B shows the size exclusion chromatography profiles of the trispecific binding proteins.

FIG. 5 shows the Biacore sensograms of the binding kinetics of three trispecific binding proteins and the parental MPER Ab antibody for an HIV gp41-derived peptide (the MPER binding site), as assessed by the standard Biacore-based kinetic assay.

FIG. 6 shows the Biacore sensograms of the binding kinetics of three trispecific binding proteins and the parental CD4BS Ab “b” antibody for recombinant HIV gp120, as assessed by the standard Biacore-based kinetic assay.

FIG. 7 shows the results of a pharmacokinetic (PK) study of the indicated proteins after intravenous (IV) injection in rhesus macaques.

FIGS. 8A-8B show schematic representations of trispecific T-cell engagers, in accordance with some embodiments. The binding sites are indicated by the dotted circles.

FIG. 9 shows binding properties of the trispecific binding proteins “Binding Protein 32” and “CD3×CD28/CD4BS Ab ‘b’” to CD3 (CD3E represents CD3epsilon protein; CD3D represents CD3delta protein), CD28, and Resurfaced Stabilized Core 3 (RSC3) protein of gp120, as well as a negative control (human IgG).

FIG. 10 shows CD8 T-cell activation using the trispecific proteins “Binding Protein 32” and “CD3×CD28/CD4BS Ab ‘b’” compared to the parental CD4BS IgG4 antibody, as well as a negative control (No mAb).

FIG. 11 shows CD4 T-cell activation using the trispecific proteins “Binding Protein 32” and “CD3×CD28/CD4BS Ab ‘b’” compared to the parental CD4BS IgG4 antibody, as well as a negative control (No mAb).

FIG. 12 shows CD3 downregulation after T cell activation by the trispecific proteins “Binding Protein 32” and “CD3×CD28/CD4BS Ab ‘b’” compared to the parental CD4BS IgG4 antibody, as well as a negative control (No mAb).

FIGS. 13A-C show fluorescence-activated cell sorting (FACS)-based cytotoxicity assay results for trispecific binding proteins against latently infected HIV-1⁺ T cells. FIG. 13A shows the results for trispecific binding proteins incubated with CEM-BaL cells. FIG. 13B shows the results for trispecific binding proteins incubated with ACH2 cells. FIG. 13C shows the results for trispecific binding proteins incubated with J1.1 cells.

DETAILED DESCRIPTION

The present disclosure provides trispecific and/or trivalent binding proteins comprising four polypeptide chains that form three antigen binding sites that specifically bind to one or more human immunodeficiency virus (HIV) target proteins and/or one or more T-cell receptor target proteins, wherein a first pair of polypeptides forming the binding protein possess dual variable domains having a cross-over orientation and wherein a second pair of polypeptides forming the binding protein possess a single variable domain.
The following description sets forth exemplary methods, parameters, and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

Definitions

As utilized in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.
The term “polynucleotide” as used herein refers to single-stranded or double-stranded nucleic acid polymers of at least 10 nucleotides in length. In certain embodiments, the nucleotides comprising the polynucleotide can be ribonucleotides or deoxyribonucleotides or a modified form of either type of nucleotide. Such modifications include base modifications such as bromuridine, ribose modifications such as arabinoside and 2′,3′-dideoxyribose, and internucleotide linkage modifications such as phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phoshoraniladate and phosphoroamidate. The term “polynucleotide” specifically includes single-stranded and double-stranded forms of DNA.
An “isolated polynucleotide” is a polynucleotide of genomic, cDNA, or synthetic origin or some combination thereof, which: (1) is not associated with all or a portion of a polynucleotide in which the isolated polynucleotide is found in nature, (2) is linked to a polynucleotide to which it is not linked in nature, or (3) does not occur in nature as part of a larger sequence.
An “isolated polypeptide” is one that: (1) is free of at least some other polypeptides with which it would normally be found, (2) is essentially free of other polypeptides from the same source, e.g., from the same species, (3) is expressed by a cell from a different species, (4) has been separated from at least about 50 percent of polynucleotides, lipids, carbohydrates, or other materials with which it is associated in nature, (5) is not associated (by covalent or noncovalent interaction) with portions of a polypeptide with which the “isolated polypeptide” is associated in nature, (6) is operably associated (by covalent or noncovalent interaction) with a polypeptide with which it is not associated in nature, or (7) does not occur in nature. Such an isolated polypeptide can be encoded by genomic DNA, cDNA, mRNA or other RNA, of synthetic origin, or any combination thereof. Preferably, the isolated polypeptide is substantially free from polypeptides or other contaminants that are found in its natural environment that would interfere with its use (therapeutic, diagnostic, prophylactic, research or otherwise).
Naturally occurring antibodies typically comprise a tetramer. Each such tetramer is typically composed of two identical pairs of polypeptide chains, each pair having one full-length “light” chain (typically having a molecular weight of about 25 kDa) and one full-length “heavy” chain (typically having a molecular weight of about 50-70 kDa). The terms “heavy chain” and “light chain” as used herein refer to any immunoglobulin polypeptide having sufficient variable domain sequence to confer specificity for a target antigen. The amino-terminal portion of each light and heavy chain typically includes a variable domain of about 100 to 110 or more amino acids that typically is responsible for antigen recognition. The carboxy-terminal portion of each chain typically defines a constant domain responsible for effector function. Thus, in a naturally occurring antibody, a full-length heavy chain immunoglobulin polypeptide includes a variable domain (V_H) and three constant domains (C_H1, C_H2, and C_H3), wherein the V_Hdomain is at the amino-terminus of the polypeptide and the C_H3domain is at the carboxyl-terminus, and a full-length light chain immunoglobulin polypeptide includes a variable domain (V_L) and a constant domain (C_L), wherein the V_Ldomain is at the amino-terminus of the polypeptide and the C_Ldomain is at the carboxyl-terminus.
Human light chains are typically classified as kappa and lambda light chains, and human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including, but not limited to, IgG1, IgG2, IgG3, and IgG4, IgM has subclasses including, but not limited to, IgM1 and IgM2. IgA is similarly subdivided into subclasses including, but not limited to, IgA1 and IgA2. Within full-length light and heavy chains, the variable and constant domains typically are joined by a “J” region of about 12 or more amino acids, with the heavy chain also including a “D” region of about 10 more amino acids. See, e.g., FUNDAMENTAL IMMUNOLOGY (Paul, W., ed., Raven Press, 2nd ed., 1989), which is incorporated by reference in its entirety for all purposes. The variable regions of each light/heavy chain pair typically form an antigen binding site. The variable domains of naturally occurring antibodies typically exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs. The CDRs from the two chains of each pair typically are aligned by the framework regions, which may enable binding to a specific epitope. From the amino-terminus to the carboxyl-terminus, both light and heavy chain variable domains typically comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
The term “CDR set” refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat et al., SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining the three CDRs. These CDRs may be referred to as Kabat CDRs. Chothia and coworkers (Chothia and Lesk, 1987, J. Mol. Biol. 196: 901-17; Chothia et al., 1989, Nature 342: 877-83) found that certain sub-portions within Kabat CDRs adopt nearly identical peptide backbone conformations, despite having great diversity at the level of amino acid sequence. These sub-portions were designated as L1, L2, and L3 or H1, H2, and H3 where the “L” and the “H” designates the light chain and the heavy chain regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan, 1995, FASEB J. 9: 133-39; MacCallum, 1996, J. Mol. Biol. 262(5): 732-45; and Lefranc, 2003, Dev. Comp. Immunol. 27: 55-77. Still other CDR boundary definitions may not strictly follow one of the herein systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, although certain embodiments use Kabat or Chothia defined CDRs. Identification of predicted CDRs using the amino acid sequence is well known in the field, such as in Martin, A. C. “Protein sequence and structure analysis of antibody variable domains,” In Antibody Engineering, Vol. 2. Kontermann R., Dübel S., eds. Springer-Verlag, Berlin, p. 33-51 (2010). The amino acid sequence of the heavy and/or light chain variable domain may be also inspected to identify the sequences of the CDRs by other conventional methods, e.g., by comparison to known amino acid sequences of other heavy and light chain variable regions to determine the regions of sequence hypervariability. The numbered sequences may be aligned by eye, or by employing an alignment program such as one of the CLUSTAL suite of programs, as described in Thompson, 1994, Nucleic Acids Res. 22: 4673-80. Molecular models are conventionally used to correctly delineate framework and CDR regions and thus correct the sequence-based assignments.
The term “Fc” as used herein refers to a molecule comprising the sequence of a non-antigen-binding fragment resulting from digestion of an antibody or produced by other means, whether in monomeric or multimeric form, and can contain the hinge region. The original immunoglobulin source of the native Fc is preferably of human origin and can be any of the immunoglobulins, although IgG1 and IgG2 are preferred. Fc molecules are made up of monomeric polypeptides that can be linked into dimeric or multimeric forms by covalent (i.e., disulfide bonds) and non-covalent association. The number of intermolecular disulfide bonds between monomeric subunits of native Fc molecules ranges from 1 to 4 depending on class (e.g., IgG, IgA, and IgE) or subclass (e.g., IgG1, IgG2, IgG3, IgA1, and IgGA2). One example of a Fc is a disulfide-bonded dimer resulting from papain digestion of an IgG. The term “Fc” as used herein is generic to the monomeric, dimeric, and multimeric forms.
A F(ab) fragment typically includes one light chain and the V_Hand C_H1domains of one heavy chain, wherein the V_H-C_H1heavy chain portion of the F(ab) fragment cannot form a disulfide bond with another heavy chain polypeptide. As used herein, a F(ab) fragment can also include one light chain containing two variable domains separated by an amino acid linker and one heavy chain containing two variable domains separated by an amino acid linker and a C_H1domain.
A F(ab′) fragment typically includes one light chain and a portion of one heavy chain that contains more of the constant region (between the C_H1and C_H2domains), such that an interchain disulfide bond can be formed between two heavy chains to form a F(ab′)₂molecule.
The term “binding protein” as used herein refers to a non-naturally occurring (or recombinant or engineered) molecule that specifically binds to at least one target antigen, and which comprises four polypeptide chains that form at least three antigen binding sites, wherein a first polypeptide chain has a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain has a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1 [II]
and a third polypeptide chain has a structure represented by the formula:
V_H3-C_H1 [III]
and a fourth polypeptide chain has a structure represented by the formula:
V_L3-C_L [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain; and
L₁, L₂, L₃, and L₄are amino acid linkers;
and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
A “recombinant” molecule is one that has been prepared, expressed, created, or isolated by recombinant means.
One embodiment of the disclosure provides binding proteins having biological and immunological specificity to between one and three target antigens. Another embodiment of the disclosure provides nucleic acid molecules comprising nucleotide sequences encoding polypeptide chains that form such binding proteins. Another embodiment of the disclosure provides expression vectors comprising nucleic acid molecules comprising nucleotide sequences encoding polypeptide chains that form such binding proteins. Yet another embodiment of the disclosure provides host cells that express such binding proteins (i.e., comprising nucleic acid molecules or vectors encoding polypeptide chains that form such binding proteins).
The term “swapability” as used herein refers to the interchangeability of variable domains within the binding protein format and with retention of folding and ultimate binding affinity. “Full swapability” refers to the ability to swap the order of both V_H1and V_H2domains, and therefore the order of V_L1and V_L2domains, in the polypeptide chain of formula I or the polypeptide chain of formula II (i.e., to reverse the order) while maintaining full functionality of the binding protein as evidenced by the retention of binding affinity. Furthermore, it should be noted that the designations V_Hand V_Lrefer only to the domain's location on a particular protein chain in the final format. For example, V_H1and V_H2could be derived from V_L1and V_L2domains in parent antibodies and placed into the V_H1and V_H2positions in the binding protein. Likewise, V_L1and V_L2could be derived from V_H1and V_H2domains in parent antibodies and placed in the V_H1and V_H2positions in the binding protein. Thus, the V_Hand V_Ldesignations refer to the present location and not the original location in a parent antibody. V_Hand V_Ldomains are therefore “swappable.”
The term “antigen” or “target antigen” or “antigen target” as used herein refers to a molecule or a portion of a molecule that is capable of being bound by a binding protein, and additionally is capable of being used in an animal to produce antibodies capable of binding to an epitope of that antigen. A target antigen may have one or more epitopes. With respect to each target antigen recognized by a binding protein, the binding protein is capable of competing with an intact antibody that recognizes the target antigen.
The term “HIV” as used herein means Human Immunodeficiency Virus. As used herein, the term “HIV infection” generally encompasses infection of a host, particularly a human host, by the human immunodeficiency virus (HIV) family of retroviruses including, but not limited to, HIV I, HIV II, HIV III (also known as HTLV-II, LAV-1, LAV-2). HIV can be used herein to refer to any strains, forms, subtypes, clades and variations in the HIV family. Thus, treating HIV infection will encompass the treatment of a person who is a carrier of any of the HIV family of retroviruses or a person who is diagnosed with active AIDS, as well as the treatment or prophylaxis of the AIDS-related conditions in such persons.
The term “AIDS” as used herein means Acquired Immunodeficiency Syndrome. AIDS is caused by HIV.
The terms “CD4bs” or “CD4 binding site” refer to the binding site for CD4 (cluster of differentiation 4), which is a glycoprotein found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic cells.
The term “CD3” is cluster of differentiation factor 3 polypeptide and is a T-cell surface protein that is typically part of the T cell receptor (TCR) complex.
“CD28” is cluster of differentiation 28 polypeptide and is a T-cell surface protein that provides co-stimulatory signals for T-cell activation and survival.
The term “glycoprotein 160” or “gp160 protein” refers to the envelope glycoprotein complex of HIV and which is a homotrimer that is cleaved into gp120 and gp41 subunits.
The term “MPER” refers to the membrane-proximal external region of glycoprotein 41 (gp41), which is a subunit of the envelope protein complex of retroviruses, including HIV.
The term “glycan” refers to the carbohydrate portion of a glycoconjugate, such as a glycoprotein, glycolipid, or a proteoglycan. In the disclosed binding proteins, glycan refers to the HIV-1 envelope glycoprotein gp120.
The term “T-cell engager” refers to binding proteins directed to a host's immune system, more specifically the T cells' cytotoxic activity as well as directed to a HIV target protein.
The term “trimer apex” refers to apex of HIV-1 envelope glycoprotein gp120.
The term “monospecific binding protein” refers to a binding protein that specifically binds to one antigen target.
The term “monovalent binding protein” refers to a binding protein that has one antigen binding site.
The term “bispecific binding protein” refers to a binding protein that specifically binds to two different antigen targets.
The term “bivalent binding protein” refers to a binding protein that has two binding sites.
The term “trispecific binding protein” refers to a binding protein that specifically binds to three different antigen targets.
The term “trivalent binding protein” refers to a binding protein that has three binding sites. In particular embodiments the trivalent binding protein can bind to one antigen target. In other embodiments, the trivalent binding protein can bind to two antigen targets. In other embodiments, the trivalent binding protein can bind to three antigen targets.
An “isolated” binding protein is one that has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would interfere with diagnostic or therapeutic uses for the binding protein, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the binding protein will be purified: (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain. Isolated binding proteins include the binding protein in situ, within recombinant cells since at least one component of the binding protein's natural environment will not be present.
The terms “substantially pure” or “substantially purified” as used herein refer to a compound or species that is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition). In some embodiments, a substantially purified fraction is a composition wherein the species comprises at least about 50% (on a molar basis) of all macromolecular species present. In other embodiments, a substantially pure composition will comprise more than about 80%, 85%, 90%, 95%, or 99% of all macromolar species present in the composition. In still other embodiments, the species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single macromolecular species.
A “neutralizing” binding protein as used herein refers to a molecule that is able to block or substantially reduce an effector function of a target antigen to which it binds. As used herein, “substantially reduce” means at least about 60%, preferably at least about 70%, more preferably at least about 75%, even more preferably at least about 80%, still more preferably at least about 85%, most preferably at least about 90% reduction of an effector function of the target antigen.
The term “epitope” includes any determinant, preferably a polypeptide determinant, capable of specifically binding to an immunoglobulin or T-cell receptor. In certain embodiments, epitope determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three-dimensional structural characteristics and/or specific charge characteristics. An epitope is a region of an antigen that is bound by an antibody or binding protein. In certain embodiments, a binding protein is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and/or macromolecules. In some embodiments, a binding protein is said to specifically bind an antigen when the equilibrium dissociation constant is ≤10⁻⁸M, more preferably when the equilibrium dissociation constant is ≤10⁻⁹M, and most preferably when the dissociation constant is ≤10⁻¹⁰M.
The dissociation constant (K_D) of a binding protein can be determined, for example, by surface plasmon resonance. Generally, surface plasmon resonance analysis measures real-time binding interactions between ligand (a target antigen on a biosensor matrix) and analyte (a binding protein in solution) by surface plasmon resonance (SPR) using the BIAcore system (Pharmacia Biosensor; Piscataway, N.J.). Surface plasmon analysis can also be performed by immobilizing the analyte (binding protein on a biosensor matrix) and presenting the ligand (target antigen). The term “K_D,” as used herein refers to the dissociation constant of the interaction between a particular binding protein and a target antigen.
The term “specifically binds” as used herein refers to the ability of a binding protein or an antigen-binding fragment thereof to bind to an antigen containing an epitope with an Kd of at least about 1×10⁻⁶M, 1×10⁻⁷M, 1×10⁻⁸M, 1×10⁻⁹M, 1×10⁻¹⁰M, 1×10⁻¹¹M, 1×10⁻¹²M, or more, and/or to bind to an epitope with an affinity that is at least two-fold greater than its affinity for a nonspecific antigen.
The term “linker” as used herein refers to one or more amino acid residues inserted between immunoglobulin domains to provide sufficient mobility for the domains of the light and heavy chains to fold into cross over dual variable region immunoglobulins. A linker is inserted at the transition between variable domains or between variable and constant domains, respectively, at the sequence level. The transition between domains can be identified because the approximate size of the immunoglobulin domains are well understood. The precise location of a domain transition can be determined by locating peptide stretches that do not form secondary structural elements such as beta-sheets or alpha-helices as demonstrated by experimental data or as can be assumed by techniques of modeling or secondary structure prediction. The linkers described herein are referred to as L₁, which is located on the light chain between the C-terminus of the V_L2and the N-terminus of the V_L1domain; and L₂, which is located on the light chain between the C-terminus of the V_L1and the N-terminus of the C_Ldomain. The heavy chain linkers are known as L₃, which is located between the C-terminus of the V_H1and the N-terminus of the V_H2domain; and L₄, which is located between the C-terminus of the V_H2and the N-terminus of the C_H1domain.
The term “vector” as used herein refers to any molecule (e.g., nucleic acid, plasmid, or virus) that is used to transfer coding information to a host cell. The term “vector” includes a nucleic acid molecule that is capable of transporting another nucleic acid to which it has been linked. One type of vector is a “plasmid,” which refers to a circular double-stranded DNA molecule into which additional DNA segments may be inserted. Another type of vector is a viral vector, wherein additional DNA segments may be inserted into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell and thereby are replicated along with the host genome. In addition, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as “recombinant expression vectors” (or simply, “expression vectors”). In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. The terms “plasmid” and “vector” may be used interchangeably herein, as a plasmid is the most commonly used form of vector. However, the disclosure is intended to include other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses, and adeno-associated viruses), which serve equivalent functions.
The phrase “recombinant host cell” (or “host cell”) as used herein refers to a cell into which a recombinant expression vector has been introduced. A recombinant host cell or host cell is intended to refer not only to the particular subject cell, but also to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but such cells are still included within the scope of the term “host cell” as used herein. A wide variety of host cell expression systems can be used to express the binding proteins, including bacterial, yeast, baculoviral, and mammalian expression systems (as well as phage display expression systems). An example of a suitable bacterial expression vector is pUC19. To express a binding protein recombinantly, a host cell is transformed or transfected with one or more recombinant expression vectors carrying DNA fragments encoding the polypeptide chains of the binding protein such that the polypeptide chains are expressed in the host cell and, preferably, secreted into the medium in which the host cells are cultured, from which medium the binding protein can be recovered.
The term “transformation” as used herein refers to a change in a cell's genetic characteristics, and a cell has been transformed when it has been modified to contain a new DNA. For example, a cell is transformed where it is genetically modified from its native state. Following transformation, the transforming DNA may recombine with that of the cell by physically integrating into a chromosome of the cell, or may be maintained transiently as an episomal element without being replicated, or may replicate independently as a plasmid. A cell is considered to have been stably transformed when the DNA is replicated with the division of the cell. The term “transfection” as used herein refers to the uptake of foreign or exogenous DNA by a cell, and a cell has been “transfected” when the exogenous DNA has been introduced inside the cell membrane. A number of transfection techniques are well known in the art. Such techniques can be used to introduce one or more exogenous DNA molecules into suitable host cells.
The term “naturally occurring” as used herein and applied to an object refers to the fact that the object can be found in nature and has not been manipulated by man. For example, a polynucleotide or polypeptide that is present in an organism (including viruses) that can be isolated from a source in nature and that has not been intentionally modified by man is naturally-occurring. Similarly, “non-naturally occurring” as used herein refers to an object that is not found in nature or that has been structurally modified or synthesized by man.
As used herein, the twenty conventional amino acids and their abbreviations follow conventional usage. Stereoisomers (e.g., D-amino acids) of the twenty conventional amino acids; unnatural amino acids and analogs such as α-,α-disubstituted amino acids, N-alkyl amino acids, lactic acid, and other unconventional amino acids may also be suitable components for the polypeptide chains of the binding proteins. Examples of unconventional amino acids include: 4-hydroxyproline, γ-carboxyglutamate, ε-N,N,N-trimethyllysine, ε-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, σ-N-methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline). In the polypeptide notation used herein, the left-hand direction is the amino terminal direction and the right-hand direction is the carboxyl-terminal direction, in accordance with standard usage and convention.
Naturally occurring residues may be divided into classes based on common side chain properties:
(1) hydrophobic: Met, Ala, Val, Leu, Ile, Phe, Trp, Tyr, Pro;
(2) polar hydrophilic: Arg, Asn, Asp, Gln, Glu, His, Lys, Ser, Thr;
(3) aliphatic: Ala, Gly, Ile, Leu, Val, Pro;
(4) aliphatic hydrophobic: Ala, Ile, Leu, Val, Pro;
(5) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln;
(6) acidic: Asp, Glu;
(7) basic: His, Lys, Arg;
(8) residues that influence chain orientation: Gly, Pro;
(9) aromatic: His, Trp, Tyr, Phe; and
(10) aromatic hydrophobic: Phe, Trp, Tyr.
Conservative amino acid substitutions may involve exchange of a member of one of these classes with another member of the same class. Non-conservative substitutions may involve the exchange of a member of one of these classes for a member from another class.
A skilled artisan will be able to determine suitable variants of the polypeptide chains of the binding proteins using well-known techniques. For example, one skilled in the art may identify suitable areas of a polypeptide chain that may be changed without destroying activity by targeting regions not believed to be important for activity. Alternatively, one skilled in the art can identify residues and portions of the molecules that are conserved among similar polypeptides. In addition, even areas that may be important for biological activity or for structure may be subject to conservative amino acid substitutions without destroying the biological activity or without adversely affecting the polypeptide structure.
The term “patient” as used herein includes human and animal subjects.
The terms “treatment” or “treat” as used herein refer to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those having the disorder as well as those prone to have a disorder or those in which the disorder is to be prevented. In particular embodiments, binding proteins can be used to treat humans infected with HIV, or humans susceptible to HIV infection, or ameliorate HIV infection in a human subject infected with HIV. The binding proteins can also be used to prevent HIV in a human patient.
It should be understood as that treating humans infected with HIV include those subjects who are at any one of the several stages of HIV infection progression, which, for example, include acute primary infection syndrome (which can be asymptomatic or associated with an influenza-like illness with fevers, malaise, diarrhea and neurologic symptoms such as headache), asymptomatic infection (which is the long latent period with a gradual decline in the number of circulating CD4⁺T cells), and AIDS (which is defined by more serious AIDS-defining illnesses and/or a decline in the circulating CD4 cell count to below a level that is compatible with effective immune function). In addition, treating or preventing HIV infection will also encompass treating suspected infection by HIV after suspected past exposure to HIV by e.g., contact with HIV-contaminated blood, blood transfusion, exchange of body fluids, “unsafe” sex with an infected person, accidental needle stick, receiving a tattoo or acupuncture with contaminated instruments, or transmission of the virus from a mother to a baby during pregnancy, delivery or shortly thereafter.
The terms “pharmaceutical composition” or “therapeutic composition” as used herein refer to a compound or composition capable of inducing a desired therapeutic effect when properly administered to a patient.
The term “pharmaceutically acceptable carrier” or “physiologically acceptable carrier” as used herein refers to one or more formulation materials suitable for accomplishing or enhancing the delivery of a binding protein.
The terms “effective amount” and “therapeutically effective amount” when used in reference to a pharmaceutical composition comprising one or more binding proteins refer to an amount or dosage sufficient to produce a desired therapeutic result. More specifically, a therapeutically effective amount is an amount of a binding protein sufficient to inhibit, for some period of time, one or more of the clinically defined pathological processes associated with the condition being treated. The effective amount may vary depending on the specific binding protein that is being used, and also depends on a variety of factors and conditions related to the patient being treated and the severity of the disorder. For example, if the binding protein is to be administered in vivo, factors such as the age, weight, and health of the patient as well as dose response curves and toxicity data obtained in preclinical animal work would be among those factors considered. The determination of an effective amount or therapeutically effective amount of a given pharmaceutical composition is well within the ability of those skilled in the art.
One embodiment of the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a binding protein.
Trispecific and/or Trivalent Binding Proteins
In one embodiment, the binding protein of the disclosure is a trispecific and/or trivalent binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more (e.g., three different) HIV target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain comprises a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1 [II]
and a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1 [III]
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-C_L [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is an immunoglobulin C_H1heavy chain constant domain; and
L₁, L₂, L₃and L₄are amino acid linkers;
and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
In one embodiment, the binding protein of the disclosure is a trispecific and/or trivalent binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more (e.g., three different) HIV target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain comprises a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1-hinge-C_H2-C_H3 [II]
and a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1-hinge-C_H2-C_H3 [III]
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-C_L [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is an immunoglobulin C_H1heavy chain constant domain;
C_H2is an immunoglobulin C_H2heavy chain constant domain;
C_H3is an immunoglobulin C_H3heavy chain constant domain;
hinge is an immunoglobulin hinge region connecting the C_H1and C_H2domains; and
L₁, L₂, L₃and L₄are amino acid linkers;
and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
In some embodiments, the first polypeptide chain and the second polypeptide chain have a cross-over orientation that forms two distinct antigen binding sites. In some embodiments, the V_H1and V_L1form a binding pair and form the first antigen binding site. In some embodiments, the V_H2and V_L2form a binding pair and form the second antigen binding site. In some embodiments, the third polypeptide and the fourth polypeptide form a third antigen binding site. In some embodiments, the V_H3and V_L3form a binding pair and form the third antigen binding site.
In some embodiments, V_L1, V_L2and V_L3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 2, 4, 10, 12, 18, 20, 26, 28, 34, 36, 42, 44, 50, 52, 58, 60, 66, 68, 74, 76, 82, 84, 90, 92, 98, 100, 106, 108, 114, 116, 122, 124, 130, 132, 138, 140, 146, 148, 154, 156, 162, 164, 170, 172, 178, 180, 186, 188, 194, 196, 202, 204, 210, 212, 218, 220, 226, 228, 233, 235, 241, 243; and V_H1, V_H2and V_H3, are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs:1, 3, 9, 11, 17, 10, 25, 27, 33, 35, 41, 43, 49, 51, 57, 59, 65, 67, 73, 75, 81, 83, 89, 91, 97, 99, 105, 107, 113, 115, 121, 123, 129, 131, 137, 139, 145, 147, 153, 155, 161, 163, 169, 171, 177, 179, 185, 187, 193, 195, 201, 203, 209, 211, 217, 219, 225, 227, 232, 234, 240, 242. In other embodiments, V_L1, V_L2and V_L3each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 266-283; and V_H1, V_H2and V_H3each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-265. In some embodiments, V_L1, V_L2and V_L3are each independently a light chain variable domain comprising a light chain variable domain sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein. In some embodiments, V_H1, V_H2and V_H3are each independently a heavy chain variable domain comprising a heavy chain variable domain sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein. In some embodiments, V_L1, V_L2and V_L3are each independently a light chain variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein. In some embodiments, V_H1, V_H2and V_H3are each independently a heavy chain variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein.
In some embodiments, V_L1, V_L2and V_L3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 303, 305, 311, 313, 319, 321, 327, 329, 335, 337, 343, 345, 351, 353, 359, 361, 367, 369, 375, 377, 383, 385, 391, 393, 399, 401, 407, 409, 415, 417, 423, 425, 431, 433, 439, 441, 447, 449, 455, 457, 463, 465, 471, 473; and V_H1, V_H2and V_H3, are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 302, 304, 310, 312, 318, 320, 326, 328, 334, 336, 342, 344, 350, 352, 358, 360, 366, 368, 374, 376, 382, 384, 390, 392, 398, 400, 406, 408, 414, 416, 422, 424, 430, 432, 438, 440, 446, 448, 454, 456, 462, 464, 470, 472. In other embodiments, V_L1, V_L2and V_L3each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 266-271, 275-277, 488-496; and V_H1, V_H2and V_H3each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-253, 257-259, 479-487.
In particular embodiments, the order of the V_H1and V_H2domains, and therefore the order of V_L1and V_L2domains, in the polypeptide chain of formula I or the polypeptide chain of formula II (i.e., to reverse the order) are swapped.
In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 4; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2.
In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 12 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 12; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 11 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 11; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 9 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 9; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 20 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 20; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 19 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 17 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 17; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 18 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 28 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 28; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 27 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 25 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 26 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 26.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 36; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 35 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 35; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 33 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 33; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 34 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 34.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 44; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 43 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 43; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 41 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 41; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 42 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 42.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 52 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 52; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 51 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 51; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 49 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 49; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 50 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 50.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 60 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 60; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 59 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 59; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 57; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 58 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 58.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 68; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 67; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 65 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 65; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 66 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 66.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 76; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 75; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 73; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 74 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 74.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 84 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 84; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 83 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 83; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 81 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 81; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 82 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 82.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 92 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:92; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 91 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 91; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 89 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 89; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 90 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 90.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 100 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 100; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 99 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 99; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 97 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 97; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 98 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 98.
In other embodiments, the first polypeptide comprises the amino acid sequence of SEQ ID NO: 108 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 108; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 107 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 107; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 105 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 105; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 106 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 106.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 116 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 116; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 115 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 115; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 113 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 113; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 114.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 124 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 124; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 123 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 123; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 121 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 121; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 122 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 122.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 132 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 132; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 131; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 129 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 129; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 130 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 130.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 140 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 140; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 139 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 139; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 137 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 137; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 138.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 148 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 148; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 147 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 147; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 145 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 145; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 146 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 146.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 156 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 156; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 155 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 155; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 153 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 153; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 154 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 154.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 164 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 164; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 163 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 163; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 161 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 161; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 162 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 162.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 172 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 172; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 171 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 171; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 169 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 169; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 170 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 170.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 180 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 180; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 179; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 177 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 177; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 178 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 178.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 188 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 188; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 187 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 187; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 185 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 185; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 186 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 186.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 196 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 196; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 195 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 195; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 193 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 193; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 194 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 194.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 204 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 204; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 203 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 203; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 201 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 201; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 202 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 202.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 212 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 212; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 211 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 211; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 209 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 209; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 210 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 210.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 220 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 220; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 219 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 219; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 217 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 217; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 218 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 218.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 228 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 228; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 227 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 227; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 225 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 225; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 226 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 226.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 235 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 235; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 234 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 234; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 232 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 232; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 233 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 233.
In other embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 243 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 243; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 242 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 242; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 240 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 240; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 241 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 241.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 305 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 305; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 304 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 304; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 302 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 302; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 303 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 303.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 313 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 313; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 312 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 312; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 310 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 310; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 311 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 311.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 321 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 321; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 320 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 320; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 318 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 318; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 319 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 319.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 329 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 329; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 328 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 328; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 326 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 326; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 327 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 327.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 337 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 337; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 336 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 336; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 334 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 334; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 335 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 335.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 345 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 345; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 344 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 344; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 342 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 342; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 343 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 343.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 353 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 353; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 352 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:352; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 350 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 350; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 351 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 351.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 361 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 361; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 360 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 360; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 358 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 358; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 359 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 359.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 369 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 369; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 368 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 368; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 366 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 366; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 367 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 367.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 377 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 377; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 376 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 376; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 374 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 374; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 375 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 375.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 385 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 385; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 384 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 384; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 382 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 382; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 383 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 383.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 393 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 393; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 392 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 392; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 390 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 390; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 391 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 391.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 401 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 401; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 400 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 400; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 398 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 398; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 399 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 399.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 409 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 409; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 408 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 408; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 406 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 406; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 407 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 407.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 417 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 417; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 416 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 416; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 414 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 414; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 415 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 415.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 425 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 425; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 424 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 424; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 422 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 422; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 423 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 423.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 433 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:433; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 432 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 432; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 430 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 430; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 431 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 431.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 441 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 441; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 440 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 440; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 438 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 438; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 439 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 439.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 449 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 449; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 448 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 448; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 446 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 446; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 447 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 447.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 457 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 457; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 456 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 456; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 454 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 454; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 455 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 455.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 465 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 465; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 464 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 464; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 462 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 462; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 463 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 463.
In another embodiment, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 473 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 473; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 472 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 472; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 470 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 470; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 471 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 471.
In other embodiments, the binding protein of the disclosure is a trispecific and/or trivalent binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more (e.g., three) HIV target antigens, wherein a first polypeptide chain has a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain has a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1-hinge-C_H2-C_H3(hole) [II]
and a third polypeptide chain has a structure represented by the formula:
V_H3-C_H1-hinge-C_H2-C_H3(knob) [III]
and a fourth polypeptide chain has a structure represented by the formula:
V_L3-C_L [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain; and
L₁, L₂, L₃and L₄are amino acid linkers;
and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
In other embodiments, the binding protein of the disclosure is a trispecific and/or trivalent binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more (e.g., three) HIV target antigens, wherein a first polypeptide chain has a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain has a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1-hinge-C_H2-C_H3(knob) [II]
and a third polypeptide chain has a structure represented by the formula:
V_H3-C_H1-hinge-C_H2-C_H3(hole) [III]
and a fourth polypeptide chain has a structure represented by the formula:
V_L3-C_L [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain; and
L₁, L₂, L₃and L₄are amino acid linkers;
and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.

Additional Examples of Trispecific Binding Proteins

In some embodiments, V_L1, V_L2and V_L3are each independently a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521. In some embodiments, V_L1, V_L2and V_L3are each independently a variable domain comprising an amino acid sequence having at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to a sequence as set forth in any one of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.
In some embodiments, V_H1, V_H2and V_H3are each independently a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508. In some embodiments, V_H1, V_H2and V_H3are each independently a variable domain comprising an amino acid sequence having at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to a sequence as set forth in any one of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.
In some embodiments, V_L1, V_L2, and V_L3comprise an amino acid sequence as set forth in SEQ ID NOs: 518, 519, and 512, respectively, and V_H1, V_H2, and V_H3comprise an amino acid sequence as set forth in SEQ ID NOs: 504, 506, and 502, respectively. In some embodiments, V_L1, V_L2, and V_L3comprise an amino acid sequence as set forth in SEQ ID NOs: 518, 519, and 513, respectively, and V_H1, V_H2, and V_H3comprises an amino acid sequence as set forth in SEQ ID NOs: 504, 506, and 503, respectively. In some embodiments, V_L1, V_L2, and V_L3comprises an amino acid sequence as set forth in SEQ ID NOs: 519, 518, and 513, respectively, and V_H1, V_H2, and V_H3comprises an amino acid sequence as set forth in SEQ ID NOs: 506, 504, and 503, respectively.
In some embodiments, V_L1, V_L2and V_L3are each independently a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521. In some embodiments, V_H1, V_H2and V_H3are each independently a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508. In some embodiments, V_L1, V_L2and V_L3are each independently a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a light chain variable domain sequence shown in Table C. In some embodiments, V_H1, V_H2and V_H3are each independently a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a heavy chain variable domain sequence shown in Table C.
In some embodiments, V_L1is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 518, V_L2is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 519, V_L3is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 512, V_H1is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 504, V_H2is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 506, and V_H3is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 502. In some embodiments, V_L1is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 518, V_L2is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 519, V_L3is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 513, V_H1is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 504, V_H, is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 506, and V_H3is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 503. In some embodiments. V_L1is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 519, V_L2is a variable domain comprising a CDR-L1. CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 518, V_L3is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 513, and V_H1is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 506, V_H2is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 504, and V_H3is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 503.
In some embodiments, V_L1, V_L2and V_L3are each independently a variable domain comprising: (a) a CDR-L1 comprising a sequence selected from the group consisting of SEQ ID NOs: 266, 269, 275, 278, 281, and 500; (b) a CDR-L2 comprising a sequence selected from the group consisting of SEQ ID NOs: 267, 270, 276, 279, 282, and 501; and/or (c) a CDR-L3 comprising a sequence selected from the group consisting of SEQ ID NOs: 268, 271, 274, 277, 280, and 283. In some embodiments, V_L1, V_L2and V_L3are each independently a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 comprising amino acid sequences as shown in Table B. In some embodiments, V_L1, V_L2and V_L3are each independently a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively.
In some embodiments, V_H1, V_H2and V_H3are each independently a variable domain comprising: (a) a CDR-H1 comprising a sequence selected from the group consisting of SEQ ID NOs: 248, 251, 254, 257, 263, and 499; (b) a CDR-H2 comprising a sequence selected from the group consisting of SEQ ID NOs: 252, 255, 258, 261, 264, and 497; and/or (c) a CDR-H3 comprising a sequence selected from the group consisting of SEQ ID NOs: 250, 253, 256, 259, 262, 265, and 498. In some embodiments, V_H1, V_H2and V_H3are each independently a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 comprising amino acid sequences as shown in Table B. In some embodiments, V_H1, V_H2and V_H3are each independently a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively.
In some embodiments, V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 500, 501, and 274, respectively; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 275, 276, and 277, respectively; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 266, 267, and 268, respectively; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 254, 255, and 256, respectively; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 257, 258, and 259, respectively; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 248, 497, and 250, respectively. In some embodiments, V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 500, 501, and 274, respectively; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 275, 276, and 277, respectively; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 269, 270, and 271, respectively; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 254, 255, and 256, respectively; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 257, 258, and 259, respectively; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 251, 252, and 253, respectively. In some embodiments, V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 275, 276, and 277, respectively; V₂comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 500, 501, and 274, respectively; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 269, 270, and 271, respectively; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 257, 258, and 259, respectively; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 254, 255, and 256, respectively; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 251, 252, and 253, respectively.
Additional Trispecific Binding Proteins Targeting One or More HIV Target Proteins and One or More T Cell Target Proteins
In some embodiments, a binding protein of the present disclosure comprises four polypeptide chains that form three antigen binding sites that specifically bind one or more (e.g., one or two) HIV target proteins and one or more (e.g., one or two) T cell target proteins, wherein a first polypeptide chain has a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I];
a second polypeptide chain has a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1 [II];
a third polypeptide chain has a structure represented by the formula:
V_H3-C_H1 [III];
and a fourth polypeptide chain has a structure represented by the formula:
V_L3-C_L [IV];
wherein
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is an immunoglobulin C_H1heavy chain constant domain; and
L₁, L₂, L₃, and L₄are amino acid linkers;
and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
In some embodiments, a binding protein of the present disclosure comprises four polypeptide chains that form three antigen binding sites that specifically bind one or more (e.g., one or two) HIV target proteins and one or more (e.g., one or two) T cell target proteins, wherein a first polypeptide chain has a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I];
a second polypeptide chain has a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1-hinge-C_H2-C_H3 [II];
a third polypeptide chain has a structure represented by the formula:
V_H3-C_H1-hinge-C_H2-C_H3 [III];
and a fourth polypeptide chain has a structure represented by the formula
V_L3-C_L [IV];
wherein
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is an immunoglobulin C_H1heavy chain constant domain;
C_H2is an immunoglobulin C_H2heavy chain constant domain;
C_H3is an immunoglobulin C_H3heavy chain constant domain;
hinge is an immunoglobulin hinge region connecting the C_H1and C_H2domains; and
L₁, L₂, L₃, and L₄are amino acid linkers;
and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
In some embodiments, the first polypeptide chain and the second polypeptide chain have a cross-over orientation that forms two distinct antigen binding sites. In some embodiments, the V_H1and V_L1form a binding pair and form the first antigen binding site. In some embodiments, the V_H2and V_L2form a binding pair and form the second antigen binding site. In some embodiments, the third polypeptide and the fourth polypeptide form a third antigen binding site. In some embodiments, the V_H3and V_L3form a binding pair and form the third antigen binding site.
In some embodiments, V_L1, V_L2and V_L3are each independently a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524. In some embodiments, V_L1, V_L2and V_L3are each independently a variable domain comprising an amino acid sequence having at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%/0, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% sequence identity to a sequence as set forth in any one of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.
In some embodiments, V_H1, V_H2and V_H3are each independently a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511. In some embodiments, V_H1, V_H2and V_H3are each independently a variable domain comprising an amino acid sequence having at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 990% sequence identity to a sequence as set forth in any one of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.
In some embodiments, V_L1, V_L2, and V_L3comprise an amino acid sequence as set forth in SEQ ID NOs: 522, 524, and 513, respectively, and V_H1, V_H2, and V_H3comprise an amino acid sequence as set forth in SEQ ID NOs: 509, 511, and 503, respectively. In some embodiments, V_L1, V _L2, and V_L3comprise an amino acid sequence as set forth in SEQ ID NOs: 524, 522, and 513, respectively, and V_H1, V_H2, and V_H3comprise an amino acid sequence as set forth in SEQ ID NOs: 511, 509, and 503, respectively.
In some embodiments, V_L1, V_L2and V_L3are each independently a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.
In some embodiments, V_H1, V_H2and V_H3are each independently a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.
In some embodiments, V_L1is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 522, V_L2is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 524, V_L3is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 513, V_H1is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 509, V_H2is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 511, and V_H3is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 503. In some embodiments, V_L1is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 524, V_L2is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence of SEQ ID NO: 522, V_L3is a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a light chain variable domain sequence of SEQ ID NO: 513, V_H1is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 511, V_H2is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 509, and V_H3is a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence of SEQ ID NO: 503.
In some embodiments, V_L1, V_L2and V_L3are each independently a variable domain comprising: (a) a CDR-L1 comprising a sequence selected from the group consisting of SEQ ID NOs: 266, 269, 275, 278, 281, 488, 491, 494 and 500; (b) a CDR-L2 comprising a sequence selected from the group consisting of SEQ ID NOs: 267, 270, 276, 279, 282, 489, 492, 495, and 501; and (c) a CDR-L3 comprising a sequence selected from the group consisting of SEQ ID NOs: 268, 271, 274, 277, 280, 283, 490, 493, and 496. In some embodiments, V_L1, V_L2and V_L3are each independently a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 comprising amino acid sequences as shown in Table B. In some embodiments, V_L1, V_L2and V_L3are each independently a variable domain comprising a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively.
In some embodiments, V_H1, V_H2and V_H3are each independently a variable domain comprising: (a) a CDR-H1 comprising a sequence selected from the group consisting of SEQ ID NOs: 248, 251, 254, 257, 263, 479, 482, 485, and 499; (b) a CDR-H2 comprising a sequence selected from the group consisting of SEQ ID NOs: 252, 255, 258, 261, 264, 480, 483, 486, and 497; and (c) a CDR-H3 comprising a sequence selected from the group consisting of SEQ ID NOs: 250, 253, 256, 259, 262, 265, 481, 484, 487, and 498. In some embodiments, V_H1, V_H2and V_H3are each independently a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 comprising amino acid sequences as shown in Table B. In some embodiments, V_H1, V_H2and V_H3are each independently a variable domain comprising a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively.
In some embodiments, V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 488, 489, and 490, respectively; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 494, 495, and 496, respectively; V_L3comprises a CDR-L1. CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 269, 270, and 271, respectively; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 479, 480, and 481, respectively; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 485, 486, and 487, respectively; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 251, 252, and 253, respectively. In some embodiments, V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 494, 495, and 496, respectively; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 488, 489, and 490, respectively; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the sequence of SEQ ID NOs: 269, 270, and 271, respectively; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 485, 486, and 487, respectively; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 479, 480, and 481, respectively; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the sequence of SEQ ID NOs: 251, 252, and 253, respectively.
In some embodiments, V_L1and V_H1are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD28 or CD28_2 described herein, V_L2and V_H2are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD3 described herein, and V_L3and V_H3are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein. In some embodiments, V_L1and V_H1are light and heavy chain variable domains comprising the six CDRs of antibody CD28 or CD28_2 described herein, V_L2and V_H2are light and heavy chain variable domains comprising the six CDRs of antibody CD3 described herein, and V_L3and V_H3are light and heavy chain variable domains comprising the six CDRs of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein.
In some embodiments, V_L1and V_H1are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD28 or CD28_2 described herein, V_L2and V_H2are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein, and V_L3and V_H3are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD3 described herein. In some embodiments, V_L1and V_H1are light and heavy chain variable domains comprising the six CDRs of antibody CD28 or CD28_2 described herein, V_L2and V_H2are light and heavy chain variable domains comprising the six CDRs of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein, and V_L3and V_H3are light and heavy chain variable domains comprising the six CDRs of antibody CD3 described herein.
In some embodiments, V_L1and V_H1are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD3 described herein, V_L2and V_H2are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD28 or CD28_2 described herein, and V_L3and V_H3are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein. In some embodiments, V_L1and V_H1are light and heavy chain variable domains comprising the six CDRs of antibody CD3 described herein, V_L2and V_H2are light and heavy chain variable domains comprising the six CDRs of antibody CD28 or CD28_2 described herein, and V_L3and V_H3are light and heavy chain variable domains comprising the six CDRs of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein.
In some embodiments, V_L1and V_H1are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD3 described herein, V_L2and V_H2are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein, and V_L3and V_H3are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD28 or CD28_2 described herein. In some embodiments, V_L1and V_H1are light and heavy chain variable domains comprising the six CDRs of antibody CD3 described herein, V_L2and V_H2are light and heavy chain variable domains comprising the six CDRs of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein, and V_L3and V_H3are light and heavy chain variable domains comprising the six CDRs of antibody CD28 or CD28_2 described herein.
In some embodiments, V_L1and V_H1are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein, V_L2and V_H2are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD28 or CD28_2 described herein, and V_L3and V_H3are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD3 described herein. In some embodiments, V_L1and V_H1are light and heavy chain variable domains comprising the six CDRs of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein, V_L2and V_H2are light and heavy chain variable domains comprising the six CDRs of antibody CD28 or CD28_2 described herein, and V_L3and V_H3are light and heavy chain variable domains comprising the six CDRs of antibody CD3 described herein.
In some embodiments, V_L1and V_H1are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein, V_L2and V_H2are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD3 described herein, and V_L3and V_H3are light and heavy chain variable domains comprising a light and heavy chain variable sequence of antibody CD28 or CD28_2 described herein. In some embodiments, V_L1and V_H1are light and heavy chain variable domains comprising the six CDRs of antibody CD4BS “a”, CD4BS “b”, MPER, MPER_100W, V1/V2 directed “a”, V1/V2 directed “b”, or V3 directed described herein, V_L2and V_H2are light and heavy chain variable domains comprising the six CDRs of antibody CD3 or CD28_2 described herein, and V_L3and V _H3 are light and heavy chain variable domains comprising the six CDRs of antibody CD28 or CD28_2 described herein.
Target Proteins
In one embodiment, the binding proteins specifically bind to one or more HIV target proteins. In some embodiments, the binding proteins are trispecific and specifically bind to MPER of the HIV-1 gp41 protein, a CD4 binding site of the HIV-1 gp120 protein, a glycan in the V3 loop of the HIV-1 gp120 protein, a trimer apex of the HIV-1 gp120 protein or gp160. In other embodiments, the binding proteins specifically bind to one or more HIV target proteins and one or more target proteins on a T-cell including T cell receptor complex. These T-cell engager binding proteins are capable of recruiting T cells transiently to target cells and, at the same time, activating the cytolytic activity of the T cells. The T-cell engager trispecific antibodies can be used to activate HIV-1 reservoirs and redirect/activate T cells to lyse latently infected HIV-1⁺ T cells. Examples of target proteins on T cells include but are not limited to CD3 and CD28, among others. In some embodiments, the trispecific binding proteins may be generated by combining the antigen binding domains of two or more monospecific antibodies (parent antibodies) into one antibody. See International Publication Nos. WO 2011/038290 A2, WO 2013/086533 A1, WO 2013/070776 A1, WO 2012/154312 A1, and WO 2013/163427 A1, which are hereby incorporated into this disclosure by reference. The binding proteins of the disclosure may be prepared using domains or sequences obtained or derived from any human or non-human antibody, including, for example, human, murine, or humanized antibodies.
In some embodiments of the disclosure, the trivalent binding protein is capable of binding three different antigen targets. In one embodiment, the binding protein is trispecific and one light chain-heavy chain pair is capable of binding two different antigen targets or epitopes and one light chain-heavy chain pair is capable of binding one antigen target or epitope. In another embodiment, the binding protein is capable of binding three different HIV antigen targets that are located on the HIV envelope glycoprotein structure composed of gp120 and gp41 subunits. In other embodiments, the binding protein is capable of inhibiting the function of one or more of the antigen targets.
In some embodiments, a binding protein of the present disclosure binds one or more HIV target proteins. In some embodiments, the binding protein is capable of specifically binding three different epitopes on a single HIV target protein. In some embodiments, the binding protein is capable of binding two different epitopes on a first HIV target protein, and one epitope on a second HIV target protein. In some embodiments, the first and second HIV target proteins are different. In some embodiments, the binding protein is capable of specifically binding three different HIV target protein. In some embodiments, the one or more HIV target proteins are one or more of glycoprotein 120, glycoprotein 41, and glycoprotein 160.
In some embodiments, a binding protein of the present disclosure binds one or more HIV target proteins and one or more T cell target proteins. In some embodiments, the binding protein is capable of specifically binding one HIV target protein and two different epitopes on a single T cell target protein. In some embodiments, the binding protein is capable of specifically binding one HIV target protein and two different T cell target proteins (e.g., CD28 and CD3). In some embodiments, the binding protein is capable of specifically binding one T cell target protein and two different epitopes on a single HIV target protein. In some embodiments, the binding protein is capable of specifically binding one T cell target protein and two different HIV target proteins. In some embodiments, the first and second polypeptide chains of the binding protein form two antigen binding sites that specifically target two T cell target proteins, and the third and fourth polypeptide chains of the binding protein form an antigen binding site that specifically binds an HIV target protein. In some embodiments, the one or more HIV target proteins are one or more of glycoprotein 120, glycoprotein 41, and glycoprotein 160. In some embodiments, the one or more T cell target proteins are one or more of CD3 and CD28.
Linkers
In some embodiments, the linkers L₁, L₂, L₃, and L₄range from no amino acids (length=0) to about 100 amino acids long, or less than 100, 50, 40, 30, 20, or 15 amino acids or less. The linkers can also be 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acids long. L₁, L₂, L₃, and L₄in one binding protein may all have the same amino acid sequence or may all have different amino acid sequences.
Examples of suitable linkers include a single glycine (Gly) residue; a diglycine peptide (Gly-Gly); a tripeptide (Gly-Gly-Gly); a peptide with four glycine residues (Gly-Gly-Gly-Gly; SEQ ID NO: 285); a peptide with five glycine residues (Gly-Gly-Gly-Gly-Gly; SEQ ID NO: 286); a peptide with six glycine residues (Gly-Gly-Gly-Gly-Gly-Gly; SEQ ID NO: 287); a peptide with seven glycine residues (Gly-Gly-Gly-Gly-Gly-Gly-Gly; SEQ ID NO: 288); a peptide with eight glycine residues (Gly-Gly-Gly-Gly-Gly-Gly-Gly-Gly; SEQ ID NO: 289). Other combinations of amino acid residues may be used such as the peptide Gly-Gly-Gly-Gly-Ser (SEQ ID NO: 290), the peptide Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser (SEQ ID NO: 291) and the peptide Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser-Gly-Gly-Gly-Gly-Ser (SEQ ID NO: 292). Other suitable linkers include a single Ser, and Val residue; the dipeptide Arg-Thr, Gln-Pro, Ser-Ser, Thr-Lys, and Ser-Leu; Thr-Lys-Gly-Pro-Ser (SEQ ID NO: 293), Thr-Val-Ala-Ala-Pro (SEQ ID NO: 294), Gln-Pro-Lys-Ala-Ala (SEQ ID NO: 295), Gln-Arg-Ile-Glu-Gly (SEQ ID NO: 296); Ala-Ser-Thr-Lys-Gly-Pro-Ser (SEQ ID NO: 297), Arg-Thr-Val-Ala-Ala-Pro-Ser (SEQ ID NO: 298), Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299), and His-Ile-Asp-Ser-Pro-Asn-Lys (SEQ ID NO: 300). The examples listed above are not intended to limit the scope of the disclosure in any way, and linkers comprising randomly selected amino acids selected from the group consisting of valine, leucine, isoleucine, serine, threonine, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine, glycine, and proline have been shown to be suitable in the binding proteins.
The identity and sequence of amino acid residues in the linker may vary depending on the type of secondary structural element necessary to achieve in the linker. For example, glycine, serine, and alanine are best for linkers having maximum flexibility. Some combination of glycine, proline, threonine, and serine are useful if a more rigid and extended linker is necessary. Any amino acid residue may be considered as a linker in combination with other amino acid residues to construct larger peptide linkers as necessary depending on the desired properties.
In some embodiments, the length of L₁is at least twice the length of L₃. In some embodiments, the length of L₂is at least twice the length of L₄. In some embodiments, the length of L₁is at least twice the length of L₃, and the length of L₂is at least twice the length of L₄. In some embodiments, L₁is 3 to 12 amino acid residues in length, L₂is 3 to 14 amino acid residues in length, L₃is 1 to 8 amino acid residues in length, and L₄is 1 to 3 amino acid residues in length. In some embodiments, L₁is 5 to 10 amino acid residues in length, L₂is 5 to 8 amino acid residues in length, L₃is 1 to 5 amino acid residues in length, and L₄is 1 to 2 amino acid residues in length. In some embodiments, L₁is 7 amino acid residues in length, L₂is 5 amino acid residues in length, L₃is 1 amino acid residue in length, and L₄is 2 amino acid residues in length.
In some embodiments, L₁, L₂, L₃, and/or L₄comprise the sequence Asp-Lys-Thr-His-Thr (SEQ ID NO: 525). In some embodiments, L₁comprises the sequence Asp-Lys-Thr-His-Thr (SEQ ID NO: 525). In some embodiments, L₃comprises the sequence Asp-Lys-Thr-His-Thr (SEQ ID NO: 525).
In some embodiments, L₁, L₂, L₃, and/or L₄comprise the sequence Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299). In some embodiments, L₁comprises the sequence Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299). In some embodiments, L₁comprises the sequence Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299), L₂comprises the sequence Thr-Lys-Gly-Pro-Ser-Arg (SEQ ID NO: 526), L₃comprises the sequence Ser, and L₄comprises the sequence Arg-Thr. In some embodiments, L₃comprises the sequence Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299). In some embodiments, L₁comprises the sequence Ser, L₂comprises the sequence Arg-Thr, L₃comprises the sequence Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299) and L₄comprises the sequence Thr-Lys-Gly-Pro-Ser-Arg (SEQ ID NO: 526).
Fc Regions and Constant Domains
In some embodiments, a binding protein of the present disclosure comprises a second polypeptide chain further comprising an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains. In some embodiments, a binding protein of the present disclosure comprises a third polypeptide chain further comprising an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains. In some embodiments, a binding protein of the present disclosure comprises a second polypeptide chain further comprising an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, and a third polypeptide chain further comprising an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains.
To improve the yields of the binding proteins, in some embodiments, the C_H3domains can be altered by the “knob-into-holes” technology which is described in detail with several examples in, for example, International Publication No. WO 96/027011, Ridgway et al., 1996, Protein Eng. 9: 617-21; and Merchant et al., 1998, Nat. Biotechnol. 16: 677-81. Specifically, the interaction surfaces of the two C_H3domains are altered to increase the heterodimerisation of both heavy chains containing these two C_H3domains. Each of the two C_H3domains (of the two heavy chains) can be the “knob,” while the other is the “hole.” The introduction of a disulfide bridge further stabilizes the heterodimers (Merchant et al., 1998; Atwell et al., 1997, J. Mol. Biol. 270: 26-35) and increases the yield. In particular embodiments, the knob is on the second pair of polypeptides with a single variable domain. In other embodiments, the knob is on the first pair of polypeptides having the cross-over orientation. In yet other embodiments, the C_H3domains do not include a knob in hole.
In some embodiments, a binding protein of the present disclosure comprises a “knob” mutation on the second polypeptide chain and a “hole” mutation on the third polypeptide chain. In some embodiments, a binding protein of the present disclosure comprises a “knob” mutation on the third polypeptide chain and a “hole” mutation on the second polypeptide chain. In some embodiments, the “knob” mutation comprises substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index. In some embodiments, the amino acid substitutions are S354C and T366W. In some embodiments, the “hole” mutation comprises substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index. In some embodiments, the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.
In some embodiments, a binding protein of the present disclosure comprises one or more mutations to improve serum half-life (See e.g., Hinton, P. R. et al. (2006) J. Immunol. 176(1):346-56). In some embodiments, the mutation comprises substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S. In some embodiments, the binding protein comprises a second polypeptide chain further comprising a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, and a third polypeptide chain further comprising a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S. In some embodiments, a binding protein of the present disclosure comprises knob and hole mutations and one or more mutations to improve serum half-life.
In some embodiments, C_H1, C_H2, C_H3and C_Lof the trispecific binding proteins described herein may comprise any of C_H1, C_H2, C_H3and C_Lsequences of binding proteins 1-53.
Nucleic Acids
Standard recombinant DNA methodologies are used to construct the polynucleotides that encode the polypeptides which form the binding proteins, incorporate these polynucleotides into recombinant expression vectors, and introduce such vectors into host cells. See e.g., Sambrook et al., 2001, MOLECULAR CLONING: A LABORATORY MANUAL (Cold Spring Harbor Laboratory Press, 3rd ed.). Enzymatic reactions and purification techniques may be performed according to manufacturer's specifications, as commonly accomplished in the art, or as described herein. Unless specific definitions are provided, the nomenclature utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Similarly, conventional techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, delivery, and treatment of patients.
Other aspects of the present disclosure relate to isolated nucleic acid molecules comprising a nucleotide sequence encoding any of the binding proteins described herein. In some embodiments, the isolated nucleic acid is operably linked to a heterologous promoter to direct transcription of the binding protein-coding nucleic acid sequence. A promoter may refer to nucleic acid control sequences which direct transcription of a nucleic acid. A first nucleic acid sequence is operably linked to a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence of a binding protein if the promoter affects the transcription or expression of the coding sequence. Examples of promoters may include, but are not limited to, promoters obtained from the genomes of viruses (such as polyoma virus, fowlpox virus, adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus, Simian Virus 40 (SV40), and the like), from heterologous eukaryotic promoters (such as the actin promoter, an immunoglobulin promoter, from heat-shock promoters, and the like), the CAG-promoter (Niwa et al., Gene 108(2): 193-9, 1991), the phosphoglycerate kinase (PGK)-promoter, a tetracycline-inducible promoter (Masui et al., Nucleic Acids Res. 33:e43, 2005), the lac system, the trp system, the tac system, the trc system, major operator and promoter regions of phage lambda, the promoter for 3-phosphoglycerate kinase, the promoters of yeast acid phosphatase, and the promoter of the yeast alpha-mating factors. Polynucleotides encoding binding proteins of the present disclosure may be under the control of a constitutive promoter, an inducible promoter, or any other suitable promoter described herein or other suitable promoter that will be readily recognized by one skilled in the art.
In some embodiments, the isolated nucleic acid is incorporated into a vector. In some embodiments, the vector is an expression vector. Expression vectors may include one or more regulatory sequences operatively linked to the polynucleotide to be expressed. The term “regulatory sequence” includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Examples of suitable enhancers may include, but are not limited to, enhancer sequences from mammalian genes (such as globin, elastase, albumin, α-fetoprotein, insulin and the like), and enhancer sequences from a eukaryotic cell virus (such as SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, adenovirus enhancers, and the like). Examples of suitable vectors may include, for example, plasmids, cosmids, episomes, transposons, and viral vectors (e.g., adenoviral, vaccinia viral, Sindbis-viral, measles, herpes viral, lentiviral, retroviral, adeno-associated viral vectors, etc.). Expression vectors can be used to transfect host cells, such as, for example, bacterial cells, yeast cells, insect cells, and mammalian cells. Biologically functional viral and plasmid DNA vectors capable of expression and replication in a host are known in the art, and can be used to transfect any cell of interest.
Other aspects of the present disclosure relate to a vector system comprising one or more vectors encoding a first, second, third, and fourth polypeptide chain of any of the binding proteins described herein. In some embodiments, the vector system comprises a first vector encoding the first polypeptide chain of the binding protein, a second vector encoding the second polypeptide chain of the binding protein, a third vector encoding the third polypeptide chain of the binding protein, and a fourth vector encoding the fourth polypeptide chain of the binding protein. In some embodiments, the vector system comprises a first vector encoding the first and second polypeptide chains of the binding protein, and a second vector encoding the third and fourth polypeptide chains of the binding protein. In some embodiments, the vector system comprises a first vector encoding the first and third polypeptide chains of the binding protein, and a second vector encoding the second and fourth polypeptide chains of the binding protein. In some embodiments, the vector system comprises a first vector encoding the first and fourth polypeptide chains of the binding protein, and a second vector encoding the second and third polypeptide chains of the binding protein. In some embodiments, the vector system comprises a first vector encoding the first, second, third, and fourth polypeptide chains of the binding protein. The one or more vectors of the vector system may be any of the vectors described herein. In some embodiments, the one or more vectors are expression vectors.
Host Cells
Other aspects of the present disclosure relate to a host cell (e.g., an isolated host cell) comprising one or more isolated polynucleotides, vectors, and/or vector systems described herein. In some embodiments, an isolated host cell of the present disclosure is cultured in vitro. In some embodiments, the host cell is a bacterial cell (e.g., an E. coli cell). In some embodiments, the host cell is a yeast cell (e.g., an S. cerevisiae cell). In some embodiments, the host cell is an insect cell. Examples of insect host cells may include, for example, Drosophila cells (e.g., S2 cells), Trichoplusia ni cells (e.g., High Five™ cells), and Spodoptera frugiperda cells (e.g., Sf21 or Sf9 cells). In some embodiments, the host cell is a mammalian cell. Examples of mammalian host cells may include, for example, human embryonic kidney cells (e.g., 293 or 293 cells subcloned for growth in suspension culture), Expi293™ cells, CHO cells, baby hamster kidney cells (e.g., BHK, ATCC CCL 10), mouse sertoli cells (e.g., TM4 cells), monkey kidney cells (e.g., CV1 ATCC CCL 70), African green monkey kidney cells (e.g., VERO-76, ATCC CRL-1587), human cervical carcinoma cells (e.g., HELA, ATCC CCL 2), canine kidney cells (e.g., MDCK, ATCC CCL 34), buffalo rat liver cells (e.g., BRL 3A, ATCC CRL 1442), human lung cells (e.g., W138, ATCC CCL 75), human liver cells (e.g., Hep G2, HB 8065), mouse mammary tumor cells (e.g., MMT 060562, ATCC CCL51), TRI cells, MRC 5 cells, FS4 cells, a human hepatoma line (e.g., Hep G2), and myeloma cells (e.g., NS0 and Sp2/0 cells).
Other aspects of the present disclosure relate to a method of producing any of the binding proteins described herein. In some embodiments, the method includes a) culturing a host cell (e.g., any of the host cells described herein) comprising an isolated nucleic acid, vector, and/or vector system (e.g., any of the isolated nucleic acids, vectors, and/or vector systems described herein) under conditions such that the host cell expresses the binding protein; and b) isolating the binding protein from the host cell. Methods of culturing host cells under conditions to express a protein are well known to one of ordinary skill in the art. Methods of isolating proteins from cultured host cells are well known to one of ordinary skill in the art, including, for example, by affinity chromatography (e.g., two step affinity chromatography comprising protein A affinity chromatography followed by size exclusion chromatography).

Use for Binding Proteins

The binding proteins can be employed in any known assay method, such as competitive binding assays, direct and indirect sandwich assays, and immunoprecipitation assays for the detection and quantitation of one or more target antigens. The binding proteins will bind the one or more target antigens with an affinity that is appropriate for the assay method being employed.
For diagnostic applications, in certain embodiments, binding proteins can be labeled with a detectable moiety. The detectable moiety can be any one that is capable of producing, either directly or indirectly, a detectable signal. For example, the detectable moiety can be a radioisotope, such as ³H, ¹⁴C, ³²P, ³⁵S, ¹²⁵I, ⁹⁹Tc, ¹¹¹In, or ⁶⁷Ga; a fluorescent or chemiluminescent compound, such as fluorescein isothiocyanate, rhodamine, or luciferin; or an enzyme, such as alkaline phosphatase, β-galactosidase, or horseradish peroxidase.
The binding proteins are also useful for in vivo imaging. A binding protein labeled with a detectable moiety can be administered to an animal, e.g., into the bloodstream, and the presence and location of the labeled antibody in the host assayed. The binding protein can be labeled with any moiety that is detectable in an animal, whether by nuclear magnetic resonance, radiology, or other detection means known in the art.
The disclosure also relates to a kit comprising a binding protein and other reagents useful for detecting target antigen levels in biological samples. Such reagents can include a detectable label, blocking serum, positive and negative control samples, and detection reagents. In some embodiments, the kit comprises a composition comprising any binding protein, polynucleotide, vector, vector system, and/or host cell described herein. In some embodiments, the kit comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, etc. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is by itself or combined with another composition effective for treating, preventing and/or diagnosing a condition (e.g., HIV infection) and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). In some embodiments, the label or package insert indicates that the composition is used for preventing, diagnosing, and/or treating the condition of choice. Alternatively, or additionally, the article of manufacture or kit may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
Therapeutic or pharmaceutical compositions comprising binding proteins are within the scope of the disclosure. Such therapeutic or pharmaceutical compositions can comprise a therapeutically effective amount of a binding protein, or binding protein-drug conjugate, in admixture with a pharmaceutically or physiologically acceptable formulation agent selected for suitability with the mode of administration.
Acceptable formulation materials are nontoxic to recipients at the dosages and concentrations employed.
The pharmaceutical composition can contain formulation materials for modifying, maintaining, or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption, or penetration of the composition. Suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine, or lysine), antimicrobials, antioxidants (such as ascorbic acid, sodium sulfite, or sodium hydrogen-sulfite), buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates, or other organic acids), bulking agents (such as mannitol or glycine), chelating agents (such as ethylenediamine tetraacetic acid (EDTA)), complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin), fillers, monosaccharides, disaccharides, and other carbohydrates (such as glucose, mannose, or dextrins), proteins (such as serum albumin, gelatin, or immunoglobulins), coloring, flavoring and diluting agents, emulsifying agents, hydrophilic polymers (such as polyvinylpyrrolidone), low molecular weight polypeptides, salt-forming counterions (such as sodium), preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide), solvents (such as glycerin, propylene glycol, or polyethylene glycol), sugar alcohols (such as mannitol or sorbitol), suspending agents, surfactants or wetting agents (such as pluronics; PEG; sorbitan esters; polysorbates such as polysorbate 20 or polysorbate 80; triton; tromethamine; lecithin; cholesterol or tyloxapal), stability enhancing agents (such as sucrose or sorbitol), tonicity enhancing agents (such as alkali metal halides—e.g., sodium or potassium chloride—or mannitol sorbitol), delivery vehicles, diluents, excipients and/or pharmaceutical adjuvants (see, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES (18th Ed., A. R. Gennaro, ed., Mack Publishing Company 1990), and subsequent editions of the same, incorporated herein by reference for any purpose).
The optimal pharmaceutical composition will be determined by a skilled artisan depending upon, for example, the intended route of administration, delivery format, and desired dosage. Such compositions can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the binding protein.
The primary vehicle or carrier in a pharmaceutical composition can be either aqueous or non-aqueous in nature. For example, a suitable vehicle or carrier for injection can be water, physiological saline solution, or artificial cerebrospinal fluid, possibly supplemented with other materials common in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Other exemplary pharmaceutical compositions comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5, which can further include sorbitol or a suitable substitute. In one embodiment of the disclosure, binding protein compositions can be prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents in the form of a lyophilized cake or an aqueous solution. Further, the binding protein can be formulated as a lyophilizate using appropriate excipients such as sucrose.
The pharmaceutical compositions of the disclosure can be selected for parenteral delivery or subcutaneous. Alternatively, the compositions can be selected for inhalation or for delivery through the digestive tract, such as orally. The preparation of such pharmaceutically acceptable compositions is within the skill of the art.
The formulation components are present in concentrations that are acceptable to the site of administration. For example, buffers are used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from about 5 to about 8.
When parenteral administration is contemplated, the therapeutic compositions for use can be in the form of a pyrogen-free, parenterally acceptable, aqueous solution comprising the desired binding protein in a pharmaceutically acceptable vehicle. A particularly suitable vehicle for parenteral injection is sterile distilled water in which a binding protein is formulated as a sterile, isotonic solution, properly preserved. Yet another preparation can involve the formulation of the desired molecule with an agent, such as injectable microspheres, bio-erodible particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads, or liposomes, that provides for the controlled or sustained release of the product which can then be delivered via a depot injection. Hyaluronic acid can also be used, and this can have the effect of promoting sustained duration in the circulation. Other suitable means for the introduction of the desired molecule include implantable drug delivery devices.
In one embodiment, a pharmaceutical composition can be formulated for inhalation. For example, a binding protein can be formulated as a dry powder for inhalation. Binding protein inhalation solutions can also be formulated with a propellant for aerosol delivery. In yet another embodiment, solutions can be nebulized.
It is also contemplated that certain formulations can be administered orally. In one embodiment of the disclosure, binding proteins that are administered in this fashion can be formulated with or without those carriers customarily used in the compounding of solid dosage forms such as tablets and capsules. For example, a capsule can be designed to release the active portion of the formulation at the point in the gastrointestinal tract where bioavailability is maximized and pre-systemic degradation is minimized. Additional agents can be included to facilitate absorption of the binding protein. Diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders can also be employed.
Another pharmaceutical composition can involve an effective quantity of binding proteins in a mixture with non-toxic excipients that are suitable for the manufacture of tablets. By dissolving the tablets in sterile water, or another appropriate vehicle, solutions can be prepared in unit-dose form. Suitable excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.
Additional pharmaceutical compositions of the disclosure will be evident to those skilled in the art, including formulations involving binding proteins in sustained- or controlled-delivery formulations. Techniques for formulating a variety of other sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. Additional examples of sustained-release preparations include semipermeable polymer matrices in the form of shaped articles, e.g. films, or microcapsules. Sustained release matrices can include polyesters, hydrogels, polylactides, copolymers of L-glutamic acid and gamma ethyl-L-glutamate, poly(2-hydroxyethyl-methacrylate), ethylene vinyl acetate, or poly-D(−)-3-hydroxybutyric acid. Sustained-release compositions can also include liposomes, which can be prepared by any of several methods known in the art.
Pharmaceutical compositions to be used for in vivo administration typically must be sterile. This can be accomplished by filtration through sterile filtration membranes. Where the composition is lyophilized, sterilization using this method can be conducted either prior to, or following, lyophilization and reconstitution. The composition for parenteral administration can be stored in lyophilized form or in a solution. In addition, parenteral compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.
Once the pharmaceutical composition has been formulated, it can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder. Such formulations can be stored either in a ready-to-use form or in a form (e.g., lyophilized) requiring reconstitution prior to administration.
The disclosure also encompasses kits for producing a single-dose administration unit. The kits can each contain both a first container having a dried protein and a second container having an aqueous formulation. Also included within the scope of this disclosure are kits containing single and multi-chambered pre-filled syringes (e.g., liquid syringes and lyosyringes).
The effective amount of a binding protein pharmaceutical composition to be employed therapeutically will depend, for example, upon the therapeutic context and objectives. One skilled in the art will appreciate that the appropriate dosage levels for treatment will thus vary depending, in part, upon the molecule delivered, the indication for which the binding protein is being used, the route of administration, and the size (body weight, body surface, or organ size) and condition (the age and general health) of the patient. Accordingly, the clinician can titer the dosage and modify the route of administration to obtain the optimal therapeutic effect.
Dosing frequency will depend upon the pharmacokinetic parameters of the binding protein in the formulation being used. Typically, a clinician will administer the composition until a dosage is reached that achieves the desired effect. The composition can therefore be administered as a single dose, as two or more doses (which may or may not contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. Appropriate dosages can be ascertained through use of appropriate dose-response data.
The route of administration of the pharmaceutical composition is in accord with known methods, e.g., orally; through injection by intravenous, intraperitoneal, intracerebral (intraparenchymal), intracerebroventricular, intramuscular, intraocular, intraarterial, intraportal, or intralesional routes; by sustained release systems; or by implantation devices. Where desired, the compositions can be administered by bolus injection or continuously by infusion, or by implantation device.
The composition can also be administered locally via implantation of a membrane, sponge, or other appropriate material onto which the desired molecule has been absorbed or encapsulated. Where an implantation device is used, the device can be implanted into any suitable tissue or organ, and delivery of the desired molecule can be via diffusion, timed-release bolus, or continuous administration.
The pharmaceutical compositions can be used to prevent and/or treat HIV infection. The pharmaceutical compositions can be used as a standalone therapy or in combination with standard anti-retroviral therapy.
In some embodiments, the present disclosure relates to a method of preventing and/or treating HIV infection in a patient. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of at least one of the binding proteins described herein. In some embodiments, the at least one binding protein is administered in combination with an anti-retroviral therapy (e.g., an anti-HIV therapy). In some embodiments, the at least one binding protein is administered before the anti-retroviral therapy. In some embodiments, the at least one binding protein is administered concurrently with the anti-retroviral therapy. In some embodiments, the at least one binding protein is administered after the anti-retroviral therapy. In some embodiments, the at least one binding protein is co-administered with any standard anti-retroviral therapy known in the art. In some embodiments, administration of the at least one binding protein results in neutralization of one or more HIV virions. In some embodiments, administration of the at least one binding protein results in elimination of one or more latently and/or chronically HIV-infected cells in the patient. In some embodiments, administration of the at least one binding protein results in neutralization of one or more HIV virions and results in elimination of one or more latently and/or chronically HIV-infected cells in the patient. In some embodiments, the patient is a human.
Without limiting the present disclosure, a number of embodiments of the present disclosure are described below for purpose of illustration.
Item 1: A binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain comprises a structure represented by the formula:
V_H1-L3-V_H2-L4-C_H1 [II]
and a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1 [III]
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-CL [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain; and
L₁, L₂, L₃, and L₄are amino acid linkers;
and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
Item 2: A binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain comprises a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1-hinge-C_H2-C_H3 [II]
and a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1-hinge-C_H2-C_H3 [III]
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-C_L [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is an immunoglobulin C_H1heavy chain constant domain;
C_H2is an immunoglobulin C_H2heavy chain constant domain;
C_H3is an immunoglobulin C_H3heavy chain constant domain;
hinge is an immunoglobulin hinge region connecting the C_H1and C_H2domains; and
L₁, L₂, L₃and L₄are amino acid linkers;
and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
Item 3: The binding protein of item 1 or item 2, wherein the one or more HIV target proteins is selected from the group consisting of glycoprotein 120, glycoprotein 41 and glycoprotein 60.
Item 4: The binding protein of item 1 or item 2, wherein the binding protein is trispecific and capable of specifically binding three different epitopes on a single HIV target protein.
Item 5: The binding protein of item 1 or item 2, wherein the binding protein is trispecific and capable of specifically binding two different epitopes on a first HIV target protein, and one epitope on a second HIV target protein, wherein the first and second HIV target proteins are different.
Item 6: The binding protein of item 1 or item 2, wherein the binding protein is trispecific and capable of specifically binding three different antigen targets.
Item 7: The binding protein of item 1 or item 2, wherein the binding protein is capable of inhibiting the function of one or more HIV target proteins.
Item 8: The binding protein of any one of items 1-7, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively.
Item 9: The binding protein of any one of items 1-7, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.
Item 10: The binding protein of any one of items 1-9, wherein V_L1comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.
Item 11: The binding protein of any one of items 1-10, wherein V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively.
Item 12: The binding protein of any one of items 1-10, wherein V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.
Item 13: The binding protein of any one of items 1-12, wherein V_L2comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.
Item 14: The binding protein of any one of items 1-13, wherein V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively.
Item 15: The binding protein of any one of items 1-13, wherein V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.
Item 16: The binding protein of any one of items 1-15, wherein V_L3comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.
Item 17: The binding protein of any one of items 1-16, wherein V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively.
Item 18: The binding protein of any one of items 1-16, wherein V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.
Item 19: The binding protein of any one of items 1-18, wherein V_H1comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.
Item 20: The binding protein of any one of items 1-19, wherein V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively, a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively.
Item 21: The binding protein of any one of items 1-19, wherein V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.
Item 22: The binding protein of any one of items 1-21, wherein V_H2comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.
Item 23: The binding protein of any one of items 1-22, wherein V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively.
Item 24: The binding protein of any one of items 1-22, wherein V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.
Item 25: The binding protein of any one of items 1-24, wherein V_H3comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.
Item 26: The binding protein of any one of items 1-25, wherein V_L1comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; V_L2comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; V_L3comprises a CDR-L1 comprising the sequence of SEQ ID NO: 266, a CDR-L2 comprising the sequence of SEQ ID NO: 267, and a CDR-L3 comprising the sequence of SEQ ID NO: 268; V_H1comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; V_H2comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; and V_H3comprises a CDR-H1 comprising the sequence of SEQ ID NO: 248, a CDR-H2 comprising the sequence of SEQ ID NO: 497, and a CDR-H3 comprising the sequence of SEQ ID NO: 250.
Item 27: The binding protein of any one of items 1-25, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 512; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504, V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 502.
Item 28: The binding protein of any one of items 1-27, wherein V_L1comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; V_L2comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; V_L3comprises a light chain variable domain comprising the sequence of SEQ ID NO: 512; V_H1comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; V_H2comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; and V_H3comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 502.
Item 29: The binding protein of any one of items 1-25, wherein V_L1comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; V_L2comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; V_L3comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; V_H1comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; V_H2comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; and V_H3comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253.
Item 30: The binding protein of any one of items 1-25, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503.
Item 31: The binding protein of any one of items 1-25 and 29-30, wherein V_L1comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; V_L2comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; V_L3comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; V_H1comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; V_H2comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; and V_H3comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503.
Item 32: The binding protein of any one of items 1-25, wherein V_L1comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; V_L2comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; V_L3comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; V_H1comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; V_H2comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; and V_H3comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253.
Item 33: The binding protein of any one of items 1-25, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503.
Item 34: The binding protein of any one of items 1-25 and 32-33, wherein V_L1comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; V_L2comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; V_L3comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; V_H1comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; V_H2comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; and V_H3comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503.
Item 35: The binding protein of item 1, wherein the second polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains.
Item 36: The binding protein of item 1, wherein the third polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains.
Item 37: The binding protein of item 1, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.
Item 38: The binding protein of item 1, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.
Item 39: The binding protein of any one of items 1, 37, and 38, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
Item 40: The binding protein of item 2, wherein the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.
Item 41: The binding protein of item 2, wherein the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.
Item 42: The binding protein of any one of items 2, 40, and 41, wherein the C_H3domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
Item 43: The binding protein of item 1 or item 2, wherein at least one of L₁, L₂, L₃, or L₄is independently 0 amino acids in length.
Item 44: The binding protein of item 1 or item 2, wherein L₁, L₂, L₃, or L₄are each independently at least one amino acid in length.
Item 45: The binding protein of any one of items 1-44, wherein L₁comprises Asp-Lys-Thr-His-Thr (SEQ ID NO: 525).
Item 46: A binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain comprises a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1 [II]
and a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1 [III]
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-C_L [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain; and
L₁, L₂, L₃, and L₄are amino acid linkers;
wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;
wherein:
(a) V_L1, V_L2and V_L3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 2, 4, 10, 12, 18, 20, 26, 28, 34, 36, 42, 44, 50, 52, 58, 60, 66, 68, 74, 76, 82, 84, 90, 92, 98, 100, 106, 108, 114, 116, 122, 124, 130, 132, 138, 140, 146, 148, 154, 156, 162, 164, 170, 172, 178, 180, 186, 188, 194, 196, 202, 204, 210, 212, 218, 220, 226, 228, 233, 235, 241, 243; or
(b) V_L1, V_L2and V_L3each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs:266-283; and
wherein:
(a) V_H1, V_H2, and V_H3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 1, 3, 9, 11, 17, 10, 25, 27, 33, 35, 41, 43, 49, 51, 57, 59, 65, 67, 73, 75, 81, 83, 89, 91, 97, 99, 105, 107, 113, 115, 121, 123, 129, 131, 137, 139, 145, 147, 153, 155, 161, 163, 169, 171, 177, 179, 185, 187, 193, 195, 201, 203, 209, 211, 217, 219, 225, 227, 232, 234, 240, 242; or
(b) V_H1, V_H2, and V_H3each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-265.
Item 47: A binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain comprises a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1-hinge-C_H2-C_H3 [II]
and a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1-hinge-C_H2-C_H3 [III]
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-C_L [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain;
C_H2is an immunoglobulin C_H2heavy chain constant domain;
C_H3is an immunoglobulin C_H3heavy chain constant domain;
hinge is an immunoglobulin hinge region connecting the C_H1and C_H2domains; and
L₁, L₂, L₃, and L₄are amino acid linkers;
wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;
wherein:
(a) V_L1, V_L2and V_L3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 2, 4, 10, 12, 18, 20, 26, 28, 34, 36, 42, 44, 50, 52, 58, 60, 66, 68, 74, 76, 82, 84, 90, 92, 98, 100, 106, 108, 114, 116, 122, 124, 130, 132, 138, 140, 146, 148, 154, 156, 162, 164, 170, 172, 178, 180, 186, 188, 194, 196, 202, 204, 210, 212, 218, 220, 226, 228, 233, 235, 241, 243; or
(b) V_L1, V_L2and V_L3each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs:266-283; and
wherein:
(a) V_H1, V_H2, and V_H3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 1, 3, 9, 11, 17, 10, 25, 27, 33, 35, 41, 43, 49, 51, 57, 59, 65, 67, 73, 75, 81, 83, 89, 91, 97, 99, 105, 107, 113, 115, 121, 123, 129, 131, 137, 139, 145, 147, 153, 155, 161, 163, 169, 171, 177, 179, 185, 187, 193, 195, 201, 203, 209, 211, 217, 219, 225, 227, 232, 234, 240, 242; or
(b) V_H1, V_H2, and V_H3each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-265.
Item 48: The binding protein of item 46, wherein the second polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains.
Item 49: The binding protein of item 46, wherein the third polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains.
Item 50: The binding protein of item 46, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.
Item 51: The binding protein of item 46, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.
Item 52: The binding protein of any one of items 46, 50, and 51, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
Item 53: The binding protein of item 47, wherein the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.
Item 54: The binding protein of item 47, wherein the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.
Item 55: The binding protein of any one of items 47, 53, and 54, wherein the C_H3domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
Item 56: The binding protein of item 46 or item 47, wherein at least one of L₁, L₂, L₃or L₄is independently 0 amino acids in length.
Item 57: The binding protein of item 46 or item 47, wherein L₁, L₂, L₃or L₄are each independently at least one amino acid in length.
Item 58: The binding protein of any one of items 46-57, wherein L₁comprises Asp-Lys-Thr-His-Thr (SEQ ID NO: 525).
Item 59: A binding protein comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain wherein:
(a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 4; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2;
(b) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 12 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 12; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 11 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 11; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 9 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 9; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10;
(c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 20 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 20; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 19 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 17 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 17; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 18 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18;
(d) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 28 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 28; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 27 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 25 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 26 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 26;
(e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 36; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 35 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 35; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 33 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 33; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 34 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 34;
(f) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 44; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 43 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 43; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 41 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 41; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 42 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 42;
(g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 52 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 52; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 51 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 51; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 49 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 49; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 50 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 50;
(h) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 60 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 60; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 59 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 59; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 57; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 58 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 58;
(i) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 68; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 67; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 65 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 65; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 66 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 66;
(j) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 76; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 75; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 73, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 74 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 74;
(k) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 84 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 84; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 83 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 83; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 81 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 81; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 82 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 82;
(l) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 92 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:92; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 91 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 91; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 89 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 89; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 90 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 90;
(m) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 100 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 100; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 99 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 99; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 97 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 97; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 98 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 98;
(n) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 108 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 108; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 107 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 107; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 105 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 105; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 106 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 106;
(o) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 116 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 116; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 115 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 115; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 113 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 113; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 114;
(p) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 124 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 124; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 123 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 123; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 121 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 121; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 122 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 122;
(q) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 132 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 132; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 131; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 129 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 129; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 130 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 130;
(r) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 140 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 140; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 139 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 139; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 137 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 137; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 138;
(s) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 148 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 148; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 147 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 147; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 145 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 145; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 146 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 146;
(t) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 156 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 156; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 155 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 155; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 153 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 153; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 154 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 154;
(u) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 164 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 164; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 163 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 163; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 161 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 161; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 162 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 162;
(v) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 172 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 172; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 171 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 171; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 169 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 169; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 170 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 170;
(w) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 180 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 180; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 179; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 177 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 177; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 178 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 178;
(x) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 188 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 188; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 187 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 187; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 185 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 185; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 186 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 186;
(y) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 196 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 196; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 195 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 195; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 193 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 193; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 194 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 194;
(z) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 204 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 204; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 203 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 203; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 201 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 201; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 202 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 202;
(aa) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 212 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 212; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 211 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 211; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 209 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 209; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 210 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 210;
(bb) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 220 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 220; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 219 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 219; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 217 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 217; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 218 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 218;
(cc) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 228 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 228; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 227 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 227; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 225 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 225; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 226 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 226;
(dd) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 235 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 235; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 234 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 234; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 232 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 232; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 233 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 233; or
(ee) first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 243 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 243; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 242 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 242; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 240 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 240; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 241 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 241.
Item 60: A binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins and one or more T cell target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I];
a second polypeptide chain comprises a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1 [II];
a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1 [III];
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-C_L [IV];
wherein
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain; and
L₁, L₂, L₃, and L₄are amino acid linkers;
and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
Item 61: A binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins and one or more T cell target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I];
a second polypeptide chain comprises a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1-hinge-C_H2-C_H3 [II];
a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1-hinge-C_H2-C_H3 [III];
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-C_L [IV];
wherein
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain;
C_H2is an immunoglobulin C_H2heavy chain constant domain;
C_H3is an immunoglobulin C_H3heavy chain constant domain;
hinge is an immunoglobulin hinge region connecting the C_H1and C_H2domains; and
L₁, L₂, L₃, and L₄are amino acid linkers;
and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.
Item 62: The binding protein of item 60 or item 61, wherein the one or more HIV target proteins are selected from the group consisting of glycoprotein 120, glycoprotein 41 and glycoprotein 160.
Item 63: The binding protein of item 60 or item 61, wherein the one or more T cell target proteins are CD3 or CD28.
Item 64: The binding protein of item 60 or item 61, wherein the binding protein is trispecific and capable of specifically binding an HIV target protein and two different epitopes on a single T cell target protein.
Item 65: The binding protein of item 60 or item 61, wherein the binding protein is trispecific and capable of specifically binding an HIV target protein and two different T cell target proteins.
Item 66: The binding protein of item 60 or item 61, wherein the binding protein is trispecific and capable of specifically binding a T cell target protein and two different epitopes on a single HIV target protein.
Item 67: The binding protein of item 60 or item 61, wherein the binding protein is trispecific and capable of specifically binding a T cell target protein and two different HIV target proteins.
Item 68: The binding protein of item 60 or item 61, wherein the first and second polypeptide chains form two antigen binding sites that specifically target two T cell target proteins, and the third and fourth polypeptide chains form an antigen binding site that specifically binds an HIV target protein.
Item 69: The binding protein of any one of items 60-68, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively.
Item 70: The binding protein of any one of items 60-68, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.
Item 71: The binding protein of any one of items 60-70, wherein V_L1comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.
Item 72: The binding protein of any one of items 60-71, wherein V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively.
Item 73: The binding protein of any one of items 60-71, wherein V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.
Item 74: The binding protein of any one of items 60-73, wherein V_L2comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.
Item 75: The binding protein of any one of items 60-74, wherein V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively.
Item 76: The binding protein of any one of items 60-74, wherein V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.
Item 77: The binding protein of any one of items 60-76, wherein V_L3comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.
Item 78: The binding protein of any one of items 60-77, wherein V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively.
Item 79: The binding protein of any one of items 60-77, wherein V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.
Item 80: The binding protein of any one of items 60-79, wherein V_H1comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.
Item 81: The binding protein of any one of items 60-80, wherein V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively.
Item 82: The binding protein of any one of items 60-80, wherein V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.
Item 83: The binding protein of any one of items 60-82, wherein V_H2comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.
Item 84: The binding protein of any one of items 60-83, wherein V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively, a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively.
Item 85: The binding protein of any one of items 60-83, wherein V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.
Item 86: The binding protein of any one of items 60-85, wherein V_H3comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.
Item 87: The binding protein of any one of items 60-86, wherein V_L1comprises a CDR-L1 comprising the sequence of SEQ ID NO: 488, a CDR-L2 comprising the sequence of SEQ ID NO: 489, and a CDR-L3 comprising the sequence of SEQ ID NO: 490; V_L2comprises a CDR-L1 comprising the sequence of SEQ ID NO: 494, a CDR-L2 comprising the sequence of SEQ ID NO: 495, and a CDR-L3 comprising the sequence of SEQ ID NO: 496; V_L3comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; V_H1comprises a CDR-H1 comprising the sequence of SEQ ID NO: 479, a CDR-H2 comprising the sequence of SEQ ID NO: 480, and a CDR-H3 comprising the sequence of SEQ ID NO: 481; V_H2comprises a CDR-H1 comprising the sequence of SEQ ID NO: 485, a CDR-H2 comprising the sequence of SEQ ID NO: 486, and a CDR-H3 comprising the sequence of SEQ ID NO: 487; and V_H3comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253.
Item 88: The binding protein of any one of items 60-86, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 522; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 524; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 509; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 511; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503.
Item 89: The binding protein of any one of items 60-88, wherein V_L1comprises a light chain variable domain comprising the sequence of SEQ ID NO: 522; V_L2comprises a light chain variable domain comprising the sequence of SEQ ID NO: 524; V_L3comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; V_H1comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 509; V_H2comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 511; and V_H3comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503.
Item 90: The binding protein of any one of items 60-86, wherein V_L1comprises a CDR-L1 comprising the sequence of SEQ ID NO: 494, a CDR-L2 comprising the sequence of SEQ ID NO: 495, and a CDR-L3 comprising the sequence of SEQ ID NO: 496; V_L2comprises a CDR-L1 comprising the sequence of SEQ ID NO: 488, a CDR-L2 comprising the sequence of SEQ ID NO: 489, and a CDR-L3 comprising the sequence of SEQ ID NO: 490; V_L3comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; V_H1comprises a CDR-H1 comprising the sequence of SEQ ID NO: 485, a CDR-H2 comprising the sequence of SEQ ID NO: 486, and a CDR-H3 comprising the sequence of SEQ ID NO: 487; V_H2comprises a CDR-H1 comprising the sequence of SEQ ID NO: 479, a CDR-H2 comprising the sequence of SEQ ID NO: 480, and a CDR-H3 comprising the sequence of SEQ ID NO: 481; and V_H3comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253.
Item 91: The binding protein of any one of items 60-86, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 524; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 522; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 511; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 509; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503.
Item 92: The binding protein of any one of items 60-86 and 90-91, wherein V_L1comprises a light chain variable domain comprising the sequence of SEQ ID NO: 524; V_L2comprises a light chain variable domain comprising the sequence of SEQ ID NO: 522; V_L3comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; V_H1comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 511; V_H2comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 509; and V_H3comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503.
Item 93: The binding protein of item 60, wherein the second polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains.
Item 94: The binding protein of item 60, wherein the third polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains.
Item 95: The binding protein of item 60, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.
Item 96: The binding protein of item 60, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.
Item 97: The binding protein of any one of items 60, 95, and 96, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
Item 98: The binding protein of item 61, wherein the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.
Item 99: The binding protein of item 61, wherein the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.
Item 100: The binding protein of any one of items 61, 98, and 99, wherein the C_H3domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
Item 101: The binding protein of item 60 or item 61, wherein at least one of L₁, L₂, L₃, or L₄is independently 0 amino acids in length.
Item 102: The binding protein of item 60 or item 61, wherein L₁, L₂, L₃, or L₄are each independently at least one amino acid in length.
1 Item 103: The binding protein of any one of items 60-102, wherein L₁is Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299).
Item 104: A binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain comprises a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1 [II]
and a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1 [III]
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-C_L [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain; and
L₁, L₂, L₃, and L₄are amino acid linkers;
wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;
wherein:
(a) V_L1, V_L2and V_L3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 303, 305, 311, 313, 319, 321, 327, 329, 335, 337, 343, 345, 351, 353, 359, 361, 367, 369, 375, 377, 383, 385, 391, 393, 399, 401, 407, 409, 415, 417, 423, 425, 431, 433, 439, 441, 447, 449, 455, 457, 463, 465, 471, 473; or
(b) V_L1, V_L2and V_L3each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 266-271, 275-277, 488-496; and
wherein:
(a) V_H1, V_H2, and V_H3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 302, 304, 310, 312, 318, 320, 326, 328, 334, 336, 342, 344, 350, 352, 358, 360, 366, 368, 374, 376, 382, 384, 390, 392, 398, 400, 406, 408, 414, 416, 422, 424, 430, 432, 438, 440, 446, 448, 454, 456, 462, 464, 470, 472; or
(b) V_H1, V_H2, and V_H3each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-253, 257-259, 479-487.
Item 105: A binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:
V_L2-L₁-V_L1-L₂-C_L [I]
and a second polypeptide chain comprises a structure represented by the formula:
V_H1-L₃-V_H2-L₄-C_H1-hinge-C_H2-C_H3 [II]
and a third polypeptide chain comprises a structure represented by the formula:
V_H3-C_H1-hinge-C_H2-C_H3 [III]
and a fourth polypeptide chain comprises a structure represented by the formula:
V_L3-C_L [IV]
wherein:
V_L1is a first immunoglobulin light chain variable domain;
V_L2is a second immunoglobulin light chain variable domain;
V_L3is a third immunoglobulin light chain variable domain;
V_H1is a first immunoglobulin heavy chain variable domain;
V_H2is a second immunoglobulin heavy chain variable domain;
V_H3is a third immunoglobulin heavy chain variable domain;
C_Lis an immunoglobulin light chain constant domain;
C_H1is the immunoglobulin C_H1heavy chain constant domain;
C_H2is an immunoglobulin C_H2heavy chain constant domain;
C_H3is an immunoglobulin C_H3heavy chain constant domain;
hinge is an immunoglobulin hinge region connecting the C_H1and C_H2domains; and
L₁, L₂, L₃, and L₄are amino acid linkers;
wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;
wherein:
(a) V_L1, V_L2and V_L3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 303, 305, 311, 313, 319, 321, 327, 329, 335, 337, 343, 345, 351, 353, 359, 361, 367, 369, 375, 377, 383, 385, 391, 393, 399, 401, 407, 409, 415, 417, 423, 425, 431, 433, 439, 441, 447, 449, 455, 457, 463, 465, 471, 473; or
(b) V_L1, V_L2and V_L3each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 266-271, 275-277, 488-496; and
wherein:
(a) V_H1, V_H2, and V_H3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 302, 304, 310, 312, 318, 320, 326, 328, 334, 336, 342, 344, 350, 352, 358, 360, 366, 368, 374, 376, 382, 384, 390, 392, 398, 400, 406, 408, 414, 416, 422, 424, 430, 432, 438, 440, 446, 448, 454, 456, 462, 464, 470, 472; or
(b) V_H1, V_H2, and V_H3each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-253, 257-259, 479-487.
Item 106: The binding protein of item 104, wherein the second polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains.
Item 107: The binding protein of item 104, wherein the third polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains.
Item 108: The binding protein of item 104, wherein the second polypeptide chain further comprises a first Fc region linked to C_Ht, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.
Item 109: The binding protein of item 104, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.
Item 110: The binding protein of any one of items 104, 108, and 109, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
Item 111: The binding protein of item 105, wherein the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.
Item 112: The binding protein of item 105, wherein the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.
Item 113: The binding protein of any one of items 105, 111, and 112, wherein the C_H3domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.
Item 114: The binding protein of item 104 or item 105, wherein at least one of L₁, L₂, L₃, or L₄is independently 0 amino acids in length.
Item 115: The binding protein of item 104 or item 105, wherein L₁, L₂, L₃, or L₄are each independently at least one amino acid in length.
Item 116: The binding protein of any one of items 104-115, wherein L₁is Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299).
Item 117: A binding protein comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain wherein:
(a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 305 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 305; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 304 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 304; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 302 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 302; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 303 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 303;
(b) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 313 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 313; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 312 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 312; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 310 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 310; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 311 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 311;
(c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 321 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 321; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 320 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 320; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 318 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 318; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 319 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 319;
(d) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 329 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 329; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 328 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 328; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 326 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 326; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 327 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 327;
(e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 337 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 337; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 336 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 336; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 334 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 334; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 335 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 335;
(f) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 345 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 345; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 344 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 344; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 342 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 342; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 343 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 343;
(g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 353 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 353; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 352 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:352; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 350 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 350; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 351 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 351;
(h) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 361 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 361; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 360 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 360; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 358 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 358; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 359 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 359;
(i) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 369 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 369; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 368 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 368; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 366 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 366; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 367 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 367;
(j) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 377 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 377; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 376 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 376; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 374 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 374; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 375 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 375;
(k) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 385 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 385; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 384 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 384; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 382 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 382; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 383 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 383;
(l) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 393 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 393; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 392 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 392; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 390 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 390; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 391 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 391;
(m) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 401 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 401; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 400 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 400; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 398 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 398; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 399 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 399;
(n) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 409 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 409; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 408 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 408; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 406 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 406; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 407 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 407;
(p) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 417 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 417; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 416 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 416; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 414 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 414; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 415 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 415;
(q) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 425 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 425; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 424 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 424; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 422 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 422; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 423 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 423;
(r) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 433 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:433; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 432 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 432; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 430 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 430; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 431 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 431;
(s) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 441 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 441; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 440 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 440; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 438 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 438; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 439 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 439;
(t) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 449 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 449; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 448 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 448; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 446 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 446; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 447 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 447;
(u) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 457 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 457; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 456 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 456; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 454 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 454; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 455 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 455;
(v) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 465 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 465; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 464 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 464; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 462 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 462; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 463 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 463; or
(w) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 473 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 473; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 472 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 472; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 470 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 470; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 471 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 471.
Item 118: An isolated nucleic acid molecule comprising a nucleotide sequence encoding the binding protein of any one of items 1-117.
Item 119: An expression vector comprising the nucleic acid molecule of item 118.
Item 120: An isolated host cell comprising the nucleic acid molecule of item 118.
Item 121: An isolated host cell comprising the expression vector of item 119.
Item 122: The isolated host cell of item 120 or item 121, wherein the host cell is a mammalian cell or an insect cell.
Item 123: A vector system comprising one or more vectors encoding a first, second, third, and fourth polypeptide chain of a binding protein of any one of items 1-117.
Item 124: The vector system of item 123, wherein the vector system comprises a first vector encoding the first polypeptide chain of the binding protein, a second vector encoding the second polypeptide chain of the binding protein, a third vector encoding the third polypeptide chain of the binding protein, and a fourth vector encoding the fourth polypeptide chain of the binding protein.
Item 125: The vector system of item 123, wherein the vector system comprises a first vector encoding the first and second polypeptide chains of the binding protein, and a second vector encoding the third and fourth polypeptide chains of the binding protein.
Item 126: The vector system of any one of items 123-125, wherein the one or more vectors are expression vectors.
Item 127: An isolated host cell comprising the vector system of any one of items 123-126.
Item 128: The isolated host cell of item 127, wherein the host cell is a mammalian cell or an insect cell.
Item 129: A method of producing a binding protein, the method comprising:
a) culturing a host cell of any one of items 120-122 and items 127-128 under conditions such that the host cell expresses the binding protein; and
b) isolating the binding protein from the host cell.
Item 130: A method of preventing and/or treating HIV infection in a patient comprising administering to the patient a therapeutically effective amount of at least one binding protein of any one of items 1-117.
Item 131: The method of item 130, wherein the binding protein is co-administered with standard anti-retroviral therapy.
Item 132: The method of item 130 or item 131, wherein administration of the at least one binding protein results in the neutralization of one or more HIV virions.
Item 133: The method of any one of items 130-132, wherein administration of the at least one binding protein results in the elimination of one or more latently and/or chronically HIV-infected cells in the patient.
Item 134: The method of any one of items 130-133, wherein the patient is a human.
Item 135: The binding protein of any one of items 1-117 for the prevention or treatment of an HIV infection in a patient.
Item 136: The binding protein of item 135, wherein the binding protein is co-administered with standard anti-retroviral therapy.
Item 137: The binding protein of item 135 or item 136, wherein the binding protein causes the neutralization of one or more HIV virions in the patient.
Item 138: The binding protein of any one of items 135-137, wherein the binding protein causes the elimination of one or more latently and/or chronically HIV-infected cells in the patient.
Item 139: The binding protein of any one of items 135-138, wherein the patient is a human.

EXAMPLES

The Examples that follow are illustrative of specific embodiments of the disclosure, and various uses thereof. They are set forth for explanatory purposes only, and should not be construed as limiting the scope of the invention in any way.

Example 1: Production of Trispecific Binding Proteins Targeting the HIV-1 Env Glycoprotein

The HIV-1 envelope glycoprotein (Env/gp160) is located on the surface of the virus particle, and is composed of a homo-trimer comprising three non-covalently-linked transmembrane gp41 and gp120 complexes. Env enables viral entry into target cells by the binding of gp120 to HIV's main receptor (CD4) and co-receptor (CCR5 or CXCR4), followed by the induction of viral/cellular membrane fusion facilitated by conformational changes in gp41, resulting in entry of the viral capsid and delivery of the viral genome into the host cell. Additionally, Env is expressed on the surface of infected cells.
Env acts as the only target for neutralizing antibodies on the HIV-1 virion. Binding of neutralizing antibodies to viral Env inhibits viral attachment/entry. Moreover, binding of neutralizing antibodies to HIV-1 infected, Env expressing cells leads to their destruction by Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC), resulting in reduction of the latent viral reservoir. Thus, neutralizing antibodies targeting Env are an attractive area for anti-viral therapy development. However, because of the high sequence diversity and mutation rate of the HIV-1 virus, developing neutralizing antibodies targeting Env has proven challenging due to the high likelihood that a given HIV-1 strain either lacks the epitope of any given neutralizing antibody, or the strain has evolved a mutation to become resistant to the antibody. Strategies must be developed to mitigate the breakthrough of viral strains when developing novel neutralizing antibodies targeting HIV-1. The studies described herein explore the development of novel trispecific binding proteins comprising four polypeptides forming three antigen binding sites that specifically bind three different epitopes on the HIV Env glycoprotein, and use of these novel trispecific binding proteins in neutralizing HIV-1.
Methods

Binding Protein Production and Purification

The vectors expressing the trispecific binding proteins were constructed by inserting the designed heavy and light chain genes into a mammalian expression vector. Corresponding heavy and light chain pairing occurred spontaneously, and heterodimer formation was promoted by Knob-in-Hole mutations engineered in the Fc region.
Binding proteins were produced in Expi293 cells by cotransfection of four expression plasmids (Life Technologies, Expi293™ Expression System Kit, Cat. No. A14635). Binding proteins were purified using a two-step purification scheme. First, binding proteins were captured on protein A affinity chromatography resin, washed, and then eluted in glycine at pH 3.0. The eluted proteins were then dialyzed in PBS, concentrated, and filtered. The filtered antibodies were further purified using a Superdex 200 SEC column to obtain monomeric binding proteins.

Affinity Measurements of the Binding Proteins

Binding affinities of anti-HIV trispecific binding proteins were measured by surface plasmon resonance (SPR) using a Biacore3000 instrument (GE Healthcare). The assay buffer used was HBS-EP (GE Healthcare).
The affinity of the indicated proteins for the MPER binding site on the HIV-1 protein gp41 was measured by surface plasmon resonance (SPR) analysis using a Biacore Instrument as follows: binding proteins were first captured on a CM5 chip coupled with anti-human Fc antibody, followed by flow through of varying concentrations (100 nM-6.25 nM) of the MPER binding peptide (Acetyl-RRRNEQELLELDKWASLWNWFDITNWLWYIRRR-Ttds-Lys-(Biotin)-NH₂) (SEQ ID NO: 284) at 30 μL per minute, and binding was detected by measurement of association for 240 seconds, and dissociation for 300 seconds on a Biacore 3000 at 25° C. HBS-EP buffer was used for sample dilution, as well as running buffer. Regeneration of the chip was done with 3 M MgCl₂at 30 μL per minute. For data analysis the BIAevaluation software v.4.1 (GE Healthcare) was used. Data were fit globally using a 1:1 Langmuir model with mass transfer. After software-based curve fitting, the ON and OFF reates at each concentration of MPER binding peptide was calculated and used to obtain a binding affinity for each binding protein.
The affinity of the indicated proteins for the CD4BS binding site on the HIV-1 protein gp120 was measured by SPR as follows: recombinant HIV-1 gp120 (Thr27-Arg498) protein (HIV-1/Clade B/C (CN54), ARCO Biosystems (Cat. # GP4-V15227)) was captured on a CM5 chip, followed by flow through of varying concentrations (100 nM-6.25 nM) of the binding proteins, and binding was detected by measurement of association for 240 seconds, and dissociation for 300 seconds on a Biacore 3000 at 25° C. HBS-EP buffer was used for sample dilution, as well as running buffer. Regeneration of the chip was done with 3 M MgCl₂at 30 μL per minute. For data analysis the BIAevaluation software v.4.1 (GE Healthcare) was used. Data were fit globally using a 1:1 Langmuir model with mass transfer. After software-based curve fitting, the ON and OFF reates at each concentration of Binding Protein was calculated and used to obtain a binding affinity for each binding protein.

Conformational Stability and Aggregation Assays

Conformational stability of the trispecific binding proteins was assessed by determining the melting point T_mand aggregation onset temperature (T_agg).
Melting point T_mmeasurements were performed by differential scanning fluorimetry (DSF). Samples were diluted in D-PBS buffer (Invitrogen) to a final concentration of 0.2 μg/μL including a 4× concentration solution of SYPRO-Orange dye (Invitrogen, 5000× stock in DMSO) in D-PBS in white sem-skirt 96-well plates (BIORAD). All measurements were done in duplicate using a MyiQ2 real time PCR instrument (BIORAD). Negative first derivative curves (−d(RFU)/dT) of the melting curves were generated in the iQ5 software v2.1 (BIORAD). Data were then exported into Excel for T_mdetermination and graphical display.
Melting Point T_mand aggregation onset temperature (T_agg) were also measured by static light scattering (SLS) using a Unit instrument (Unchained Labs). 9 μL of each sample was loaded undiluted into a multicuvette array. The samples were then heated from 20° C. to 95° C. at a heating rate of 0.3° C./minute. The barycentric mean (BCM) of the tryptophan fluorescence spectra was used to measure the protein melting curve, and determine the T_mvalues. The 266 nm static light scattering (SLS) signal was used to measure the aggregation curve and determine the T_agg. Data analysis was performed using the Unit analysis software v2.1.
Results
A novel strategy was developed for improving neutralizing antibody efficacy against HIV-1, while concomitantly limiting the likelihood of viral breakthrough due to high sequence diversity and/or viral mutation. This strategy involved the generation of trispecific binding proteins comprising four polypeptides that formed three antigen binding sites that specifically bind three different epitopes on the HIV Env glycoprotein (FIG. 1). Each antigen binding site comprised the V_Hand V_Ldomain from a different HIV-1 neutralizing antibody that targeted a distinct epitope on the Env glycoprotein. The trispecific binding proteins contained a first pair of polypeptides that possessed dual variable domains having a cross-over orientation forming two distinct antigen binding sites (called the CODV Ig format), and a second pair of polypeptides, each with a single variable domain that formed a third antigen binding site (FIGS. 1A and 1B).
The first pair of polypeptides (that possessed the dual variable domains) comprised a first polypeptide having the structure V_L2-Linker-V_L1-Linker-Immunoglobulin light chain constant domain, and a second polypeptide having the structure V_H1-Linker-V_H2-Linker-Immunoglobulin C_H1, hinge, C_H2, and C_H3heavy chain constant domains, resulting in a pair of polypeptides which had a cross over orientation that formed two distinct antigen binding sites: V_H1-V_L1and V_H2-V_L2(FIGS. 1C and 1D, see light and heavy chains B). The second pair of polypeptides (that each possessed a single variable domain) comprised a first polypeptide having the structure V_H3-Immunoglobulin C_H1, hinge, C_H2, and C_H3heavy chain constant domains, and a second polypeptide having the structure V_L3-Immunoglobulin light chain constant domain, resulting in a pair of polypeptides that formed a third antigen binding site: V_H3-V_L3(FIGS. 1C and 1D, see light and heavy chains A). In addition, the trispecific binding proteins were constructed to include an LS mutation. Furthermore, the trispecific binding proteins were constructed such that within one binding protein, one C_H3domain included a knob mutation and the other C_H3domain included a hole mutation to facilitate heterodimerization of the heavy chains (FIG. 1).
Using the above described approach for trivalent binding protein design, three trispecific binding proteins (Binding Proteins 2, 3, and 24) were generated. These trispecific binding proteins were created by grafting onto a trispecific binding protein framework the V_Hand V_Ldomains isolated from antibodies targeting three distinct epitopes on the HIV-1 Env glycoprotein: MPER Ab (targeting the MPER epitope on gp41), CD4BS Ab “b” (targeting the CD4 Binding Site on gp120), and V1/V2 directed Ab “a” (targeting the V1/V2 domain on gp120). Binding Protein 2 was constructed such that the first pair of polypeptides (which formed two antigen binding sites) targeted the HIV-1 Env glycoprotein epitopes MPER and V1/V2, and the second pair of polypeptides (which formed the single antigen binding site) targeted the HIV-1 Env glycoprotein epitope CD4BS (Binding Protein 2=MPER×V1/V2/CD4BS). Binding Protein 3 was constructed such that the first pair of polypeptides (which formed two antigen binding sites) targeted the HIV-1 Env glycoprotein epitopes V1/V2 and MPER, and the second pair of polypeptides (which formed the single antigen binding site) targeted the HIV-1 Env glycoprotein epitope CD4BS (Binding Protein 3=V1/V2×MPER/CD4BS). Binding Protein 24 was constructed such that the first pair of polypeptides (which formed two antigen binding sites) targeted the HIV-1 Env glycoprotein epitopes V1/V2 and CD4BS, and the second pair of polypeptides (which formed the single antigen binding site) targeted the HIV-1 Env glycoprotein epitope MPER (Binding Protein 24=V1/V2×CD4BS/MPER). The three trispecific binding proteins, as well as their parental antibodies, were purified over protein A affinity resin (FIGS. 2A and 3A) followed by size exclusion chromatography (FIGS. 2B and 3B) to obtain monomeric proteins suitable for further characterization. All three trispecific binding proteins were stable and formed monomers at high frequency.
To test the potential for developing binding proteins targeting two different HIV-1 Env protein epitopes (instead of three), bispecific binding proteins were designed based upon the above described CODV Ig format (See WO 2012/135345), using two different V_Hand V_Ldomains from the same parental antibodies used to create the trispecific binding proteins. However, the bispecific binding proteins with these specific variable domains did not purify well as monomers, showing significantly increased aggregate formation when compared to the corresponding trispecific binding proteins (FIGS. 4A and 4B).
Next, the binding affinity of the purified trispecific binding proteins (and their parental antibodies) was measured for the HIV-1 Env glycoprotein epitopes on gp41 and gp120. First, the binding affinity for gp41 was measured for the three trispecific binding proteins, as well as the parental MPER antibody, by Biacore assay using the MPER binding peptide (FIG. 5). The binding affinity for the MPER antibody was calculated to be 18.7 nM. Surprisingly, the three trispecific binding proteins all had a higher affinity for the MPER binding peptide than did the parental antibody (Table 3), with Binding Protein 2 having an approximately 3.1 fold higher affinity than the MPER antibody (6.05 nM vs. 18.7 nM, respectively).

TABLE 3

Affinity measurements for the MPER binding peptide

								MW
		ka	kd	Rmax	KA	KD		MPER
Antibody	Analyte	(1/Ms)	(1/s)	(RU)	(1/M)	(M)	Chi2	(kDa)

MPER Ab	Gp41-	5.85E+04	1.09E−03	47.5	5.35E+07	1.87E−08	0.55	5.25
	MPER JPT
Binding	Gp41-	1.15E+05	6.97E−04	29.0	1.65E+08	6.05E−09	0.27	2.29
Protein 2	MPER JPT
Binding	Gp41-	4.67E+04	7.79E−04	38.5	6.00E+07	1.67E−08	0.41	5.14
Protein 3	MPER JPT
Binding	Gp41-	6.28E+04	8.06E−04	35.5	7.80E+07	1.28E−08	0.48	5.24
Protein 24	MPER JPT

Similarly, the binding affinity for the CD4 Binding Site on gp120 was measured for the three trispecific binding proteins, as well as the parental CD4BS antibody, by Biacore assay (FIG. 6). The three trispecific binding proteins all had a similar affinity for the CD4 Binding Site when compared to the parental antibody (Table 4).

TABLE 4

Affinity measurements for the CD4BS binding site

Antibody	ka (1/Ms)	kd (1/s)	Rmax (RU)	KD (M)	Chi2

CD4BS	2.79E+05	2.32E−04	31.4	8.30E−10	1.17
Ab “b”
Binding	2.31E+05	2.41E−04	34.0	1.04E−09	0.74
Protein 2
Binding	7.58E+04	2.75E−04	38.2	3.63E−09	0.19
Protein 3
Binding	1.46E+05	2.52E−04	41.6	1.73E−09	0.38
Protein 24

Thus, the trispecific binding proteins were able to bind both of the tested target epitopes on the HIV-1 Env glycoprotein (Table 5). Moreover, all three trispecific binding proteins bound the target epitopes with affinities approximately equal to or exceeding those of their parental antibodies. Binding affinity of the V1/V2 directed Ab “a”, as well as of the V1/V2 directed Ab “a” binding sites within the three trispecific binding proteins 2, 3, and 24 could not be determined by Biacore analysis because this required a specific gp120 protein antigen which was unavailable.

TABLE 5

Summary of binding capabilities of tested binding proteins

	Binding on	Binding on
Sample	gp120?	gp41?

MPER Ab	No	Yes
CD4BS Ab “b”	Yes	No
V1/V2 directed	No	No
Ab “a”
Binding	Yes	Yes
Protein 2
Binding	Yes	Yes
Protein 3
Binding	Yes	Yes
Protein 24

The biophysical properties were tested for the trispecific binding proteins and parental antibodies (Table 6). All of the tested proteins had similar stabilities and limited propensities to form aggregates.

TABLE 6

Conformational stability/aggregation of the binding proteins

			SLS at
		Intrinsic AA	266 nm
	DSF T_m	Fluo T_m	T_agg
Sample	(° C.)	(° C.)	(° C.)

MPER Ab	69/75	68	71
CD4BS Ab “b”	69	66	68
V1/V2 directed	69	64	67
Ab “a”
Binding	60/70	54	58
Protein 2
Binding	57/70	55	56
Protein 3
Binding	56/71	53	54
Protein 24

These experiments indicated that stable, monomeric, trispecific binding proteins targeting three distinct epitopes on the HIV-1 Env glycoprotein could be constructed and efficiently purified. Furthermore, the trispecific binding proteins retained their ability to bind their target epitopes, having similar or improved affinity relative to their parental antibodies. Finally, the trispecific binding proteins had suitable biophysical properties, and showed significantly less aggregation than the corresponding bispecific binding proteins.

Example 2: Characterization of the Binding Proteins

Due to the success of developing three trispecific binding proteins with appropriate biophysical properties and binding abilities (as described in Example 1), 21 additional trispecific binding proteins were developed and tested. The experiments described herein explored the ability of the 24 trispecific binding proteins to neutralize HIV-1 in vitro, and the pharmacokinetic properties of a number of these trispecific binding proteins in vivo.
Neutralization assays were performed using the TZM-b1 assay which measures neutralization as a function of reductions in HIV-1 Tat-regulated firefly luciferase (Luc) reporter gene expression after a single round of infection with Env-pseudotyped viruses. The assays were performed as described in Marcella Sarzotti-Kelsoe et al., J. Immunological Methods, 409:131-146 (2014). The neutralization results of various antibodies are shown in Tables 8-10.
Methods

Production of Env-Pseudotyped Viruses

Assay stocks of Env-pseudotyped viruses were produced in 293T/17 cells by co-transfection with two plasmids: an Env expression plasmid and a plasmid expressing the entire HIV-1 genome except for Env. Co-transfection of these plasmids produced infectious pseudovirus particles which were capable of delivering the Tat gene into target cells, but infections with these pseudovirions could not themselves produce infectious viral progeny.

Viral Neutralization Assay

Neutralization of HIV infection using TZM-b1 cells (also known as JC53BL-13 cells) was performed as described previously (Marcella Sarzotti-Kelsoe et al., J. Immunological Methods, 409:131-146 (2014)). Briefly, a single round of infection using the Env-pseudotyped HIV-1 virions was carried out in TZM-b1 cells (a CXCR-4-positive HeLa cell clone). TZM-b1 cells were engineered to express CD4 and CCR5, and to contain integrated reporter genes for firefly luciferase and E. coli β-galactosidase under the control of an HIV long-terminal repeat. Reporter gene expression was induced in trans by viral Tat protein (delivered by the pseudotyped viruses) soon after single cycle infection. Luciferase activity was quantified as relative luminescence units (RLU), and was directly proportional to the number of infectious virus particles present in the initial inoculum over a wide range of values. Neutralization was measured as a function of decreased Tat-regulated Firefly luciferase (Luc) reporter gene expression after administration of varying concentrations of the indicated binding proteins. Neutralization titers were identified as the protein dilution at which RLUs were reduced by 80% compared to virus control wells after subtraction of background RLUs. The assay was performed in 96-well plates for high throughput capacity, and well-characterized reference strains were utilized for uniformity across studies.

Pharmacokinetic (PK) Measurements

Female Indian rhesus macaques weighing between 3 and 6 kg were randomly assigned to groups according to body weight (two macaques per group) and were intravenously injected with the indicated concentration of binding proteins. Blood was collected from the animals before the injection on day 0, and 30 minutes, 6 hours, 1 day, 2 days, 4 days, 7 days, 14 days, 21 days and 28 days after injection. The serum concentration of each binding protein was quantified in the plasma from the collected blood using an RSC3-based ELISA assay.
Results
21 additional trispecific binding proteins targeting three distinct HIV-1 Env glycoprotein epitopes were generated and purified as described in Example 1. These 21 additional trispecific binding proteins (Binding Proteins 1 and 4-23) were created by grafting onto a trispecific binding protein framework the V_Hand V_Ldomains isolated from antibodies targeting distinct HIV-1 epitopes on the HIV-1 Env glycoprotein: the anti-MPER antibodies MPER Ab “a” and MPER Ab “b” (targeting the MPER epitope on gp41), the anti-CD4BS antibodies CD4BS Ab “a” and CD4BS Ab “b” (targeting the CD4 Binding Site on gp120), the anti-V1/V2 antibodies V1/V2 directed Ab “a” and V1/V2 directed Ab “b” (targeting the V1/V2 domain on gp120), and the anti-V3 antibody V3 directed Ab (targeting the V3 loop on gp120) (Table 7).

TABLE 7

Epitope binding site composition of the
trispecific binding proteins

	Binding
	Protein:	Epitope Binding Site:

	1	MPER × V1/V2 directed/CD4BS
	2	MPER × V1/V2 directed/CD4BS
	3	V1/V2 directed × MPER/CD4BS
	4	MPER × V1/V2 directed/CD4BS
	5	MPER × V3 directed/CD4BS
	6	V1/V2 directed × MPER/CD4BS
	7	V3 directed × V1/V2 directed/CD4BS
	8	MPER × V1/V2 directed/CD4BS
	9	MPER × V1/V2 directed/CD4BS
	10	V1/V2 directed × MPER/CD4BS
	11	MPER × V1/V2 directed/CD4BS
	12	MPER × V3 directed/CD4BS
	13	MPER × V3 directed/V1/V2 directed
	14	V1/V2 directed × MPER/CD4BS
	15	MPER × V3 directed/V1/V2 directed
	16	MPER × V3 directed/CD4BS
	17	V1/V2 directed × V3 directed/CD4BS
	18	V3 directed × MPER/CD4BS
	19	V3 directed × V1/V2 directed/MPER
	20	V3 directed × V1/V2 directed/CD4BS
	21	MPER × CD4BS/V1/V2 directed
	22	CD4BS × MPER/V1/V2 directed
	23	CD4BS × V1/V2 directed/MPER
	24	V1/V2 directed × CD4BS/MPER

The viral neutralization capabilities of five of the trispecific binding proteins (and their parental antibodies) at varying concentrations were tested against a panel of 208 different HIV-1 Env-pseudotyped viruses (Table 8). Binding protein-mediated neutralization of the pseudotyped HIV-1 isolates was measured using the TZM-b1 luciferase reporter gene assay. The inhibitory dose for each binding protein was calculated for each pseudotyped virus as the dilution that caused an 80% reduction in luminescence (IC₈₀) after infection. Surprisingly, the IC₈₀geometric means calculated for each of the tested trispecific binding proteins was lower than the parental antibodies, suggesting that these trispecific binding proteins were more potent at neutralizing pseudotyped HIV-1 than their parental neutralizing antibodies.

TABLE 8

IC₈₀measurements from viral neutralization assay

Parental Antibody:

V1/V2

V3

Binding Protein:

MPER

directed

CD4BS

	15	1	2	19	20	3	Ab	Ab “a”	Ab	Ab “b”	Ab “a”

# Viruses	208	208	208	208	208	208	208	208	208	208	208
Total VS
Neutralized:
IC₈₀<50 μg/mL	190	202	206	198	206	206	203	151	113	202	183
IC₈₀<10 μg/mL	180	199	206	180	206	206	193	149	109	200	175
IC₈₀<1.0 μg/mL	166	169	191	145	188	186	61	133	98	184	108
IC₈₀<0.1 μg/mL	122	109	136	80	144	123	10	99	72	79	10
IC₈₀<0.01 μg/mL	74	7	70	22	54	47	5	24	26	6	0
% VS
Neutralized:
IC₈₀<50 μg/mL	91	97	99	95	99	99	98	73	54	97	88
IC₈₀<10 μg/mL	87	96	99	87	99	99	93	72	52	96	84
IC₈₀<1.0 μg/mL	80	81	92	70	90	89	29	64	47	88	52
IC₈₀<0.1 μg/mL	59	52	65	38	69	59	5	48	35	38	5
IC₈₀<0.01 μg/mL	36	3	34	11	26	23	2	12	13	3	0
Median IC₈₀	0.033	0.088	0.026	0.164	0.029	0.045	1.69	0.037	0.054	0.149	0.780
Geometric Mean	0.033	0.135	0.028	0.199	0.034	0.051	1.34	0.063	0.057	0.144	0.814

Next, the viral neutralization capabilities of a larger panel of trispecific binding proteins (and their parental antibodies) at varying concentrations were tested against 20 pseudotyped viruses representing 10 different HIV-1 clades (Table 9). The trispecific binding proteins provided robust protection against infection with these 20 viruses (Table 10).

TABLE 9

20 representative viruses used for
viral neutralization assay

	Virus	Clade

	KER2008.12.SG3	A
	620345.c1.SG3	AE
	DJ263.8.SG3	AG
	T266-60.SG3	AG
	T278-50.SG3	AG
	BL01.DG.SG3	B
	BR07.DG.SG3	B
	CNE57.SG3	B
	H086.8.SG3	B
	QH0692.42.SG3	B
	SS1196.01.SG3	B
	CNE21.SG3	BC
	6471.V1.C16.SG3	C
	CAP210.E8.SG3	C
	DU156.12.SG3	C
	DU422.01.SG3	C
	TV1.29.SG3	C
	ZM106.9.SG3	C
	3817.v2.c59.SG3	CD
	X2088.c9.SG3	G

TABLE 10

IC₈₀measurements from viral neutralization assay of 20 representative viruses

Total VS

Neutralized

% VS Neutralized

	IC₈₀	IC₈₀	IC₈₀	IC₈₀	Median	Geometric
# Viruses	<50 μg/mL	<1 μg/mL	<50 μg/mL	<1 μg/mL	IC₈₀	Mean

Binding Protein 4	20	17	11	85	55	0.474	0.398
Binding Protein 5	20	14	11	70	55	0.199	0.324
Binding Protein 6	20	16	9	80	45	0.453	0.449
Binding Protein 7	20	16	9	80	45	0.523	0.312
Binding Protein 8	20	17	12	85	60	0.578	0.488
Binding Protein 9	20	14	9	70	45	0.836	0.531
Binding Protein 10	20	16	12	80	60	0.222	0.173
Binding Protein 11	20	18	15	90	75	0.310	0.181
Binding Protein 12	20	17	12	85	60	0.526	0.566
Binding Protein 13	20	19	12	95	60	0.202	0.189
Binding Protein 14	20	17	15	85	75	0.208	0.088
Binding Protein 15	20	17	10	85	50	0.345	0.378
Binding Protein 16	20	18	11	90	55	0.228	0.314
Binding Protein 17	20	17	12	85	60	0.086	0.180
Binding Protein 18	20	15	10	75	50	0.536	0.501
Binding Protein 19	20	18	11	90	55	0.563	0.538
Binding Protein 20	20	18	14	90	70	0.224	0.229
Binding Protein 21	20	15	9	75	45	0.627	0.501
Binding Protein 2	20	18	13	90	65	0.375	0.222
Binding Protein 22	20	13	8	65	40	0.856	0.634
Binding Protein 23	20	17	6	85	30	1.930	1.129
Binding Protein 3	20	18	12	90	60	0.469	0.287
Binding Protein 24	20	16	7	80	35	2.130	1.054
MPER Ab “a”	20	16	8	80	40	1.007	0.981
MPER Ab “b”	20	16	16	80	80	0.071	0.024
CD4BS A “b”	20	15	9	75	45	0.181	0.399
V1/V2 directed Ab “a”	20	11	9	55	45	0.060	0.094
V3 directed Ab	20	12	10	60	50	0.183	0.136
CD4BS Ab “a”	20	10	1	50	5	1.530	1.811
V1/V2 directed Ab “b”	20	9	9	45	45	0.051	0.039

Finally, the pharmacokinetics (PK) of a subset of the trispecific binding proteins and parental antibodies were tested in rhesus macaques. Briefly, 10 or 20 mg/kg of the proteins were intravenously injected into female rhesus macaques, and ELISA assays were performed on the plasma from blood samples taken prior to injection, and on the plasma from blood samples taken at many time points after the injection (up to 42 days) (FIG. 7). All of the trispecific binding proteins could be detected at least 14 days after IV administration, with Binding Protein 1 remaining detectable at least 35 days after injection, showing that the binding proteins were stable in vivo.
Taken together, this data suggested that broadly neutralizing trispecific binding proteins could be constructed which targeted three distinct epitopes on the HIV-1 Env glycoprotein. These binding proteins showed similar or increased potency/much improved neutralizing capabilities (breadth) relative to the parental neutralizing antibodies. Furthermore, these trispecific binding proteins appeared to be well tolerated in vivo. Without wishing to be bound by theory, the development of broadly neutralizing trispecific binding proteins targeting multiple epitopes on HIV may allow for improved anti-viral therapy relative to monospecific or bispecific antibodies, as HIV viral particles are less likely to be resistant to all three antigen binding sites on the neutralizing trispecific binding proteins than the single or dual antigen binding sites on monospecific or bispecific neutralizing antibodies, respectively.

Example 3: Characterization of T-Cell Engagers

As noted above, Env is expressed on the surface of HIV-infected cells. Because of this, Env can act as an antibody target to identify infected cells, and induce Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC), resulting in reduction of the latent viral reservoir. The studies described herein explore the development of novel trispecific binding proteins (termed “T cell engagers”) that contain three antigen binding sites targeting three different antigens (HIV-1 Env glycoprotein, CD3, and CD28). These novel proteins not only include antigen binding sites from neutralizing antibodies, but also the ability to bind effector T cells, bringing them into close proximity to infected target cells, thus inducing HIV-infected cell lysis.
Methods

Binding Properties of T-Cell Engagers

The binding properties of the T-cell engagers was measured by ELISA assay using a horse radish peroxidase-conjugated anti-Fab probe to detect T-cell engager binding to the surface of ELISA plates coated with CD3, CD28, or Resurfaced Stabilized Core 3 (RSC3) protein of gp120. Human CD3ge-hIgG4 (KIH) (Cat. No: 03-01-0051) from Cambridge Biologics, MA, USA; Human CD28-hIgG4 (Cat. No: 03-01-0303) from Cambridge Biologics, MA, USA.

T-Cell Activation Assay

CD4 and CD8 T cell activation were measured as follows: peripheral blood mononuclear cells (PBMCs) were enriched from buffy coats obtained from naïve donors (NIH blood bank) using magnetic beads (Miltenyi Biotec). These cells were co-cultured for 14-16 hours with either uninfected or HIV-1 infected CEM cells in the presence of increasing concentrations of the binding proteins (0.01-1.0 μg/mL) with brefeldin A. The cells were then stained for surface expression of T-cell markers (CD3, CD4, and CD8) and activation markers (CD25 and CD69), followed by intracellular staining for cytokines (IFN-γ, TNF-α, and IL-2) using fluorescently conjugated antibodies (BD Biosciences, eBiosciences, Biolegend). The number of CD4 and CD8 T cells expressing each cytokine or activation marker was determined by running the samples on an LSRII flow cytometer and analyzing the data with Flowjo software (Treeestar).

CD3 Downregulation

CD3 downregulation after T cell activation by the T-cell engagers was measured by staining activated PBMCs with non-competing mouse anti-human CD3 antibody and quantitated using flow cytometry.

Cytotoxicity Assay

Cytotoxicity of the T-cell engagers to CEM-BaL, ACH2, and J1.1 cells was monitored by flow cytometry as follows: latent cell lines (ACH2, J1.1, OM10) were obtained from the NIH AIDS Reagent Program. The activation of these cells was performed by culturing the cells in the presence or absence of TNF-α (10 ng/mL) for 14-16 hours. Activation was measured by determining the expression of cell surface HIV envelope glycoprotein by flow cytometry using an allophycocyanin-conjugated anti-HIV Env antibody (2G12). The CEM-IIIb, ACH2, J1.1 and OM10 cells were labeled with the membrane dye PKH-26 (Sigma) and used as target cells in a cytotoxicity assay. These labeled target cells were co-cultured for 14-16 hours at an E:T ratio of 10:1 with enriched human T cells as effector cells in the presence of increasing amounts of the binding proteins. The extent of cell lysis in the target cells was determined by staining with a live/dead cell marker (Life technologies) and measuring the number of dead cells in the labeled target cell population by running the samples on an LSRII flow cytometer followed by analysis using Flowjo software (Treestar).
Results
The capacity to develop T cell engagers with antigen binding sites targeting both T cell surface proteins and neutralizing epitopes on HIV-1 was explored. T cell engagers were constructed which contained two antigen binding sites targeting two different T cell surface receptors (CD3 and CD28), and a third antigen binding site targeting the HIV-1 Env glycoprotein (FIGS. 8A and 8B). In addition, the T cell engagers were constructed to include an LS mutation. Furthermore, the T cell engagers were constructed such that within one binding protein, one C_H3domain included a knob mutation and the other C_H3domain included a hole mutation to facilitate heterodimerization of the heavy chains (FIGS. 8A and 8B).
Using this approach, two T cell engagers were constructed which targeted both T cell surface proteins and the HIV-1 Env glycoprotein (Binding Protein 32 and CD3×CD28/CD4BS “b” Ab). These two T cell engagers were created by grafting onto a trispecific binding protein framework the V_Hand V_Ldomains isolated from parental antibodies targeting the T cell surface proteins CD3 and CD28, and the anti-HIV-1 antibody CD4BS Ab “b” (targeting the CD4 Binding Site on gp120). Binding Protein 32 was constructed such that the first pair of polypeptides (which formed two antigen binding sites) targeted the T cell surface receptors CD28 and CD3, and the second pair of polypeptides (which formed the single antigen binding site) targeted the HIV-1 antigen CD4BS (Binding Protein 32=CD28×CD3/CD4BS). The CD3×CD28/CD4BS “b” Ab trispecific binding protein was constructed such that the first pair of polypeptides (which formed two antigen binding sites) targeted the T cell surface receptors CD3 and CD28, and the second pair of polypeptides (which formed the single antigen binding site) targeted the HIV-1 antigen CD4BS (Table 11).

TABLE 11

Format of T-cell engagers

Arm

1	Arm 2	Arm 3
Format	Name of Construct	Antigen	Antigen	Antigen

T cell engagers,	CD3 × CD28/CD4BS	CD4BS	CD3	CD28
trispecific	Ab “b”
T cell engagers,	Binding Protein 32	CD4BS	CD28	CD3
trispecific
Monospecific	CD4BS IgG4	CD4BS	CD4BS	—

The ability of the two T cell engagers to bind to each of their three target antigens was tested by ELISA assay. The T cell engagers were capable of binding both the CD3 and CD28 T cell surface proteins with the CD3 and CD28 antigen binding sites in either orientation in the bispecific arms of the T cell engagers (i.e., CD3×CD28 for CD3×CD28/CD4BS Ab “b” or CD28×CD3 for Binding Protein 32). Both T cell engagers were also capable of binding to gp120 (as measured using the HIV-1 RSC3 protein, a gp120 variant lacking the V1, V2, and V3 variable regions) (FIG. 9).
The effect on T cell activity was next tested for both of the T cell engagers. Incubation of the T cell engagers with monocytes revealed that the T cell engagers induced robust CD8⁺ T cell activation (FIG. 10). Similarly, the T cell engagers were capable of inducing significant CD4⁺ T cell activation on PBMCs alone, or PBMCs incubated with either of the HIV-1 infected T cell lines CEM-NKr cells or CEM-BaL cells (FIG. 11). Additionally, both of the T cell engagers reduced cell surface expression of CD3 on activated T cells (FIG. 12).
Finally, the ability of the T cell engagers to induce lysis of HIV-infected cells was tested. The T cell engagers (and positive and negative control bispecific binding proteins targeting CD3 and an HIV antigen) were incubated with the HIV-1 infected T cell line CEM-BaL cells. Incubation of the T cell engagers with the infected cells induced robust cell lysis over a wide range of concentrations (FIG. 13A). Likewise, incubation of these T cell engagers induced lysis of the latently infected T cell line ACH2 cells (FIG. 13B), as well as J1.1 cells (FIG. 13C). Surprisingly, the T cell engagers showed comparable or better cytotoxic activity against chronic and latent HIV-infected cell lines when compared to the bispecific binding proteins.
Taken together, the novel T cell engagers described herein retained the ability from their parental antibodies to bind their target antigens on the HIV-1 Env glycoprotein gp120 on HIV-infected cells, as well as the cell-surface exposed T cell proteins CD3 and CD28. The T cell engagers induced robust CD4⁺ and CD8⁺ T cell activation, and diminished CD3 surface expression. Finally, these T cell engagers induced significant lysis of HIV-1 infected T cells. Without wishing to be bound by theory, these T cell engagers may provide a novel strategy for anti-viral therapeutics by reducing/eliminating the latent viral reservoir through T cell engagement in HIV/AIDS patients.
While the present disclosure includes various embodiments, it is understood that variations and modifications will occur to those skilled in the art. Therefore, it is intended that the appended claims cover all such equivalent variations that come within the scope of the disclosure. In addition, the section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
Each embodiment herein described may be combined with any other embodiment or embodiments unless clearly indicated to the contrary. In particular, any feature or embodiment indicated as being preferred or advantageous may be combined with any other feature or features or embodiment or embodiments indicated as being preferred or advantageous, unless clearly indicated to the contrary.
All references cited in this application are expressly incorporated by reference herein.

SEQUENCES

TABLE 1

Heavy and light chain SEQ ID NOs for binding proteins 1-53
and the target antigens to which the binding proteins are directed.

Binding
Protein	SEQ ID NOs	Target

1	4, 3, 1, 2	MPER × V1/V2 directed/CD4BS
2	12, 11, 9, 10	MPER × V1/V2 directed/CD4BS
3	20, 9, 17, 18	V1/V2 directed × MPER/CD4BS
4	28, 27, 25, 26	MPER × V1/V2 directed/CD4BS
5	36, 35, 33, 34	MPER × V3 directed/CD4BS
6	44, 43, 41, 42	V1/V2 directed × MPER/CD4BS
7	52, 51, 49, 50	V3 directed × V1/V2 directed/CD4BS
8	60, 59, 57, 58	MPER × V1/V2 directed/CD4BS
9	68, 67, 65, 66	MPER × V1/V2 directed/CD4BS
10	76, 75, 73, 74	V1/V2 directed × MPER/CD4BS
11	84, 83, 81, 82	MPER × V1/V2 directed/CD4BS
12	92, 91, 89, 90	MPER × V3 directed/CD4BS
13	100, 99, 97, 98	MPER × V3 directed/V1/V2 directed
14	108, 107, 105, 106	V1/V2 directed × MPER/CD4BS
15	116, 115, 113, 114	MPER × V3 directed/V1/V2 directed
16	124, 123, 121, 122	MPER × V3 directed/CD4BS
17	132, 131, 129, 130	V1/V2 directed × V3 directed/CD4BS
18	140, 139, 137, 138	V3 directed × MPER/CD4BS
19	148, 147, 145, 146	V3 directed × V1/V2 directed/MPER
20	156, 155, 153, 154	V3 directed × V1/V2 directed/CD4BS
21	164, 163, 161, 162	MPER × CD4BS/V1/V2 directed
22	172, 171, 169, 170	CD4BS × MPER/V1/V2 directed
23	180, 179, 177, 178	CD4BS × V1/V2 directed/MPER
24	188, 187, 185, 186	V1/V2 directed × CD4BS/MPER
25	196, 195, 193, 194	MPER × V1/V2 directed/CD4BS
26	204, 203, 201, 202	MPER × V1/V2 directed/CD4BS
27	212, 211, 209, 210	MPER × V1/V2 directed/CD4BS
28	220, 219, 217, 218	MPER × V1/V2 directed/CD4BS
29	228, 227, 225, 226	MPER × V1/V2 directed/CD4BS
30	235, 234, 232, 233	MPER × V1/V2 directed/CD4BS
31	243, 242, 240, 241	MPER × V1/V2 directed/CD4BS
32	305, 304, 302, 303	CD28 × CD3/CD4BS
33	313, 312, 310, 311	CD28 × CD3/CD4BS
34	321, 320, 318, 319	CD28 × CD3/V1/V2 directed
35	329, 328, 326, 327	CD28 × CD3/V1/V2 directed
36	337, 336, 334, 335	CD28 × CD3/CD4BS
37	345, 344, 342, 343	CD28 × CD3/CD4BS
38	353, 352, 350, 351	CD4BS × CD3/CD28
39	361, 360, 358, 359	CD4BS × CD3/CD28
40	369, 368, 366, 367	CD3 × CD4BS/CD28
41	377, 376, 374, 375	CD3 × CD4BS/CD28
42	385, 384, 382, 383	CD4BS × CD3/CD28
43	393, 392, 390, 391	CD4BS × CD3/CD28
44	401, 400, 398, 399	CD3 × CD4BS/CD28
45	409, 408, 406, 407	CD3 × CD4BS/CD28
46	417, 416, 414, 415	V1/V2 directed × CD3/CD28
47	425, 424, 422, 423	V1/V2 directed × CD3/CD28
48	433, 432, 430, 431	CD3 × V1/V2 directed/CD28
49	441, 440, 438, 439	CD3 × V1/V2 directed/CD28
50	449, 448, 446, 447	V1/V2 directed × CD3/CD28
51	457, 456, 454, 455	V1/V2 directed × CD3/CD28
52	465, 464, 462, 463	CD3 × V1/V2 directed/CD28
53	473, 472, 470, 471	CD3 × V1/V2 directed/CD28

TABLE 2

Heavy and light chain sequences of binding proteins. CDR sequences are
bolded and italicized.

Binding Protein 1 Amino Acid Sequences

Heavy chain A	Qvqlvqsggqmkkpgesmriscrasgyef wirlapgkrpewmg	SEQ ID
	rvtmtrdvysdtaflelrsltvddtavyfctr	NO: 1
	wgrgtpvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalt
	sgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd
	kthtcppcpapellggpsvflfppkpkdtimisrtpevtcvvvdvshedpevkfnw
	yvdgvevhnaktkpreegynstyrvvsvltvlhqdwlngkeykckvsnkalpapi
	ektiskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvlhealhshytqkslslspg

Light chain A	Eivltqspgtlslspgetaiisc wqqrpgqaprlviy gipdrf	SEQ ID
	sgsrwgpdynltisnlesgdfgvyyc fgqgtkvqvdiktrtvaapsvfifpps	NO: 2
	deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsst
	ltlskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Evrtvesggglvkpggslrlscsas mtwvrqppgkglewvgr	SEQ ID
	dyaesvkgrftisrdntkntlylemnnvrtedtgyyfcar	NO: 3
	wgqgtlvivssdkthtqvhltqsgpevrkpgtsvkvsckapgntlktyd
	lhwvrsvpgqglqwmgwishegdkkviverfkakvtidwdrstntaylqlsgltsg
	dtavyy gqgtavtvssdkt
	htastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvhtfpav
	lqssglysissvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkthtcppcp
	apellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevh
	naktkpreegynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakg
	qprepqvytlppcrdeltknqvslwclvkgfypsdiavewesngqpennykttpp
	vldsdgsfflyskltvdksrwqqgnvfscsvlhealhshytqkslslspg

Light chain B	Dfvltqsphslsvtpgesasisckss lawyvqkpgrspqlliy s	SEQ ID
	rasgvpdrfsgsgsdkdftlkisrvetedvgtyyc gqgtkvdikdkt	NO: 4
	ht
	aseltqdpavsvalkqtvtitc wyqkkpgqapvllfy gi
	pdrfsgsasgnrasltitgaqaedeadyyc fgggtkltvldkthtrtv
	aapsvfifppsdeqlksgtusvvcllnnfypreakvqwkvdnalqsgnsqesvteq
	dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 1 Nucleotide Sequences

Heavy chain A	caggtgcagctggtgcagtctggcggccagatgaagaaacccggcgagagcatgcg	SEQ ID
	gatcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcaga	NO: 5
	ctggcccctggcaagcggcctgagtggatgggatggctgaagcctagaggcggagc
	cgtgaactacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacag
	cgataccgccttcctggaactgcggagcctgaccgtggatgataccgccgtgtacttct
	gcacccggggcaagaactgcgactacaactgggacttcgagcactggggcagaggc
	acccctgtgatcgtgtcaagcgcgcgtcgaccaagggccccagcgtgttccctctggccc
	ctagcagcaagageacatctggcggaacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgca
	cacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgaca
	gtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagccca
	gcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacac
	ctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttcccccc
	aaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggt
	ggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaa
	gtgcacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccgggt
	ggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtg
	caaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaa
	gggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctg
	accaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgc
	cgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctg
	tgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccgg
	tggcagcagggcaacgtgttcagctgctccgtgctgcacgaggccctgcacagccact
	acacccagaagtccctgagcctgagccccggc

Light chain A	Gagatcgtgctgacacagagccctggcaccctgagcctgtctccaggcgagacaac	SEQ ID
	catcatcagctgccggacaagccagtacggcagcctggcctggtatcagcagaggcc	NO: 6
	tggacaggcccccagactcgtgatctacagcggcagcacaagagccgccggaatcc
	ccgatagattcagcggctccagatggggccctgactacaacctgaccatcagcaacct
	ggaaagcggcgacttcggcgtgtactactgccagcagtacgagttcttcggccagggc
	accaaggtgcaggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttcc
	cacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaa
	cttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcg
	gcaacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctg
	agcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctg
	cgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga
	gtgt

Heavy chain B	gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc	SEQ ID
	ctgagctgttctgcctccggctttgatttcgataacgcctgaataacctgggtcaggcag	NO: 7
	cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgaggactg
	gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca
	agaataccttgtatttggagaigaacaacgtgagaactgaagacaccggatattacttct
	gtgccagaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatat
	tttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccatacccag
	gtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaaggtg
	tcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcgcagc
	gtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaaga
	aagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagcacca
	acaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtactactg
	cgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacggcg
	ccctgaactgggccgtggatgtggactacctgagcaacctagaattctggggccaggg
	cacagccgtgaccgtgtcatctgataagacccacaccgcttccaccaagggcccatcg
	gtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggct
	gcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccct
	gaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctca
	gcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgt
	gaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtga
	caaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagt
	cttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtca
	catgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtatgtt
	gacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca
	gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaa
	ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat
	ctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgcc
	gggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggcttctatccc
	agcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaaga
	ccacgcctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtgg
	acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgctgcatgaggctct
	gcacagccactacacgcagaagagcctctccctgtctccgggt

Light chain B	gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc	SEQ ID
	agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg	NO: 8
	gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca
	gcagagccagcggcatgcccgatagattttctggcageggcagcgacaaggacttca
	ccctgaagatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagg
	gcagagagagcccctggacctttggccagggcaccaaggtggacatcaaggacaaa
	acccataccgcatccgaactgactcaggaccctgccgtctctgtggcactgaagcaga
	ctgtgactattacttgccgaggcgactcactgcggagccactacgcttcctggtatcaga
	agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccatctgg
	catccccgaccgcttttctggcagtgcatcagggaaccgagccagtctgaccattaccg
	gcgcccaggctgaggacgaagccgattactattgcagctcccgggataagagcggct
	ccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacccatac
	ccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagt
	ccggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagt
	gcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgacc
	gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgagcaa
	ggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgt
	ctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 2 Amino Acid Sequences

Heavy chain A	Rahlvqsgtamkkpgasvrvscqtsgyfftahilfwfrqapgrglewvgwikpqy	SEQ ID
	gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda	NO: 9
	wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal
	tsgvhtfpavlqssglyslssvvtvpssslgtqtvicnvnhkpsntkvdkkvepkscd
	kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw
	yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi
	ektiskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsdgsfflvskltvdksrwqqgnvscsvlhealhshytqkslslspg

Light chain A	yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv	SEQ ID
	psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsde	NO: 10
	qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltls
	kadvekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr	SEQ ID
	itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk	NO: 11
	yydfwsgyppgeeyfqdwgqgtlvivssdkthtqvhltqsgpevrkpgtsv
	kvsckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkak
	vtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwav
	dvdylsnlefwgygtavtvssdkthtastkgpsvfplapsskstsggtaalgcl
	vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyi
	cnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdt
	lmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynsty
	rvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlp
	pcrdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdgs
	fflyskltvdksrwqqgnvfscsvlhealhshytqkslslspg

Light chain B	dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr	SEQ ID
	asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikdkth	NO: 12
	taseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi
	pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtv
	aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteq
	dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 2 Nucleotide Sequences

Heavy chain A	agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg	SEQ ID
	gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag	NO: 13
	gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg
	aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag
	atcgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactgcg
	ccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagggc
	acaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggcccc
	tagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggacta
	ctttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgcac
	acctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgacagt
	gcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagcccag
	caacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacacct
	gtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccccccaa
	agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg
	atgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaagt
	gcacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccgggtg
	gtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgc
	aaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaag
	ggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctga
	ccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgcc
	gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt
	gctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccggt
	ggcagcagggcaacgtgttcagctgctccgtgctgcacgaggccctgcacagccact
	acacccagaagtccctgagcctgagccccggc

Light chain A	tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtga	SEQ ID
	ccatcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaa	NO: 14
	gcctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgt
	gcccagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagcgatc
	tgcaggccgacgacattgccacctactattgtcaggtgctgcagttcacggcagaggc
	agcagactgcacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctag
	cgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacc
	cccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacag
	ccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctgagcagca
	ccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtga
	cccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc	SEQ ID
	ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag	NO: 15
	cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg
	gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca
	agaataccttgtatttggagatgaacaacatgagaactaaaaacaccggatattacttct
	gtgccagaacaggcaaatactacgacttgtggtccggctatccccctggcgaggaatat
	tttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccatacccag
	gtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaaggtg
	tcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcgcagc
	gtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaaga
	aagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagcacca
	acaccgcctacctgcagctgagcggcctaacctctggcgataccgccgtgtactactg
	cgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacggcg
	ccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggccaggg
	cacagccgtgaccgtgtcatctgataagacccacaccgcttccaccaagggcccatcg
	gtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggct
	gcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccct
	gaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctca
	gcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgt
	gaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtga
	caaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagt
	cttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtca
	catgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtatgtt
	gacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca
	gcacgtaccgtatggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaa
	ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat
	ctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgcc
	gggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggcttctatccc
	agcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaaga
	ccacgcctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtgg
	acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgctgcatgaggctct
	gcacagccactacacgcagaagagcctctccctgtctccgggt

Light chain B	gacttcgtgctgacccagagccctcacagcctgagcgtacacctggcgagagcgcc	SEQ ID
	agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg	NO: 16
	gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca
	gcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttca
	ccctgaagatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagg
	gcagagagagcccctggacctttggccagggcaccaaggtggacatcaaggacaaa
	acccataccgcatccgaactgactcaggaccctgccgtctctgtggcactgaagcaga
	ctgtgactattacttgccgaggcgactcactgcggagccactacgcttcctggtatcaga
	agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccatctgg
	catccccgaccgcttttctggcagtgcatcagggaaccgagccagtctgaccattaccg
	gcgcccaggctgaggacgaagccgattactattgcagctcccgggataagagcggct
	ccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacccatac
	ccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagt
	ccggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagt
	gcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgacc
	gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgagcaa
	ggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgt
	ctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 3 Amino Acid Sequences

Heavy chain A	rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqyg	SEQ ID
	avnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswaldaw	NO: 17
	gqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalts
	gvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkt
	htcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyv
	dgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiekt
	iskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpenny
	kttppvldsdgsfflvskltvdksrwqqgnvfscsvlhealhshytqkslslspg

Light chain A	yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv	SEQ ID
	psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsde	NO: 18
	glksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltls
	kadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmg	SEQ ID
	wishegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgsk	NO: 19
	hrlrdyalydddgalnwavdvdylsnlefwgqgtavtvssdkthtevrlves
	ggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgritgpgeg
	wsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgkyydfws
	gyppgeeyfqdwgqgtlvivssdkthtastkgpsvfplapsskstsggtaalg
	clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqt
	yicnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpk
	dtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqyns
	tyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvyt
	lppcrdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsd
	gsfflyskltvdksrwqqgnvfscsvlhealhshytqkslslspg

Light chain B	aseltqdpavsvalkqtvtitcrgdsltshyaswyqkkpgqapvllfygknnrpsgip	SEQ ID
	drfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtdfvlt	NO: 20
	qsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassrasgv
	pdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikdkthtrtva
	apsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqds
	kdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 3 Nucleotide Sequences

Heavy chain A	agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg	SEQ ID
	gtatcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag	NO: 21
	gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg
	aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag
	atcgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactgcg
	ccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagggc
	acaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggcccc
	tagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggacta
	ctttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgcac
	acctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgacagt
	gcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagcccag
	caacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacacct
	gtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccccccaa
	agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg
	atgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaagt
	gcacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccgggtg
	gtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgc
	aaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaag
	ggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctga
	ccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgcc
	gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt
	gctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccggt
	ggcagcagggcaacgtgttcagctgctccgtgctgcacgaggccctgcacagccact
	acacccagaagtccctgagcctgagccccggc

Light chain A	tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtga	SEQ ID
	ccatcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaa	NO: 22
	gcctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgt
	gcccagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagcgatc
	tgcaggccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagaggc
	agcagactgcacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctag
	cgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacc
	cccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacag
	ccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctgagcagca
	ccctgacactgagcaaggccgactacgagaaacacaaggtgtacgcctacgaagtga
	cccaccagggcctatctagccccgtgaccaagagatcaaccagggcgagtgt

Heavy chain B	caggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctct	SEQ ID
	gtgaaggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgca	NO: 23
	ctgggtgcgcagcgtgccaggacagggactgcagtggatgggctggatcag
	ccacgagggcgacaagaaagtgatcgtggaacggttcaaggccaaagtgac
	catcgactgggacagaagcaccaacaccgcctacctgcagctgagcggcctg
	acctctggcgataccgccgtgtactactgcgccaagggcagcaagcaccggc
	tgagagactacgccctgtacgacgatgacggcgccctgaactgggccgtgga
	tgtggactacctgagcaacctggaattaggggccagggcacagccgtgacc
	gtgtcatctgacaaaacccataccgaggttagactggtggagtcaggaggggg
	gcttgtgaagcccggtgggtctctccgcctgagagttctgcctccggctttgatt
	tcgataacgcctggatgacctgggtcaggcagcaccaggtaagggactgga
	gtgggtgggaagaatcacaggtccaggcgagggctggtccgtggactacgc
	ggaatctgttaaagggcggtttacaatctcaagggacaataccaagaataccttg
	tatttggagatgaacaacgtgagaactgaagacaccggatattacttctgtgcca
	gaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatattt
	tcaagactggggtcagggaacccttgttatcgtgtcctccgataagacccacac
	cgcttccaccaagggcccatcggtcttccccctggcaccctcctccaagagcac
	ctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaac
	cggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacacctt
	cccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgt
	gccctccagcagcttgggcacccagacctacatagcaacgtgaatcacaagc
	ccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaact
	cacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtctt
	cctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggt
	cacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaact
	ggtatgttgacggcgtggaggtgcataatgccaagacaaagccgcgggagga
	gcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccagg
	actggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctccca
	gcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaacca
	caggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaagtcag
	cctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtggga
	gagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctgga
	ctccgacggctccttcttcactactcaaaactcaccgtggacaagagcaggtg
	gcagcaggggaacgtatctcatgctccgtgctgcatgaggctctscacagcc
	actacacgcagaagagcctctccctgtctccgggt

Light chain B	gcatccgaactgactcaggaccctgccgtctctgtggcactgaagcagactgtgactat	SEQ ID
	tacttgccgaggcgactcactgcggagccactacgcttcctggtatcagaagaaaccc	NO: 24
	ggccaggcacctgtgctgctgttctacggaaagaacaataggccatctggcatccccg
	accgcttttctggcagtgcatcagggaaccgagccagtctgaccattaccggcgccca
	ggctgaggacgaagccgattactattgcagctcccaggataaaagcggctccagact
	gagcgtgttcggaagaggaactaaactgaccgtcctcgacaaaacccataccgacttc
	gtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgccagcatc
	agctgcaagagcagccactccctgatccacggcgaccggaacaactacctggcttggt
	acgtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcagag
	ccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttcaccctgaa
	gatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcagag
	agagcccctggacctttgaccagggcaccaaggtggacatcaagaataagacccata
	cccgtacaatggccgctcccagcgtgacatcttcccacctagcgacgagcagctgaa
	gtccggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaa
	gtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtga
	ccgagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgagc
	aaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcct
	gtctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 4 Amino Acid Sequences

Heavy chain A	qvqlvqsggqmkkpgesmriscrasgyefidctlnwirlapgkrpewmgwlkpr	SEQ ID
	ggavnyarplqgrvtmtrdvysdtaflelrsltvddtavyfctrgkncdynwdfehw	NO: 25
	grgtpvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalts
	gvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkt
	htcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyv
	dgvevhnaktkpreegynstyrvvsvltvlhqdwlngkeykckvsnkalpapiekt
	iskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpenny
	kttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain A	Eivltqspgtlslspgetaiiscrtsqygslawyqqrpgqaprlviysgstraagipdrf	SEQ ID
	sgsrwgpdynltisnlesgdfgvyycqqyeffgqgtkvqvdikrtvaapsvfifpps	NO: 26
	deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsst
	ltlskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgri	SEQ ID
	tgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk	NO: 27
	yydfwwgyppgeeyfqdwgqgtlvivssdkthtqvhltqgpevrkpgts
	vkvsckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfka
	kvtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwa
	vdvdylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalg
	clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqt
	yicnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpk
	dtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqyns
	tyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvyt
	lppcrdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsd
	gsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr	SEQ ID
	asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikdkth	NO: 28
	taseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi
	pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtv
	aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteq
	dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 4 Nucleotide Sequences

Heavy chain A	caggtgcagctggtgcagtctggcggccagatgaagaaacccggcgagagcatgcg	SEQ ID
	gatcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcaga	NO: 29
	ctggcccctggcaagcggcctgagtggatgggatggctgaagcctagaggcggagc
	cgtgaactacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacag
	cgataccgccttcctggaactgcggagcctgaccgtggatgataccgccgtgtacttct
	gcacccggggcaagaactgcgactacaactgggacttcgagcactggggcagaggc
	acccctgtgatcgtgtcaagcgcatcgaccaagggccccagcgtgttccctctggccc
	ctagcagcaagagcacatctgacggaacagccgccagggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgca
	cacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgaca
	gtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagccca
	gcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacac
	ctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttcccccc
	aaagcccaaggacaccctgatgatcagccgaacccccgaagtgacctgcatggtggt
	ggatgtgtcccacgaggaccctgaagtgaagttcaattggtacatggacgacgtggaa
	gtgcacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccgggt
	ggtgtccgtgctgaccgtgagcaccaggactggctgaacggcaaagagtacaagtg
	caaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaa
	gggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctg
	accaagaaccagatgtccctgagagtaccatgaaaggcttctacccctccgatatcgc
	cgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctg
	tgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccgg
	tggcagcagggcaacgtgttcagagaccgtgatgcacgaggccctgcacaaccact
	acacccagaagtccagagcctgagccccggc

Light chain A	Gagatcgtgctgacacagagccaggcaccctgagcctgtctccaggcgagacagc	SEQ ID
	catcatcagtgccggacaagccagtacggcagcctggcctggtatcagcagaggcc	NO: 30
	tggacaggcccccagactcgtgatctacagcggcagcacaagagccgccggaatcc
	ccgatagattcagcggctccagatggggccagactacaacctgaccatcagcaacct
	ggaaagcgacgacttcgacgtgtactactgccagcaatacgagttcttcggccagggc
	accaaggtgcaggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttcc
	cacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaa
	cttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcg
	gcaacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctg
	agcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctg
	cgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga
	gtgt

Heavy chain B	gaggttagactggtggagtcaggagaggggcttgtgaagcccggtgggtctctccgc	SEQ ID
	ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag	NO: 31
	cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg
	gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca
	agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct
	gtgccagaacaggcaaatactacgacttctggtggggctatccccctggcgaggaata
	ttttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccataccca
	ggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaaggt
	gtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcgcag
	cgtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaag
	aaaggatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagcacc
	aacaccgcctacctacaactgagcggcctaacctctggcgataccgccgtgtactact
	gcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacggc
	gccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggccagg
	gcacagccgtgaccgtgtcatctgataagacccacaccgcttccaccaagggcccatc
	ggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctggg
	ctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgcc
	ctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccct
	cagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaac
	gtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtg
	acaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcag
	tcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtca
	catgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtatgtt
	gacggcgtagaggtgcataataccaagacaaagccgcgggaggagcagtacaaca
	gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatagcaa
	ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat
	ctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgcc
	gggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaattggcttctatccc
	agcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaaga
	ccacgcctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtgg
	acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgctgcatgaggctct
	gcacagccactacacgcagaagagcctctccctgtctccgggt

Light chain B	gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc	SEQ ID
	agcatcagctgcaagagcagccactccctgatccacggcgaccgaaacaactacctg	NO: 32
	gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca
	gcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttca
	ccctgaagatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagg
	gcagagagagcccctggacctttggccagggcaccaaggtggacatcaaggacaaa
	acccataccgcatccgaactgactcaggaccctgccgtctctgtggcactgaagcaga
	ctgtgactattacttgccgaggcgactcactgcggagccactacgcttcctagtatcaga
	agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccatctgg
	catccccgaccgcttttctggcagtgcatcagggaaccgagccagtctgaccattaccg
	gcgcccaggctgaggacgaagccgattactattgcagctcccgggataagagcggct
	ccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacccatac
	ccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagt
	ccggcacagcctctatcgtgtgcctgctgaacaacttctacccccgcgaggccaaagt
	gcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgacc
	gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgagcaa
	ggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgt
	ctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 5 Amino Acid Sequences

Heavy chain A	Qvqlvqsggqmkkpgesmriscrasgyefidctlnwirlapgkrpewmgwlkpr	SEQ ID
	ggavnyarplqgrvtmtrdvysdtaflelrsltvddtavyfctrgkncdynwdfehw	NO: 33
	grgtpvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalts
	gvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkt
	htcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyv
	dgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiekt
	iskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpenny
	kttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain A	Eivltqspgtlslspgetaiiscrtsqygslawyggrpgqaprlviysgstraagipdrfs	SEQ ID
	gsrwgpdynltisnlesgdfgvyycqqyeffgqgtkvqvdikrtvaapsvfifppsd	NO: 34
	eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt
	lskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr	SEQ ID
	itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk	NO: 35
	yydfwwgyppgeeyfqdwgqgtlvivssdkthtqmqlqesgpglvkpse
	tlsltcsvsgasisdsywswirrspgkglewigyvhksgdtnyspslksrvnl
	sldtsknqvslslvaataadsgkyycartlhgrriygivafnewftyfymdvw
	gngtqvtvssdkthtastkgpsvfplapsskstsggtaalgclvkdyfpepvtv
	swnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntk
	vdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcv
	vvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqd
	wlngkeykckvsnkalpapiektiskakgqprepqvytlppcrdeltknqv
	slwclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdks
	rwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	Sdisvapgetariscgekslgsravqwyqhragqapsliiynnqdrpsgiperfsgsp	SEQ ID
	dspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtaseltqdp	NO: 36
	avsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdrfsgsas
	gnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaapsvfifp
	psdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysls
	stltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 5 Nucleotide Sequences

Heavy chain A	Caggtgcagctggtgcagtctggcggccagatgaagaaacccggcgagagcatgc	SEQ ID
	ggatcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcag	NO: 37
	actggcccctggcaagcggcctgagtggatgggatggctgaagcctagaggcggag
	ccgtgaactacgccagacctctgcagggcagagtgaccatgacccgggacgtgtaca
	gcgataccgccttcctggaactgcggagcctgaccgtggatgataccgccgtgtacttc
	tgcacccggggcaagaactgcgactacaactgggacttcgagcactggggcagagg
	cacccctgtgatcgtgtcaagc
	gcgtcgaccaagggccccagcgtgttccctctggcccctagcagcaagagcacatct
	ggcggaacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgacc
	gtgtcctagaattctgacgccctgaccagcggcgtgcacacctttccagctgtgctgca
	gtccagcggcctgtacagcctgagcagcgtcgtgacagtgcccagcagctctctggg
	cacccagacctacatctgcaacgtgaaccacaagcccagcaacaccaaggtggacaa
	gaaggtggaacccaagagctgcgacaagacccacacctgtcccccttgtcctgcccc
	cgaactgctgggaggcccttccgtgttcctgttccccccaaagcccaaggacaccctg
	atgatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccacgaggac
	cctgaagtgaagttcaattggtacgtggacggcgtggaagtgcacaacgccaagacca
	agccaagagaggaacagtacaacagcacctaccgggtggtgtccgtgctgaccgtgc
	tgcaccaggactggctgaacggcaaagagtacaagtgcaaggtatccaacaaggccc
	tgcctgcccccatcgagaaaaccatcagcaaggccaagggccagccccgcgaaccc
	caggtgtgcacactgcccccaagcagggacgagctgaccaagaaccaggtgtccctg
	agctgtgccgtgaaaggcttctacccctccgatatcgccgtggaatgggagagcaacg
	gccagcccgagaacaactacaagaccaccccccctgtgctggacagcgacggctcat
	tcttcctggtgtccaaactgacagtggacaagtcccggtggcagcagggcaacgtgttc
	agctctccgtgatgcacgaggccctgcacaaccactacacccagaagtccctgagc
	ctgagccccggc

Light chain A	Gagatcgtgctgacacagagccctggcaccctgagcctgtctccaggcgagacagc	SEQ ID
	catcatcagctgccggacaagccagtacggcagcctggcctggtatcagcagaggcc	NO: 38
	tggacaggcccccagactcgtgatctacagcggcagcacaagagccgccggaatcc
	ccgatagattcagcggctccagatggggccctgactacaacctgaccatcagcaacct
	ggaaagcggcgacttcggcgtgtactactgccagcagtacgagttcttcggccagggc
	accaaggtgcaggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttcc
	cacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaa
	cttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcg
	gcaacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctg
	agcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctg
	cgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga
	gtgt

Heavy chain B	gaggttagactggtggagtcaggaggggggcttgtgaagcccagtgggtctctccgc	SEQ ID
	ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag	NO: 39
	cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg
	gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca
	agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct
	gtgccagaacaggcaaatactacgacttctggtggggctatccccctggcgaggaata
	ttttcaagactggggtcaaggaacccttgttatcgtgtcctccgacaaaacccataccca
	gatacagctgcaggagagcggccctggactcgtgaagcccagcgagaccctgaacc
	tgacatgcagcgtgagcggcgccagcatcagcgacagctactggagctggatcagga
	ggagccctggcaagggcctggagtggatcggctacgtgcacaagagcggcgacacc
	aactacagcccctccctgaagtccagggtgaacctgtccctggacaccagcaagaacc
	aggtgagcctgtccctggtggctgccacagctgctgacagcggcaagtactactgtgc
	caggaccctgcacggcaggaggatctacggcatcgtggccttcaacgagtggttcacc
	tacttctacatggacgtgtggggcaacggcacccaggtgaccgtgagctccgataaga
	cccacaccgcttccaccaagggcccatcggtcttccccctggcaccctcctccaagag
	cacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaacc
	ggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggc
	tgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagca
	gcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggt
	ggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca
	gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggaca
	ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacga
	agaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatgccaaga
	caaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcacc
	gtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaa
	gccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgaga
	accacaggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaagtcag
	cctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtgggagagc
	aatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacgg
	ctccttcttcctctactcaaaactcaccgtggacaagagcaggtggcagcaggggaac
	gtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcct
	ctccctgtctccaggt

Light chain B	tccgacatcagcgtggcccccggagagacagccaggatctcctgcggcgagaagag	SEQ ID
	cctgggaagcagggctgtgcagtagtaccaacacagggccggacaggctcccagcc	NO: 40
	tgatcatctacaacaaccaggacaggcccagcggcatccctgagaggttcagcggaa
	gccccgacagccccttcggaaccacagccaccctgaccatcacaagcgtggaagcc
	ggcgacgaggccgactactactgccacatctgggacagcagggtgcccaccaagtg
	ggtgtttggcggcggcaccaccctgaccgtgctggacaaaacccataccgcatccga
	actgactcaggaccctgccgtctctgtggcactgaagcagactgtgactattacttgccg
	aggcgactcactgcggagccactacgcttcctggtatcagaagaaacccggccaggc
	acctgtgctgctgttctacggaaagaacaataggccatctggcatccccgaccgcttttc
	tggcagtgcatcagggaaccgagccagtctgaccattaccggcgcccaggctgagga
	cgaagccgattactattgcagctcccgggataagagcggctccagactgagcgtgttc
	ggaggaggaactaaactgaccgtcctcgataagacccatacccgtacggtggccgct
	cccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctctgt
	cgtgtgcctgagaacaacttctacccccgcgaggccaaagtgcagtggaaggtggac
	aacgccctgcagagcggcaacaaccaggaaagcgtgaccgagcaggacagcaag
	gactccacctacagcctgagcagcaccctgacactgagcaaggccgactacgagaag
	cacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaag
	agcttcaaccggggcgagtgt

Binding Protein 6 Amino Acid Sequences

Heavy chain A	Qvqlvqsggqmkkpgesmriscrasgyefidctlnwirlapgkrpewmgwlkpr	SEQ ID
	ggavnyarplqgrvtmtrdvysdtaflelrsltvddtavyfctrgkncdynwdfehw	NO: 41
	grgtpvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalts
	gvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkt
	htcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyv
	dgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiekt
	iskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpenny
	kttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain A	Eivltqspgtlslspgetaiiscrtsqygslawyqqrpgqaprlviysgstraagipdrfs	SEQ ID
	gsrwgpdynltisnlesgdfgvyycqqyeffgqgtkvqvdikrtvaapsvfifppsd	NO: 42
	eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt
	lskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmg	SEQ ID
	wishegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgsk	NO: 43
	hrlrdyalydddgalnwavdvdylsnlefwgqgtavtvssdkthtevrlves
	ggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgritgpgeg
	wsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgkyydfw
	wgyppgeeyfqdwgqgtlvivssdkthtastkgpsvfplapsskstsggtaa
	lgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgt
	qtyicnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppk
	pkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqy
	nstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepq
	vytlppcrdeltknqvstwclvkgfypsdiavewesngqpennykttppvl
	dsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	Aseltqdpavsvalkqvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi	SEQ ID
	pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtdfv	NO: 44
	ltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassrasg
	vpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqatkvdikdkthtrtv
	aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteq
	dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 6 Nucleotide Sequences

Heavy chain A	caggtgcagctggtgcagtctggcggccagatgaagaaacccggcgagagcatgcg	SEQ ID
	gatcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcaga	NO: 45
	ctggcccctggcaaacggcctgagtggatgggatggctgaagcctagaggcggagc
	cgtgaactacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacag
	cgataccgccttcctggaactgcggagcctgaccgtggatgataccgccgtgtacttct
	gcacccggggcaagaactgegactacaactgggacttcgagcactggggcagaggc
	acccctgtgatcgtgtcaagcgcgtcgaccaagggccccagcgtgttccctctggccc
	ctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgca
	cacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgaca
	gtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagccca
	gcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacac
	ctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttcccccc
	aaagcccaaggacaccctgatgatcagccgaacccccgaagtgacctgcgtggtggt
	ggatgtgtcccacgaggaccctgaagtgaagttcaattggtacatggacgacgtggaa
	gtgcacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccgggt
	ggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtg
	caaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaa
	gggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctg
	accaagaaccaggtgtccctgagctgtgccatgaaaggcttctacccctccgatatcgc
	cgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctg
	tgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccgg
	tggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccact
	acacccagaagtccctgagcctgagccccggc

Light chain A	gagatcgtgctgacacagagccctggcaccctgagcctgtctccaggcgagacagcc	SEQ ID
	atcatcagctgccggacaagccagtacggcagcctggcctggtatcagcagaggcct	NO: 46
	ggacaggcccccagactcgtgatctacagcggcagcacaagagccgccggaatccc
	cgatagattcagcggctccagatggggccctgactacaacctgaccatcagcaacctg
	gaaagcggcgacttcggcgtgtactactgccagcagtacgagttcttcggccagggca
	ccaaggtgcaggtggacatcaagcgtacggtggccgctcccagcatgttcatcttccc
	acctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaac
	ttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcgg
	caacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctga
	gcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgc
	gaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga
	gtgt

Heavy chain B	caggtgcacctgacacaaagcggacccgaagtgcggaagcctagcacctctgtgaa	SEQ ID
	ggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcg	NO: 47
	cagcgtgccaggacagggactgcagtggatgggctggatcagccacgagggcgac
	aagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagc
	accaacaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtact
	actgcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgac
	ggcgccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggcc
	agggcacagccgtgaccgtgtcatctgacaaaacccataccgaggttagactggtgga
	gtcaggaggggggcttgtgaagcccggtgggtctctccgcctgagctgttctgcctcc
	ggctttgatttcgataacgcctggatgacctgggtcaggcagcctccaggtaagggact
	ggagtgggtgggaagaatcacaggtccaggcgagggctggtccgtggactacgcgg
	aatctgttaaagggcggtttacaatctcaagggacaataccaagaataccttgtatttgga
	gatgaacaacgtgagaactgaagacaccagatattacttctgtgccagaacaggcaaa
	tactacgacttctggtggggctatccccctggcgaggaatattttcaagactggggtcag
	ggaacccttgttatcgtgtcctccgataagacccacaccgcttccaccaagggcccatc
	ggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctggg
	ctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgcc
	ctgaccagcggcgtgcaccttcccggctcgtcctacagtcctcaggactctactccct
	cagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaac
	gtgaatcacaagcccagcaacaccaaggtgaacaagaaagttgagcccaaatcttgtg
	acaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcag
	tcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtca
	catgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtatgtt
	gacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca
	gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaa
	ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat
	ctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgcc
	gggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggcttctatccc
	agcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaaga
	ccacgcctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtgg
	acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctct
	gcacaaccactacacgcagaagagcctctccctgtctccgggt

Light chain B	Gcatccgaactgactcaggaccctgccgtctctgtggcactgaagcagactgt	SEQ ID
	gactattacttgccgaggcgactcactgcggagccactacgcttcctggtatca	NO: 48
	gaagaaacccggccaggcacctgtgctgctgttctacggaaagaacaatagg
	ccatctggcatccccgaccgcttttctggcagtgcatcagggaaccgagccagt
	ctgaccattaccggcgcccaggctgaggacgaagccgattactattgcagctc
	ccgggataagagcggctccagactgagcgtgttcggaggaggaactaaactg
	accgtcctcgacaaaacccataccgacttcgtgctgacccagagccctcacag
	cctgagcgtgacacctggcgagagcgccagcatcagctgcaagagcagcca
	ctccctgatccacggcgaccggaacaactacctggcttggtacgtgcagaagc
	ccggcagatccccccagctgctgatctacctggccagcagcagagccagcgg
	cgtgcccgatagattttctggcagcggcagcgacaaggacttcaccctgaagat
	cagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcaga
	gagagcccctggacctttggccagggcaccaaggtggacatcaaggataaga
	cccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacg
	agcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacc
	cccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggc
	aacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagc
	ctgagcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgt
	acgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttc
	aaccggggcgagtgt

Binding Protein 7 Amino Acid Sequences

Heavy chain A	Qvqlvqsggqmkkpgesmriscrasgyefidctlnwirlapgkrpewmgwlkpr	SEQ ID
	ggavnyarplqgrvtmtrdvysdtaflelrsltvddtavyfctrgkncdynwdfehw	NO: 49
	grgtpvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalts
	gvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkt
	htcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyv
	dgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiekt
	iskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpenny
	kttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain A	Eivltqspgtlslspgetaiiscrtsqygslawyqqrpgqaprlviysgstraagipdrfs	SEQ ID
	gsrwgpdynltisnlesgdfgvyycqqyeffgqgtkvqvdikrtvaapsyfifppsd	NO: 50
	eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt
	lskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	qmqlqesgpglvkpsetlsltcsvsgasisdsywswirrspgkglewigyvh	SEQ ID
	ksgdtnyspslksrvnlsldtsknqvslslvaataadsgkyycartlhgrriygi	NO: 51
	vafnewftyfymdvwgngtqvtvssdkthtQvhltqsgpevrkpgtsvkv
	sckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkakvti
	dwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwavdv
	dylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgclvk
	dyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicn
	vnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlm
	isrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrv
	vsvltvlhqdwlngkeykekvsnkalpapiektiskakgqprepqvytlpp
	crdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsf
	flyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	Dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr	SEQ ID
	asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikdkth	NO: 52
	tsdisvapgetariscgekslgsravqwyqhragqapsliiynnqdrpsgiperfsgs
	pdspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtrtvaaps
	vfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnqesvteqdskd
	styslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 7 Nucleotide Sequences

Heavy chain A	caggtgcagaggtgcagtctggcggccagatgaagaaacccggcgagagcatacg	SEQ ID
	gatcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcaga	NO: 53
	ctggcccctggcaagcggcctgagtggatgggatggagaagcctagaggcggagc
	cgtgaactacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacag
	cgataccgcctcctggaactgcggagcctgaccgtggatgataccgccgtgtacttct
	gcacccggggcaagaactgcgactacaactgggacttcgagcactggggcagaggc
	acccctgtgatcgtgtcaagcgcgtcgaccaagggccccagcgtgttccctctggccc
	ctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgca
	cacctttccagagtgagcagtccagcggcctgtacagcctgagcagcgtcgtgaca
	gtacccagcagctactgagcacccagacctacatctgcaacgtgaaccacaagccca
	acaacaccaaggtagacaagaaggtgaaacccaagagctacgacaagacccacac
	ctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttcccccc
	aaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggt
	ggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaa
	gtgcacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccgggt
	ggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtg
	caagatgtccaacaaggccctgcctacccccatcgagaaaaccatcagcaaggccaa
	gggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctg
	accaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgc
	cgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctg
	tgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccgg
	tggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccact
	acacccagaagtccctgagcctgagccccggc

Light chain A	gagatcgtgctgacacagagccctggcaccctgagcctgtctccaggcgagacagcc	SEQ ID
	atcatcagagccggacaagccagtacggcagcctagcctggtatcaacagaggcct	NO: 54
	ggacaggcccccagactcgtgatctacagcggcagcacaagagccgccggaatccc
	cgatagattcagcggaccagatggggccctgactacaacctgaccatcagcaacctg
	gaaagcggcgacttcggcgtgtactactgccagcagtacgagttcttcggccagggca
	ccaaggtgcaggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttccc
	acctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaac
	ttctacccccgcgaggccaaagtgcagtggaaaggtggacaacgccctgcagagcgg
	caacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctga
	gcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgc
	gaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga
	gtgt

Heavy chain B	cagatgcagctgcaggagagcggccctggactcgtgaagcccagcgagaccctgag	SEQ ID
	cctgacatgcagcgtgagcggcgccagcatcagcgacagctactggagctggatcag	NO: 55
	gaggagccctggcaagggcctggagtggatcggctacgtgcacaagagcgacgac
	accaactacagcccctccctgaagtccagggtgaacctgtccctggacaccagcaaga
	accaggtgagcctgtccctggtggctgccacagctgctgacagcggcaagtactactg
	tgccaggaccctgcacggcaggaggatctacggcatcgtggccttcaacgagtggttc
	acctacttctacatggacgtggggcaacggcacccaggtgaccgtgagctccgaca
	aaacccatacccaggtgcacctgacacagagcggacccgaagtgcggaagcctggc
	acctagtgaagatgtcctgcaagacccaggcaacaccctgaaaacctacgacctgc
	actgggtgcgcagcgtgccaggacagggactgcagtggatgggctggatcagccac
	gagggcgacaagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgg
	gacagaagcaccaacaccgcctacctgcagctgagcggcctgacctctggcgatacc
	gccgtgtactactgcgccaagggcagcaagcaccggctgagagactacgccctgtac
	gacgatgacggcgccctgaactgggccgtggatgtggactacctgagcaacctggaa
	ttctgaggccaggacacaaccatgaccatgtcatctgataagacccacaccgcttcca
	ccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcac
	agcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtgg
	aactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcag
	gactctactccctcagcagcgtggtgaccgtgccctccagcttgcttgggcacccagac
	ctacatagcaacgtgaatcacaagcccagcaacaccaaggtgaacaagaaagttga
	gcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcagg
	ggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccgg
	acccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaag
	ttcaactggtatgttgacggcgtggaggtgcataatgccaagacaaagccgcgggagg
	agcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactg
	gctgaatggcaaggaatacaagtgcaaggtctccaacaaagccctcccagcccccat
	cgagaaaaccataccaaagccaaagggcagccccgagaaccacaggtgtacaccc
	tgcccccatgccgaaataagctgaccaaaaatcaagtcagcctgtggtacctggtaaa
	aggctctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggaga
	acaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctactcaa
	aactcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat
	gcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggt

Light chain B	Gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgaga	SEQ ID
	gcgccagcatcagctgcaagagcagccactccctgatccacggcgaccggaa	NO: 56
	caactacctggcttggtacgtgcagaagcccggcagatccccccagctgctga
	tctacctggccagcagcagagccagcggcgtgcccgatagattttctggcagc
	ggcagcgacaaggacttcaccctgaagatcagccgggtggaaaccgaggac
	gtgggcacctactactgtatgcagggcagagagagcccctggacctttggcca
	gggcaccaaggtggacatcaaggacaaaacccatacctccgacatcagcgtg
	gcccccggagagacagccaggatctcctgcggcgagaagagcctgggaag
	cagggctgtgcagtggtaccaacacagggccggacaggctcccagcctgatc
	atctacaacaaccaggacaggcccageggcatccctgagaggttcagcggaa
	gccccgacagccccttcggaaccacagccaccctgaccatcacaagcgtgga
	agccggcgacgaggccgactactactgccacatctgggacagcagggtgcc
	caccaagtgggtgtttggcggcggcaccaccctgaccgtgctggataagaccc
	atacccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagc
	agctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctaccccc
	gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaac
	agccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctg
	agcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtac
	gcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaa
	ccggggcgagtgt

Binding Protein 8 Amino Acid Sequences

Heavy chain A	Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqy	SEQ ID
	gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda	NO: 57
	wgqgttvvvsaastkapsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal
	tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd
	kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw
	yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi
	cktiskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsdgsffvskltvdksrwqqgnvfscsvlhealhshytqkslslspg

Light chain A	Yihvtqspsslsvsigdrvtincqtsqvgsdlhwyqhkpgrapkllihhtssvedg	SEQ ID
	vpsrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsd	NO: 58
	eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt
	lskadyekhkvyacevthqglsspvtksthrgec

Heavy chain B	Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqpgkglewvgr	SEQ ID
	itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk	NO: 59
	yydfwwgyppgeeyfqdwgqgtlvivssdkthtqvqlvesgggvvqpgt
	slrlscaasqfrfdgygmhwvrqapgkglewvasishdgikkyhaekvwg
	rftisrdnskntlylqmnslrpedtalyycakdlredeceewwsdyydfgkq
	lpcaksrgglvgiadnwgqgtmvtvssdkthtastkgpsvfplapsskstsg
	gtaalgclvkdyfpepvtvswnsgaltsgvhtfpavlssglyslssvvtvpss
	slgtqtyicnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflf
	ppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpr
	eeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqpr
	epqvytlppcrdeltknqvslwelvkgfypsdiavewesngqpennykttp
	pvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	Qsvltqppsvsaapgqkvtiscsgntsnignnfvswyqqrpgrapqlliyetdkrps	SEQ ID
	gipdrfsasksgtsgtlaitglqtgdeadyycatwaaslssarvftgtkvivldkthtas	NO: 60
	eltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdr
	fsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaap
	svfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdsk
	dstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 8 Nucleotide Sequences

Heavy chain A	agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg	SEQ ID
	gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggca	NO: 61
	ggcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccg
	tgaacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcg
	agatcgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactg
	cgccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagg
	gcacaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggc
	ccctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaagg
	actactttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtg
	cacacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtga
	cagtacccaacaactctctgggcacccagacctacatagcaacgtgaaccacaagc
	ccagcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagaccca
	cacctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccc
	cccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggt
	ggtggatgtgtcccacgaggaccctgaagtgaattcaattggtacgtggacggcgtg
	gaagtgcacaacgccaagaccaagccaagagaggaacagtacaacagcacctacc
	gggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtaca
	agtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaagg
	ccaagggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacga
	gctgaccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgat
	atcgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccc
	cccctgtgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaag
	tcccggtggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcac
	aaccactacacccagaagtccctgagcctgagccccggcaag

Light chain A	Tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgaca	SEQ ID
	gagtgaccatcaactgccagacctctcagggcgtgggcagcgacctgcactg	NO: 62
	gtatcagcacaagcctggcagagcccccaagctgctgatccaccacacaagc
	agcgtggaagatggcgtgcccagcagattttccggcagcggcttccacacca
	gcttcaacctgaccatcagcgatctgcaggccgacgacattgccacctactatt
	gtcaggtgctgcagttcttcggcagaggcagcagactgcacatcaagcgtacg
	gtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtcc
	ggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaa
	agtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaa
	gcgtgaccgagcaggacagcaaggactccacctacagcctgagcagcaccc
	tgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagt
	gacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga
	gtgt

Heavy chain B	gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc	SEQ ID
	ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag	NO: 63
	cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg
	gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca
	agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct
	gtgccagaacaggcaaatactacgacttctggtggggctatccccctggcgaggaata
	ttttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccataccca
	ggtgcagttggtggagtctgggggaggcgtggtccagcctgggacgtccctgagact
	ctcctgtgcagcctctcaattcaggtttgatggttatgacatgcactgggtccgccaggc
	cccaggcaaggggctggagtgggtggcatctatatcacatgatggaattaaaaagtat
	cacgcagaaaaagtgtggggccgcttcaccatctccagagacaattccaagaacaca
	ctgtatctacaaatgaacagcctgcgacctgaggacacggctctctactactgtgcgaa
	agatttgcgagaagacgaatgtgaagagtggtggtcggattattacgattttgggaaac
	aactcccttgcgcaaagtcacgcggcggcttggttggaattgctgataactggggcca
	agggacaatggtcaccgtctcttcagataagacccacaccgcttccaccaagggccca
	tcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgg
	gctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgc
	cctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccc
	tcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaa
	cgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgt
	gacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtca
	gtcttcctcttccccccaaaacccaaggacaccctcatgatctcccgaacccctgaggt
	cacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtat
	gttgacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa
	cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc
	aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaacc
	atctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgc
	cgggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggcttctatcc
	cagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaag
	accacgcctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtg
	gacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatacatgaggct
	ctgcacaaccactacacgcagaagagcctctccctgtctccgggt

Light chain B	Cagtctgtgctgacgcagccgccctcagtgtctgcggccccaggacagaagg	SEQ ID
	tcaccatctcctgactggaaacacctccaacattggcaataattttgtgtcctggt	NO: 64
	atcaacagcgccccggcagagccccecaactcctcatttatgaaactgacaag
	cgaccctcagggattcctgaccgattctctgcttccaagtctggtacgtcaggca
	ccctggccatcaccgggctgcagactggggacgaggccgattattactgcgc
	cacatgggctgccagcctgagttccgcgcgtgtatcggaactgggaccaagg
	tcatcgtcaggacaaaacccataccgcatccgaactgactcaggaccctgcc
	gtctctgtggcactgaagcagactgtgactattacttgccgaggcgactcactgc
	ggagccactacgcttcctggtatcagaagaaacccggccaggcacctgtgctg
	ctgttctacggaaagaacaataggccatctggcatccccgaccgcttttctggca
	gtgcatcagggaaccgagccagtctgaccattaccggcgcccaggctgagga
	cgaagccgattactattgcagctcccgggataagagcggctccagactgagcg
	tgttcggaggaggaactaaactgaccgtcctcgataagacccatacccgtacg
	gtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtcc
	ggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaa
	agtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaa
	gcgtgaccgagcaggacagcaaggactccacctacagcctgagcagcaccc
	tgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagt
	gacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga
	gtgt

Binding Protein 9 Amino Acid Sequences

Heavy chain A	Qvqlvqsggqmkkpgesmriscrasgyefidctlnwirlapgkrpewmgwlkpr	SEQ ID
	ggavnyarplqgrvtmtrdvysdtaflelrsltvddtavyfctrgkncdynwdfehw	NO: 65
	grgtpvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalts
	gvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkt
	htcppcpapellggpsvflfppkpkdtlmisrtpevrcvvvdvshedpevkfnwyv
	dgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiekt
	iskakaqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpenny
	kttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain A	Eivltqspgtlslspgetaiiscrtsqygslawyqqrpgqaprlviysgstraagipdrfs	SEQ ID
	gsrwgpdynltisnlesgdfgvyycqqyeffgqgtkvqvdikrtvaapsvfifppsd	NO: 66
	eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt
	lskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqpgkglewvgr	SEQ ID
	itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk	NO: 67
	yydfwwgyppgeeyfqdwgqgtlvivssdkthtqvqlvesgggvvqpgt
	slrlscaasqfrfdgygmhwvrqapgkglewvasishdgikkyhaekvwg
	rftisrdnskntlylqmnslrpedtalyycakdlredeceewwsdyydfgkq
	lpcaksrgglvgiadnwgqgtmvtvssdkthtastkgpsvfplapsskstsg
	gtaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpss
	slgtqtyicnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflf
	ppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpr
	eeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqpr
	epqvytlppcrdeltknqvslwclvkgfypsdiavewesngqpennykttp
	pvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	qsvltqppsvsaapgqkvtiscsgntsnignnfvswyqqrpgrapqlliyetdkrps	SEQ ID
	gipdtgsasksgtsgtlaitglqtgdeadyycatwaaslssarvfgtgtkvivldkthtas	NO: 68
	eltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdr
	fsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaap
	svfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdsk
	dstyslsstlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 9 Nucleotide Sequences

Heavy chain A	caggtgcagctggtgcagtctggcggccagatgaagaaacccggcgagagcatgcg	SEQ ID
	gatcagctgcagagccagcggctacgagttcatcgadgcaccctgaactggatcaga	NO: 69
	ctggcccctggcaagcggcctgagtggatgggatggctgaagcctagaggcggagc
	cgtgaactacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacag
	cgataccaccttcctagaactacgaagcctgaccgtagatgataccgccgtgtacttct
	gcacccggggcaagaactgcgactacaactgggacttcgagcactggggcagaggc
	acccctgtgatcgtgtcaagcgcgtcgaccaagggccccagcgtgttccctctggccc
	ctagcagcaagageacatctggcggaacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgca
	cacctttccagctgtactacagtccagcggcctgtacaacctgagcagcgtcgtgaca
	gtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagccca
	gcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacac
	ctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttcccccc
	aaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggt
	ggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaa
	gtacacaacaccaagaccaagccaagagaggaacagtacaacageacctaccggat
	ggtgtccgtgctgaccgtgctgcaccaggactgactgaacggcaaagagtacaagtg
	caaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaa
	gggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctg
	accaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgc
	cgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctg
	tgaggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccgg
	tggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccact
	acacccagaagtccctgagcctgagccccggc

Light chain A	gagatcgtgctgacacagagccctggcaccctgagcctgtctccaggcgagacagcc	SEQ ID
	atcatcagctgccggacaagccagtacggcagcctggcctggtatcagcagaggcct	NO: 70
	ggacaggcccccagactcgtgatctacagcggcagcacaagagccgccggaatccc
	cgatagattcagcggaccagatggggccctgactacaacctgaccatcagcaacctg
	gaaagcggcgacttcggcgtgtactactgccagcagtacgagttcttcggccagggca
	ccaagatgcaggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttccc
	acctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaac
	ttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcgg
	caacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctga
	gcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgc
	gaagtgacccaccagggcctgtctagccccatgaccaagagatcaaccggggcga
	gtgt

Heavy chain B	gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctaccgc	SEQ ID
	ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag	NO: 71
	cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg
	gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca
	agaataccttgtatttggagatgaacaacatgagaactgaagacaccggatattacttct
	gtaccagaacaggcaaatactacgacttctggtggggctatccccctggcgaggaata
	ttttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccataccca
	ggtgcagttggtggagtctgggggaggcgtggtccagcctgggacgtccctgagact
	ctcctgtgcagcctctcaattcaggtttgatggttatggcatgcactgggtccgccaggc
	cccaggcaaggggctggagtgggtggcatctatatcacatgatggaattaaaaagtatc
	acgcagaaaaagtgtagggccgcttcaccatctccagagacaattccaagaacacact
	gtatctacaaataaacaacctgcgacctgaggacacggctctctactactgtgcgaaag
	atttgcgagaagacgaatgtgaagagtggtggtcggattattacgattttgggaaacaac
	tcccttgcgcaaagtcacgcggcggcttggttggaattgctgataactggggccaagg
	gacaatggtcaccgtacttcagataagacccacaccgcttccaccaagggcccatcg
	gtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggct
	gcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccct
	gaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctca
	gcagcgtggtgaccgtaccctccagcagcttgggcacccagacctacatctgcaacgt
	gaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtga
	caaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagt
	cttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtca
	catgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtatgtt
	gacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca
	gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaa
	ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat
	ctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgcc
	gggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggcttctatccc
	agcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaaga
	ccacgcctcccgtgctgaactccgacggctccttatcctctactcaaaactcaccgtgg
	acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctct
	gcacaaccactacacgcagaagagcctctccctgtctccgggt

Light chain B	cagtctgtgctgacgcagccgccctcagtatctgcgaccccaggacagaaggtcacc	SEQ ID
	atctcctgactggaaacacctccaacattggcaataattttgtgtcctggtatcaacagc	NO: 72
	gccccggcagagccccccaactcctcatttatgaaactgacaagcgaccctcagggat
	tcctgaccgattctctgcttccaagtctggtacgtcaggcaccetggccatcaccgggct
	gcagactggggacgaggccgattattactgcgccacatgggctgccagcctgagttcc
	gcgcgtgtcttcggaactgggaccaaggtcatcgtcctg
	gacaaaacccataccgcatccgaactgactcaggaccctgccgtctctgtggcactga
	agcagactgtgactattacttgccgaggcgactcactgcggagccactacgcttcagg
	tatcagaagaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggc
	catctggcatccccgaccgcttttaggcagtacatcagggaaccgagccagtctgacc
	attaccggcacccaaactgaggacgaagccaattactattgcaactcccgggataaga
	gcggctccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagac
	ccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcag
	ctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggc
	caaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagc
	gtgaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgacact
	gagcaaggccgactacgagaagcacaagatgtacacctgcgaagtgacccaccagg
	gcctatctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 10 Amino Acid Sequences

Heavy chain A	Qvqlvqsggqmkkpgesmriscrasgyefidctlnwirlapgkrpewmgwlkpr	SEQ ID
	ggavnyarplqgrvtmtrdvysdtaflelrsltvddtavyfctrgkncdynwdfehw	NO: 73
	grgtpvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalts
	gvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkt
	htcppepapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyv
	dgvevnnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiekt
	iskakaqprepqvctlppsrdeltknqvslscavkgypsdiavewesngqpenny
	kttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain A	Eivltqspgtlslspgetaiiscrtsqygslawyqqrpgqaprlviysgstraagipdrfs	SEQ ID
	gsrwgpdynltisnlesgdfgvyycqqyeffgqgtkvqvdikrtvaapsvfifppsd	NO: 74
	eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt
	lskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	qvqlvesgggvvqpgtslrlscaasqfrfdgygmhwvrqapgkglewvas	SEQ ID
	ishdgikkyhaekvwgrftisrdnskntlylqmnslrpedtalyycakdlred	NO: 75
	eceewwsdyydfgkqlpcaksrgglvgiadnwgqgtmvtvssdkthtevr
	lvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgritgp
	gegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgkyyd
	fwwgyppgeeyfqdwgqgtlvivssdkthtastkgpsvfplapsskstsgg
	taalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpsss
	lgtqtyicnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfp
	pkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpree
	qynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqpre
	pqvytlppcrdeltknqvslwclvkgfypsdiavewesngqpennykttpp
	vldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	aseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgip	SEQ ID
	drfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtqsvlt	NO: 76
	qppsvsaapgqkvtiscsgntsnignnfvswyqqrpgrapqlliyetdkrpsgipdr
	fsasksgtsgtlaitglqtgdeadyycatwaaslssarvfgtgtkvivldkthtrtvaaps
	vfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskd
	styslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 10 Nucleotide Sequences

Heavy chain A	caggtgcagctggtgcagtctggcggccagatgaagaaacccggcgagagcatgcg	SEQ ID
	gatcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcaga	NO: 77
	ctggcccctggcaagcggcctgagtggatgggatggctgaagcctagaggcggagc
	cgtgaactacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacag
	cgataccgccttcctggaactgcggagcctgaccgtggatgataccgccgtgtacttct
	gcacccggggcaagaactgcgactacaactgggacttcgagcactggggcagaggc
	acccctgtgatcgtgtcaagcgcgtcgaccaagggccccagcgtgttccctctggccc
	ctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgca
	cacctttccagctgtgctgcagtccagcggcctgtacaacctgagcagcgtcgtgaca
	gtacccagcagctctctgagcacccagacctacatctgcaacgtgaaccacaagccc
	agcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccaca
	cctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccccc
	caaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtg
	gtggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtgg
	aagtacacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccg
	ggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaa
	gtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggc
	caagggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgag
	ctgaccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatat
	cgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccc
	cctgtgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtc
	ccggtggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaa
	ccactacacccagaagtccctgagcctgagccccggc

Light chain A	gagatcgtgctgacacagagccctggcaccctgagcctgtctccaggcgagacagcc	SEQ ID
	atcatcagctgccggacaagccagtacggcagcctggcctggtatcagcagaggcct	NO: 78
	ggacaggcccccagactcgtgatctacagcggcagcacaagagccgccggaatccc
	cgatagattcagcggctccagatggggccctgactacaacctgaccatcagcaacctg
	gaaagcggcgacttcggcgtgtactactgccagcagtacgagttcttcggccagggca
	ccaaggtgcaggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttccc
	acctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaac
	ttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcgg
	caacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctg
	agcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctg
	cgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcg
	agtgt

Heavy chain B	caggtgcagttggtggagtctgggggaggcgtggtccagcctgggacgtccctgaga	SEQ ID
	ctctcctgtgcagcctctcaattcaggtttgatggttatggcatgcactgggtccgccag	NO: 79
	gccccaggcaaggggctggagtgggtggcatctatatcacatgatggaattaaaaagt
	atcacgcagaaaaagtgtggggccgcttcaccatctccagagacaattccaagaacac
	actgtatctacaaatgaacagcctgcgacctgaggacacggctctctactactgtgcga
	aagatttgcgagaagacgaatgtgaagagtggtggtcggattattacgattttgggaaa
	caactcccttgcgcaaagtcacgcggcggcttggttggaattgctgataactggggcc
	aagggacaatggtcaccgtctcttcagacaaaacccataccgaggttagactggtgga
	gtcaggaggggggcttgtgaagcccggtgggtctctccgcctgagctgttctgcctcc
	ggctttgatttcgataacgcctggatgacctgggtcaggcagcctccaggtaagggact
	ggagtgggtgggaagaatcacaggtccaggcgagggctggtccgtggactacgcgg
	aatctgttaaagggcggtttacaatctcaagggacaataccaagaataccttgtatttgga
	gatgaacaacgtgagaactgaagacaccggatattacttctgtgccagaacaggcaaa
	tactacgacttctggtccggctatccccctggcgaggaatattttcaagactggggtcag
	ggaacccttgttatcgtgtcctccgataagacccacaccgcttccaccaagggcccatc
	ggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctggg
	ctacctggtcaaggactacttccccgaaccggtgacggtatcatggaactcaggcgcc
	ctgaccagcagcgtgcacaccttcccggctgtcctacagtcctcaggactctactccct
	cagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaa
	cgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgt
	gacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtca
	gtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggt
	cacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtat
	gttgacggcgtggaggtgcataataccaagacaaagccgcgggaggagcagtacaa
	cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc
	aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaacc
	atctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgc
	cgggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggcttctatcc
	cagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaag
	accacgcctcccgtgctgaactccgaeggctcatatcctctactcaaaactcaccatg
	gacaagaacaggtgacaacaagggaacatcttctcataaccatgatgcataaggct
	ctacacaaccactacacgcagaagaacctaccagtaccgggt

Light chain B	gcatccgaactgactcaggaccctgccgtctctgtggcactgaagcagactgt	SEQ ID
	gactattacttgccgaggcgactcactgcggagccactacgcttcctggtatca	NO: 80
	gaagaaacccggccaggcacctgtgctgctgttctacggaaagaacaatagg
	ccatctggcatccccgaccgctatctggcagtgcatcagggaaccgagccagt
	ctgaccattaccggcgcccaggctgaggacgaagccgattactattgcagctc
	ccgggataagagcggctccagactgagcgtgttcggaggaggaactaaactg
	accgtcctcgacaaaacccatacc
	cagtctgtgctgacgcagccgccctcagtgtctgcggccccaggacagaagg
	tcaccatctcctgctctggaaacacctccaacattggcaataattttgtgtcctggt
	atcaacagcgccccggcagagccccccaactcctcatttatgaaactgacaag
	cgaccctcagggattcctgaccgattctctgcttccaagtctggtacgtcaggca
	ccctggccatcaccgggctgcagactggggacgaggccgattattactgcgc
	cacatgggctgccagcctgagttccgcgcgtgtcttcggaactgggaccaagg
	tcatcgtcctg
	gataagacccatacccgtacggtggccgctcccagcgtgacatcttcccacct
	agcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaa
	cttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcag
	agcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactccac
	ctacagcctgagcagcaccctgacactgagcaaggccgactacgagaagca
	caaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgacc
	aagagcttcaaccggggcgagtgt

Binding Protein 11 Amino Acid Sequences

Heavy chain A	Rahlvgsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqy	SEQ ID
	gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda	NO: 81
	wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal
	tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd
	kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpeakfnw
	yvdgvevhnaktkpreegynstvvvsvltvlhqdwlngkeykckvsnkalpapi
	ektiskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslsp
	g

Light chain A	yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv	SEQ ID
	psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsde	NO: 82
	qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltls
	kadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgri	SEQ ID
	tgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk	NO: 83
	yydfwwgyppgeeyfqdwgqgtlvivssdkthtgvhltqsgpevrkpgts
	vkvsckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfka
	kvtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwa
	vdvdylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalg
	clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqt
	yicnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpk
	dtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqyns
	tyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgrqprepqvyt
	lppcerdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsd
	gsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrsplliylassr	SEQ ID
	asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikdkth	NO: 84
	taseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi
	pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtv
	aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteq
	dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 11 Nucleotide Sequences

Heavy chain A	agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg	SEQ ID
	gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag	NO: 85
	gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg
	aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag
	atcgcctacatggacatccggagcctgaagcccgatgacaccgccgtatactactgca
	ccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagggc
	acaaccgtggtggtgtctgccgcctctacaatttgggccccagcgtgttccctctggcccc
	tagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggacta
	ctttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgcac
	acctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgacagt
	gcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagcccag
	caacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacacct
	gtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccccccaa
	agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg
	atgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaagt
	gcacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccgggtg
	gtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgc
	aaggtgtccaacaagaccctgcctgcccccatcgagaaaaccatcagcaaggccaag
	ggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctga
	ccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgcc
	gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt
	gctggacagcgacggctcattcttcaggtgtccaagetgacagtggacaagtcccggt
	ggcagcagagcaacatgttcagctgaccgtgatacacgaggccctacacaaccact
	acacccagaagtccctgagcctgagccccggcaag

Light chain A	tacatccacgtgacccagagccecagcagcctgtccgtgtccatcggcgacag	SEQ ID
	agtgaccatcaactgccagacctctcagggcgtgggcagcgacctgcactggt	NO: 86
	atcagcacaagcctggcagagcccccaagagctgatccaccacacaagcag
	cgtggaagatggcgtgcccagcagattttccggcagcggcttccacaccagct
	tcaacctgaccatcagcgatctgcaggccgacgacattgccacctactattgtca
	ggtgctgcagttcttcggcagaggcagcagactgcacatcaagcgtacggtgg
	ccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggc
	acagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtg
	cagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgt
	gaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgac
	actgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacc
	caccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc	SEQ ID
	ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag	NO: 87
	cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg
	gtccgtagactacgcggaatctgttaaagagcggtttacaatacaagagacaatacca
	agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct
	gtgccagaacaggcaaatactacgacttctggtggggctatccccctggcgaggaata
	ttttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccataccca
	ggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaaggt
	gtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcgcag
	cgtgccaggacagggactgcagtggatgggaggatcagccacgagggcgacaag
	aaagtgatcgtagaacggttcaaggccaaagtgaccatcgactgggacagaagcacc
	aacaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtactact
	gcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacggc
	gccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggccagg
	gcacagccgtgaccgtgtcatctgataagacccacaccgcttccaccaagggcccatc
	ggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctggg
	ctgcctggtcaaggactacttccccgaaccggtgacgatgtcgtggaactcaggcgcc
	ctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccct
	cagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaac
	gtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtg
	acaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcag
	tcttcctcttccccccaaaacccaaggacaccacatgatacccggacccctgaggtca
	catgcatggtggtagacgtgagccacgaagaccctgaggtcaagttcaactggtatgtt
	gacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaaca
	gcacgtaccgtgtggtcagectcctcaccgtcctgcaccaggactggctgaatggcaa
	ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat
	ctccaaagccaaagggcagcccegagaaccacaggtgtacaccctgcccccatgcc
	gggatgaactgaccaagaatcaagtcagcctgtggtgcctgataaaaggcttctatccc
	agcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaaga
	ccacgcctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtag
	acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctct
	gcacaaccactacacgcagaagagcctctccctgtctccgggt

Light chain B	gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgaga	SEQ ID
	gcgccagcatcagctgcaagagcagccactccctgatccacggcgaccggaa	NO: 88
	caactacctggcttggtacgtgcagaagcccggcagatccccccagctgctga
	tctacctggccagcagcagagccagcgcgtgcccgatagattttctggcagc
	ggcagcgacaaggacttcaccctgaagatcagccgggtggaaaccgaggac
	gtgggcacctactactgtatgcagggcagagagagcccctggacctttggcca
	gggcaccaaggtggacatcaaggacaaaacccataccgcatccgaactgact
	caggaccctgccgtctctgtggcactgaagcagactgtgactattacttgccga
	ggcgactcactgcggagccactacgcttcctggtatcagaagaaacccggcca
	ggcacctgtgctgctgttctacggaaagaacaataggccatctggcatccccga
	ccgcttttctggcagtgcatcagggaaccgagccagtctgaccattaccggcgc
	ccaggctgaggacgaagccgattactattgcagctcccgggataagagcggct
	ccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacc
	catacccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgag
	cagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacccc
	cgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaa
	cagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcct
	gagcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgta
	cgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttca
	accggggcgagtgt

Binding Protein 12 Amino Acid Sequences

Heavy chain A	Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqy	SEQ ID
	gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda	NO: 89
	wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal
	tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd
	kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw
	yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi
	ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslsp
	g

Light chain A	yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv	SEQ ID
	psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsde	NO: 90
	qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltls
	kadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgri	SEQ ID
	tgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk	NO: 91
	yydfwwgyppgeeyfqdwgqgtlvivssdkthtqmqlqesgpglvkpse
	tlsltcsvsgasisdsywswirrspgkglewigyvhksgdtnyspslksrvnl
	sldtsknqvslslvaataadsgkyycartlhgrriygivafnewftyfymdvw
	gngtqvtvssdkthtastkgpsvfplapsskstsggtaalgclvkdyfpepvtv
	swnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntk
	vdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcv
	vvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqd
	wlngkeykckvsnkalpapiektiskakgqprepqvytlppcrdeltknqv
	slwclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdks
	rwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	sdisvapgetariscgekslgsravqwyqhragqapsliiynnqdrpsgiperfsgsp	SEQ ID
	dspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtaseltqdp	NO: 92
	avsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdrfsgsas
	gnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthrttvaapsvfifp
	psdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysls
	stltlskadyekhkvyacevthqglsspytksfnrgec

Binding Protein 12 Nucleotide Sequences

Heavy chain A	agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg	SEQ ID
	gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag	NO: 93
	gcccctggcagaggactggaatgggttgggatggatcaagccccagtatggcgccgtg
	aacttcggcggaggcttccgggatagagtaaccctgacccgggacgtgtaccgcgag
	atcgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactgcg
	ccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagggc
	acaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggcccc
	tagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggacta
	ctttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgcac
	acctttccaactatgctgcagtccagcggcctgtacagcctaagcagcgtcgtgacagt
	gcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagcccag
	caacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacacct
	gtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccccccaa
	agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg
	atgtgtcccacgaaaaccctgaagtaaaattcaattagtacgtggacggcgtgaaaat
	gcacaacgccaagaccaagccaagagaagaacaatacaacagcacctaccgggta
	gtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgc
	aaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaag
	ggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctga
	ccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgcc
	gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt
	gctggacagcgacgactcattatcaggtatccaagagacaatggacaagtcccggt
	ggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccact
	acacccagaagtccctgagcctgagccccggcaag

Light chain A	tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacag	SEQ ID
	agtgaccatcaactgccagacctacagggcgtgggcagcgacctgcactggt	NO: 94
	atcagcacaagectggcagagcccccaagctgctgatccaccacacaagcag
	cgtggaagatggcgtgcccagcagattttccggcagcggcttccacaccagct
	tcaacctgaccatcagcgatctgcaggccgacgacattgccacctactattgtca
	ggtgctgcagttcttcggcagaggcagcagactgcacatcaagcgtacggtgg
	ccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggc
	acagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtg
	cagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgt
	gaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgac
	actgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacc
	caccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	gaggttagactggtgaagtcaagagaggggatgtgaagcccaatggatactccac	SEQ ID
	ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag	NO: 95
	cctccaggtaaggggactggagtgggtgggaagaatcacaggtccaggcgagggctg
	gtccgtggactacgcggaatctgttaaagggcggatacaatctcaagggacaatacca
	agaataccctgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct
	gtgccagaacaggcaaatactacgacttctggtggggctatccccctggcgaggaata
	ttttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccataccca
	gatgcagctgcaggagagcggccctggactcgtgaagcccagcgagaccctgagcc
	tgacatgcagcgtgagcggcgccagcatcagcgacagctactggagctggatcagga
	ggagccctggcaagggcctggagtggatcggctacgtgcacaagageggegacacc
	aactacagcccctccctgaagtccagggtgaacctgtccctggacaccagcaagaacc
	aggtgagcctgtccctggtggctgccacagctgctgacagcggcaagtactactgtgc
	caggaccctacacggcaggaggatctacggcatcgtagccttcaacgagtagttcacc
	tacttctacatgaacatgtggggcaacggcacccaggtgaccgtgagctccgataaga
	cccacaccgcttccaccaagggcccatcggtcttccccctggcaccctcctccaagag
	cacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaacc
	ggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggc
	tgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagca
	gcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggt
	ggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca
	gcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggaca
	ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacga
	agaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatgccaaga
	caaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcacc
	gtcctgcaccaggactggctgaatagcaaggagtacaagtgcaagataccaacaaa
	gccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgaga
	accacaggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaagtcag
	cctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtgggagagc
	aatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacgg
	ctccttcttcctctactcaaaactcaccatggacaagagcaggtagcagcaggggaac
	gtcttctcatactccatgatgcatgaggctctgcacaaccactacacacagaagagcct
	ctccctgtctccgggt

Light chain B	tccgacatcagcgtggcccccggagagacagccaggatctcctgcggcgag	SEQ ID
	aagagcctgggaagcagggctgtgcagtggtaccaacacagggccggacag	NO: 96
	gctcccagcctgatcatctacaacaaccaggacaggcccagcggcatccctga
	gaggttcagcggaagccccgacagccccttcggaaccacagccaccctgacc
	atcacaagcgtggaagccggcgacgaggccgactactactgccacatctggg
	acagcagggtgcccaccaagtgggtgtttggcggcggcaccaccctgaccgt
	gctggacaaaacccataccgcatccgaactgactcaggaccctgccgtctctgt
	ggcactgaagcagactgtgactattacttgccgaggcgactcactgcggagcc
	actacgcttcctggtatcagaagaaacccggccaggcacctgtgctgctgttcta
	cggaaagaacaataggccatctggcatccccgaccgatttctggcagtgcatc
	agggaaccgagccagtctgaccattaccggcgcccaggctgaggacgaagc
	cgattactattgcagctcccgggataagagcggctccagactgagcgtgacgg
	aggaggaactaaactgaccgtcctcgataagacccatacccgtacggtggccg
	ctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcaca
	gcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcag
	tggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgacc
	gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactga
	gcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccacc
	agggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 13 Amino Acid Sequences

Heavy chain A	qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwishe	SEQ ID
	gdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydd	NO: 97
	dgalnwavdvdylsnlefwgqgtavtvssastkgpsvfplapsskstsggtaalgcl
	vkdvfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvn
	hkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevt
	cvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltylhqdwl
	ngkeykckvsnkalpapiektiskakgqprepqvctlppsrdeltknqvslscavkg
	fypsdiavewesngqpennykttppvldsdgsfflvskltvdksrwqqgnvfscsv
	mhealhnhytqkslslspg

Light chain A	dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr	SEQ ID
	asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikrtva	NO: 98
	apsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqd
	skdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr	SEQ ID
	itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk	NO: 99
	yydfwwgyppgeeyfqdwgqgtlvivssdkthtqmqlqesgpglvkpse
	tlsltcsvsgasisdsywswirrspgkglewigyvhksgdtnyspslksrvnl
	sldtskngyslslvaataadsgkyycartlhgrriygivafnewftyfymdv
	wgngtqvtvssdkthtastkgpsvfplapsskstsggtaalgclvkdyfpepv
	tvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsn
	tkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdttmisrtpevt
	evvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlh
	qdwlngkeykckvsnkalpapiektiskakgqprepqvytlppcrdeltkn
	qvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltv
	dksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	sdisvapgetariscgekslgsravgwyqhragqapsliiynnqdrpsgiperfsgsp	SEQ ID
	dspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtaseltqd	NO: 100
	pavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdrfsgs
	asgnrasltitgaqacdeadyycssrdksgsrlsvfgggtkltvldkthtrtvaapsvfif
	ppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstys
	lsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 13 Nucleotide Sequences

Heavy chain A	caggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaa	SEQ ID
	ggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgagtgcg	NO: 101
	cagcgtgccaggacagggactacagtggatgaactagatcaaccacgaggacgac
	aagaaagtgatcatggaacggttcaaggccaaagtgaccatcgactaggacagaagc
	accaacaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtact
	actgcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgac
	ggcgccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggc
	cagggcacagccgtgaccgtgtcatctgcttcgaccaagggccccagcgtgttccctc
	tggcccctagcagcaagagcacataggcggaacagccgccagggctgcctcgtga
	aggactactacccgagcccgtgaccgtgtcaggaattaggcgccctgaccagcgg
	cgtgcacacctttccaactatgctgcagtccagcggcctgtacagcctgagcagcgtc
	gtgacagtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccaca
	agcccagcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagac
	ccacacctgtcccccagtcctgcccccgaactgctgggaggcccttccgtgttcctgtt
	ccccccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcg
	tggtggtggatgtatcccacgaggaccagaaatgaagttcaattggtacgtagacgg
	cgtggaagtgcacaacgccaagaccaagccaagagaggaacagtacaacagcacct
	accgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagt
	acaagtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagca
	aggccaagggccagccccgcgaaccccaggtgtgcacactgcccccaagcaggga
	cgagagaccaagaaccaggtgtccctgagagtgccgtgaaaggatctacccacc
	gatatcgccgtagaatgggagagcaacagccagcccgagaacaactacaagaccac
	cccccctgtgctggacagcgacggctcattcttcctggtgtccaagctgacagtggaca
	agtcccggtggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgc
	acaaccactacacccagaagtccctgagcctgagccccggcaag

Light chain A	gacacgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc	SEQ ID
	agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg	NO: 102
	gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca
	gcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttca
	ccctgaagatcagccgggtggaaaccgaggacgtaggcacctactactgtatgcagg
	gcagagagaacccaggacattggccagagcaccaaagtggacatcaaacgtacg
	gtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggca
	cagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtg
	gaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagca
	ggacagcaaggactccacctacagcctgagcagcaccagacactgagcaaggccg
	actacgagaagcacaaggtgtacgcctacgaagtgacccaccaaggcctgtctagcc
	ccgtgaccaagagatcaaccgaggcgagtat

Heavy chain B	gaggttagactggtggagtcaggaggggggcagtgaagcccggtgggtctctccgc	SEQ ID
	ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag	NO: 103
	cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg
	gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca
	agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct
	gtgccagaacaggcaaatactacgacttctggtggggctatccccctggcgaggaata
	ttttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccataccca
	gatgcagctgcaggagagcggccctggactcgtgaagcccagcgagaccctgagcc
	tgacatgcagcgtgagcggcgccagcatcagcgacagctactggagctggatcagg
	aggagccctggcaagggcctggagtggatcggctacgtgcacaagagcggcgaca
	ccaactacagcccctccctgaagtccagagtgaacctatccaggacaccagcaaga
	accaggtgagcctgtccaggtggctgccacagctgctgacagcggcaagtactactg
	tgccaggaccctgcacggcaggaggatctacggcatcgtggccttcaacgagtggttc
	acctacttctacatggacgtgtggggcaacggcacccaggtgaccgtgagctccgata
	agacccacaccgcttccaccaagggcccatcggtcttccccctggcaccctcctccaa
	gagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccga
	accggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttccc
	ggctgtcctacaatcctcaggactctactccctcagcagcgtggtgaccgtgccacca
	gcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacacca
	aggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtg
	cccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaag
	gacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagcc
	acgaagaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatgc
	caagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcc
	tcaccgtcctgcaccaggactggctgaatggcaaggagtacaaatgcaaggtctccaa
	caaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagcccc
	gagaaccacaggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaag
	tcagcctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtggga
	gagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccg
	acggctccttcttcctctactcaaaactcaccgtggacaagagcaggtggcagcaggg
	gaacgtcttctcatgctccgtgatacatgaggctctacacaaccactacacgcagaaga
	gcctctccctgtctccgggt

Light chain B	tccgacatcagcgtggcccccggagagacagccaggatctcctgcggcgag	SEQ ID
	aagagcctgggaagcagggctgtgcagtggtaccaacacagggccggacag	NO: 104
	gctcccagcctgatcatctacaacaaccaggacaggcccagcggcatccctg
	agaggttcagcggaagccccgacagccccttcggaaccacagccaccctga
	ccatcacaagcgtggaagccggegacgaggccgactactactgccacatctg
	ggacagcagggtgcccaccaagtgggtgtttggcggcggcaccaccctgac
	cgtgctggacaaaacccataccgcatccgaactgactcaggaccctgccgtct
	ctgtggcactgaagcagactgtgactattacttgccgaggcgactcactgcgga
	gccactacgcttcctggtatcagaagaaacccggccaggcacctgtgctgctgt
	tctacggaaagaacaataggccatctggcatccccgaccgcttttctggcagtg
	catcagggaaccgagccagtctgaccattaccggcgcccaggctgaggacg
	aagccgattactattgcagctcccgggataagagcggctccagactgagcgtg
	ttcggaggaggaactaaactgaccgtcctcgataagacccatacccgtacggt
	ggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccg
	gcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaa
	gtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaag
	cgtgaccgagcaggacagcaaggactccacctacagcctgagcagcaccct
	gacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagt
	gacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga
	gtgt

Binding Protein 14 Amino Acid Sequences

Heavy chain A	Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqy	SEQ ID
	gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda	NO: 105
	wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal
	tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd
	kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw
	yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi
	ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslsp
	g

Light chain A	yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedg	SEQ ID
	vpsrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsd	NO: 106
	eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt
	lskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmg	SEQ ID
	wishegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgsk	NO: 107
	hrlrdyalydddgalnwavdvdylsnlefwgqgtavtvssdkthtevrlves
	ggglvkpggslrlscsasgfdfdnawmtwvalppgkgtewvgritgpgeg
	wsvdyaesvkgrftisrdnktntlylemnnvrtedtgyyfcartgkyydfw
	wgyppgeeyfqdwgqgtlvivssdkthtastkgpsvfplapsskstsggtaa
	lgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgt
	qtyicnvnhkpsnkvdkkvepkscdkthtcppcpapellggpsvflfppk
	pkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeq
	ynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprep
	qvytlppcrdeltknqvslwclvkgfypsdiavewesngqpennykttppv
	ldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	aseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi	SEQ ID
	pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtdfv	NO: 108
	ltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqliiylassrasg
	vpdrfsgsgsdkdftlkisrvetedvatyycmqgrespwtfgqtkvdikdkthtrt
	vaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvte
	qdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 14 Nucleotide Sequences

Heavy chain A	aaagcccacctaatgcagtctagcaccgccataaaaaaaccagacgcctctatgcgg	SEQ ID
	gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggca	NO: 109
	ggcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccg
	tgaacttcgacggaggcttccggaatagaatgaccctaacccaggacgtgtaccgcg
	agatcgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactg
	cgccagagacagaagctacggcgacagcaactgggctctagatgcttggggccagg
	gcacaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggc
	ccctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaagg
	actactttcccgagcccgtgaccgtgtcctggaattaggcgccctgaccagcggcgtg
	cacacctttccagagtgctgcagtccagcggcctgtacagcctgagcagcgtcgtga
	cagtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagc
	ccagcaacaccaaggtggacaagaaggtggaacccaagagagcgacaagaccca
	cacctgtcccccttgtcctgcccccgaactgctgggaggcccttccatgttcctgttccc
	cccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggt
	ggtggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtg
	gaagtgcacaacgccaagaccaagccaagagaggaacagtacaacagcacctacc
	gggtggtgtccgtgagaccgtgagcaccaggactggctgaacggcaaagagtaca
	agtgcaaggtgtccaacaaggccagcctgcccccatcgagaaaaccatcagcaagg
	ccaagggccagccccgcgaaccccaggtgtgcacactgcccccaaacagggacga
	gctgaccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgat
	atcgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccc
	cccctgtgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaag
	tcccggtggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcac
	aaccactacacccagaagtccctgagcctgagccccggcaag

Light chain A	tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacag	SEQ ID
	agtgaccatcaactgccagacctctcagggcgtgggcagcgacctgcactggt	NO: 110
	atcagcacaagcctggcagagcccccaagctgctgatccaccacacaagcag
	cgtggaagatggcgtgcccagcagattttccggcagcggcttccacaccagct
	tcaacctgaccatcagcgatctgcaggccgacgacattgccacctactattgtc
	aggtgctgcagttcttcggcagaggcagcagactgcacatcaagcgtacggtg
	gccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccgg
	cacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagt
	gcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcg
	tgaccgagcaggacagcaaggactccacctacagcctgagcagcaccctga
	cactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtga
	cccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtg
	t

Heavy chain B	caggtgcacctgacacagagcggacccgaagtgcggaagcctagcacctagtgaa	SEQ ID
	ggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcg	NO: 111
	cagcgtgccaggacagggactgcagtggatgggctggatcagccacgagggcgac
	aagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagc
	accaacaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtact
	actgcgccaagggcagcaagcaccggctgagagactacaccctgtacgacgatgac
	ggcgccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggc
	cagggcacagccgtgaccgtgtcatctgacaaaacccataccgaggttagactggtg
	gagtcaggaggggggcagtgaagcccggtgggtctctccgcctgagctgttctgcct
	ccggctttgatttcgataacgcctggatgacctgggtcaggcagcctccaggtaaggg
	actggagtgggtgggaagaatcacaggtccaggcgagggaggtccgtggactacg
	cggaatctgttaaagggcggtttacaatctcaagggacaataccaagaataccttgtattt
	ggagatgaacaacgtgagaactgaagacaccggatattacttctgtgccagaacaggc
	aaatactacgacttctggtggggctatccccctggcgaggaatattttcaagactggggt
	cagggaacccttgttatcgtgtcctccgataagacccacaccgcttccaccaagggcc
	catcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccct
	gggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcagg
	cgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctact
	ccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctg
	caacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatc
	ttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggacc
	gtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctg
	aggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaact
	ggtatgttgacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcag
	tacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctga
	atggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgaga
	aaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgccc
	ccatgccgggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggct
	tctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaac
	tacaagaccacgcctcccatgaggactccgacggaccttcttcactactcaaaactc
	accgtagacaagagcaggtggcagcaggagaacgtatacatgctccgtgatacat
	gaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggt

Light chain B	gcatccgaactgactcaggaccctgccgtctctgtggcactgaagcagactgt	SEQ ID
	gactattacttgccgaggcgactcactgcggagccactacgcttcctggtatca	NO: 112
	gaagaaacccggccaggcacctgtgctgctgttctacggaaagaacaatagg
	ccatctggcatccccgaccgcttttctggcagtgcatcagggaaccgagccagt
	ctgaccattaccggcgcccaggctgaggacgaagccgattactattgcagctc
	ccgggataagagcggctccagactgagcgtgttcggaggaggaactaaactg
	accgtcctcgacaaaacccataccgacttcgtgctgacccagagccctcacag
	cctgagcgtgacacctggcgagagcgccagcatcagctgcaagagcagcca
	ctccctgatccacggcgaccggaacaactacctggcttggtacgtgcagaagc
	ccggcagatccccccagctgctgatctacctggccagcagcagagccagcgg
	cgtgcccgatagattttctggcagcggcagcgacaaggacttcaccctgaaga
	tcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcag
	agagagcccctsgacctttggccagggcaccaaggtggacatcaaggataag
	acccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagcgac
	gagcagctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttctac
	ccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcgg
	caacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacag
	cctgagcagcaccctgacactgagcaaggccgactacgagaagcacaaggt
	gtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagc
	ttcaaccggggcgagtgt

Binding Protein 15 Amino Acid Sequences

Heavy chain A	qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwishe	SEQ ID
	gdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydd	NO: 113
	dgalnwavdvdylsnlefwgqgtavtvssastkgpsvfplapsskstsggtaalgcl
	vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvn
	hkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevt
	cvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwl
	ngkeykckvsnkalpapiektiskakgqprepqvctlppsrdeltknqvslscavkg
	fypsdiavewesngqpennykttppvldsdgsfflvskltvdksrwqqgnvfscsv
	mhealhnhytqkslslspg

Light chain A	dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr	SEQ ID
	asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikrtva	NO: 114
	apsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqds
	kdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr	SEQ ID
	itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk	NO: 115
	yydfwsgyppgeeyfqdwgqgtlvivssdkthtqmqlqesgpglvkpset
	lsltcsvsgasisdsywswirrspgkglewigyvhksgdtnyspslksrvnls
	ldtsknqvslslvaataadsgkyycartlhgrriygivafnewftyfymdvw
	gngtqvtvssdkthtastkgpsvfplapsskstsggtaalgclvkdyfpepvtv
	swnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntk
	vdkkvepkscdkthtcppcpapellggpsvfifppkpkdtlmisrtpevtcv
	vvdvshedpevkfnwyydgvevhnaktkpreeqynstyrvvsvltvlhqd
	wlngkeykckvsnkalpapiektiskakgqprepqvytlppcrdeltknqv
	slwclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdks
	rwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	sdisvapgetariscgekslgsravqwyqhraaqapsliiynnqdrpsgiperfsgsp	SEQ ID
	dspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtaseltgdp	NO: 116
	avsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdrfsgsas
	gnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaapsvfifp
	psdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysls
	stltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 15 Nucleotide Sequences

Heavy chain A	caggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaa	SEQ ID
	ggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcg	NO: 117
	cagcgtgccaggacagggactgcagtggatgggctggatcagccacgagggcgac
	aagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagc
	accaacaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtact
	actgcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgac
	ggcgccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggcc
	agggcacagccgtgaccgtgtcatctgcttcgaccaagggccccagcgtgttccctct
	ggcccctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtga
	aggactactttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcgg
	cgtacacacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtc
	gtgacagtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccaca
	agcccagcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagac
	ccacacctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgtt
	ccccccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgt
	ggtggtggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggc
	gtggaagtgcacaacgccaagaccaagccaagagaggaacagtacaacagcaccta
	ccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagta
	caagtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaa
	ggccaagggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggac
	gagctgaccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccg
	atatcgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccacc
	ccccctgtgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaa
	gtcccggtggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgca
	caaccactacacccagaagtccctgagcctgagccccggcaag

Light chain A	gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc	SEQ ID
	agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg	NO: 118
	gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca
	gcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttca
	ccctgaagatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagg
	gcagagagagcccctggacctttggccagggcaccaaggtggacatcaagcgtacg
	gtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggca
	cagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtgg
	aaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcagg
	acagcaaggactccacctacagcctgagcagcaccctgacactgagcaaggccgact
	acgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccg
	tgaccaagagcttcaaccggggcgagtgt

Heavy chain B	gaggttagactggtggagtcaggaggggggcttgtgaagcccagtgggtctctccgc	SEQ ID
	ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag	NO: 119
	cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg
	gtccgtggactacgcggaatctgaaaagggcggatacaatctcaagggacaatacca
	agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacact
	gtgccagaacaggcaaatactacgacactagtccggctatccccctggcgaggaatat
	tttcaagactagggtcaaggaacccttgttatcgtgtcctccaacaaaacccatacccag
	atgcagctgcaggagageggccaggactcgtaaaacccagcgagaccctgagcct
	gacatgcagcgtgagcggcgccagcatcagcgacagctactggagctggatcagga
	ggagccctggcaagggcctggagtggatcggctacgtgcacaagagcggcgacacc
	aactacagcccctccctgaagtccagggtgaacctgtccctggacaccagcaagaacc
	aggtgagcctgtccctggtggctgccacagctgctgacagcagcaagtactactgtgc
	caggaccctacacggcaggaggatctacggcatcgtaaccttcaacgagtaattcacc
	tacttctacatggacgtgtggggcaacggcacccaggtgaccgtgagctccgataaga
	cccacaccgcttccaccaagggcccatcggtcaccccctggcaccctcctccaagag
	cacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaacc
	ggtgacggtgtcgtggaactcaagcgccctgaccagcggcatgcacaccttcccggc
	tgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagca
	gcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggt
	ggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgccca
	gcacctgaactcctggggggaccgtcagtcttcctcttcccccccaaaaccaaggaca
	ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacga
	agaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatgccaaga
	caaagccacgggaggagcagtacaacagcacataccatgtagtcagcgtcctcacc
	gtcctgcaccaggactggctgaatagcaaggagtacaagtgcaagataccaacaaa
	gccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgaga
	accacaggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaagtcag
	cctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtgggagagc
	aatgggcagceggagaacaactacaagaccacgcctcccgtgctggactccgacgg
	ctccttcttcctctactcaaaactcaccgtagacaaaagcaggtggcagcaggagaac
	gtcttctcatgctccgtaatacatgaagctctacacaaccactacacgcagaagagcct
	ctccctgtctccaggt

Light chain B	tccgacatcagcgtggcccccggagagacagccaggatctcctgcggcgag	SEQ ID
	aagagcctgggaagcagggctgtgcagtggtaccaacacagggccggacag	NO: 120
	gctcccagcctgatcatctacaacaaccaggacaggcccagcggcatccctga
	gaggttcagcggaagccccgacagccccttcggaaccacagccaccctgacc
	atcacaagcgtggaagccggcgacgaggccgactactactgccacatctggg
	acagcagggtgcccaccaagtgggtgtttggcggcggcaccaccctgaccgt
	gctggacaaaacccataccgcatccgaactgactcaggaccctgccgtctctgt
	ggcactgaagcagactgtgactattacttgccgaggcgactcactgcggagcc
	actacgcttcctggtatcagaagaaacccggccaggcacctgtgctgctgttcta
	cggaaagaacaataggccatctggcatccccgaccgcttactggcagtgcatc
	agggaaccgagccagtctgaccattaccggcgcccaggctgaggacgaagc
	cgattactattgcagctcccgggataagagcggctccagactgagcgtgttcgg
	aggaggaactaaactgaccgtcctcgataagacccatacccgtacggtggccg
	ctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcaca
	gcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcag
	tggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgacc
	gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactga
	gcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccacc
	agggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 16 Amino Acid Sequences

Heavy chain A	Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqy	SEQ ID
	gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda	NO: 121
	wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal
	tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd
	kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw
	yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi
	ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslsp
	g

Light chain A	yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv	SEQ ID
	psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsde	NO: 122
	qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltls
	kadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr	SEQ ID
	itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk	NO: 123
	yydfwsgyppgeeyfqdwgqgtlvivssdkthtqmqlqesgpglvkpset
	lsltcsvsgasisdsywswirrspgkglewigyvhksgdtnyspslksrvnls
	ldtsknqvslslvaataadsgkyycartlhgrriygivafnewftyfymdvw
	gngtqvtvssdkthtastkgpsvfplapsskstsggtaalgclvkdyfpepvtv
	swnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntk
	vdkkvepkscdkthtcppcpapellggpsvfifppkpkdtlmisrtpevtcv
	vvdvshedpevkfnwyydgvevhnaktkpreeqynstyrvvsvltvlhqd
	wlngkeykckvsnkalpapiektiskakgqprepqvytlppcrdeltknqv
	slwclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdks
	rwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	sdisvapgetariscgekslgsravqwyqhragqapsliiynnqdrpsgiperfsgsp	SEQ ID
	dspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtaseltqdp	NO: 124
	avsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdrfsgsas
	gnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaapsvfifp
	psdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysls
	stltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 16 Nucleotide Sequences

Heavy chain A	agaacccacctggtacagtctggcaccgccatgaagaaaccaggcgcctctgtacgg	SEQ ID
	gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag	NO: 125
	gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg
	aacttcggcggaggcttccggaatagaatgaccctaacccgagacgtgtaccgcgag
	atcgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactgcg
	ccagagacagaagctacggcgacagcagctgaactctagatacttgggaccagggc
	acaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggcccc
	tagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggacta
	ctttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgcac
	acctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgacagt
	gcccagcagctctctgggcacccagacctacatagcaacgtgaaccacaagcccag
	caacaccaaggtggacaagaaggtggaacccaagagagcgacaagacccacacct
	gtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgaccccccaa
	agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg
	atgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaagt
	gcacaacaccaagaccaagccaagagaggaacagtacaacagcacctaccgggtg
	gtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgc
	aaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaag
	ggccagccccgcgaaccccaggtgtgcacactacccccaagcagggacgagctga
	ccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgcc
	gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt
	gctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccggt
	ggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccact
	acacccagaagtccctgagcctgagccccgacaag

Light chain A	tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacag	SEQ ID
	agtgaccatcaactgccagacctacagggcgtgggcagcgacctgcactggt	NO: 126
	atcagcacaagcctggcagagcccccaagctgctgatccaccacacaagcag
	cgtggaagatggcgtgcccagcagattttccggcagcggcttccacaccagct
	tcaacctgaccatcagcgatctgcaggccgacgacattgccacctactattgtca
	ggtgctgcagttcttcggcagaggcagcagactgcacatcaagcgtacggtgg
	ccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggc
	acagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtg
	cagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgt
	gaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgac
	actgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacc
	caccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctaccgc	SEQ ID
	ctaagctgactgcctccggattgatttcaataacgcctgaataacctgaatcaggcag	NO: 127
	cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg
	gtccgtggactacgcggaatctgttaaagggcggtttacaatctcoogggacaatacca
	agaataccttgtataggagatgaacaacgtgagaactgaagacaccggatattacact
	gtgccagaacaggcaaatactacgacactggtccggctatccccctggcgaggaatat
	tttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccatacccag
	atgcagctgcaggagagcggccaggactcgtgaaacccagcgagaccctgagcct
	gacatgcagcgtgagcggcgccagcatcagcgacagctactggagctggatcagga
	ggagccctggcaagggcctggagtggatcggctacgtgcacaagagcggcgacacc
	aactacagcccctccctgaagtccagggtgaacctgtccaggacaccagcaagaacc
	aggtgagcctgtccctggtggctgccacagctgctgacagcggcaagtactactgtgc
	caggaccctacacggcaggaggatctacggcatcgtaaccttcaacgagtaattcacc
	tacttctacatgaacatgtggggcaacggcacccaggtgaccgtgagctccgataaga
	cccacaccgcttccaccaagggcccatcggtcttccccctggcaccctcctccaagag
	cacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaacc
	ggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggc
	tgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagca
	gcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggt
	ggacaagaaaattaagcccaaatcagtgacaaaactcacacatgcccaccgtaccca
	gcacctgaactcctggaaggaccatcagtcttcctcttccccccaaaacccaaggaca
	ccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacga
	agaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatgccaaga
	caaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcacc
	gtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaa
	gccctcccagcccccatcgagaaaaccatctccaaaaccaaagggcagccccgaga
	accacaggtatacaccctgcccccataccaggatgaactaaccaagaatcaaatcag
	cctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtgggagagc
	aatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacgg
	ctccttcttcctctactcaaaactcaccgtggacaagagcaggtggcagcaggggaac
	gtcttctcatgctccdgatgcatgaggctctgcacaaccactacacgcagaagagcct
	ctccctgtctccgggt

Light chain B	tccgacatcagcgtggcccccggagagacagccaggatctcctgcggcgag	SEQ ID
	aagagcctgggaagcagggctgtgcagtggtaccaacacagggccggacag	NO: 128
	gctcccagcctgatcatctacaacaaccaggacaggcccagcggcatccctga
	gaggttcagcggaagccccgacagcccatcggaaccacagccaccctgacc
	atcacaagcgtggaagccggcgacgaggccgactactactgccacatctggg
	acagcagggtgcccaccaagtgggtgtttggcggcggcaccaccctgaccgt
	gctggacaaaacccataccgcatccgaactgactcaggaccctgccgtctctgt
	ggcactgaagcagactgtgactattacttgccgaggcgactcactgcggagcc
	actacgcttcctggtatcagaagaaacccggccaggcacctgtgctgctgttcta
	cggaaagaacaataggccatctggcatccccgaccgatttaggcagtgcatc
	agggaaccgagccagtctgaccattaccggcgcccaggctgaggacgaagc
	cgattactattgcagctcccgggataagagcggctccagactgagcgtgttcgg
	aggaggaactaaactgaccgtcctcgataagacccatacccgtacggtggccg
	ctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcaca
	gcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcag
	tggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgacc
	gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactga
	gcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccacc
	agggcctgtctagccccgtgacaagagcttcaaccggggcgagtgt

Binding Protein 17 Amino Acid Sequences

Heavy chain A	Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqy	SEQ ID
	gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda	NO: 129
	wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal
	tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd
	kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw
	yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi
	ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslsp
	g

Light chain A	yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv	SEQ ID
	psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsde	NO: 130
	qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltls
	kadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmg	SEQ ID
	wishegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgsk	NO: 131
	hrlrdyalydddgalnwavdvdylsnlefwgqgtavtvssdkthtqmqlqe
	sgpglvkpsetlsltcsvsgasisdsywswirrspgkglewigyvhksgdtn
	yspslksrvnlsldtsknqvslslvaataadsgkyycartlhgrriygivafne
	wftyfymdvwgngtqvtvssdkthtastkgpsvfplapsskstsggtaalgc
	lvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqty
	icnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkd
	tlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynst
	yrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytl
	ppcrdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdg
	sfflyskltvdksrwgqgnvfscsvmhealhnhytqkslslspg

Light chain B	sdisvapgetariscgekslgsravqwyqhragapsliiynnqdrpsgiperfsgsp	SEQ ID
	dspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtdfvltqsp	NO: 132
	hslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassrasgvpdrf
	sgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikdkthtrtvaaps
	vfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskd
	styslsstltskadyekhkvyacevthqglsspvtksfhrgec

Binding Protein 17 Nucleotide Sequences

Heavy chain A	agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg	SEQ ID
	gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag	NO: 133
	gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg
	aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag
	atcgcctacatggacatccggggcagaagcccgatgacaccgccgtgtactactgcg
	ccagagacagaagaacggcgacagcagagagactagatgatgggaccagggc
	acaaccgtggtggtgtagccgcactacaaagggccccagcgtgttccctaggcccc
	tagcagcaagagcacataggcggaacagccgccagggagcacgtgaaggacta
	ctttcccgagcccgtgaccgtgtcaggaattaggcgccctgaccagcggcgtgcac
	accctttccagagtgagcagtccagcggcagtacagcagagcagcgtcgtgacagt
	gcccagcagactagggcacccagacctacatagcaacgtgaaccacaagcccag
	caacaccaaggtggacaagaaggtggaacccaagagagcgacaagacccacaca
	gtcccccttgtcagcccccgaactgagggaggcccttccgtgttcagttccccccaa
	agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg
	atgtgtcccacgaggaccagaagtgaagttcaattggtacgtggacggcgtggaagt
	gcacaacgccaagaccaagccaagagaggaacagtacaacagcacaaccgggtg
	gtatccgtgagaccgtgagcaccaggaaggagaacgacaaagagtacaagtgc
	aaggtgtccaacaaggccagcctacccccatcgagaaaaccatcagcaaggccaag
	ggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagaga
	ccaagaaccaggtgtccagagagtgccgtgaaaggatctacccctccgatatcgcc
	gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt
	gctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccggt
	ggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccact
	acacccagaagtccctgagcctgagccccggcaag

Light chain A	tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacag	SEQ ID
	agtgaccatcaactgccagacctacagggcgtgggeagcgacctgcactggt	NO: 134
	atcagcacaagcctggcagagcccccaagctgctgatccaccacacaagcag
	cgtggaagatggcgtgcccagcagattttccggcagcggcttccacaccagct
	tcaacctgaccatcagcgatctgcaggccgacgacattgccacctactattgtca
	ggtgctgcagttcttcggcagaggcagcagactgcacatcaagcgtacggtgg
	ccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggc
	acagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtg
	cagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgt
	gaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgac
	actgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacc
	caccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	caggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaa	SEQ ID
	ggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcg	NO: 135
	cagcgtgccaggacagggactgcagtggatgggctggatcagccacgagggcgac
	aagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgagacagaagc
	accaacaccgcctacctacagctaagcggcctgacctaggcgataccgccgtgtact
	actgcaccaaaagcagcaagcaccgactaagaaactacgccctgtacgacgatgac
	ggcgccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggcc
	agggcacagccgtgaccgtgtcatctgacaaaacccatacccagatgcagctgcagg
	agagcggccctggactcgtgaagcccagcgagaccctgagcctgacatgcagcgtg
	agcggcgccagcatcagcgacagetactggagctggatcaggaggagccctggcaa
	gggcctgaagtagatcggctacgtgcacaagagcaacgacaccaactacagcccct
	ccctgaagtccagggtgaacctgtccaggacaccagcaagaaccaggtgagcctgt
	ccctggtggctgccacagctgctgacagcggcaagtactactgtgccaggaccctgca
	cggcaggaggatctacggcatcgtggccttcaacgagtggttcacctacttctacatgg
	acgtgtggggcaacgcacccaggtgaccgtgagctccgataagacccacaccgctt
	ccaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctggggg
	cacagcagccctaggctgcctgatcaagaactacttccccaaaccaatgacggtgtc
	gtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcc
	tcagaactctactccctcagcagcatggtgaccgtgccaccagcagataggcaccc
	agacctacatagcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaag
	ttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactc
	ctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctc
	ccggaacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggt
	caagttcaactagtatgttgacggcgtaaaggtgcataataccaaaacaaagccgcgg
	gaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccag
	gactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcc
	cccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgta
	caccctgcccccatgccgggatgagctgaccaagaatcaagtcagcctgtggtgcctg
	gtaaaagacttctatcccaacgacatcaccatggagtaagagagcaatgggcagccg
	gagaacaactacaagaccacgcctcccatgaggactccaacggaccacttcctcta
	ctcaaaactcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctcc
	gtgatgcatgaggactgcacaaccactacacgcagaagagcctctccctgtctccgg
	gt

Light chain B	tccgacatcagcgtggcccccggagagacagccaggatctcctgcggcgag	SEQ ID
	aagagcctgggaagcagggctgtgcagtggtaccaacacagggccggacag	NO: 136
	gctcccagcctgatcatctacaacaaccaggacaggcccagcggcatccctga
	gaggttcagcggaagccccgacagcccatcggaaccacagccaccctgacc
	atcacaagcgtggaagccggcgacgaggccgactactactgccacatctggg
	acagcagggtgcccaccaagtgggtgtttggcggcggcaccaccctgaccgt
	gctggacaaaacccataccgacttcgtgctgacccagagccctcacagcctga
	gcgtgacacctggcgagagcgccagcatcagctgcaagagcagccactccct
	gatccacggcgaccggaacaactacctggcttggtacgtgcagaagcccggc
	agatccccccagctgagatctacctggccagcagcagagccagcggcgtgc
	ccgatagattttctggcagcggcagcgacaaggacttcaccctgaagatcagc
	cgggtggaaaccgaggacgtgggcacctactactgtatgcagggcagagag
	agcccctggacctttggccagggcaccaaggtggacatcaaggataagaccc
	atacccgtacggtggccgctcccagcgtgttcatatcccacctagcgacgagc
	agctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttctaccccc
	gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaac
	agccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctg
	agcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtac
	gcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaa
	ccggggcgagtgt

Binding Protein 18 Amino Acid Sequences

Heavy chain A	Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqy	SEQ ID
	gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda	NO: 137
	wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal
	tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd
	kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw
	yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi
	ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslsp
	g

Light chain A	yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv	SEQ ID
	psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsde	NO: 138
	qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl
	skadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	qmqlqesgpglvkpsetlsltcsvsgasisdsywswirrspgkglewigyvh	SEQ ID
	ksgdtnyspslksrvnlsldtsknqvslslvaataadsgkyycartlhgrriygi	NO: 139
	vafnewftyfymdvwgngtqvtvssdkthtevrlvesggglvkpggslrls
	csasgfdfdnawmtwvrqppgkglewvgritgpgegwsvdyaesvkgrf
	tisrdntkntlylemnnyrtedtgyyfcartgkyydfwsgyppgeeyfqdw
	gqgtlvivssdkthtastkgpsvfplapsskstsggtaalgclvkdyfpepvtv
	swnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntk
	vdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcv
	vvdvshedpevkfnwyvdgvevhnaktkpreegynstyrvvsvltvlhqd
	wlngkeykckvsnkalpapiektiskakgqprepqvytlppcrdeltknqv
	slwclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdks
	rwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	aseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgip	SEQ ID
	drfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtsdis	NO: 140
	vapgetariscgekslgsravqwyqhragqapsliiynnqdrpsgiperfsgspdsp
	fgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtrtvaapsvfif
	ppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstys
	lsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 18 Nucleotide Sequences

Heavy chain A	agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg	SEQ ID
	gtgtcctatcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag	NO: 141
	gcccaggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg
	aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag
	atcgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactgcg
	ccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagggc
	acaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggcccc
	tagcagcaagagcacatctggcggaacagccaccctaggctgcctcgtgaaggacta
	ctttcccgagcccgtgaccgtgtcctagaattctgacgccctgaccagcggcgtgcac
	acctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgacagt
	gcccagcagctctctgggcacccaaacctacatagcaacgtgaaccacaagcccag
	caacaccaaggtggacaagaaggtggaacccaagagagcgacaagacccacacct
	gtcccccttgtcctgcccccaaactactaagagacccttccgtgttcctattccccccaa
	agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg
	atgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaagt
	gcacaacgccaagaccaagccaagagaggaacagtacaacagcacctaccgggtg
	gtgtccgtgctgaccatgctgcaccaggactggctgaacggcaaagagtacaagtgc
	aaggtgtccaacaaggccctgcctacccccatcgagaaaaccatcagcaaggccaag
	ggccagccccgcgaaccccaagtgtgcacactgcccccaagcagggacaagctga
	ccaagaaccaggtatccctgaactatgccgtaaaaggcactacccctccgatatcgcc
	gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt
	gctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccggt
	ggcagcagggcaacgtgacagctgctccgtgatgcacgaggccctgcacaaccact
	acacccagaagtccagagcctgagccccgacaag

Light chain A	tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacag	SEQ ID
	agtgaccatcaactgccagacctctcagggcgtgggcagcgacctgcactggt	NO: 142
	atcagcacaagcctggcagagcccccaagctgctgatccaccacacaagcag
	cgtggaagatggcgtgcccagcagattttccggcagcggcttccacaccagct
	tcaacctgaccatcagcgatctgcaggccgacgacattgccacctactattgtca
	ggtgctgcagttcttcggcagaggcagcagactgcacatcaagcgtacggtgg
	ccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggc
	acagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtg
	cagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgt
	gaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgac
	actgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacc
	caccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	cagatgcagctgcaggagagcgaccctggactcgtgaagcccagcgagaccctgag	SEQ ID
	cctgacatgcagcgtgagcagcgccagcatcagcgacagctactagagctggatcag	NO: 143
	gaggagccctggcaagggcaggaatggatcggctacgtgcacaaaagcggcgac
	accaactacagcccctccctgaagtccaggatgaacctatccctggacaccagcaaga
	accaggtaagcctgtccctggtggctgccacagctgctgacagcgacaagtactactg
	tgccaggaccctgcacgacaggaggatctacggcatcgtggccttcaacgagtggttc
	acctacactacatggacgtgtgaggcaacggcacccaggtgaccgtgagctccgaca
	aaacccataccgaggttagactggtggagtcaggaggggggcttgtgaagcccggtg
	ggtctctccgcctgagctgttctgcctccggctttgatttcgataacgcctggatgacctg
	ggtcaggcagcctccaggtaagaaactggagtgaatggaaaaaatcacaagtccag
	gcgagggctggtccgtggactacgcggaatctgttaaagggcggtttacaatctcaag
	ggacaataccaagaataccttgtatttggagatgaacaacgtgagaactgaagacacc
	ggatattacttagtgccagaacaggcaaatactacgacttctggtccagctatccccct
	ggcgaggaatattttcaagactggggtcagagaacccttgttatcgtgtcctccaataag
	acccacaccgcttccaccaagggcccatcggtcttccccaggcaccctcctccaaga
	gcacctagggggcacageggccagggctgcaggtcaaggactacttccccgaac
	cggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccgg
	ctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagc
	agcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaag
	gtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcc
	cagcacctgaactcctggaaggaccgtcagtatcctatccccccaaaacccaagga
	caccctcatgatctcccgaacccctgaggtcacatgcatggtggtgaacatgaaccac
	gaagaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatgccaa
	gacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctca
	ccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaaca
	aagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccga
	gaaccacaggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaagtc
	aacctgtagtgcctggtaaaaggatctatcccagcgacatcgccgtggagtgggaga
	acaataggcagccggagaacaactacaagaccacgcacccgtactagactccgac
	ggctcatatcactactcaaaactcaccgtgaacaagagcaggtggcagcagggga
	acgtatctcatgaccgtgatgcatgaggctctgcacaaccactacacgcagaagagc
	ctaccctgtctccgggt

Light chain B	gcatccgaactgactcaggaccctgccgtctctgtggcactgaagcagactgtg	SEQ ID
	actattacttgccgaggcgactcactgcggagccactacgcacctggtatcaga	NO: 144
	agaaacccggccaggcacctgtgctgctgttaacggaaagaacaataggcca
	tctggcatccccgaccgcttttctggcagtgcatcagggaaccgagccagtctg
	accattaccggcgcccaggctgaggacgaagccgattactattgcagctcccg
	ggataagagcggctccagactgagcgtgttcggaggaggaactaaactgacc
	gtcctcgacaaaacccatacctccgacatcagcgtggcccccggagagacag
	ccaggatacctgcggcgagaagagcagggaagcagggctgtgcagtggta
	ccaacacagggccggacaggctcccagcctgatcatctacaacaaccaggac
	aggcccagcggcatccctgagaggttcagcggaagccccgacagccccttcg
	gaaccacagccaccctgaccatcacaagcgtggaagccggcgacgaggccg
	actactactgccacatctgggacagcagggtgcccaccaagtgggtgtttggc
	ggcggcaccaccctgaccgtgctggataagacccatacccgtacggtggccg
	ctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcaca
	gcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcag
	tggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgacc
	gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactga
	gcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccacc
	agggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 19 Amino Acid Sequences

Heavy chain A	evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgritgpg	SEQ ID
	egwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgkyydfwsgy	NO: 145
	ppgeeyfqdwgqgtlvivssastkgpsvfplapsskstsggtaalgclvkdyfpepv
	tvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvd
	kkvepkscdkthtcppcpapellggpsvflfppkdtlmisrtpevtcvvvdvshe
	dpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckv
	snkalpapiektiskakgqprepqvctlppsrdeltknqvslscavkgfypsdiave
	wesngqpennykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnh
	ytqkslslspg

Light chain A	aseltqdpavsvalkqtvtitcrgdslrshyaswygkkpgqapvllfygknnrpsgip	SEQ ID
	drfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvlsqpkaaps	NO: 146
	vtlfppsseelqankatlvclisdfypgavtvawkadsspvkagvetttpskqsnnky
	aassylsltpeqwkshrsyscqvthegstvektvaptecs

Heavy chain B	qmqlqesgpglvkpsetlsltcsvsgasisdsywswirrspgkglewigyvh	SEQ ID
	ksgdtnyspslksrvnlsldtsknqvslslvaataadsgkyycartlhgrriygi	NO: 147
	vafnewftyfymdvwgngtqvtvssdkthtQvhltqsgpevrkpgtsvkv
	sckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkakvti
	dwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwavdv
	dylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgclvk
	dyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicn
	vnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlm
	isrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrv
	vsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqytlpp
	crdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsf
	flyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr	SEQ ID
	asgvpdrfsgsgsdkdftlkisrvetedvgtyycmggrespwtfgqgtkvdikdkth	NO: 148
	tsdisvapgetariscgekslgsravqwyqhragqapsliiynnqdrpsgiperfsgs
	pdspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtrtvaaps
	vfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskd
	styslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 19 Nucleotide Sequences

Heavy chain A	gaggttagactggtggagtcaggaggggggcagtgaagcccggtgggtctctccgc	SEQ ID
	ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag	NO: 149
	cctccagataagggactagagtgggtgggaagaatcacagatccagacgagggctg
	gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca
	agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct
	gtgccagaacaggcaaatactacgacttaggtccggctatccccaggcgaggaatat
	tttcaagactggggtcagggaacccttgttatcgtgtcctccgcgtcgaccaagggccc
	cagcgtgttccactggcccctagcagcaagageacataggcggaacagccgccct
	gggctgcctcgtgaaggactactttcccgagcccgtgaccgtgtcctagaattaggcg
	ccctgaccagcggcgtgcacacctttccagctgtgctgcagtccagcggcctgtacag
	cctgagcagcgtcgtgacagtgcccagcagctctctgggcacccagacctacatctgc
	aacgtgaaccacaageccageaacaccaaggtggacaagaaggtggaacccaaga
	gctgcgacaagacccacacctgtcccccttgtcctgcccccgaactgagggaggccc
	ttccgtgttcctgttccccccaaagcccaaggacaccctgatgatcaaccggaccccca
	aagtgacctgcgtggtggtagatgtgtcccacgaggaccctgaagtgaagttcaattgg
	tacgtggacggcgtggaagtgcacaacgccaagaccaagccaagagaggaacagta
	caacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaac
	ggcaaagagtacaagtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaa
	accatcagcaaggccaagggccagccccgcgaaccccaggtgtgcacactgccccc
	aagcagggacgagagaccaagaaccaggtgtccctgagagtgccgtgaaaggctt
	ctacccctccgatatcgccgtagaatgggagagcaacagccagcccgagaacaacta
	caagaccaccccccctatgaggacagcgacgactcattatcaggtatccaagaga
	cagtggacaagtcccggtggcagcagggcaacgtgttcagctgctccgtgatgcacg
	aggcccggcacaaccactacacccagaagtccctgagcctgagccccggcaag

Light chain A	gcatccgaactgactcaggaccctgccgtctctgtggcactgaagcagactgtg	SEQ ID
	actattacttgccgaggcgactcactgcggagccactacgcttcctggtatcaga	NO: 150
	agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggcca
	tctggcatccccgaccgcttttctggcagtgcatcagggaaccgagccagtctg
	accattaccggcgcccaggctgaggacgaagccgattactattgcagctcccg
	ggataagagcggctccagactgagcgtgttcggaggaggaactaaactgacc
	gtcctcagtcagcccaaggctgccccctcggtcactctgttcccgccctcgagt
	gaggagatcaagccaacaaggccacactggtgtgtctcataagtgacttctac
	ccgggagccgtgacagtggcaggaaggcagatagcagccccgtcaaggcg
	ggagtggagaccaccacaccctccaaacaaagcaacaacaagtacgcggcc
	agcagctacctgagcctgacgcctgagcagtggaagtcccacagaagctaca
	gctgccaggtcacgcatgaagggagcaccgtggagaagacagtggccccta
	cagaatgttca

Heavy chain B	cagatgcagctgcaggaganggccctggactcgtgaagcccagcgagaccctgag	SEQ ID
	cctgacatgcagcgtgagcggcgccagcatcagcgacagctactggagctggatcag	NO: 151
	gaggagccctggcaagggcctggagtggatcggctacgtgcacaagagcggcgac
	accaactacagcccctccctgaagtccagggtgaacctgtccctggacaccagcaaga
	accaggtgagcctgtccctggtggctgccacagctgctgacagcggcaagtactactg
	tgccaggaccctgcacggcaggaggatctacggcatcgtggccttcaacgagtggttc
	acctacttctacatggacatgtagggcaacggcacccaggtaaccgtgagctccgaca
	aaacccatacccaaatgcacctaacacagaacggacccgaagtgcggaagcctggc
	acctagtgaaggigtcctgcaaggcccctggcaacaccctgaaaacctacgacctgc
	actgggtgcgcagcgtgccaggacagggactgcagtggatgggctggatcagccac
	gagggcgacaagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgg
	gacagaagcaccaacaccgcctacctgcagctgagcggcctgacctctggcgatacc
	gccgtgtactactgcgccaagggcagcaagcaccggctgagagactacgccctgtac
	gacgatgacggcgccagaactgggccgtagatgtgaactacctgagcaacctggaa
	ttctgaggccaggacacaaccatgaccatgtcatctgataaaacccacaccgcttcca
	ccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcac
	agcggccctgggctgcaggtcaaggactacttccccgaaccggtgacggtgtcgtgg
	aactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcaacagtcctcag
	gactctactccctcagcgtggtgaccgtgccctccagcagcttgggcacccagac
	ctacatagcaacgtaaatcacaagcccagcaacaccaaagtgaacaagaaagttga
	gcccaaatatatgacaaaactcacacatgcccaccgtacccaacacctgaactcagg
	ggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccgg
	acccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaag
	ttcaactggtatgttgacggcgtggaggtgcataatgccaagacaaagccgcgggagg
	agcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactg
	gctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccat
	cgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccc
	tgcccccatgccgggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaa
	aggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggaga
	acaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctactcaa
	aactcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgat
	gcatgaggctctgcacaaccactacacgcagaagagcctaccctgtctccgggt

Light chain B	gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgaga	SEQ ID
	gcgccagcatcagctgcaagagcagccactccctgatccacggcgaccggaa	NO: 152
	caactacctggcttggtacgtgcagaagcccggcagatccccccagctgctga
	tctacctggccagcagcagagccagcggcgtgcccgatagattttctggcagc
	ggcagcgacaaggacttcaccctgaagatcagccgggtggaaaccgaggac
	gtgggcacctactactgtatgcagggcagagagagccectggacctttggcca
	gggcaccaaggtggacatcaaggacaaaacccatacctccgacatcagcgtg
	gcccccggagagacagccaggatctcctgcggcgagaagagcctgggaag
	cagggctgtgcagtggtaccaacacagggccggacaggctcccagcctgatc
	atctacaacaaccaggacaggcccagcggcatccagagaggttcagcggaa
	gccccgacagccccttcggaaccacagccaccctgaccatcacaagcgtgga
	agccggcgacgaggccgactactactgccacatctgggacagcagggtgcc
	caccaagtgggtgtttggcggcggcaccaccctgaccgtgctggataagaccc
	atacccgtacggtggccgctcccagcgtgttcatatcccacctagcgacgagc
	agctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctaccccc
	gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaac
	agccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctg
	agcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtac
	gcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaa
	ccggggcgagtgt

Binding Protein 20 Amino Acid Sequences

Heavy chain A	Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqy	SEQ ID
	gavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswalda	NO: 153
	wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal
	tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd
	kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw
	yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi
	ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslsp
	g

Light chain A	yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv	SEQ ID
	psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikrtvaapsvfifppsde	NO: 154
	qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltls
	kadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	qmqlqesgpglvkpsetlsltcsvsgasisdsywswirrspgkglewigyvh	SEQ ID
	ksgdtnyspslksrvnlsldtsknqvslslvaataadsgkyycartlhgrriygi	NO: 155
	vafnewftyfymdvwgngtqvtvssdkthtQvhltqsgpevrkpgtsvkv
	sckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkakvti
	dwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwavdv
	dylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgclvk
	dyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicn
	vnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlm
	isrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrv
	vsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlpp
	crdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsf
	flyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr	SEQ ID
	asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikdkth	NO: 156
	tsdisvapgetariscgekslgsravqwyqhragqapsliiynnqdrpsgiperfsgs
	pdspfgttatltitsveagdeadyychiwdsrvptkwvfgggttltvldkthtrtvaaps
	vfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskd
	styslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 20 Nucleotide Sequences

Heavy chain A	agagcccacctggtgcagtaggcaccgccatgaagaaaccaggcgcctagtgcgg	SEQ ID
	gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgactggttccggca	NO: 157
	ggcccctggcagaggactggaatgagtgggatagatcaagccccagtatggcacca
	tgaacttcagcgaaggcaccaggatagagtgaccctgacccgggacgtgtaccacg
	agatcgcctacatggacatccggggectgaagcccgatgacaccgccgtatactacta
	cgccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagg
	gcacaaccgtagtggtgtctgccgcctctacaaagggccccagcgtgttccactgac
	ccctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaagg
	actactttcccgagcccgtgaccgtgtcctggaattctagcgccctgaccagcggcgtg
	cacacctttccagctgtgctgcagtccagcgacctgtacagcctgagcagcatcatga
	cagtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagcc
	cagcaacaccaaggtagacaagaaggtggaacccaagagctgcgacaagacccac
	acctgtcccccttgtcctgcccccgaactgagggaggcccaccgtattcctgttcccc
	ccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtg
	gtggatgtgtcccacgaagaccctgaagtgaagacaattggtacgtggacggcgtgg
	aagtgcacaacgccaagaccaagccaagagaggaacagtacaacaacacctaccgg
	gtgatgtccatgctgaccatgctgcaccaagactggctgaacggcaaagagtacaagt
	gcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggcca
	agggccagccccgcgaaccccaggtatgcacactgcccccaagcagggacgagct
	gaccaagaaccaggtgtccctgagctgtgccgtaaaaggcttctacccctccgatatcg
	ccgtggaatgggagagcaacggccaacccgagaacaactacaagaccaccccccct
	gtgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccg
	gtggcagcagggcaacgtgacagctgctccgtgatgcacgaggccctgcacaacca
	ctacacccagaagtccctgagcctgagccccggcaag

Light chain A	tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacag	SEQ ID
	agtgaccatcaactgccagacctctcagggcgtgggcagcgacctgcactggt	NO: 158
	atcagcacaagcctggcagagcccccaagctgctgatccaccacacaagcag
	cgtggaagatggcgtgcccagcagattttccggcagcggcttccacaccagct
	tcaacctgaccatcagcgatctgcaggccgacgacattgccacctactattgtca
	ggtgctgcagttcttcggcagaggcagcagactgcacatcaagcgtacggtgg
	ccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggc
	acagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtg
	cagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgt
	gaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgac
	actgagcaaggccgactacgagaageacaaggtgtacgcctgcgaagtgacc
	caccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	cagatgcagctgcaggagagcggccctggactcgtgaagcccagcgagaccctgag	SEQ ID
	cctgacatgcagcgtgagcggcgccagcatcagcgacagctactggagctggatcag	NO: 159
	gaggagccctggcaagggcctggagtggatcggctacgtgcacaagagcggcgac
	accaactacagcccctccctgaagtccagggtgaacctgtccctagacaccaacaaga
	accaagtgagcctatccctggtaactaccacagctgctgacaacggcaagtactactg
	tgccagaaccctgcacgacaaaaggatctacggcatcgtggccttcaacaagtagttc
	acctacttctacatggacgtgtggggcaacggcacccaggtgaccgtgagctccgaca
	aaacccatacccaggtgcacctgacacagagcggacccgaagtgcggaagcctggc
	acctctgtgaaggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgc
	actgggtgcgcagcgtgccagaacagggactgcagtggatgggctggatcagccac
	gagggcgacaagaaagtgatcgtggaacaattcaaggccaaagtgaccatcgactg
	ggacaaaaacaccaacaccgcctacctacaactaagcggcctgacctctggcgatac
	cgccgtatactactacgccaaggacaacaagcaccggctgagagactacaccctata
	cgacgatgacggcgccctgaactgggccgtggatgtggactacctgagcaacctgga
	attctggggccagggcacagccgtgaccgtgtcatctgataagacccacaccgcttcc
	accaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggca
	cagcgaccctaggctgcctggtcaaggactacttccccgaaccgatgacggtgtcgtg
	gaactcaggcgccctgaccagcgacgtgcacaccttcccggctgtcctacagtcctca
	ggactctactccctcagcagcgtagtgaccgtgccctccaacaacttgggcacccaga
	cctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttga
	gcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctgg
	ggggaccgtcagtcttcctcttccccccaaaacccaaggacaccacatgatctcccgg
	acccctgaggtcacatacgtggtgatggacgtgagccacgaagaccagagatcaag
	ttcaactggtatgttgacggcgtggaggtgcataatgccaagacaaagccgcgggag
	gagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggact
	ggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagccccca
	tcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacacc
	ctgcccccataccgggatgaactaaccaagaatcaagtcagcagtggtgcctgataa
	aaggcttctatcccagcaacatcgccgtagagtgggagagcaatgggcaaccggag
	aacaactacaagaccacgcctcccatgaggactccaacggctccttcttcctctactca
	aaactcaccgtggacaagagcaggtggcagcaggggaacgtatctcatgctccgtg
	atgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggt

Light chain B	gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgaga	SEQ ID
	gcgccagcatcagctgcaagagcagccactccctgatccacggcgaccgga	NO: 160
	acaactacctggcttggtacgtgcagaagcccggcagatccccccagctgctg
	atctacctggccagcagcagagccagcggcgtgcccgatagattttctggcag
	cggcagcgacaaggacttcaccctgaagatcagccgggtggaaaccgagga
	cgtgggcacctactactgtatgcagggcagagagagcccaggaccatggcc
	agggcaccaaggtggacatcaaggacaaaacccatacctccgacatcagcgt
	ggcccccggagagacagccaggatctcctgcggcgagaagagcctgggaa
	gcagggctgtgcagtggtaccaacacagggccggacaggctcccagcctgat
	catctacaacaaccaggacaggcccagcggcatccctgagaggttcagcgga
	agccccgacagccccttcggaaccacagccaccctgaccatcacaagcgtgg
	aagccggcgacgaggccgactactactgccacatagggacagcagggtgc
	ccaccaagtgggtgtttggcggcggcaccaccagaccgtgctggataagacc
	catacccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgag
	cagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacccc
	cgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaa
	cagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcct
	gagcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgta
	cgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttca
	accggggcgagtgt

Binding Protein 21 Amino Acid Sequences

Heavy chain A	qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwishe	SEQ ID
	gdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydd	NO: 161
	dgalnwavdvdylsnlefwgqgtavtvssastkgpsvfplapsskstsggtaalgcl
	vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvn
	hkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevt
	cvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwl
	ngkeykckvsnkalpapiektiskakgqprepqvctlppsrdeltknqvslscavkg
	fypsdiavewesngqpennykttppvldsdgsfflvskltvdksrwqqgnvfscsv
	mhealhnhytqkslslspg

Light chain A	dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr	SEQ ID
	asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikrtva	NO: 162
	apsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqds
	kdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr	SEQ ID
	itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk	NO: 163
	yydfwsgyppgeeyfqdwgqgtlvivssdktht
	rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwik
	pqygavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygd
	sswaldawgqgttvvvsadkthtastkgpsvfplapsskstsggtaalgclvk
	dyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicn
	vnhkpsntkvdkkvepkscdkthtcppcpapellggpsvfifppkpkdtlm
	isrtpevtcvvvdvshedpevkfnwyydgvevhnaktkpreeqynstyrv
	vsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlpp
	crdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsf
	flyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv	SEQ ID
	psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikdkthtaseltqdpavs	NO: 164
	valkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdrfsgsasgnr
	asltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaapsvfifppsd
	eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt
	lskadyekkhvyacevthqglsspvtksfnrgec

Binding Protein 21 Nucleotide Sequences

Heavy chain A	caggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaa	SEQ ID
	ggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcg	NO: 165
	cagcgtgccaggacagggactgcagtggatgggctggatcagccacgagggcgac
	aagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagc
	accaacaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtact
	actgcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgac
	ggcgccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggcc
	agggcacagccgtgaccgtgtcatctgcttcgaccaagggccccagcgtgttccctct
	ggcccctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtga
	aggactactttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcgg
	cgtacacacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtc
	gtgacagtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccaca
	agcccagcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagac
	ccacacctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgtt
	ccccccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgt
	ggtggtggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggc
	gtggaagtgcacaacgccaagaccaagccaagagaggaacagtacaacagcaccta
	ccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagta
	caagtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaa
	ggccaagggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggac
	gagctgaccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccg
	atatcgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccacc
	ccccctgtgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaa
	gtcccggtggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgca
	caaccactacacccagaagtccctgagcctgagccccggcaag

Light chain A	gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc	SEQ ID
	agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg	NO: 166
	gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca
	gcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttca
	ccctgaagatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagg
	gcagagagagcccctggacctttggccagggcaccaaggtggacatcaagcgtacg
	gtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggca
	cagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtgg
	aaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcagg
	acagcaaggactccacctacagcctgagcagcaccctgacactgagcaaggccgact
	acgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccg
	tgaccaagagcttcaaccggggcgagtgt

Heavy chain B	gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc	SEQ ID
	ctgaactgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaagcag	NO: 167
	cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg
	gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca
	agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct
	gtgccagaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatat
	tttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccataccaga
	gcccacctggtacaatctggcaccgccatgaagaaaccaggcgcctctgtgcgggtg
	tcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcaggc
	ccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtgaa
	cttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgagat
	cgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactgcgc
	cagagacagaagctacggcgacagcagctgggctctggatgcttggggccagggca
	caaccgtggtggtgtctgccgataagacccacaccgcttccaccaagggcccatcggt
	cttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctg
	cctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctg
	accagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcag
	cagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtg
	aatcacaagcccagcaacaccaaggtggacaagaaagagagcccaaatcttgtgaca
	aaactcacacatgcccaccgtgcccagcacctgaactcctaaggggaccgtcagtat
	cctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaagtcacat
	gcgtggtggtagacgtgagccacgaagaccctgaggtcaagttcaactggtatattga
	cggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagc
	acgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaagg
	agtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctc
	caaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgccggg
	atgaactaaccaagaatcaagtcagcctgtgatgcctaataaaaggcttctatcccagc
	aacatcgccgtagagtgggagagcaatggacaaccagagaacaactacaagaccac
	gcctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtggacaa
	gagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcac
	aaccactacacgcagaagagcctctccctgtctccgggt

Light chain B	tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtga	SEQ ID
	ccatcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaa	NO: 168
	gcctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgt
	gcccagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagcgatc
	tgcaggccgacgacattaccacctactattgtcaaatgctgcagttcttcggcagaagc
	agcagactgcacatcaaggacaaaacccataccgcatccgaactgactcaggaccct
	gccgtctctgtggcactgaagcagactgtgactattacttgccgaggcgactcactgcg
	gagccactacgcttcctggtatcagaagaaacccggccaggcacctgtgctgctgttct
	acggaaagaacaataggccatctggcatccccgaccgcttttctggcagtgcatcagg
	gaaccgagccagtctgaccattaccggcgcccaggctgaggacgaagccgattacta
	ttgcagctcccgaaataagagcggctccagactgagcgtgttcggaagagaaactaa
	actgaccgtcctcgataagacccatacccgtacggtggccgctcccagcgtgttcatctt
	cccacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaac
	aacttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagc
	ggcaacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcct
	gagcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcct
	gcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggc
	gagtgt

Binding Protein 22 Amino Acid Sequences

Heavy chain A	qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwishe	SEQ ID
	gdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydd	NO: 169
	dgalnwavdvdylsnlefwgqgtavtvssastkgpsvfplapsskstsggtaalgcl
	vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvn
	hkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevt
	cvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwl
	ngkeykckvsnkalpapiektiskakgqprepqvctlppsrdeltknqvslscavkg
	fypsdiavewesngqpennykttppvldsdgsfflvskltvdksrwqqgnvfscsv
	mhealhnhytqkslslspg

Light chain A	dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr	SEQ ID
	asgvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikrtva	NO: 170
	apsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqds
	kdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwik	SEQ ID
	pqygavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygd	NO: 171
	sswaldawgqgttvvvsadkthtevrlvesggglvkpggslrlscsasgfdfd
	nawmtwvrqppgkglewvgritgpgegwsvdyaesvkgrftisrdntknt
	lylemnnvrtedtgyyfcartgkyydfwsgyppgeeyfqdwgqgtlvivss
	dkthtastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgalts
	gvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepk
	scdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshed
	pevkfnwyvdgvevhnaktkpreeqynstytvvsvltvlhqdwlngkey
	kckvsnkalpapiektiskakgqprepqvytlppcrdeltknqvslwclvkg
	fypsdiavewesngqpennykttppvldsdgsf

Light chain B	aseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgip	SEQ ID
	drfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvl dktht	NO: 172
	Yihvtqspsslsvsigdrvtincqtsqtsqgvsdhwyqhkpgrapkllihhtssvedg
	vpsrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrasrlhik
	dkthtrtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgns
	qesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 22 Nucleotide Sequences

Heavy chain A	caggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaa	SEQ ID
	ggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcg	NO: 173
	cagcgtgccaggacagggactgcagtggatgggctggatcagccacgagggcgac
	aagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagc
	accaacaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtact
	actgcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgac
	ggcgccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggcc
	agggcacagccgtgaccgtgtcatctgcttcgaccaagggccccagcgtgttccctct
	ggcccctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtga
	aggactactttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcgg
	cgtacacacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtc
	gtgacagtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccaca
	agcccagcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagac
	ccacacctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgtt
	ccccccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgt
	ggtggtggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggc
	gtggaagtgcacaacgccaagaccaagccaagagaggaacagtacaacagcaccta
	ccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagta
	caagtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaa
	ggccaagggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggac
	gagctgaccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccg
	atatcgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccacc
	ccccctgtgctggacagcgacggctcattcttcctggtgtccaagctgacagtggacaa
	gtcccggtggcagcagggcaacgtgttcagctgctccgtgatgcacgaggccctgca
	caaccactacacccagaagtccctgagcctgagccccggcaag

Light chain A	gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc	SEQ ID
	agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg	NO: 174
	gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca
	gcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttca
	ccctgaagatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagg
	gcagagagagcccctggacctttggccagggcaccaaggtggacatcaagcgtacg
	gtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggca
	cagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtgg
	aaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcagg
	acagcaaggactccacctacagcctgagcagcaccctgacactgagcaaggccgact
	acgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccg
	tgaccaagagcttcaaccggggcgagtgt

Heavy chain B	agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg	SEQ ID
	gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag	NO: 175
	gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg
	aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag
	atcgcctacatagacatccagggcctaaaacccgatgacaccaccatgtactactgcg
	ccagagacagaagctacggcgacagcagctgaactctagatacttgggaccagggc
	acaaccgtgatggtgtctgccgacaaaacccataccgaggttagactggtggagtcag
	gaggggggcttgtgaagcccggtgggtactccgcctgagagactgcctccggcttt
	gatttcgataacgcctggatgacctgggtcaggcagcctccaggtaagggactggagt
	gggtgggaagaatcacaggtccaggcgagggctggtccgtggactacgcggaatct
	gttaaagggcggtttacaatctcaagggacaataccaagaataccttgtatttggagatg
	aacaacgtgagaactgaagacaccgaatattacttctgtgccagaacaggcaaatacta
	cgacttctggtccggctatccccctggcgaggaatattttcaagactggggtcagggaa
	cccttgttatcgtgtcctccgataagacccacaccgcttccaccaagggcccatcggtct
	tccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcc
	tggtcaaggactacttccccgaaccagtgacggtgtcgtggaactcaggcgccctgac
	cagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagca
	gcgtggtaaccgtaccctccagcagcttgggcacccagacctacatctgcaacgtgaa
	tcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaa
	actcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcct
	cttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgc
	gtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtatgttgacg
	gcgtggaggtgcataatgccaagacaaagccgcgggaggaacagtacaacagcac
	gtaccgtatggtcagcgtcctcaccgtcctgcaccaggactggctgaatgacaaggag
	tacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctcca
	aagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgccgggat
	gagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggcttctatcccagcga
	catcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgc
	ctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtggacaaga
	gcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaa
	ccactacacgcagaagagcctctccctgtctccgggt

Light chain B	gcatccgaactgactcaggaccctgccgtctctgtggcactgaagcagactgtg	SEQ ID
	actattacttgccgaggcgactcactgcggagccactacgcttatggtatcaga	NO: 176
	agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggcca
	tctggcatccccggccgctttctggcagtgcatcagggaaccgagccagtctg
	accattaccggcgcccaggctgaggacgaagccgattactattgcagctcccg
	ggataagagcggctccagactgagcgtgttcggaggaggaactaaactgacc
	gtcctcgacaaaacccatacctacatccacgtgacccagagccccagcagcct
	gtccgtgtccatcggcgacagagtgaccatcaactgccagacctctcagggcg
	tgggcagcgacctgcactggtatcagcacaagcctggcagagcccccaagct
	gctgatccaccacacaagcagcgtggaagatggcgtgcccagcagattttccg
	gcagcggcttccacaccagcttcaacctgaccatcagcgatctgcaggccgac
	gacattgccacctactattgtcaggtgctgcagttcttcggcagaggcagaga
	ctgcacatcaaggataagacccatacccgtacggtggccgctcccagcgtgtt
	catcttcccacctagcgacgagcagctgaagtccggcacagcctagtcgtgtg
	cctgctgaacaacttctacccccgcgaggccaaagtgcagtggaaggtggac
	aacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacag
	caaggactccacctacagcctgagcagcaccctgacactgagcaaggccgac
	tacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtcta
	gccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 23 Amino Acid Sequences

Heavy chain A	evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgritgpg	SEQ ID
	egwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgkyydfwsgy	NO: 177
	ppgeeyfqdwgqgtlvivssastkgpsvfplapsskstsggtaalgclvkdyfpepv
	tvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsnkvd
	kkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshe
	dpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckv
	snkalpapiektiskakgqprepqvctlppsrdeltknqvslscavkgfypsdiave
	wesngqpennykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnh
	ytqkslslspg

Light chain A	Aseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi	SEQ ID
	pdrfsgsasgnrasltitaaqaedeadyycssrdksgsrlsvfgggtkltvlsqpkaap	NO: 178
	svtlfppsseelqankatlvclisdfypgavtvawkadsspvkagvetttpskgsnnk
	yaassylsltpeqwkshrsyscqvthegstvektvaptecs

Heavy chain B	rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwik	SEQ ID
	pqygavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygd	NO: 179
	sswaldawgqgttvvvsadkthtQvhltqsgpevrkpgtsvkvsckapgnt
	lktydlhwvrsvpgqglqwmgwishegdkkviverfkakvtidwdrstnt
	aylqlsgltsgdtavyycakgskhrlrdyalydddgalnwavdvdylsnlef
	wgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgclvkdyfpepv
	tvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsn
	tkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtlmisrtpevt
	cvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlh
	qdwlngkeykckvsnkalpapiektiskakgqprepqvytlppcrdeltkn
	qvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvd
	ksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr	SEQ ID
	asgvpdrfsgsgsdkdflkisrvetedvgtyycmqgrespwtfgqgtkvdikdkth	NO: 180
	t
	yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv
	psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikdkthtrtvaapsvfifp
	psdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysls
	stltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 23 Nucleotide Sequences

Heavy chain A	gaggttagactggtggagtcaggaggggggcagtgaagcccggtgggtctctccgc	SEQ ID
	ctgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag	NO: 181
	cctccagataagggactagagtgggtgggaagaatcacagatccagacgagggctg
	gtccgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaatacca
	agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct
	gtgccagaacaggcaaatactacgacttaggtccggctatccccaggcgaggaatat
	tttcaagactggggtcagggaacccttgttatcgtgtcctccgcgtcgaccaagggccc
	cagcgtgttccactggcccctagcagcaagageacataggcggaacagccgccct
	gggctgcctcgtgaaggactactttcccgagcccgtgaccgtgtcctagaattaggcg
	ccctgaccagcggcgtgcacacctttccagctgtgctgcagtccagcggcctgtacag
	cctgagcagcgtcgtgacagtgcccagcagctctctgggcacccagacctacatctgc
	aacgtgaaccacaageccageaacaccaaggtggacaagaaggtggaacccaaga
	gctgcgacaagacccacacctgtcccccttgtcctgcccccgaactgagggaggccc
	ttccgtgttcctgttccccccaaagcccaaggacaccctgatgatcaaccggaccccca
	aagtgacctgcgtggtggtagatgtgtcccacgaggaccctgaagtgaagttcaattgg
	tacgtggacggcgtggaagtgcacaacgccaagaccaagccaagagaggaacagta
	caacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaac
	ggcaaagagtacaagtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaa
	accatcagcaaggccaagggccagccccgcgaaccccaggtgtgcacactgccccc
	aagcagggacgagagaccaagaaccaggtgtccctgagagtgccgtgaaaggctt
	ctacccctccgatatcgccgtagaatgggagagcaacagccagcccgagaacaacta
	caagaccaccccccctatgaggacagcgacgactcattatcaggtatccaagaga
	cagtggacaagtcccggtggcagcagggcaacgtgttcagctgctccgtgatgcacg
	aggcccggcacaaccactacacccagaagtccctgagcctgagccccggcaag

Light chain A	gcatccgaactgactcaggaccctgccgtetctgtggcactgaagcagactgtg	SEQ ID
	actattacttgccgaggcgactcactgcggagccactacgcttcctggtatcaga	NO: 182
	agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggcca
	tctggcatccccgaccgcttttctggcagtgcatcagggaaccgagccagtctg
	accattaccggcgcccaggctgaggacgaagccgattactattgcagctcccg
	ggataagagcggctccagactgagcgtgttcggaggaggaactaaactgacc
	gtcctcagtcagcccaaggctgccccctcggtcactctgttcccgccctcgagt
	gaggagatcaagccaacaaggccacactggtgtgtctcataagtgacttctac
	ccgggagccgtgacagtggcaggaaggcagatagcagccccgtcaaggcg
	ggagtggagaccaccacaccctccaaacaaagcaacaacaagtacgcggcc
	agcagctacctgagcctgacgcctgagcagtggaagtcccacagaagctaca
	gctgccaggtcacgcatgaagggagcaccgtggagaagacagtggccccta
	cagaatgttca

Heavy chain B	agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg	SEQ ID
	gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcag	NO: 183
	gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg
	aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag
	atcgcctacatagacatccggggcctgaagcccgatgacaccgccgtgtactactgcg
	ccagagacagaagctacggcgacagcagctgggctctggatacttggggccagggc
	acaaccgtggtggtgtctgccgacaaaacccatacccaggtgcacctgacacagagc
	ggacccgaagtgcggaagcctggcacctctgtgaaggtgtcctgcaaggcccctggc
	aacaccctgaaaacctacgacctgcactgggtgcgcagcgtgccaggacagggactg
	cagtggatgggctggatcagccacgagggcgacaagaaagtgatcgtggaacggttc
	aaggccaaagtgaccatcgactgggacagaagcaccaacaccgcctacctgcagctg
	agcggcctgacctctggcgataccgccgtgtactactgcgccaagggcagcaagcac
	cggctgagagaetacgccctgtacgacgatgacggcgccctgaactgggccgtggat
	gtggactacctgagcaacctggaattctggggccagggcacagccgtgaccgtgtcat
	ctgataagacccacaccgcttccaccaagggcccatcggtcttccccctggcaccctcc
	tccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttcc
	ccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacacct
	tcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccct
	ccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaaca
	ccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccacc
	gtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaaccca
	aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgag
	ccacgaagaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatg
	ccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtc
	ctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctcca
	acaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccc
	cgagaaccacaggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaa
	gtcagcctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtggg
	agagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactcc
	gacggctccttcttcctctactcaaaactcaccgtggacaagagcaggtggcagcagg
	ggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaag
	agcctctccctgtctccgggt

Light chain B	gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgaga	SEQ ID
	gcgccagcatcagctgcaagagcagccactccctgatccacggcgaccggaa	NO: 184
	caactacctggcttggtacgtgcagaagcccggcagatccccccagctgctga
	tctacctggccagcagcagagccagcggcgtgcccgatagattttctggcagc
	ggcagcgacaaggacttcaccctgaagatcagccgggtggaaaccgaggac
	gtgggcacctactactgtatgcagggcagagagagcccctggacctttggcca
	gggcaccaaggtggacatcaaggacaaaacccatacctacatccacgtgacc
	cagagccccagcagcctgtccgtgtccatcggcgacagagtgaccatcaactg
	ccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaagcct
	ggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggc
	gtgcccagcagattaccggcagcggcttccacaccagcttcaacctgaccatc
	agcgatctgcaggccgacgacattgccacctactattgtcaggtgctgcagttct
	tcggcagaggcagcagactgcacatcaaggataagacccatacccgtacggt
	ggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccg
	gcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaa
	gtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaag
	cgtgaccgagcaggacagcaaggactccacctacagcctgagcagcaccctg
	acactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtga
	cccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtg
	t

Binding Protein 24 Amino Acid Sequences

Heavy chain A	evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgritgpge	SEQ ID
	gwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgkyydfwsgypp	NO: 185
	geeyfqdwgqgtlvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvs
	wnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkve
	pkscdkthtcppcpapellggpsvflfppkdtlmisrtpevtcvvvdvshedpev
	kfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkal
	papiektiskakgqprepqvctlppsrdeltknqvslscavkgfypsdiavewesngq
	pennykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslsls
	pg

Light chain A	aseltqdpavsvalkqtvtitcrgdslrshyaswygkkpgqapvllfygknnrpsgip	SEQ ID
	drfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvlsqpkaapsv	NO: 186
	tlfppsseelqankatlvclisdfypgavtvawkadsspvkagvetttpskqsnnkya
	assylsltpeqwkshrsyscqvthegstvektvaptecs

Heavy chain B	Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmg	SEQ ID
	wishegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskh	NO: 187
	rlrdyalydddgalnwavdvdylsnlefwgqgtavtvss
	dkthtrahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewv
	gwikpqygavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrs
	ygdsswaldawgqgttvvvsadkthlastkgpsvfplapsskstsggtaalgc
	lvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyi
	cnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdtl
	misrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyr
	vvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlpp
	crdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffl
	yskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain B	yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv	SEQ ID
	psrfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikdkthtdfvltqsphsls	NO: 188
	vtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassrasgvpdrfsgsg
	sdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikdkthtrtvaapsvfifpp
	sdeqlksgasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsst
	ltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 24 Nucleotide Sequences

Heavy chain A	gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgcc	SEQ ID
	tgagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcagcc	NO: 189
	tccagataagggactggaatgggtgggaagaatcacagatccaagcgagggctggtc
	cgtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaataccaaga
	ataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttctgtgc
	cagaacaggcaaatactacgacactggtccggctatccccctggcgaggaatattttca
	agactggggtcagggaacccttgttatcgtgtcctccgcgtcgaccaagggccccagcg
	tgttccctctggcccctagcagcaagagcacataggcggaacagccgccctgggctg
	cctcgtgaaggactactttcccgagcccgtgaccgtgtcaggaattaggcgccagac
	cagcggcgtgcacacctttccagagtactacaatccagcggcctatacaacctgagca
	gcgtcgtgacagtgcccagcagctactgggcacccagacctacatagcaacgtgaac
	cacaagcccagcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaa
	gacccacacctgtcccccagtcctgcccccgaactgctgggaggcccttccgtgacct
	gttccccccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgc
	gtggtggtggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacgg
	cgtggaagtgcacaacgccaagaccaagccaagagaggaacagtacaacagcaccta
	ccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtac
	aagtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaagg
	ccaagggccagecccgcgaaccccaggtgtgcacactgcccccaagcagggacgag
	ctgaccaagaaccaggtgtccctgagagtgccgtgaaaggatctacccaccgatatc
	gccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccc
	tgtgctggacagcgacggctcattcttcctgatgtccaagctgacagtagacaaatccca
	gtggcagcagggcaacgtgttcagctgaccgtgatgcacgaggccctgcacaaccac
	tacacccagaagtccctgagcctgagccccggcaag

Light chain A	gcatccgaactgactcaggaccctgccgtctctgtggcactgaagcagactgtg	SEQ ID
	actattacttgccgaggcgactcactgcggagccactacgcttcctggtatcaga	NO: 190
	agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccat
	ctggcatccccgaccgcattctggcagtgcatcagggaaccgagccagtctga
	ccattaccggcgcccaggctgaggacgaagccgattactattgcagctcccgg
	gataagagcggctccagactgagcgtgttcggaggaggaactaaactgaccgt
	cctcagtcagcccaaggctgccccctcggtcactagttcccgccctcgagtgag
	gagcttcaagccaacaaggccacactggtgtgtctcataagtgacttctacccgg
	gagccgtgacagtggcctggaaggcagatagcagccccgtcaaggcgggagt
	ggagaccaccacaccctccaaacaaagcaacaacaagtacgcggccagcagc
	tacctgagcctgacgcctgagcagtggaagtcccacagaagctacagctgcca
	ggtcacgcatgaagggagcaccgtggagaagacagtggcccctacagaatgtt
	ca

Heavy chain B	tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtga	SEQ ID
	ccatcaactgccagacctacagggcgtgggcagcgacctgcactggtatcagcacaa	NO: 191
	gcctggcagagcccccaagagagatccaccacacaagcagcgtggaagatggcgt
	gcccagcagattaccggcagcagatccacaccagatcaacctgaccatcagcgatct
	gcaggccgacgacattaccacctactattgtcaggtgctgcagttctteggcagaggca
	gcagactgcacatcaaggacaaaacccataccgacttcgtgctgacccagagccctca
	cagcctgagcgtgacacctggcgagagcgccagcatcagagcaagagcagccactc
	cctgatccacggcgaccggaacaactacctggcttggtacgtgcagaagcccggcaga
	tccccccagctgctgatctacctggccagcagcagagccagcggcgtgcccgatagatt
	ttctggcagcagcagcgacaaggacttcaccctgaagatcagccgggtggaaaccga
	ggacgtgggcacctactactgtatgcagggcagagagagcccaggacctaggccag
	ggcaccaaggtggacatcaaggataagacccatacccgtacggtggccgctcccagc
	gtgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgc
	ctgctgaacaacttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccc
	tgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactccacc
	tacagcctgagcagcaccagacactgagcaaggccgactacgagaagcacaaggtg
	tacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagatcaacc
	ggggcgagtgt

Light chain B	tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacag	SEQ ID
	agtgaccatcaactgccagacctctcagggcgtgggcagcgacctgcactggt	NO: 192
	atcagcacaagcctggcagagcccccaagctgagatccaccacacaagcagc
	gtggaagatggcgtgcccagcagattttccggcagcggcttccacaccagcttc
	aacctgaccatcagcgatctgcaggccgacgacattgccacctactattgtcagg
	tgctgcagttcttcggcagaggcagcagactgcacatcaaggacaaaacccata
	ccgacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgag
	agcgccagcatcagctgcaagagcagccactccctgatccacggcgaccgga
	acaactacctggcttggtacgtgcagaagcccggcagatccccccagctgctga
	tctacctggccagcagcagagccagcggcgtgcccgatagattttctggcagcg
	gcagcgacaaggacttcaccctgaagatcagccgggtggaaaccgaggacgt
	gggcacctactactgtatgcagggcagagagagcccctggacctttggccagg
	gcaccaaggtggacatcaaggataagacccatacccgtacggtggccgctccc
	agcgtgttcatcttccacctagcgacgagcagctgaagtccggcacagcact
	gtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtggaag
	gtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcag
	gacagcaaggactccacctacagcctgagcagcaccctgacactgagcaagg
	ccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcct
	gtctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 25 Amino Acid Sequences

Heavy chain A	qvqlvqsggqmkkpgesmriscrasgyefi wirlapgkrpewmg	SEQ ID
	rvtmtrdvysdtaflelrsltvddtavyfctr wgr	NO: 193
	gtpvivssastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvh
	tfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkthtcp
	pcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgve
	vhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskak
	gqprepqvctlppsrdeltknqvslscavkgfypsdiavewesgqpennykttppv
	ldsdgsfflvskltvdksrwqqgnvfscsvlhealhshytqkslslspg

Light chain A	eivltqspgtlslspgetaiisc awyqqrpgqaprlviy gipdrfs	SEQ ID
	gsrwvgpdynltisnlesgdfgvyy fgqgtkvqvdikrtvaapsvfifppsde	NO: 194
	qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltls
	kadyekhkvyacevthqglsspvcksfnrgec

Heavy chain B	evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgrit	SEQ ID
	gpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgkyy	NO: 195
	dfwsgyppgeeyfqdwgqgtlvivssdkthtqvqlvesgggvvqpgtslrls
	caasqfrfdgygmhwvrqapgkglewvasishdgikkyhaekvwgrftisr
	dnskntlylqmnslrpedtalyycakdlredeceewwsdyydfgkqlpcaks
	rgglvgiadnwgqgtmvtvssdkthtastkgpsvfplapsskstsggtaalgcl
	vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyic
	nvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvtlfppkpkdtl
	misrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyr
	vvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlpp
	crdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffl
	yskltvdksrwqqgnvfscsvlhealhshylqkslslspg

Light chain B	qsvltqppsvsaapgqkvtiscsgntsnignnfvswyqqrpgrapqlliyetdkrpsgi	SEQ ID
	pdrfsasksgtsgtlaitgtqtgdeadyycatwaaslssarvfgtgtkvivldkthtaselt	NO: 196
	gdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdrfsg
	sasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaapsvfif
	ppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysl
	sstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein

25 Nucleotide Sequences

Heavy chain A	cagatgcagctggtgcagtctggcggccagataaaaaaacccagcgagaacatgcgg	SEQ ID
	atcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcagact	NO: 197
	ggcccctggcaagcggcctgagtggatgggatggctgaagcctagaggcggagccgt
	gaactacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacagcgat
	accgccttcctggaactgcggagcctgaccgtggatgataccgccgtgtacttctgcacc
	cggggcaagaactgcgactacaactgggacttcgagcactggggcagaggcacccct
	gtgatcgtatcaagcgcgtcgaccaagggccccagcgtgttccactaacccctagcaa
	caagagcacataggcagaacaaccaccctaggctgcctcgtgaaggactactttcccg
	agcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgcacaccatcca
	gctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtgacagtgcccagca
	gctactaggcacccagacctacatagcaacgtgaaccacaagcccagcaacaccaa
	ggtggacaagaaggtggaacccaagagagcgacaagacccacacagtcccccttgt
	cctgcccccgaactgagggaggcccttccgtgacctgttccccccaaagcccaagga
	caccctgatgatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccacg
	aggaccctgaagtgaagttcaattggtacgtggacggcgtggaagtgcacaacgccaa
	gaccaagccaagagaggaacagtacaacagcacctaccgggtggtgtccgtgctgac
	cgtgctgcaccaggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaag
	gccctgcctgcccccatcgagaaaaccatcagcaaggccaagggccagccccgcgaa
	ccccaggtgtacacactgcccccaaacagggacgaactaaccaagaaccaaatgtcc
	ctgagctgtgccgtgaaaggcttctacccctccgatatcgccgtggaatgggagagcaa
	cggccagcccgagaacaactacaagaccaccccccctgtgctggacagcgacggctc
	attcttcctggtgtccaagctgacagtggacaagtcccggtggcagcagggcaacgtgtt
	cagctgctccgtgctgcatgaggctctgcacagccactacacgcagaagagcctctccc
	tgtctccgggt

Light chain A	Gagatcgtgctgacacagagccaggcaccctgagcctgtctccaggegagacagcc	SEQ ID
	atcatcagctgccggacaagccagtacggcagcctggcctggtatcagcagaggcctg	NO: 198
	gacaggcccccagactcgtgatctacagcggcagcacaagagccgccggaatccccg
	atagattcagcggctccagatggaaccctaactacaacctgaccatcagcaacctgaaa
	agcggcgacttcggcgtgtactactgccagcagtacgagttcttcggccagggcaccaa
	ggtgcaggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctag
	cgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctaccc
	ccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagcc
	aggaaagcgtgaccgagcaggacagcaaggactccacctacagcctgagcagcacc
	ctgacactgagcaagaccgactacgagaaacacaaggtgtacgcctacgaagtgacc
	caccagggcctatctagccccgtgaccaagagcttcaaccagggcgagtgt

Heavy chain B	gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgcct	SEQ ID
	gagctgactgcctccggattgatacgataacgcctggatgacctgggtcaggcagcct	NO: 199
	ccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctggtcc
	gtggactacgcggaatctgtaaagggcggnacaatctcaagggacaataccaagaat
	accttgtatttgaagatgaacaacgtaagaactgaagacaccagatattacttctatgcca
	gaacagacaaatactacgacttctggtccagctatccccctggcgaggaatattttcaaa
	actggggtcagggaacccttgttatcgtgtcctccgacaaaacccatacccaggtgcagt
	tggtggagtctgggggaggcgtggtccagcctgggacgtccctgagactctcctgtgca
	gcactcaattcaggtttgatggttatggcatgcactgggtccgccaggccccaggcaag
	gggctggagtgggtggcatctatatcacatgatggaattaaaaagtatcacgcagaaaaa
	gtgtggggccgcttcaccataccagagacaattccaagaacacactgtatctacaaatg
	aacagcctgcgacctgaggacacggctctctactactgtgcgaaagatttgcgagaaga
	cgaatgtgaagagtggtggtcggattattacgattttgggaaacaactcccttgcgcaaag
	tcacgcggcggcttggttggaattgctgataactggggccaagggacaatggtcaccgt
	ctcttcagataagacccacaccgcttccaccaagggcccatcggtcttccccctggcacc
	ctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactac
	ttccccgaaccggtgacggtgtcgtggaactcaggcgccagaccagcggcgtgcaca
	ccttcccagagtcctacagtcctcaggactctactccctcagcagcgtagtgaccatgc
	cctccagcagatggacacccagacctacatagcaacgtgaatcacaagcccagcaac
	accaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccacc
	gtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaa
	ggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagcc
	acgaagaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatgcc
	aagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctc
	accgtcagcaccaggactggctgaatgacaaggagtacaagtacaaggtaccaaca
	aagccacccaacccccatcgagaaaaccatctccaaagccaaagagcaaccccgag
	aaccacaggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaagtcag
	cctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtgggagagca
	atgggcagccggagaacaactacaagaccacgcctcccgtgaggactccgacggctc
	cttcttcactactcaaaactcaccgtggacaagagcaggtggcagcaggggaacgtat
	ctcatgctccgtgctgcatgaggctctgcacagccactacacgcagaagagcctctccct
	ataccgggt

Light chain B	cagtctgtgctgacgcagccgccctcagtgtctgcsgccccaggacagaaggt	SEQ ID
	caccatctcctgactggaaacacctccaacattggcaataattttgtgtcctggtat	NO: 200
	caacagcgccccggcagagccccccaactcctcatttatgaaactgacaagcga
	ccctcagggattcctgaccgattctctgcttccaagtctggtacgtcaggcaccct
	ggccatcaccgggctgcagactggggacgaggccgattattactgcgccacat
	gggctgccagectgagaccgcgcgtgtcttcggaactgggaccaaggtcatcg
	tcctggacaaaacccataccgcatccgaactgactcaggaccctgccgtctctgt
	ggcactgaagcagactgtgactattacttgccgaggcgactcactgcggagcca
	ctacgcttcctggtatcagaagaaacccggccaggcacctgtgctgctgttctac
	ggaaagaacaataggccatctggcatccccgaccgcttttctggcagtgcatcag
	ggaaccgagccagtctgaccattaccggcgcccaggctgctggacgaagccga
	ttactattgcagctcccgggataagagcggctccagactgagcgtgttcggagg
	aggaactaaactgaccgtcctcgataagacccatacccgtacggtggccgctcc
	cagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctct
	gtcgtgtgcctgagaacaacttctacccccgcgaggccaaagtgcagtggaag
	gtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcag
	gacagcaaggactccacctacagcctgagcagcaccctgacactgagcaagg
	ccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcct
	gtctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 26 Amino Acid Sequences

Heavy chain A	Rahlvqsgtamkkpgasvrvscqts lfwfrqapgrglewvgw	SEQ ID
	nfgggfrdrvtltrdvyreiaymdirglkpddtavyycar wg	NO: 201
	qgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgv
	htfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkthtc
	ppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgv
	evhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiska
	kgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpennykttpp
	vldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain A	yihvtqspsslsvsigdrvtincqts lhwyqhkpgrapkllihhtssvedgvp	SEQ ID
	srfsgsgf fnltisdlqaddiatyyc rgsrlhikrtvaapsvfifppsdeql	NO: 202
	ksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlska
	dyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgrit	SEQ ID
	gpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgkyy	NO: 203
	dfwsgyppgeeyfqdwgqgtlvivssdkthtqvqlvesgggvvqpgtslrls
	caasqfrfdgygmhwvrqapgkglewvasishdgikkyhaekvwgrftisr
	dnskntlylqmnslrpedtalyycakdlredeceewwsdyydfgkqlpcaks
	rgglvgiadnwgqgtmvtvssdkthtastkgpsvfplapsskstsggtaalgcl
	vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyic
	nvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvtlfppkpkdtl
	misrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyr
	vvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlpp
	crdeltknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffl
	yskltvdksrwqqgnvfscsvlhealhshylqkslslspg

Light chain B	qsvltqppsvsaapgqkvtiscsgntsnignnfvswyqqrpgrapqlliyetdkrpsgi	SEQ ID
	pdrfsasksgtsgtlaitgtqtgdeadyycatwaaslssarvfgtgtkvivldkthtaselt	NO: 204
	gdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdrfsg
	sasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaapsvfif
	ppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysl
	sstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 26 Nucleotide Sequences

Heavy chain A	agagcccacctggtgcagtaggcaccgccatgaagaaaccaggcgcctagtgcggg	SEQ ID
	tgtcctgtcagacaagcggctacaccttcaccgcccacatcctgactggaccggcagg	NO: 205
	cccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtgaa
	cttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgagatc
	gcctacatagacatccggggcctaaaacccgatgacaccaccatgtactactgcgcca
	gagacagaagctacggcgacagcagctgaactctagatacttgggaccagggcacaa
	ccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggcccctagca
	gcaagagcacatctggcggaacagccgccctgggctgcctcgtgaaggactactttccc
	gagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtgcacacctttcc
	agctgtgctgcagtccagcggcctgtacaacctgagcagcgtcgtgacgtgcccagc
	agctctctggacacccagacctacatctgcaacgtgaaccacaagcccagcaacacca
	aggtggacaagaaggtggaacccaagagctgcgacaagacccacacctgtcccccttg
	tcctgcccccgaactgctgggaggcccttccgtgttcctgttccccccaaagcccaaaga
	caccctgatgatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccacg
	aggaccctgaagtgaagttcaattggtacgtggacggcgtggaagtgcacaacgccaa
	gaccaagccaagagaggaacagtacaacagcacctaccgggtggtatccgtgctgac
	cgtactacaccaggactagctgaacggcaaagagtacaagtgcaagatgtccaacaag
	gccagcctgcccccatcgagaaaaccatcagcaaggccaagggccagccccgcgaa
	ccccaggtgtgcacactgcccccaagcagggacgagatgaccaagaaccaggtatcc
	ctgagctgtgccgtgaaaggcttctacccaccgatatcgccgtggaatgggagagcaa
	cggccagcccgagaacaactacaagaccaccccccctgtgctggacagcgacggctc
	attcttcctgatgtccaagctaacagtagacaaatcccagtggcagcagggcaacatgtt
	cagctgctccgtgctgcatgaagctctacacagccactacacgcagaagagcctctccc
	tgtctccgggt

Light chain A	tacatccacatgacccaaagccccaacagcctgtccatgtccatcggcaacagagtga	SEQ ID
	ccatcaactgccaaacactcaggacgtaggcagcaacctacactgatatcagcacaa	NO: 206
	gcctggcagagcccccaagctgctgatccaccacacaagcagcgtgaaaaatgacgt
	gcccagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagcgatct
	gcaggccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagaggcag
	cagactgcacatcaagcgtacggtggccgctcccagcgtgttcatcacccacctagcga
	cgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacccccg
	cgaggccaaagtacagtggaagatggacaacaccctacagagcggcaacagccagg
	aaagcgtgaccgagcaggacagcaaggactccacctacagcctgagcagcaccctga
	cactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccacc
	agggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgcct	SEQ ID
	gagctgttctgcctccggctttgatttcgataacgcctggatgacctgggtcaggcagcct	NO: 207
	ccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctggtcc
	gtggactacgcggaatctgttaaagggcggtttacaatctcaagggacaataccaagaat
	accttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttctgtgcca
	gaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatattttcaag
	actggggtcagggaacccttgttatcgtgtcctccgacaaaacccatacccaggtgcagt
	tggtggagtctgggggaggcgtggtccagcctgggacgtccctgagactctcctgtgca
	gcctctcaattcaggtttgatggttatggcatgcactgggtccgccaggccccaggcaag
	gggctggagtgggtggcatctatatatcatgatggaattaaattagtatcacgcagaaaaa
	gtgtggggccgcttcaccatctccagagacaattccaagaacacactgtatctacaaatg
	aacagcctgcgacctgaggacacggctctctactactgtgcgaaagatttgcgagaaga
	cgaatgtgaagagtggtggtcggattattacgattttgggaaacaactcccttgcgcaaag
	tcacgcggcggcttggttggaattgctgataactggggccaagggacaatggtcaccgt
	ctcttcagataagacccacaccgcttccaccaagggcccatcggtcttccccctggcacc
	ctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcattggactac
	ttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcaca
	ccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgc
	cctccagcagcttgggcacccagacctacatctgcaacgtgaattacaagcccagcaac
	accaaggtggacaagaaagttgagcccaaatcttgtgacaaaacicacacatgcccacc
	gtgcccagcacctgaactcctggggggaccgtcttgtcttcctcttccccccaaaacccaa
	ggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagcc
	acgaagaccctgaggtcaagttcaactggtatgttgacggcgtggaggtgcataatgcc
	aagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctc
	accgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaaca
	aagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgag
	aaccacaggtgtacaccctgcccccatgccgggatgagctgaccaagaatcaagtcag
	cctgtggtgcctggtaaaaggcttctatcccagcgacatcgccgtggagtgggagagca
	atgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctc
	cttcttcctccactcaaaactcaccgtggacaagagcaggtggcagcaggggaacgtctt
	ctcatgctccgtgctgcatgaggctctgcacagccactacacgcagaagagcctctccct
	gtctccgggt

Light chain B	cagtctgtgctgacgcagccgccctcagtgtctgcggccccaggacagaaggtcaccat	SEQ ID
	ctcctgactggaaacacctccaacattggcaataattagtgtcctggtatcaacagcgcc	NO: 208
	ccggcagagccccccaactcctcatttataaaactgacaagcgaccctcagggattcctg
	accgattctctgcttccaagtctggtacgtcaggcaccctggccatcaccgggctgcaga
	ctggggacgaggccgattattactgcgccacatgggctgccagcctgagttccgcgcgt
	gtcttcggaactgggaccaaggtcatcgtcctggacaaaacccataccgcatccgaact
	gactcaggaccctgccgtactgtggcactgaagcagactgtgactattacttgccgagg
	cgactcactgcggagccactacgcttcaggtatcagaagaaacccggccaggcacct
	gtgctgagttctacggaaagaacaataggccataggcatccccgaccaatttaggca
	gtgcatcagggaaccgagccagtctgaccattaccggcgcccaggctgaggacgaag
	ccgattactattgcagctcccgggataagagcggctccagactgagcgtgttcggagga
	ggaactaaactgaccgtcctcgataagacccatacccgtacggtggccgctcccagcgt
	gttcatatcccacctagcgacgagcagctgaagtccggcacagcctagtcgtgtgcct
	gctgaacaacttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctg
	cagagcggcaacaaccaggaaagcgtgaccgagcaggacagcaaggactccaccta
	cagcctgagcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgta
	cgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccgg
	ggcgagtgt

Binding Protein 27 Amino Acid Sequences

Heavy chain A	Rahlvqsgtamkkpgasvrvscqts lfwfrqapgrglewvgw	SEQ ID
	nfgggfrdrvtltrdvyreiaymdirglkpddtavyycar wg	NO: 209
	qgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgv
	htfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdkthtc
	ppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgv
	evhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiska
	kgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpennykttpp
	vldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain A	yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv	SEQ ID
	psrfsgsgfhtsfnltisdlqaddiatyycqlqffgrgsrlhikrtvaapsvfifppsdeq	NO: 210
	lksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlsk
	adyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgri	SEQ ID
	tgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgky	NO: 211
	ydfwsgyppgeeyfqdwgqgtlvivssdkthtqvhltqsgpevrkpgtsvk
	vsckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkakvti
	dwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwavdvd
	ylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgclvkdy
	fpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnh
	kpsntkvdkkvepkscdkthtcppcpapellggpsvilfppkpkdtlmisrtp
	evtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltv
	lhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppcrdeltk
	nqvslwclvkgfypsdiavevvesngqpennykttppvldsdgsfllyskltv
	dksrwqqgnvfscsvlhealhshytqkslslspg

Light chain B	dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassra	SEQ ID
	sgvpdrfsgsgsdkdftikisrvetedvgtyycmqgrespwtfgqgtkvdikdkthta	NO: 212
	seltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgipdr
	fsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtvaaps
	vfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdst
	yslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 27 Nucleotide Sequences

Heavy chain A	agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg	SEQ ID
	gtgtcctgtcagacaagcggctacaccttcaccgcccacatccgttctggttccggcag	NO: 213
	gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgt
	gaacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcga
	gatcacctacatagacatccagggcctaaaacccgatgacaccaccatgtactactgc
	gccagagacagaagctacggcgacagcagctgggctctggatgcttggggccaggg
	cacaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggccc
	ctagcagcaagagcacatctggcggaacagccgccagggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaattaggcgccctgaccagcgggtgca
	cacctttccagctatgctgcagtccagcaacctgtacagcctaagcagcgtcgtgaca
	atgcccagcagctactgggcacccagacctacatctacaacatgaaccacaaaccca
	gcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacac
	ctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttcccccc
	aaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggt
	ggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaa
	gtgcacaacgccaagaccaagccaagagaaaaacaatacaacagcacctaccaggt
	ggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtg
	caaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaa
	gggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctg
	accaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgc
	cgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctg
	tgctgaacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccga
	tggcagcagggcaacgtgttcagctgctccgtgctgcacgaggccctgcacagccact
	acacccagaagtccctgagcctgagccccggc

Light chain A	tacatccacgtaacccagaaccccagcagcctatccgtatccatcgacgacaaagtga	SEQ ID
	ccatcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaa	NO: 214
	gcctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgt
	gcccagcagattttccggcagcggcttccacaccagcttccagagaccatcagcgatc
	tgcaggccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagaggc
	agcagactgcacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctag
	cgacgagcagagaagtccggcacagcctctgtcgtgtgcctgagaacaacttctacc
	cccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacag
	ccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctgagcagca
	ccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtga
	cccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc	SEQ ID
	ctgagctgactgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag	NO: 215
	cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg
	gtccgtgactacgcggaatctgttaaaggcggatacaatctcaaggpacaatacca
	agaataccttgtatttgaagatgaacaacgtaagaactgaagacaccaaatattacttct
	gtgccagaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatat
	tttcaagactggggtcagggaacccagttatcgtgtcctccgacaaaacccatacccag
	gtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaaggtg
	tcctgcaaggcccctagcaacaccctgaaaacctacgacctgcactgggtgcgcagc
	gtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaaga
	aagtgatcgtggaacagttcaaggccaaaatgaccatcgactaagacagaagcacca
	acaccgcctacctgagctgagcggcctgacctctggcgataccgccgtgtactactg
	cgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacggcg
	ccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggccagg
	gcacagccgtgaccgtgtcatctgataagacccacaccgcttccaccaagagcccatc
	ggtcttccccctggcaccctcctccaagagcacctctgggaacacaacggccctgaa
	ctgcctgatcaagaactacttccccaaaccaatgacggtgtcgtaaaactcagacgcc
	ctgaccagcggcatgcacaccttcccggagtcctacaatcctcaaaactctactccct
	cagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaac
	gtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtg
	acaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcag
	tcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtca
	catgcgtggtagtgaacatgagccacgaagaccctgaggtcaaattcaactggtatgtt
	gacggcgtgaaggtgcataatgccaagacaaagccgcaggaggagcagtacaaca
	gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaa
	ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat
	ctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgcc
	gggatgagctgaccaagaatcaagtcagcctgtggtgcctagtaaaaggcttctatccc
	agcgacatcgccatggagtgagagagcaataggcagccggagaacaactacaaga
	ccacgcctcccgtgaggactccgacggctccttcacctctactcaaaactcaccgtgg
	acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgctgcatgaggctct
	gcacagccactacacgcagaagagcctctccctgtctccgggt

Light chain B	gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc	SEQ ID
	agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg	NO: 216
	gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca
	gcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttca
	ccctgaagatcaaccgggtagaaaccgaggacgtaggcacctactactgtatgcagg
	gcagagagagcccctggacctttagccaggacaccaagatggacatcaagaacaaa
	acccataccgcatccgaactgactcaggaccctgccgtctctgtggcactgaagcaga
	ctgtgactattacttgccgaggcgactcactgcggagccactacgcttcctggtatcaga
	agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccatctgg
	catccccgaccgcttttctggcagtgcatcagggaaccgagccagtctgaccattaccg
	gcgcccaggctgaggacgaagccgattactattgcagctcccgggataagagcggct
	ccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacccatac
	ccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagt
	ccggcacagcactgtcgtgtacctgagaacaacttctacccccgcgagaccaaagt
	gcagtggaaggtggacaacaccctgcagagcggcaacagccaggaaagcgtgacc
	gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgagcaa
	ggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgt
	ctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 28 Amino Acid Sequences

Heavy chain A	Rahlvqsgtamkkpgasvrvscqts lfwfrqapgrglewvgw	SEQ ID
	nfgggfrdrvtltrdvyreiaymdirglkpddtavyycar	NO: 217
	wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal
	tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd
	kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw
	yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi
	ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain A	yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv	SEQ ID
	psrfsgsgfhtsfnltisdlqaddiatyycqlqffgrgsrlhikrtvaapsvfifppsde	NO: 218
	qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl
	skadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr	SEQ ID
	itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgky	NO: 219
	ydfwsgyppgeeyfqdwgqgtlvivssdkthtqvhltqsgpevrkpgtsv
	kvsckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkak
	vtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwav
	dvdylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgcl
	vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyi
	cnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdt
	lmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynsty
	rvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlp
	pcrdeltknqvslwclvkgfypsdiavevvesngqpennykttppvldsdgs
	fllyskltvdksrwqqgnvfscsvlhealhshytqkslslspg

Light chain B	dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr	SEQ ID
	asgvpdrfsgsgsdkdftikisrvetedvgtyycmqgrespwtfgqgtkvdikdkth	NO: 220
	taseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi
	pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtv
	aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteq
	dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 28 Nucleotide Sequences

Heavy chain A	agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg	SEQ ID
	gtgtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggca	NO: 221
	ggcccctcgcagaggactggaatgggtggatggatcaagccccagtatggcgccg
	tgaacttcagcggaggcaccaggatagagtaaccagacccgggacgtgtaccacg
	agatcgcctacatggacatccggggcctgaagcccgatgacaccgccgtgtactactg
	cgccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagg
	gcacaaccgtggtggtgtagccgcctctacaaagggccccagcgtgttccactggc
	ccctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtggagg
	actactttcccgagcccatgaccatgtcctggaattaggcaccctgaccagcggcgtg
	cacacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtga
	cagtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagc
	ccagcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagaccca
	cacctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccc
	cccaaagcccaaagacaccctgatgatcagccggacccccgaagtaacctacgtggt
	ggtggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacgacgtg
	gaagtgcacaacgccaagaccaagccaagagaaaaacaatacaacagcacctacc
	gggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtaca
	agtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaagg
	ccaagggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacga
	gctgaccaagaaccaggtatccctgaactatgccgtgaaaggcttctacccctccgata
	tcgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccc
	cctgtgctggacaacgacggctcattcttcctagtgtccaaactgacagtggacaagtc
	ccggtggcagcagggcaacgtgttcagctgctccgtgctgcacgaggccctgcacag
	ccactacacccagaagtccctgagcctgagccccggc

Light chain A	tacatccacgtaacccagaaccccagcagcctatccgtatccatcgacgacaaagtg	SEQ ID
	accatcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcac	NO: 222
	aagcctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagaagg
	cgtgcccagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagc
	aatctgcaggccgacgacattgccacctactattgtcaggtactgcagttcttcggcaaa
	ggcagcagactgcacatcaagcgtacaatggccgctcccagcgtgttcatcttcccac
	ctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaactt
	ctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggc
	aacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctga
	gcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgc
	gaagtgacccaccagagcctgtctagccccgtaaccaagaacttcaaccggagcga
	gtgt

Heavy chain B	gaggttagactggtggaatcaggaggggggcttgtgaagcccggtgggtctctccgc	SEQ ID
	ctgagctgttctgcaccagctttgatttcgataacgcctggatgacctgggtcagacaa	NO: 223
	cctccaggtaagggactaaagtgggtaggaagaatcacaggtccaggcgaaggctg
	gtccatggactacacggaatctgttaaagggcggtttacaatctcaaaggacaatacca
	agaataccttgtatttggagatgaacaacgtgagaactgaagacaccggatattacttct
	gtgccagaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatat
	tttcaagactggggtcagggaacccttgttatcgtgtcctccgacaaaacccatacccag
	gtgcacctgacacagagcggacccgaagtgcgaaaacctggcacctagtgaaggt
	gtcctgcaagacccaggcaacaccctgaaaacctacgacctgcactggatgcgcag
	cgtaccaggacaaggactgcaatggatgggctgaatcagccacgagggcgacaag
	aaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagcacc
	aacaccgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtactact
	gcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacgg
	cgccctgaactgagccgtggatgtggactacctgagcaacctggaattaggggccag
	ggcacagccatgaccgtgtcatctgataagacccacaccgcttccaccaagggcccat
	cggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgg
	gctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgc
	cctgaccagcggcgtgcacaccttcccggagtcctacagtcctcaggactctactccc
	tcagcagcgtagtgaccgtgccctccaacagcttgggcacccagacctacatctgcaa
	cgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgt
	gacaaaactcacacatgcccaccgtgcccagcacctaaactcctggggaaaccgtca
	gtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggt
	cacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtat
	gttgacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaa
	cagcacgtaccgtgtggtcaacgtcctcaccgtcctgcaccaggactggctgaatgac
	aaggaatacaagtacaaggtaccaacaaagccctcccagcccccatcgagaaaacc
	atctccaaagccaaagggcagccccgagaaccacaggtgtacaccctacccccatgc
	cgggatgagctgaccaagaatcaagtcagcctgtggtgcctggtaaaaggcttctatcc
	cagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaag
	accacgcctcccgtgctggactccgacggctccttcttcctctactcaaaactcaccgtg
	gacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgctgcatgaggctc
	tgcacagccactacacgcagaagagcctaccagtctccggat

Light chain B	gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc	SEQ ID
	agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg	NO: 224
	gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca
	gcagagccagcggcdgcccgatagatataggcagcggcagcgacaaggacttca
	ccctgaagatcagccgaatggaaaccaaggacatgggcacctactactgtatacagg
	gcagagagagcccaggacctttggccagggcaccaaggtggacatcaaggacaaa
	acccataccgcatccgaactgactcaggaccctgccgtctctgtggcactgaagcaga
	ctgtgactattacttgccgaggcgactcactgcggagccactacgcttcctggtatcaga
	agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccatctgg
	catccccaaccgcttttctggcaatgcatcagagaaccaagccagtctgaccattaccg
	gcacccaagagaggacaaaaccaattactattacaactcccgggataagagcgact
	ccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacccatac
	ccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaag
	tccggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagt
	gcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcggacc
	gagcaagacagcaaggactccacctacagcctgaacaacaccctgacactgagcaa
	ggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgt
	ctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 29 Amino Acid Sequences

Heavy chain A	Rahlvqsgtamkkpgasvrvscqts lfwfrqapgrglewvgw	SEQ ID
	nfgggfrdrvtltrdvyreiaymdirglkpddtavyycar	NO: 225
	wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal
	tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd
	kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw
	yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi
	ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain A	yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedav	SEQ ID
	psrfsgsgfhtsfnltisdlqaddiatyycqlqffgrgsrlhikrtvaapsvfifppsde	NO: 226
	qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl
	skadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr	SEQ ID
	itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk	NO: 227
	yydfwsgyppgeeyfqdwgqgtlvivssdkthtqvhltqsgpevrkpgtsv
	kvsckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkak
	vtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwav
	dvdylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgcl
	vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyi
	cnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdt
	lmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynsty
	rvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlp
	pcrdeltknqvslwclvkgfypsdiavevvesngqpennykttppvldsdgs
	fllyskltvdksrwqqgnvfscsvlhealhshytqkslslspg

Light chain B	dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr	SEQ ID
	asgvpdrfsgsgsdkdftikisrvetedvgtyycmqgrespwtfgqgtkvdikdkth	NO: 228
	taseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi
	pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtv
	aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteq
	dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 29 Nucleotide Sequences

Heavy chain A	agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg	SEQ ID
	gtgtcctgtcagacaagcggctacaccttcaccgcccacatccgttctggttccggcag	NO: 229
	gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg
	aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag
	atcacctacatagacatccagggcctaaaacccgatgacaccaccatgtactactgcg
	ccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagggc
	acaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggcccc
	tagcagcaagagcacatctggcggaacagccgccagggctgcctcgtgaaggacta
	ctttcccgagcccgtgaccgtgtcctggaattaggcgccctgaccagcgggtgcac
	acctttccagctatgctgcagtccagcaacctgtacagcctaagcagcgtcgtgacagt
	gcccagcagctactgggcacccagacctacatctacaacatgaaccacaaacccag
	caacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacacct
	gtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccccccaa
	agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg
	atgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaagt
	gcacaacgccaagaccaagccaagagaaaaacaatacaacagcacctaccgggtg
	gtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgc
	aaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaag
	ggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctga
	ccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgcc
	gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt
	gctgaacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccggt
	ggcagcagggcaacgtgttcagctgctccgtgctgcacgaggccctgcacagccact
	acacccagaagtccctgagcctgagccccggc

Light chain A	tacatccacgtaacccagaaccccagcagcctatccgtatccatcgacgacaaagtga	SEQ ID
	ccatcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaa	NO: 230
	gcctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgt
	gcccagcagattttccggcagcggcttccacaccagcttccagagaccatcagcgatc
	tgcaggccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagaggc
	agcagactgcacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctag
	cgacgagcagagaagtccggcacagcctctgtcgtgtgcctgagaacaacttctacc
	cccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacag
	ccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctgagcagca
	ccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtga
	cccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc	SEQ ID
	ctgagctgactgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag	NO: 231
	cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg
	gtccgtgactacgcggaatctgttaaaggcggatacaatctcaaggpacaatacca
	agaataccttgtatttgaagatgaacaacgtaagaactgaagacaccaaatattacttct
	gtgccagaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatat
	tttcaagactggggtcagggaacccagttatcgtgtcctccgacaaaacccatacccag
	gtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaaggtg
	tcctgcaaggcccctagcaacaccctgaaaacctacgacctgcactgggtgcgcagc
	gtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaaga
	aagtgatcgtggaacagttcaaggccaaaatgaccatcgactaagacagaagcacca
	acaccgcctacctgagctgagcggcctgacctctggcgataccgccgtgtactactg
	cgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacggcg
	ccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggccaggg
	cacagccgtgaccgtgtcatctgataagacccacaccgcttccaccaagagcccatcg
	gtcttccccctggcaccctcctccaagagcacctctgggaacacaacggccctgggct
	gcctgatcaagaactacttccccaaaccaatgacggtgtcgtaaaactcagacgccct
	gaccagcggcatgcacaccttcccggagtcctacaatcctcaaaactctactccctca
	gcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgt
	gaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtga
	caaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagt
	cttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtca
	catgcgtggtagtgaacatgagccacgaagaccctgaggtcaaattcaactggtatgtt
	gacggcgtgaaggtgcataatgccaagacaaagccgcaggaggagcagtacaaca
	gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaa
	ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat
	ctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgcc
	gggatgagctgaccaagaatcaagtcagcctgtggtgcctagtaaaaggcttctatccc
	agcgacatcgccatggagtgagagagcaataggcagccggagaacaactacaaga
	ccacgcctcccgtgaggactccgacggctccttcacctctactcaaaactcaccgtgg
	acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgctgcatgaggctct
	gcacagccactacacgcagaagagcctctccctgtctccgggt

Light chain B	gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgcc	SEQ ID
	agcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctg	NO: 301
	gcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagca
	gcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttca
	ccctgaagatcaaccgggtagaaaccgaggacgtaggcacctactactgtatgcagg
	gcagagagagcccctggacctttagccaggacaccaagatggacatcaagaacaaa
	acccataccgcatccgaactgactcaggaccctgccgtctctgtggcactgaagcaga
	ctgtgactattacttgccgaggcgactcactgcggagccactacgcttcctggtatcaga
	agaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccatctgg
	catccccgaccgcttttctggcagtgcatcagggaaccgagccagtctgaccattaccg
	gcgcccaggctgaggacgaagccgattactattgcagctcccgggataagagcggct
	ccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacccatac
	ccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagt
	ccggcacagcactgtcgtgtacctgagaacaacttctacccccgcgagaccaaagt
	gcagtggaaggtggacaacaccctgcagagcggcaacagccaggaaagcgtgacc
	gagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgagcaa
	ggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgt
	ctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 30 Amino Acid Sequences

Heavy chain A	Rahlvqsgtamkkpgasvrvscqts lfwfrqapgrglewvgwi	SEQ ID
	nfgggfrdrvtltrdvyreiaymdirglkpddtavyycar	NO: 232
	wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal
	tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd
	kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw
	yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi
	ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain A	yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedav	SEQ ID
	psrfsgsgfhtsfnltisdlqaddiatyycqlqffgrgsrlhikrtvaapsvfifppsde	NO: 233
	qlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl
	skadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr	SEQ ID
	itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk	NO: 234
	yydfwsgyppgeeyfqdwgqgtlvivssdkthtqvhltqsgpevrkpgtsv
	kvsckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkak
	vtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwav
	dvdylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgcl
	vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyi
	cnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdt
	lmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynsty
	rvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlp
	pcrdeltknqvslwclvkgfypsdiavevvesngqpennykttppvldsdgs
	fllyskltvdksrwqqgnvfscsvlhealhshytqkslslspg

Light chain B	dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr	SEQ ID
	asgvpdrfsgsgsdkdftikisrvetedvgtyycmqgrespwtfgqgtkvdikdkth	NO: 235
	taseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi
	pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtv
	aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteq
	dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 30 Nucleotide Sequences

Heavy chain A	agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg	SEQ ID
	gtgtcctgtcagacaagcggctacaccttcaccgcccacatccgttctggttccggcag	NO: 236
	gcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtg
	aacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgag
	atcacctacatagacatccagggcctaaaacccgatgacaccaccatgtactactgcg
	ccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagggc
	acaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggcccc
	tagcagcaagagcacatctggcggaacagccgccagggctgcctcgtgaaggacta
	ctttcccgagcccgtgaccgtgtcctggaattaggcgccctgaccagcgggtgcac
	acctttccagctatgctgcagtccagcaacctgtacagcctaagcagcgtcgtgacagt
	gcccagcagctactgggcacccagacctacatctacaacatgaaccacaaacccag
	caacaccaaggtggacaagaaggtggaacccaagagctgcgacaagacccacacct
	gtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccccccaa
	agcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtggtgg
	atgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtggaagt
	gcacaacgccaagaccaagccaagagaaaaacaatacaacagcacctaccgggtg
	gtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgc
	aaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaaggccaag
	ggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacgagctga
	ccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgatatcgcc
	gtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgt
	gctgaacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtcccggt
	ggcagcagggcaacgtgttcagctgctccgtgctgcacgaggccctgcacagccact
	acacccagaagtccctgagcctgagccccggc

Light chain A	tacatccacgtaacccagaaccccagcagcctatccgtatccatcgacgacaaagtga	SEQ ID
	ccatcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaa	NO: 237
	gcctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgt
	gcccagcagattttccggcagcggcttccacaccagcttccagagaccatcagcgat
	ctgcaggccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagagg
	cagcagactgcacatcaagcgtacggtggccgctcccagcgtgttcatcttcccaccta
	gcgacgagcagagaagtccggcacagcctctgtcgtgtgcctgagaacaacttctac
	ccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaaca
	gccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctgagcag
	caccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagt
	gacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc	SEQ ID
	ctgagctgactgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag	NO: 238
	cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg
	gtccgtgactacgcggaatctgttaaaggcggatacaatctcaaggpacaatacca
	agaataccttgtatttgaagatgaacaacgtaagaactgaagacaccaaatattacttct
	gtgccagaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatat
	tttcaagactggggtcagggaacccagttatcgtgtcctccgacaaaacccatacccag
	gtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaaggtg
	tcctgcaaggcccctagcaacaccctgaaaacctacgacctgcactgggtgcgcagc
	gtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaaga
	aagtgatcgtggaacagttcaaggccaaaatgaccatcgactaagacagaagcacca
	acaccgcctacctgagctgagcggcctgacctctggcgataccgccgtgtactactg
	cgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacggcg
	ccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggccaggg
	cacagccgtgaccgtgtcatctgataagacccacaccgcttccaccaagagcccatcg
	gtcttccccctggcaccctcctccaagagcacctctgggaacacaacggccctgggct
	gcctgatcaagaactacttccccaaaccaatgacggtgtcgtaaaactcagacgccct
	gaccagcggcatgcacaccttcccggagtcctacaatcctcaaaactctactccctca
	gcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgt
	gaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtga
	caaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagt
	cttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtca
	catgcgtggtagtgaacatgagccacgaagaccctgaggtcaaattcaactggtatgtt
	gacggcgtgaaggtgcataatgccaagacaaagccgcaggaggagcagtacaaca
	gcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaa
	ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccat
	ctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgcc
	gggatgagctgaccaagaatcaagtcagcctgtggtgcctagtaaaaggcttctatccc
	agcgacatcgccatggagtgagagagcaataggcagccggagaacaactacaaga
	ccacgcctcccgtgaggactccgacggctccttcacctctactcaaaactcaccgtgg
	acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgctgcatgaggctct
	gcacagccactacacgcagaagagcctctccctgtctccgggt

Light chain B	Gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgc	SEQ ID
	cagcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacct	NO: 239
	ggcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagc
	agcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttc
	accctgaagatcaaccgggtagaaaccgaggacgtaggcacctactactgtatgcag
	ggcagagagagcccctggacctttagccaggacaccaagatggacatcaagaacaa
	aacccataccgcatccgaactgactcaggaccctgccgtctctgtggcactgaagcag
	actgtgactattacttgccgaggcgactcactgcggagccactacgcttcctggtatcag
	aagaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccatctg
	gcatccccgaccgcttttctggcagtgcatcagggaaccgagccagtctgaccattacc
	ggcgcccaggctgaggacgaagccgattactattgcagctcccgggataagagcggc
	tccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacccata
	cccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaa
	gtccggcacagcactgtcgtgtacctgagaacaacttctacccccgcgagaccaaa
	gtgcagtggaaggtggacaacaccctgcagagcggcaacagccaggaaagcgtga
	ccgagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgagc
	aaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcct
	gtctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 31 Amino Acid Sequences

Heavy chain A	Rahlvqsgtamkkpgasvrvscqts ilfwfrqapgrglewvgw	SEQ ID
	nfgggfrdrvtltrdvyreiaymdirglkpddtavyycar	NO: 240
	wgqgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgal
	tsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscd
	kthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnw
	yvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapi
	ektiskakgqprepqvetlppsrdeltknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsdgsfflvskltvdksrwqqgnvfscsvmhealhnhytqkslslspg

Light chain A	Yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssveda	SEQ ID
	vpsrfsgsgfhtsfnltisdlqaddiatyycqlqffgrgsrlhikrtvaapsvfifppsd	NO: 241
	eqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt
	lskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Evrlvesggglvkpggslrlscsasgfdfdnawmtwvrqppgkglewvgr	SEQ ID
	itgpgegwsvdyaesvkgrftisrdntkntlylemnnvrtedtgyyfcartgk	NO: 242
	yydfwsgyppgeeyfqdwgqgtlvivssdkthtqvhltqsgpevrkpgtsv
	kvsckapgntlktydlhwvrsvpgqglqwmgwishegdkkviverfkak
	vtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddgalnwav
	dvdylsnlefwgqgtavtvssdkthtastkgpsvfplapsskstsggtaalgcl
	vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyi
	cnvnhkpsntkvdkkvepkscdkthtcppcpapellggpsvflfppkpkdt
	lmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynsty
	rvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlp
	pcrdeltknqvslwclvkgfypsdiavevvesngqpennykttppvldsdgs
	fllyskltvdksrwqqgnvfscsvlhealhshytqkslslspg

Light chain B	dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassr	SEQ ID
	asgvpdrfsgsgsdkdftikisrvetedvgtyycmqgrespwtfgqgtkvdikdkth	NO: 243
	taseltqdpavsvalkqtvtitcrgdslrshyaswyqkkpgqapvllfygknnrpsgi
	pdrfsgsasgnrasltitgaqaedeadyycssrdksgsrlsvfgggtkltvldkthtrtv
	aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteq
	dskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 31 Nucleotide Sequences

Heavy chain A	agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgg	SEQ ID
	gtgtcctgtcagacaagcggctacaccttcaccgcccacatccgttctggttccggca	NO: 244
	ggcccctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccg
	tgaacttcggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcg
	agatcacctacatagacatccagggcctaaaacccgatgacaccaccatgtactactg
	cgccagagacagaagctacggcgacagcagctgggctctggatgcttggggccagg
	gcacaaccgtggtggtgtctgccgcctctacaaagggccccagcgtgttccctctggc
	ccctagcagcaagagcacatctggcggaacagccgccctgggctgcctcgtgaagg
	actactttcccgagcccgtgaccgtgtcctggaattctggcgccctgaccagcggcgtg
	cacacctttccagctgtgctgcagtccagcggcctgtacagcctgagcagcgtcgtga
	cagtgcccagcagctctctgggcacccagacctacatctgcaacgtgaaccacaagc
	ccagcaacaccaaggtggacaagaaggtggaacccaagagctgcgacaagaccca
	cacctgtcccccttgtcctgcccccgaactgctgggaggcccttccgtgttcctgttccc
	cccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggt
	ggtggatgtgtcccacgaggaccctgaagtgaagttcaattggtacgtggacggcgtg
	gaagtgcacaacgccaagaccaagccaagagaaaaacagtacaacagcacctacc
	gggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtaca
	agtgcaaggtgtccaacaaggccctgcctgcccccatcgagaaaaccatcagcaagg
	ccaagggccagccccgcgaaccccaggtgtgcacactgcccccaagcagggacga
	gctgaccaagaaccaggtgtccctgagctgtgccgtgaaaggcttctacccctccgata
	tcgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccc
	cctgtgctgaacagcgacggctcattcttcctggtgtccaagctgacagtggacaagtc
	ccggtggcagcagggcaacgtgttcagctgctccgtgctgcacgaggccctgcacag
	ccactacacccagaagtccctgagcctgagccccggc

Light chain A	tacatccacgtaacccagaaccccagcagcctatccgtatccatcgacgacagagtg	SEQ ID
	accatcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcac	NO: 245
	aagcctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatgc
	cgtgcccagcagattttccggcagcggcttccacaccagcttccagagaccatcagc
	gatctgcaggccgacgacattgccacctactattgtcaggtgctgcagttcttcggcaga
	ggcagcagactgcacatcaagcgtacggtggccgctcccagcgtgttcatcttcccac
	ctagcgacgagcagagaagtccggcacagcctctgtcgtgtgcctgagaacaactt
	ctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggc
	aacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctga
	gcagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgc
	gaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga
	gtgt

Heavy chain B	gaggttagactggtggagtcaggaggggggcttgtgaagcccggtgggtctctccgc	SEQ ID
	ctgagctgactgcctccggctttgatttcgataacgcctggatgacctgggtcaggcag	NO: 246
	cctccaggtaagggactggagtgggtgggaagaatcacaggtccaggcgagggctg
	gtccgtgactacgcggaatctgttaaaggcggatacaatctcaaggpacaatacca
	agaataccttgtatttgaagatgaacaacgtaagaactgaagacaccaaatattacttct
	gtgccagaacaggcaaatactacgacttctggtccggctatccccctggcgaggaatat
	tttcaagactggggtcagggaacccagttatcgtgtcctccgacaaaacccatacccag
	gtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaaggt
	gtcctgcaaggcccctagcaacaccctgaaaacctacgacctgcactgggtgcgcag
	cgtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaag
	aaagtgatcgtggaacagttcaaggccaaaatgaccatcgactaagacagaagcacc
	aacaccgcctacctgagctgagcggcctgacctctggcgataccgccgtgtactact
	gcgccaagggcagcaagcaccggctgagagactacgccctgtacgacgatgacgg
	cgccctgaactgggccgtggatgtggactacctgagcaacctggaattctggggccag
	ggcacagccgtgaccgtgtcatctgataagacccacaccgcttccaccaagagcccat
	cggtcttccccctggcaccctcctccaagagcacctctgggggcacaacggccctgg
	gctgcctgatcaagaactacttccccaaaccaatgacggtgtcgtaaaactcaggcgc
	cctgaccagcggcatgcacaccttcccggagtcctacaatcctcaaaactctactccc
	tcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaa
	cgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgt
	gacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtca
	gtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggt
	cacatgcgtggtagtgaacatgagccacgaagaccctgaggtcaaattcaactggtat
	gttgacggcgtgaaggtgcataatgccaagacaaagccgcaggaggagcagtacaa
	cagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc
	aaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaacc
	atctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatgc
	cgggatgagctgaccaagaatcaagtcagcctgtggtgcctagtaaaaggcttctatcc
	cagcgacatcgccatggagtgagagagcaataggcagccggagaacaactacaag
	accacgcctcccgtgaggactccgacggctccttcacctctactcaaaactcaccgtg
	gacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgctgcatgaggctc
	tgcacagccactacacgcagaagagcctctccctgtctccgggt

Light chain B	Gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgc	SEQ ID
	cagcatcagctgcaagagcagccactccctgatccacggcgaccggaacaactacct	NO: 247
	ggcttggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagc
	agcagagccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttc
	accctgaagatcaaccgggtagaaaccgaggacgtaggcacctactactgtatgcag
	ggcagagagagcccctggacctttagccaggacaccaagatggacatcaagaacaa
	aacccataccgcatccgaactgactcaggaccctgccgtctctgtggcactgaagcag
	actgtgactattacttgccgaggcgactcactgcggagccactacgcttcctggtatcag
	aagaaacccggccaggcacctgtgctgctgttctacggaaagaacaataggccatctg
	gcatccccgaccgcttttctggcagtgcatcagggaaccgagccagtctgaccattacc
	ggcgcccaggctgaggacgaagccgattactattgcagctcccgggataagagcgg
	ctccagactgagcgtgttcggaggaggaactaaactgaccgtcctcgataagacccat
	acccgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctga
	agtccggcacagcactgtcgtgtacctgagaacaacttctacccccgcgagaccaa
	agtgcagtggaaggtggacaacaccctgcagagcggcaacagccaggaaagcgtg
	accgagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgag
	caaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcc
	tgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 32 Amino Acid Sequences

Heavy chain A	Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqyq	SEQ ID
	avnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswaldawg	NO: 302
	qgttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgv
	htfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcpp
	cpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvev
	hnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakg
	qprepqvytlppcqeemtknqvslwclvkgfypsdiavewesngqpennykttpp
	vldsdgsfflyskltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv	SEQ ID
	psrfsgsgfhtsfnltisdlqaddiatyycqlqffgrgsrlhikrtvaapsvfifppsdeq	NO: 303
	lksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlsk
	adyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvqlvqsgaevvkpgasvkvsckas ihwvrqapgqglewigs	SEQ ID
	nyaqkfqgratltvdtsistaymelsrlrsddtavyyc	NO: 304
	wgkgttvlvsssqvqlvesgggvvqpgrslrlscaas mhw
	vrqapgkqlewvaq yatyyadsvkgrftisrddskntlylqmmslr
	aedtavyy wgqgtlvtvssrtastkgpsvfplapcsrstses
	taalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpsssl
	gtktytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkp
	kdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfns
	tyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctl
	ppsqeemtknqvslscavkgfypsdiavewesngqpennykttppvldsd
	gsfflvskltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain B	Divmtqtplslsvtpgqpasisckss lswylqkpgqspgsliy	SEQ ID
	nrfsgvpdrfsgsgsgtdftlkisrveaedvgvyyc ftfgsgtkveikgqpk	NO: 305
	aapdiqmtqspsslsasvgdrvtitcqas lnwyqqkpgkapklliykasnl
	htgvpsrfsgsgsgtdftltisslqpediatyyc fgqgtkleiktkpsrtv
	aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqd
	skdstyslsstltlskadyekhkvyacevthqglsspvtksfngec

Binding Protein 32 Nucleotide Sequences

Heavy chain A	agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgggt	SEQ ID
	gtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcaggcc	NO: 306
	cctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtgaactt
	cggcggaggcttccgggatagaatgaccctgacccaggacgtgtaccgcgagatcgcc
	tacatggacatccggggcctgaagcccgatgacaccgccatgtactactgcgccagaga
	cagaagctacggcgacagcagctgggctctggatgcttggggccagggcacaaccgtg
	gtggtgtctgccgcctctacaaagggcccctcggtgaccctctggccccttgcagcagaa
	gcaccagcgaatctacagccgccctgggctgcctcgtgaaggactacatcccgagcccg
	tgaccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgct
	ccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgg
	gcaccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaa
	gcgggtggaatctaagtacggccctccctgccctccttgcccagcccctgaatactgggc
	ggaccctccgtgttcctgttccccccaaagcccaaggacaccctgatgatcagccggacc
	cccgaagtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaat
	tggtacgtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagt
	tcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacg
	gcaaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaacc
	atcagcaaggccaagggccagccccgcgagcctcaagtgtataccagcccccttgcca
	ggaagagatgaccaagaaccaggtgtccagtagtgtacgtgaaaggcactaccccag
	cgacattaccgtggaatgggagagcaacggccagcccgagaacaactacaagaccacc
	ccccctgtgctggacagcgacggctcattcttcctgtactccaagctgaccgtggacaaga
	gccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaac
	cactacacccagaagtccctgtctctgtccctgggcaag

Light chain A	Tacatccacgtgacccaaagccccaacaacctgtccatgtccatcggcaacagaatgac	SEQ ID
	catcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaagc	NO: 307
	ctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcc
	cagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagcgatctgcag
	gccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagagcagcagac
	tgcacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagc
	agctgaagtccggcacagcctctgtcgtgtgcctgctgattcaacttctacccccgcgagg
	ccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcg
	tgaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgag
	caaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcag
	tctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc	NO: 308
	ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact
	acgcccagaagaccagggcagagccaccctgaccgtgaacaccagcatcagcaccgc
	ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt
	cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg
	tctagcagccaggtgcagaggtggaataggcggcggagtggtgcagcaggcagaa
	gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg
	tgcgccaggcccaggaaagcagctggaatgggtggcccagatcaaggacaagagcaa
	cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac
	gacagcaagaacaccctatacctgcagatgaacagcctacgggccgaggacaccacca
	tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac
	cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc
	cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaactctggcgactgacaagcggcgtgcaca
	cctttccagccatgaccagagcagcagcctgtactactgagcagcgtcgtgacagtgcc
	cagcagcagcctgggcaccaagacctacacctataacatggaccacaaacccaacaac
	accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc
	cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga
	tgatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc
	gaggtgcagttcaattggtacgtggacggctgtggaagtgcacaacgccaagaccaagcc
	cagagaagaacagttcaacagcacctaccaggtgatgtccatgctgaccatgctgcacc
	aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag
	ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta
	ccctgccccctagccaggaagagatgaccaagaaccaggtgtccctgagctgtgccgtg
	aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga
	acaactacaagaccaccccccctgtgaggacagcgacggctcattcttcctggtgtccaa
	gctgaccgtggacaagagccagtgacaggaaggcaacgtgttcagctgctccgtgatgc
	acgaggccctgcacaaccactacacccagaagtccctgtactgtccctgggcaag

Light chain B	gacatcgtgatgacccagacccccctgagcctaagcgtgacacctggacagcctgccag	SEQ ID
	catcagctgcaagagcagccagagcctggtacacaacaacaccaacacctacctgagct	NO: 309
	ggtatctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagat
	tcagcggcgtgcccgacagatctccggcagcggctctggcaccgacttcaccctgaag
	atcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagta
	ccccttcacctttggcagcggcaccaaggtggaaatcaagggccagcccaaggccgcc
	cccgacatccagatgacccagagccccagcagcagtctgccagcgtgggcgacagag
	tgaccatcacctgtcaggccagccagaacatctacgtgtggctgaactggtatcagcaga
	agcccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgt
	gcccagcagattttctgacaacggctccgacaccgacttcaccctgacaatcagctccctg
	cagcccgaggacattgccacctactactgccagcagaaccagacctacccctacaccttt
	ggccagggcaccaagaggaaatcaagaccaagggccccagccgtacggtggccgct
	cccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctagtc
	gtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtggaaggtggacaa
	cgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactc
	cacctacagcctgagcagcaccctgacactgagcaaggccgactacgagaagcacaag
	gtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaac
	cggggcgagtgt

Binding Protein 33 Amino Acid Sequences

Heavy chain A	Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikpqyga	SEQ ID
	vnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdsswaldawgqg	NO: 310
	ttvvvsaastkgpsvfplapsskstsggtaalgclvkdyfpepvtvswnsgaltsgvhtfp
	avlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpape
	flggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktk
	preeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqv
	ytlppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsff
	lyskltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgvp	SEQ ID
	srfsgsgfhtsfnltisdlqaddiatyycqlqffgrgsrlhikrtvaapsvfifppsdeqlks	NO: 311
	gtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskadye
	khkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwa	SEQ ID
	gggtnynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysm	NO: 312
	dywgqgttvtvsssqvqlvesgggvvqpgrslrlscaasgftftkawmhwvrq
	apgkqlewvaqikdksnsyatyyadsvkgrftisrddskntlylqmmslraedt
	avyycrgvyyalspfdywgqgtlvtvssrtastkgpsvfplapcsrstsestaalg
	clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktyt
	cnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtlmis
	rtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvlt
	vlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsqeemt
	knqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvskltv
	dksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain B	Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgqspgsliykvsnr	SEQ ID
	fsgvpdrfsgsgsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveikgqpkaa	NO: 313
	pdivltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnv
	esgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleiktkgpsrt
	vaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqd
	skdstyslsstltlskadyekhkvyacevthqglsspvtksfngec

Binding Protein 33 Nucleotide Sequences

Heavy chain A	agagcccacctggtgcagtctggcaccgccatgaagaaaccaggcgcctctgtgcgggt	SEQ ID
	gtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcaggcc	NO: 314
	cctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtgaactt
	cggcggaggcttccgggatagaatgaccctgacccaggacgtgtaccgcgagatcgcc
	tacatggacatccggggcctgaagcccgatgacaccgccatgtactactgcgccagaga
	cagaagctacggcgacagcagctgggctctggatgcttggggccagggcacaaccgtg
	gtggtgtctgccgcctctacaaagggcccctcggtgaccctctggccccttgcagcagaa
	gcaccagcgaatctacagccgccctgggctgcctcgtgaaggactacatcccgagcccg
	tgaccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgct
	ccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgg
	gcaccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaa
	gcgggtggaatctaagtacggccctccctgccctccttgcccagcccctgaatactgggc
	ggaccctccgtgttcctgttccccccaaagcccaaggacaccctgatgatcagccggacc
	cccgaagtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaat
	tggtacgtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagt
	tcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacg
	gcaaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaacc
	atcagcaaggccaagggccagccccgcgagcctcaagtgtataccagcccccttgcca
	ggaagagatgaccaagaaccaggtgtccagtagtgtacgtgaaaggcactaccccag
	cgacattaccgtggaatgggagagcaacggccagcccgagaacaactacaagaccacc
	ccccctgtgctggacagcgacggctcattcttcctgtactccaagctgaccgtggacaaga
	gccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaac
	cactacacccagaagtccctgtctctgtccctgggcaag

Light chain A	Tacatccacgtgacccaaagccccaacaacctgtccatgtccatcggcaacagaatgac	SEQ ID
	catcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaagc	NO: 315
	ctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcc
	cagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagcgatctgcag
	gccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagagcagcagac
	tgcacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagc
	agctgaagtccggcacagcctctgtcgtgtgcctgctgattcaacttctacccccgcgagg
	ccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaagcg
	tgaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgacactgag
	caaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcag
	tctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct	SEQ ID
	gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagc	NO: 316
	cacctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaacta
	caaccccagcctgaagtccagaaagaccatcagcaaggacaccagcaagaaccaggtg
	tccctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagaga
	caagggctacagctactactacagcatggactactggggccagggcaccaccgtgaccg
	tgtcatcctctcaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa
	gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg
	tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa
	cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac
	gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg
	tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac
	cctcgtgaccgtgtctagtcggaccgcttcgaccaagggcccatcggtgttccctctggcc
	ccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggacta
	ctttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcacac
	ctttccagccatgctccagagcagcagcctgtactctctgagcaacgtcgtaacagtgccc
	agcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaaca
	ccaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagccc
	ctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctgat
	gatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatcccg
	aggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagccc
	agagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacca
	ggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccagc
	tccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgtac
	cctgccccctagccaggaagagatgaccaagaaccaggtgtccctgagctgtgccgtga
	aaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgagaa
	caactacaagaccaccccccctgtgctggacagcgacggctcattcttcctggtgtccaag
	ctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgca
	cgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag

Light chain B	gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag	SEQ ID
	catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct	NO: 317
	ggtatctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagat
	tcagcggcgtgcccgacagattctccggcagcggctctggcaccgacttcaccctgaag
	atcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagta
	ccccttcacctttggcagcggcaccaaggtggaaatcaagggccagcccaaggccgcc
	cccgacatcgtgctgacacagagccctgctagcctggccgtgtctcctggacagagggc
	caccatcacctgtagagccagcgagagcgtggaatattacgtgaccagcctgatgcagtg
	gtatcagcagaagcccggccagccccccaagctgctgattttcgccgccagcaacgtgg
	aaagcggcgtgccagccagattttccggcagcggctctggcaccgacttcaccctgacca
	tcaaccccgtggaagccaacgacgtggccaactactactgccagcagagccggaaggt
	gccctacacctttggccagggcaccaagctggaaatcaagaccaagggccccagccgta
	cggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggca
	cagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtgga
	aggtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggac
	agcaaggactccacctacagcctgagcagcaccctgacactgagcaaggccgactacg
	agaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgacc
	aagagcttcaaccggggcgagtgt

Binding Protein 34 Amino Acid Sequences

Heavy chain A	Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwisheg	SEQ ID
	dkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddga	NO: 318
	lnwavdvdylsnlefwgqgtavtvssastkgpsvfplapcsrstsestaalgclvkdyfp
	epvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkv
	dkrveskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpe
	vqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkgl
	pssiektiskakgqprepqvytlppcqeemtknqvslwclvkgfypsdiavewesng
	qpennykttppvldsdgsfflyskltvdksrwqegnvfscsvmhealhnhytqkslsls
	lgk

Light chain A	Dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassras	SEQ ID
	gvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikrtvaapsv	NO: 319
	fifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstys
	lsstltlskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvqlvqsgaevvkpgasvkvsckas ihwvrqapgqglewigs	SEQ ID
	nyaqkfqgratltvdtsistaymelsrlrsddtavyyc	NO: 320
	wgkgttvlvsssqvqlvesgggvvqpgrslrlscaas mhwvrq
	apgkqlewvaq yatyyadsvkgrftisrddskntlylqmmslraedt
	avyyc wgqgtlvtvssrtastkgpsvfplapcsrstsestaalg
	clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktyt
	cnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtlmis
	rtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvlt
	vlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsqeemt
	knqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvskltv
	dksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain B	Divmtqtplslsvtpgqpasisckss lswylqkpgqspgsliykvsnr	SEQ ID
	fsgvpdrfsgsgsgtdftlkisrveaedvgvyyc ftfgsgtkveikgqpkaap	NO: 321
	diqmtqspsslsasvgdrvtitcqasq lnwyqqkpgkapklliy nlhtgv
	psrfsgsgsgtdftltisslqpediatyyc fgqgtkleiktkpsrtvaapsvf
	ifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysl
	sstltlskadyekhkvyacevthqglsspvtksfngec

Binding Protein 34 Nucleotide Sequences

Heavy chain A	caggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaagg	SEQ ID
	tgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcgcagc	NO: 322
	gtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaagaaa
	gtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagcaccaacac
	cgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtactactgcgccaa
	gggcagcaagcaccggctgagagactacgccctgtacgacgatgacggcgccctgaac
	tgggccgtggatgtggactacctgagcaacctggaattctggggccagggcacagccgt
	gaccgtgtcatctgcttcgaccaagggcccctcggtgttccctctgaccccttgcagcaga
	agcaccagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagccc
	gtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtg
	ctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcct
	gggcaccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggac
	aagcgggtggaatctaagtacggccctccctgccctccttgcccagcccctgaatttctgg
	gcggaccctccgtgttcctgttccccccaaagcccaaggacaccctgatgatcagccgga
	cccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttca
	attggtacgtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaaca
	gttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaa
	cggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaa
	accatcagcaaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttg
	ccaggaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccc
	cagcgacattgccgtggaatgggagagcaacggccagcccgagaacaactacaagacc
	accccccctgtgctggacagcgacggctcattcttcctgtactccaagctgaccgtggaca
	agagccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcac
	aaccactacacccagaagtccctgtctctgtccctgggcaag

Light chain A	gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgccag	SEQ ID
	catcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctggctt	NO: 323
	ggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcaga
	gccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttcaccctgaa
	gatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcagagag
	agcccctggacctttggccagggcaccaaggtggacatcaagcgtacggtggccgctcc
	cagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctctgtcgtg
	tgcctgctgaacaacttctacccccgcgaggccaaagtgcagtggaaggtggacaacgc
	cctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactccac
	ctacagcctgagcagcaccctgacactgagcaaggccgactacgagaagcacaaggtg
	tacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccg
	gggcgagtgt

Heavy chain B	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc	NO: 324
	ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact
	acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt
	cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg
	tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa
	gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg
	tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa
	cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac
	gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg
	tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac
	cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc
	cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca
	cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc
	cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac
	accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc
	cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga
	tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc
	gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc
	cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc
	aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag
	ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta
	ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg
	aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga
	acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa
	gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc
	acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag

Light chain B	gacatcgtgatgacccagacccccctgagcctaagcgtgacacctggacagcctgccag	SEQ ID
	catcagctgcaagagcagccagagcctggtacacaacaacaccaacacctacctgagct	NO: 325
	ggtatctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagat
	tcagcggcgtgcccgacagatctccggcagcggctctggcaccgacttcaccctgaag
	atcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagta
	ccccttcacctttggcagcggcaccaaggtggaaatcaagggccagcccaaggccgcc
	cccgacatccagatgacccagagccccagcagcagtctgccagcgtgggcgacagag
	tgaccatcacctgtcaggccagccagaacatctacgtgtggctgaactggtatcagcaga
	agcccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgt
	gcccagcagattttctgacaacggctccgacaccgacttcaccctgacaatcagctccctg
	cagcccgaggacattgccacctactactgccagcagaaccagacctacccctacaccttt
	ggccagggcaccaagaggaaatcaagaccaagggccccagccgtacggtggccgct
	cccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctagtc
	gtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtggaaggtggacaa
	cgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactc
	cacctacagcctgagcagcaccctgacactgagcaaggccgactacgagaagcacaag
	gtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaac
	cggggcgagtgt

Binding Protein 35 Amino Acid Sequences

Heavy chain A	Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwisheg	SEQ ID
	dkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrdyalydddga	NO: 326
	lnwavdvdylsnlefwgqgtavtvssastkgpsvfplapcsrstsestaalgclvkdyfp
	epvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkv
	dkrveskygppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpe
	vqfnwyvdgvevhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkgl
	pssiektiskakgqprepqvytlppcqeemtknqvslwclvkgfypsdiavewesng
	qpennykttppvldsdgsfflyskltvdksrwqegnvfscsvmhealhnhytqkslsls
	lgk

Light chain A	Dfvltqsphslsvtpgesasiscksshslihgdrnnylawyvqkpgrspqlliylassras	SEQ ID
	gvpdrfsgsgsdkdftlkisrvetedvgtyycmqgrespwtfgqgtkvdikrtvaapsv	NO: 327
	fifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstys
	lsstltlskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwa	SEQ ID
	gggtnynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysm	NO: 328
	dywgqgttvtvsssqvqlvesgggvvqpgrslrlscaasgftftkawmhwvrq
	apgkqlewvaqikdksnsyatyyadsvkgrftisrddskntlylqmmslraedt
	avyycrgvyyalspfdywgqgtlvtvssrtastkgpsvfplapcsrstsestaalg
	clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktyt
	cnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtlmis
	rtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvlt
	vlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsqeemt
	knqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvskltv
	dksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain B	Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgqspgsliykvsnr	SEQ ID
	fsgvpdrfsgsgsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveikgqpkaa	NO: 329
	pdivltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnv
	esgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleiktkgpsrt
	vaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqd
	skdstyslsstltlskadyekhkvyacevthqglsspvtksfngec

Binding Protein 35 Nucleotide Sequences

Heavy chain A	caggtgcacctgacacagagcggacccgaagtgcggaagcctggcacctctgtgaagg	SEQ ID
	tgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcactgggtgcgcagc	NO: 330
	gtgccaggacagggactgcagtggatgggctggatcagccacgagggcgacaagaaa
	gtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacagaagcaccaacac
	cgcctacctgcagctgagcggcctgacctctggcgataccgccgtgtactactgcgccaa
	gggcagcaagcaccggctgagagactacgccctgtacgacgatgacggcgccctgaac
	tgggccgtggatgtggactacctgagcaacctggaattctggggccagggcacagccgt
	gaccgtgtcatctgcttcgaccaagggcccctcggtgttccctctgaccccttgcagcaga
	agcaccagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagccc
	gtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtg
	ctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcct
	gggcaccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggac
	aagcgggtggaatctaagtacggccctccctgccctccttgcccagcccctgaatttctgg
	gcggaccctccgtgttcctgttccccccaaagcccaaggacaccctgatgatcagccgga
	cccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttca
	attggtacgtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaaca
	gttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaa
	cggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaa
	accatcagcaaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttg
	ccaggaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccc
	cagcgacattgccgtggaatgggagagcaacggccagcccgagaacaactacaagacc
	accccccctgtgctggacagcgacggctcattcttcctgtactccaagctgaccgtggaca
	agagccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcac
	aaccactacacccagaagtccctgtctctgtccctgggcaag

Light chain A	gacttcgtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgccag	SEQ ID
	catcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctggctt	NO: 331
	ggtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcaga
	gccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttcaccctgaa
	gatcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcagagag
	agcccctggacctttggccagggcaccaaggtggacatcaagcgtacggtggccgctcc
	cagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctctgtcgtg
	tgcctgctgaacaacttctacccccgcgaggccaaagtgcagtggaaggtggacaacgc
	cctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactccac
	ctacagcctgagcagcaccctgacactgagcaaggccgactacgagaagcacaaggtg
	tacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccg
	gggcgagtgt

Heavy chain B	caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct	SEQ ID
	gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagc	NO: 332
	cacctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaacta
	caaccccagcctgaagtccagaaagaccatcagcaaggacaccagcaagaaccaggtg
	tccctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagaga
	caagggctacagctactactacagcatggactactggggccagggcaccaccgtgaccg
	tgtcatcctctcaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa
	gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg
	tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa
	cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac
	gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg
	tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac
	cctcgtgaccgtgtctagtcggaccgcttcgaccaagggcccatcggtgttccctctggcc
	ccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggacta
	ctttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcacac
	ctttccagccatgctccagagcagcagcctgtactctctgagcaacgtcgtaacagtgccc
	agcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaaca
	ccaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagccc
	ctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctgat
	gatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatcccg
	aggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagccc
	agagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacca
	ggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccagc
	tccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgtac
	cctgccccctagccaggaagagatgaccaagaaccaggtgtccctgagctgtgccgtga
	aaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgagaa
	caactacaagaccaccccccctgtgctggacagcgacggctcattcttcctggtgtccaag
	ctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgca
	cgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag

Light chain B	gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag	SEQ ID
	catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct	NO: 333
	ggtatctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagat
	tcagcggcgtgcccgacagattctccggcagcggctctggcaccgacttcaccctgaag
	atcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagta
	ccccttcacctttggcagcggcaccaaggtggaaatcaagggccagcccaaggccgcc
	cccgacatcgtgctgacacagagccctgctagcctggccgtgtctcctggacagagggc
	caccatcacctgtagagccagcgagagcgtggaatattacgtgaccagcctgatgcagtg
	gtatcagcagaagcccggccagccccccaagctgctgattttcgccgccagcaacgtgg
	aaagcggcgtgccagccagattttccggcagcggctctggcaccgacttcaccctgacca
	tcaaccccgtggaagccaacgacgtggccaactactactgccagcagagccggaaggt
	gccctacacctttggccagggcaccaagctggaaatcaagaccaagggccccagccgta
	cggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggca
	cagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtgga
	aggtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggac
	agcaaggactccacctacagcctgagcagcaccctgacactgagcaaggccgactacg
	agaagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgacc
	aagagcttcaaccggggcgagtgt

Binding Protein 36 Amino Acid Sequences

Heavy chain A	Qvqlvqsggqmkkpgesmriscrasgyefidctlnwirlapgkrpewmgwlkprg	SEQ ID
	gavnyarplqgrvtmtrdvysdtaflelrsltvddtavyftrgkncdynwdfehwgrg	NO: 334
	tpvivssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfp
	avlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpape
	flggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktk
	preeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqv
	ytlppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsff
	lyskltvdksrwqegnvfscsvmheallnhytqkslslslgk

Light chain A	Eivltqspgtlslspgetaiiscrtsqygslawyqqrpgqaprlviysgstraagipdrfsg	SEQ ID
	srwgpdynltisnlesgdfgvyycqqyeffgqgtkvqvdikrtvaapsvfifppsdeql	NO: 335
	ksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskad
	yekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvqlvqsgaevvkpgasvkvsckas ihwvrqapgqglewigs	SEQ ID
	nyaqkfqgratltvdtsistaymelsrlrsddtavyyc	NO: 336
	wgkgttvlvsssqvqlvesgggvvqpgrslrlscaas mhwvrq
	apgkqlewvaq yatyyadsvkgrftisrddskntlylqmmslraedt
	avyyc wgqgtlvtvssrtastkgpsvfplapcsrstsestaalg
	clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktyt
	cnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtlmis
	rtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvlt
	vlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsqeemt
	knqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvskltv
	dksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain B	Divmtqtplslsvtpgqpasisckss lswylqkpgqspgsliykvsnr	SEQ ID
	fsgvpdrfsgsgsgtdftlkisrveaedvgvyyc ftfgsgtkveikgqpkaap	NO: 337
	diqmtqspsslsasvgdrvtitcqas lnwyqqkpgkapklliykasnlhtgv
	psrfsgsgsgtdftltisslqpediatyyc gqgtkleiktkpsrtvaapsvf
	ifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstysl
	sstltlskadyekhkvyacevthqglsspvtksfngec

Binding Protein 36 Nucleotide Sequences

Heavy chain A	caggtacagctggtgcagtctggcggccagatgaagaaacccggcgagagcatgcgga	SEQ ID
	tcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcagactgg	NO: 338
	cccctggcaagcggcctgagtggatgggatggctgaagcctagaggcggagccgtgaa
	ctacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacagcgataccg
	ccttcctggaactgcggagcctgaccgtggatgataccgccgtgtacttctgcacccggg
	gcaagaactgcgactacaactgggacttcgagcactggggcagaggcacccctgtgatc
	gtgtcaagcgcgtcgaccaagagcccctcggtgttccctctggccccttgcagcagaagc
	accagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtg
	accgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctcc
	agagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggc
	accaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagc
	gggtggaatctaagtacggccctccctgccctccttgcccagcccctgaatttagggcgg
	accctccgtgttcctgttccccccaaagcccaaggacaccctgatgatcagccggacccc
	cgaagtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattg
	gtacgtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagttc
	aacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacgg
	caaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaacca
	tcagcaaggccaagggccagccccgcgagcctcaagtgtgtaccctgcccccttgccag
	gaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagc
	gacattgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccc
	cccctgtgctggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagag
	ccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaacc
	actacacccagaagtccctgtctctgtccctgggcaag

Light chain A	Gagatcgtgctgacacagagccctggcaccctgagcctgtctccaggcgagacagccat	SEQ ID
	catcagctgccggacaagccagtacggcagcctggcctggtatcagcagaggcctgga	NO: 339
	caggcccccagactcgtgatctacagcggcagcacaagagccgccggaatccccgata
	gattcagcggctccagatggggccctgactacaacctgaccatcagcaacctggaaagc
	ggcgacttcggcatgtactactgccagcagtacgagttcttcggccagggcaccaaggtg
	caggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctagcgac
	gagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgc
	gaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaa
	agcgtgaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgacac
	tgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccaggg
	cctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc	NO: 340
	ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact
	acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt
	cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg
	tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa
	gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg
	tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa
	cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac
	gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg
	tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac
	cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc
	cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca
	cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc
	cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac
	accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc
	cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga
	tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc
	gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc
	cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc
	aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag
	ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta
	ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg
	aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga
	acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa
	gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc
	acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag

Light chain B	gacatcgtgatgacccagacccccctgagcctaagcgtgacacctggacagcctgccag	SEQ ID
	catcagctgcaagagcagccagagcctggtacacaacaacaccaacacctacctgagct	NO: 341
	ggtatctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagat
	tcagcggcgtgcccgacagatctccggcagcggctctggcaccgacttcaccctgaag
	atcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagta
	ccccttcacctttggcagcggcaccaaggtggaaatcaagggccagcccaaggccgcc
	cccgacatccagatgacccagagccccagcagcagtctgccagcgtgggcgacagag
	tgaccatcacctgtcaggccagccagaacatctacgtgtggctgaactggtatcagcaga
	agcccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgt
	gcccagcagattttctgacaacggctccgacaccgacttcaccctgacaatcagctccctg
	cagcccgaggacattgccacctactactgccagcagaaccagacctacccctacaccttt
	ggccagggcaccaagaggaaatcaagaccaagggccccagccgtacggtggccgct
	cccagcgtgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctagtc
	gtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtggaaggtggacaa
	cgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactc
	cacctacagcctgagcagcaccctgacactgagcaaggccgactacgagaagcacaag
	gtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaac
	cggggcgagtgt

Binding Protein 37 Amino Acid Sequences

Heavy chain A	Qvqlvqsggqmkkpgesmriscrasgyefidctlnwirlapgkrpewmgwlkprg	SEQ ID
	gavnyarplqgrvtmtrdvysdtaflelrsltvddtavyftrgkncdynwdfehwgrg	NO: 342
	tpvivssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfp
	avlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpape
	flggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktk
	preeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqv
	ytlppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsff
	lyskltvdksrwqegnvfscsvmheallnhytqkslslslgk

Light chain A	Eivltqspgtlslspgetaiiscrtsqygslawyqqrpgqaprlviysgstraagipdrfsg	SEQ ID
	srwgpdynltisnlesgdfgvyycqqyeffgqgtkvqvdikrtvaapsvfifppsdeql	NO: 343
	ksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskad
	yekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwa	SEQ ID
	gggtnynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysm	NO: 344
	dywgqgttvtvsssqvqlvesgggvvqpgrslrlscaasgftftkawmhwvrq
	apgkqlewvaqikdksnsyatyyadsvkgrftisrddskntlylqmmslraedt
	avyycrgvyyalspfdywgqgtlvtvssrtastkgpsvfplapcsrstsestaalg
	clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktyt
	cnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtlmis
	rtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsvlt
	vlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsqeemt
	knqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvskltv
	dksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain B	Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgqspgsliykvsnr	SEQ ID
	fsgvpdrfsgsgsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveikgqpkaa	NO: 345
	pdivltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnv
	esgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleiktkgpsrt
	vaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqd
	skdstyslsstltlskadyekhkvyacevthqglsspvtksfngec

Binding Protein 37 Nucleotide Sequences

Heavy chain A	caggtacagctggtgcagtctggcggccagatgaagaaacccggcgagagcatgcgga	SEQ ID
	tcagctgcagagccagcggctacgagttcatcgactgcaccctgaactggatcagactgg	NO: 346
	cccctggcaagcggcctgagtggatgggatggctgaagcctagaggcggagccgtgaa
	ctacgccagacctctgcagggcagagtgaccatgacccgggacgtgtacagcgataccg
	ccttcctggaactgcggagcctgaccgtggatgataccgccgtgtacttctgcacccggg
	gcaagaactgcgactacaactgggacttcgagcactggggcagaggcacccctgtgatc
	gtgtcaagcgcgtcgaccaagagcccctcggtgttccctctggccccttgcagcagaagc
	accagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtg
	accgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctcc
	agagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggc
	accaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagc
	gggtggaatctaagtacggccctccctgccctccttgcccagcccctgaatttagggcgg
	accctccgtgttcctgttccccccaaagcccaaggacaccctgatgatcagccggacccc
	cgaagtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattg
	gtacgtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagttc
	aacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacgg
	caaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaacca
	tcagcaaggccaagggccagccccgcgagcctcaagtgtgtaccctgcccccttgccag
	gaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagc
	gacattgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccc
	cccctgtgctggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagag
	ccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaacc
	actacacccagaagtccctgtctctgtccctgggcaag

Light chain A	Gagatcgtgctgacacagagccctggcaccctgagcctgtctccaggcgagacagccat	SEQ ID
	catcagctgccggacaagccagtacggcagcctggcctggtatcagcagaggcctggac	NO: 347
	aggcccccagactcgtgatctacagcggcagcacaagagccgccggaatccccgatag
	attcagcggctccagatggggccctgactacaacctgaccatcagcaacctggaaagcg
	gcgacttcggcgtgtactactgccagcagtacgagttcttcggccagggcaccaaggtgc
	aggtggacatcaagcgtacggtggccgctcccagcgtgttcatcttcccacctagcgacg
	agcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcga
	ggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccaggaaag
	cgtgaccgagcaggacagcaaggactccacctacagcctgagcagcaccctgacactg
	agcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcc
	tgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	caggtgcagagcagaatctggccctggcctcgtgaagcctaccagaccctgagcct	SEQ ID
	gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagcc	NO: 348
	acctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaactaca
	accccagcctgaagtccagaaagaccatcagcaaggacaccagcaagaaccaggtgtc
	cctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagagaca
	agggctacagctactactacagcatgaactactggagccaggacaccaccgtgaccgtg
	tcatcctctcaggtgcagctggtagaatctggcggcggagtggtgcagcctggcagaagc
	ctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctagatacactaggtg
	cgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaac
	agctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggacg
	acagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccgt
	gtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaacc
	ctcgtgaccgtatctaatcagaccgcttcgaccaagagcccatcagtgttccctaggccc
	cttgcagcagaagcaccagcgaatctacagccaccctgaactgcctcatgaaggactact
	ttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctt
	tccagccgtgctccagagcagcggcctgtactctagagcagcgtcgtgacagtgcccag
	cagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaacacc
	aaggtggacaagcgggtggaatctaagtacggccaccctgccaccttgcccagcccct
	gaatttctgagcggaccctccgtgttcctgttccccccaaaacccaaggacaccctgatga
	tcagccggacccccgaagtgacctgcgtggtaatggatgtgtcccaggaagatcccgag
	gtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcccag
	agaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcaccagg
	actggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccagacc
	atcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgtaccct
	gccccctagccaggaagagatgaccaagaaccaggtgtccctgagagtgccgtgaaag
	gcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgagaacaa
	ctacaagaccaccccccctgtgctggacagcgacggctcattcttcctggtgtccaagctg
	accgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacga
	ggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag

Light chain B	gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag	SEQ ID
	catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct	NO: 349
	ggtatctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagat
	tcagcggcgtgcccgacagattaccggcagcggctaggcaccgacttcaccagaaga
	tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac
	cccttcaccatggcagcggcaccaaggtagaaatcaagggccagcccaaggccgcccc
	cgacatcgtgctgacacagagccctgctagcctggccgtgtctcctggacagagggcca
	ccatcacctgtagagccagcgagagcgtggaatattacgtgaccagcctgatgcagtggt
	atcagcagaagcccggccagccccccaagctgctgaattcgccgccagcaacgtggaa
	agcggcgtgccagccagattttccggcagcggctctggcaccgacttcaccctgaccatc
	aaccccgtggaagccaacgacgtggccaactactactgccagcagagccggaagatgc
	cctacacctttggccagggcaccaagctggaaatcaagaccaagggccccagccgtacg
	gtggccgctcccagcgtgacatcttcccacctagcgacgagcagctgaagtccggcaca
	gcctctgtcgtgtgcctgctgaacaacttctacceccgcgaggccaaagtgcagtggaag
	gtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagc
	aaggactccacctacagcctgagcagcaccctgacactgagcaaggccgactacgaga
	agcacaaggtgtacgcctgcgaagtgacccaccagggcctatctagccccgtgaccaag
	agcttcaaccggggcgagtgt

Binding Protein 38 Amino Acid Sequences

Heavy chain A	Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv	SEQ ID
	ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv	NO: 350
	tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl
	qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg
	gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre
	eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp
	pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk
	ltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv	SEQ ID
	psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps	NO: 351
	deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl
	skadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikp	SEQ ID
	qygavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdssw	NO: 352
	aldawgqgttvvvsasqvqlvesgggvvqpgrslrlscaasgftftkawmhw
	vrqapgkqlewvaqikdksnsyatyyadsvkgrftisrddskntlylqmnslra
	edtavyycrgvyyalspfdywgqgtlvtvssrtastkgpsvfplapcsrstsesta
	algclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtk
	tytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtl
	misrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvv
	svltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsqee
	mtknqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvskl
	tvdkstwqegnvfscsvmhealhnhytqkslslslgk

Light chain B	Divimtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgqspqsliykvsnr	SEQ ID
	fsgvpdrfsgsgsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveikgqpkaa	NO: 353
	pyilwtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgv
	psrfsgsathtsfnltisdlqaddiatyycqvlqffgrgsrlhiktkgpsrtvaapsvfifpp
	sdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstlt
	lskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 38 Nucleotide Sequences

Heavy chain A	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactaggtacgccaggc	NO: 354
	ccctggacaggaactggaatgaatcggcagcatctaccccggcaacgtaaacaccaact
	acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgagccggctgagaagcgacgacaccgccgtgactactgcacccggt
	cccactacggcaggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtgt
	ctagcgcgtcgaccaagggcccctcggtgaccctctggccccttgcagcagaagcacca
	gcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgaccg
	tgtccggaactctggcgctctgacaagcagcgtgcacaccatccagccgtgaccagag
	cagcggcctgtactactgagcagcgtcgtgacagtgcccagcagcagcctgggcacca
	agacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcgggt
	ggaatctaagtacggccctccagccctccttgcccagcccagaatactgggcggaccc
	tccgtgttcctgttccccccaaagcccaaggacaccagatgatcagccggacccccgaa
	gtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacg
	tggacgacgtagaagtgcacaacgccaagaccaaacccagagaggaacagttcaacag
	cacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaag
	agtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccatcagc
	aaggccaagggccagccccgcgagcctcaagtgtataccctgcccccagccaggaaga
	gatgaccaagaaccaggtgtccagtggtgtacgtgaaaggcttctaccccagcgacatt
	gccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccct
	gtgctggacagcgacggctcattatcctatactccaagctgaccgtgaacaagagccggt
	ggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccactac
	acccagaagtccctgtctctgtccctaggcaag

Light chain A	Gacatccagatgacccagagccccagcagcctgtctgccagcgtggacgacagagtga	SEQ ID
	ccatcacctgtcaggccagccagaacatctacgtgtggctgaactggtatcagcagaagc	NO: 355
	ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc
	cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagctccctgcag
	cccgaggacattgccacctactactgccagcagggccagacctacccctacacctttggc
	cagggcaccaagctggaaatcaagcgtacggtagccactcccaacgtattcatatccca
	cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttct
	acccccgcgaggccaaggtgcagtggaaggtggacaatgccctgcagagcggcaaca
	gccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctgagcagca
	ccctgaccagagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgac
	ccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	agagcccacctggtgcagtaggcaccgccatgaagaaaccaggcgcctctgtgcgggt	SEQ ID
	gtcctgtcagacaagcggctacaccttcaccgcccacatcctgttctggttccggcaggcc	NO: 356
	cctggcagaggactggaatgggtgggatggatcaagccccagtatggcgccgtgaactt
	cggcggaggatccgggatagatttgacccttacccgggacgtgtaccgcgagatcgcct
	acatggacatccggggcctgaagcccgatgacaccgccgtgtactactgcgccagagac
	agaagctacggcgacagcaactaggactagatgatgggaccagggcacaaccatgg
	tggtgtctgcctctcaggtgcagctggtggaatctggcggcggagtggtgcagcctggca
	gaagcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcact
	gggtgcgccaggcccctggaaagcagaggaatgggtggcccagatcaaggacaaga
	gcaacagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgg
	gacgacagcaagaacaccctatacctgcagatgaacagcctgcgggccgaggacacca
	ccgtgtactactgtcggggcgtatactatgccctgagcccatcgattactagggccaggg
	aaccctcgtgaccgtgtctagtcggaccgcacgaccaagggcccatcggtgttccctctg
	gccccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaagga
	ctactttcccgagcccgtgaccgtgtcaggaaactggcgctctgacaagcggcgtgcac
	acctttccagccgtgaccagagcagcggcctgtactactgagcagcgtcgtgacagtgc
	ccagcagcagcctggacaccaagacctacacctgtaacgtgaaccacaagcccagcaa
	caccaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagc
	ccctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctg
	atgatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc
	gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc
	cagagaggaacagttcaacagcacctaccgggtggtgtccgtgagaccgtgagcacc
	aggactggctgaacaacaaagagtacaagtgcaaagtgtccaacaagggcctgcccag
	ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta
	ccctgccccctagccaggaagagatgaccaagaaccaggtgtccctgagctgtgccgtg
	aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga
	acaactacaagaccaccccccctgtgaggacagcgacggctcattcttcctggtgtccaa
	gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgaccgtgatgc
	acgaggccagcacaaccactacacccagaagtccagtactgtccagggcaag

Light chain B	Gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgcca	SEQ ID
	gcatcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgag	NO: 357
	ctggtatctacagaaacccggccagagcccccagtccagatctacaaggtgtccaacag
	attcagcggcgtgcccgacagattaccggcagcggctaggcaccgacttcaccctgaa
	gatcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagt
	accccttcacctttggcagcggcaccaaggtggaaatcaagggccagcccaaggccgcc
	ccctacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagt
	gaccatcaactgccagacctctacagggcgtgggcagcgacctgcactggtatcagcaca
	agcctggcagaacccccaagagagatccaccacacaagcagcatggaagatggcgt
	gcccagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagcgatctg
	caggccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagaggcagca
	gactgcacatcaagaccaagggccccagccgtacggtggccgctcccagcgtgttcatct
	tcccacctagcgacgagcagctgaagtccggcacagcactgtcgtgtgcctgctgaaca
	acttctacccccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcgg
	caacagccaggaaagcgtgaccgagcaggacagcaaggactccacctacagcctgag
	cagcaccctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaa
	gtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 39 Amino Acid Sequences

Heavy chain A	Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv	SEQ ID
	ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv	NO: 358
	tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl
	qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg
	gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre
	eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp
	pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk
	ltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv	SEQ ID
	psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps	NO: 359
	deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl
	skadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikp	SEQ ID
	qygavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdssw	NO: 360
	aldawgqgttvvvsadkthtqvqlvesgggvvqpgrslrlscaasgftftkaw
	mhwvrqapgkqlewvaqikdksnsyatyyadsvkgrftisrddskntlylqm
	nslraedtavyycrgvyyalspfdywgqgtlvtvssdkthtastkgpsvfplapc
	srstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvt
	vpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfp
	pkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeq
	fnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvc
	tlppsqeemtknqvslscavkgfypsdiavewesngqpennykttppyldsd
	gsfflvskltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain B	Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgqspqsliykvsnr	SEQ ID
	fsgvpdrfsgsgsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveikdkthtyih	NO: 361
	vtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgvpsrfs
	gsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikdkthtrtvaapsvfifppsdeql
	ksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskad
	yekhkvyacevthqglsspvtksfnrgec

Binding Protein 39 Nucleotide Sequences

Heavy chain A	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactaggtacgccaggc	NO: 362
	ccctggacaggaactggaatgaatcggcagcatctaccccggcaacgtaaacaccaact
	acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgagccggctgagaagcgacgacaccgccgtgactactgcacccggt
	cccactacggcaggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtgt
	ctagcgcgtcgaccaagggcccctcggtgaccctctggccccttgcagcagaagcacca
	gcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgaccg
	tgtccggaactctggcgctctgacaagcagcgtgcacaccatccagccgtgaccagag
	cagcggcctgtactactgagcagcgtcgtgacagtgcccagcagcagcctgggcacca
	agacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcgggt
	ggaatctaagtacggccctccagccctccttgcccagcccagaatactgggcggaccc
	tccgtgttcctgttccccccaaagcccaaggacaccagatgatcagccggacccccgaa
	gtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacg
	tggacgacgtagaagtgcacaacgccaagaccaaacccagagaggaacagttcaacag
	cacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaag
	agtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccatcagc
	aaggccaagggccagccccgcgagcctcaagtgtataccctgcccccagccaggaaga
	gatgaccaagaaccaggtgtccagtggtgtacgtgaaaggcttctaccccagcgacatt
	gccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccct
	gtgctggacagcgacggctcattatcctatactccaagctgaccgtgaacaagagccggt
	ggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccactac
	acccagaagtccctgtctctgtccctaggcaag

Light chain A	gacatccagatgacccagagccccagcagcctgtctgccgcgtgggcgacagagtga	SEQ ID
	ccatcacctgtcaggccagccagaacatctacgtatggctgaactggtatcaacagaagc	NO: 363
	ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc
	cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagcccctgcag
	cccgaggacattgccacctactactgccagcagggccagacctacccctacacattggc
	cagggcaccaagctggaaatcaagcgtacagtggccgctcccagcgtgttcatcttccca
	cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacnct
	acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca
	gccaggaaagcgtaaccgaacaggacagcaaggactccacctacaacctgaacaaca
	ccctgaccctgagcaaggccgactacgagaagcacaagatgtacgcctgcgaagtgac
	ccaccagggcctatctagccccgtgaccaagagatcaaccgggcgagtgt

Heavy chain B	agagcccacctggtgcagtctggcaccgccatgaagaaaccaagcgcctctgtgcgggt	SEQ ID
	gtcctgtcagacaagcagctacaccttcaccgcccacatcctgttctggttccggcagacc	NO: 364
	cctggcagaggactggaatgagtgggatggatcaagccccagtatggcgccgtgaactt
	cggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgagatcacct
	acatggacatccggggcctgaagcccgatgacaccgccgtggggctactgcgccagagac
	agaagctacggcgacagcagagggctctggatgcttggggccagggcacaaccgtgg
	tggtgtctgccgacaaaacccatacccaagtgcaactaatggaatctagcgacggagtg
	gtgcagcctgacaaaaacctgaaactgaactatgccgccagcgacttcaccttcaccaa
	ggcctggatgcactgggtgcgccaggcccctggaaagcagaggaatgggtggcccag
	atcaaggacaagagcaacagctacgccacctactacgccgacagcgtgaagggccagtt
	caccatcagccgggacgacagcaagaacaccagtacctgcagatgaacagcctgcag
	gccgagaacaccgccgtatactactgtcggggcgtgtactatgccctgaaccccttgatt
	actggggccaaagaaccctcgtaaccgtatctaatgataagacccacaccgcttcgacca
	agggcccatcggtgttccctctgacccatgcagcagaagcaccagcgaatctacagccg
	ccctgggctgcctcgtgaaggactactttcccgagcccgtgaccgtgtcctggaactctgg
	cgctctgacaagcggcgtgcacacctttccagccgtgctccagagcagcgacctgtactc
	tctgagcagcgtcgtgacagtgcccagcagcagcctgagcaccaaaacctacacctgta
	acgtggaccacaagcccagcaacaccaagatggacaagcgggtggaatctaagtacga
	ccctccctgccctccttgcccagcccctgaatactgagcgaaccctccgtgttcctattccc
	cccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtg
	gtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacgtggacggcgtggaa
	gtgcacaacgccaagaccaagcccagagaggaacagttcaacagcacctaccgggtgg
	tgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgcaag
	gtgtccaacaagggcctgcccagctccatcgagaaaaccatcagcaaggccaagggcc
	agccccgcgagcctcaagtgtgtaccctgccccctagccagaaaaagatgaccaagaac
	caggtgtccctaagctgtgccgtgaaaggcttctaccccagcaacattgccgtaaaatgg
	gagagcaacggccagcccgagaacaactacaagaccaccccccctgtgctggacagcg
	acggctcattcttcctggtgtccaagctgaccgtggacaagagccggtggcaggaaggca
	acgtattcagctgctccgtgatgcacgaggccctgcacaaccactacacccagaagtccc
	tgtctctgtccctagacaag

Light chain B	gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag	SEQ ID
	catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct	NO: 365
	ggtatctgcagaagcccggccagaacccccagtccctgatctacaagatgtccaacagat
	tcagcggcgtgcccaacagattctccggcagcggctaggcaccgacttcaccctaaaaa
	tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac
	cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccatacctacatc
	cacgtgacccagagccccagcagcctgtccgigtccatcggcgacagagtgaccatcaa
	ctgccagacctctcagagcgtgggcagcgacctgcactagtatcagcacaagcctggca
	gagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcccagcag
	attttccggcaacggcttccacaccagatcaacctgaccatcaacgatctgcaggccgac
	gacattgccacctactattgtcaggtgagcagttatcggcagaggcagcagactacacat
	caaggataagacccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagc
	gacgagcagctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttctaccccc
	gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccagg
	aaaacgtgaccgagcaggacaacaaggactccacctacagcctgagcagcaccctaac
	actgaacaaggccgactacgagaagcacaaggtatacgcctgcgaagtaacccaccag
	ggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 40 Amino Acid Sequences

Heavy chain A	Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv	SEQ ID
	ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv	NO: 366
	tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl
	qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg
	gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre
	eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp
	pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk
	ltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv	SEQ ID
	psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps	NO: 367
	deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl
	skadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvqlvesgggvvqpgrslrlscaasgftftkawmhwvrqapgkqlewvaqi	SEQ ID
	kdksnsyatyyadsvkgrftisrddskntlylqmnslraedtavvycrgvyyal	NO: 368
	spfdywgqgtlvtvsssrahlvqsgtamkkpgasvrvscqtsgytftahilfwfr
	qapgrglewvgwikpqygavnfgggfrdrvtltrdvyreiaymdirglkpddt
	avyycardrsygdsswaldawgqgttvvvsartastkgpsvfplapcsrstsest
	aalgclvkdyfpepvtvswnsgaltsgvhtfpaviqssglysissvvtvpssslgt
	ktytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtl
	misrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrv
	vsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsq
	eemtknqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvs
	kltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain B	Yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgvp	SEQ ID
	srfsgsgthtsfnltisdlqaddiatyycqvlqffgrgsrlhikgqpkaapdivmtqtplsl	NO: 369
	svtpgqpasiscksaqslvhnnantylswylqkpggspqsliykvsnrfsgvpdrfsgs
	gsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveiktkgpsrtvaapsvfifpps
	deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl
	skadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 40 Nucleotide Sequences

Heavy chain A	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactaggtacgccaggc	NO: 370
	ccctggacaggaactggaatgaatcggcagcatctaccccggcaacgtaaacaccaact
	acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgagccggctgagaagcgacgacaccgccgtgactactgcacccggt
	cccactacggcaggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtgt
	ctagcgcgtcgaccaagggcccctcggtgaccctctggccccttgcagcagaagcacca
	gcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgaccg
	tgtccggaactctggcgctctgacaagcagcgtgcacaccatccagccgtgaccagag
	cagcggcctgtactactgagcagcgtcgtgacagtgcccagcagcagcctgggcacca
	agacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcgggt
	ggaatctaagtacggccctccagccctccttgcccagcccagaatactgggcggaccc
	tccgtgttcctgttccccccaaagcccaaggacaccagatgatcagccggacccccgaa
	gtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacg
	tggacgacgtagaagtgcacaacgccaagaccaaacccagagaggaacagttcaacag
	cacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaag
	agtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccatcagc
	aaggccaagggccagccccgcgagcctcaagtgtataccctgcccccagccaggaaga
	gatgaccaagaaccaggtgtccagtggtgtacgtgaaaggcttctaccccagcgacatt
	gccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccct
	gtgctggacagcgacggctcattatcctatactccaagctgaccgtgaacaagagccggt
	ggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccactac
	acccagaagtccctgtctctgtccctaggcaag

Light chain A	gacatccagatgacccagagccccagcagcctgtctgccgcgtgggcgacagagtga	SEQ ID
	ccatcacctgtcaggccagccagaacatctacgtatggctgaactggtatcaacagaagc	NO: 371
	ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc
	cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagcccctgcag
	cccgaggacattgccacctactactgccagcagggccagacctacccctacacattggc
	cagggcaccaagctggaaatcaagcgtacagtggccgctcccagcgtgttcatcttccca
	cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacnct
	acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca
	gccaggaaagcgtaaccgaacaggacagcaaggactccacctacaacctgaacaaca
	ccctgaccctgagcaaggccgactacgagaagcacaagatgtacgcctgcgaagtgac
	ccaccagggcctatctagccccgtgaccaagagatcaaccgggcgagtgt

Heavy chain B	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc	NO: 372
	ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact
	acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt
	cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg
	tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa
	gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg
	tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa
	cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac
	gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg
	tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac
	cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc
	cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca
	cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc
	cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac
	accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc
	cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga
	tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc
	gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc
	cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc
	aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag
	ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta
	ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg
	aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga
	acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa
	gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc
	acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag

Light chain B	tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcsacaga	SEQ ID
	gtgaccatcaactgccagacctctcaggctgggcagegacctgcactggtatc	NO: 373
	agcacaagcctggcagagcceccaagagctgatccaccacacaagcagcgtg
	gaagatggcgtgcccagcagattaccggcagcggcttccacaccagcttcaacc
	tgaccatcagcgatagcaggccgacgacattgccacctactattgtcaggtgctg
	cagttcttcggcagaggcagcagactgcacatcaagggccagcccaaggccgc
	ccccgacatcgtgatgacccaacccccagagcctgagcgtgacacctggaca
	gcctgccagcatcagctgcaagagcagccagagcctggtgcacaacaacgcca
	acacctacctgagctggtatctgcagaagcccggccagagcccccagtccctgat
	ctacaaggtgtccaacagattcagcgcgtgcccgacagattctccggcagcgg
	ctctggcaccgacttcaccctgaagatcagccgggtggaagccgaggacgtggg
	cgtgtactattgtggccagggcacccagtaccccttcacattggcagcggcacca
	aggtggaaatcaagaccaagggccccagccgtacggtggccgctcccagcgtg
	ttcatcttcccacctagcgacgagcagctgaagtccggcacagcactgtcgtgtg
	cctgctgaaacttctacccccgcgaggccaaagtgcagtggaaggtggacaa
	cgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaag
	gactccacctacagcctgagcagcaccctgacactgacaaggccgactacga
	aagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtg
	accaagagcttcaaccggggcgagtgt

Binding Protein 41 Amino Acid Sequences

Heavy chain A	Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv	SEQ ID
	ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv	NO: 374
	tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl
	qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg
	gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre
	eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp
	pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk
	ltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv	SEQ ID
	psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps	NO: 375
	deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl
	skadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvqlvesgggvvqpgrslrlscaasgftftkawmhwvrqapgkqlewvaqi	SEQ ID
	kdksnsyatyyadsvkgrftisrddskntlylqmnslraedtavvycrgvyyal	NO: 376
	spfdywgqgtlvtvsssrahlvqsgtamkkpgasvrvscqtsgytftahilfwfr
	qapgrglewvgwikpqygavnfgggfrdrvtltrdvyreiaymdirglkpddt
	avyycardrsygdsswaldawgqgttvvvsartastkgpsvfplapcsrstsest
	aalgclvkdyfpepvtvswnsgaltsgvhtfpaviqssglysissvvtvpssslgt
	ktytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtl
	misrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrv
	vsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsq
	eemtknqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvs
	kltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain B	Yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgvp	SEQ ID
	srfsgsgthtsfnltisdlqaddiatyycqvlqffgrgsrlhikgqpkaapdivmtqtplsl	NO: 377
	svtpgqpasiscksaqslvhnnantylswylqkpggspqsliykvsnrfsgvpdrfsgs
	gsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveiktkgpsrtvaapsvfifpps
	deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl
	skadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 41 Nucleotide Sequences

Heavy chain A	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactaggtacgccaggc	NO: 378
	ccctggacaggaactggaatgaatcggcagcatctaccccggcaacgtaaacaccaact
	acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgagccggctgagaagcgacgacaccgccgtgactactgcacccggt
	cccactacggcaggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtgt
	ctagcgcgtcgaccaagggcccctcggtgaccctctggccccttgcagcagaagcacca
	gcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgaccg
	tgtccggaactctggcgctctgacaagcagcgtgcacaccatccagccgtgaccagag
	cagcggcctgtactactgagcagcgtcgtgacagtgcccagcagcagcctgggcacca
	agacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcgggt
	ggaatctaagtacggccctccagccctccttgcccagcccagaatactgggcggaccc
	tccgtgttcctgttccccccaaagcccaaggacaccagatgatcagccggacccccgaa
	gtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacg
	tggacgacgtagaagtgcacaacgccaagaccaaacccagagaggaacagttcaacag
	cacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaag
	agtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccatcagc
	aaggccaagggccagccccgcgagcctcaagtgtataccctgcccccagccaggaaga
	gatgaccaagaaccaggtgtccagtggtgtacgtgaaaggcttctaccccagcgacatt
	gccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccct
	gtgctggacagcgacggctcattatcctatactccaagctgaccgtgaacaagagccggt
	ggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccactac
	acccagaagtccctgtctctgtccctaggcaag

Light chain A	gacatccagatgacccagagccccagcagcctgtctgccgcgtgggcgacagagtga	SEQ ID
	ccatcacctgtcaggccagccagaacatctacgtatggctgaactggtatcaacagaagc	NO: 379
	ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc
	cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagcccctgcag
	cccgaggacattgccacctactactgccagcagggccagacctacccctacacattggc
	cagggcaccaagctggaaatcaagcgtacagtggccgctcccagcgtgttcatcttccca
	cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacnct
	acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca
	gccaggaaagcgtaaccgaacaggacagcaaggactccacctacaacctgaacaaca
	ccctgaccctgagcaaggccgactacgagaagcacaagatgtacgcctgcgaagtgac
	ccaccagggcctatctagccccgtgaccaagagatcaaccgggcgagtgt

Heavy chain B	caggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaagcctgagact	SEQ ID
	gagctgtgccgccaacggatcaccttcaccaaggcctggatgcactgggtacgccagg	NO: 380
	cccctggaaagcagaggaatgggtggcccagatcaaggacaagagcaacagctacgc
	cacctactacgccgacagcgtgaagggccggttcaccatcagccgggacgacagcaag
	aacaccctgtacctgcagatgaacagcctgcgggccgaggacaccaccatgtactactgt
	cggggcgtgtactatgccagagccccttcgattactggggccagggaaccctcgtgacc
	gtgtctagtgacaaaacccataccaaagcccacctagtgcagtctggcaccgccatgaag
	aaaccaggcgcctctgtacggatgtcctgtcagacaagcggctacaccttcaccgcccac
	atcctgttctggttccggcaggcccctaacaaaggactggaatgagtggaataaatcaag
	ccccagtatggcgccgtgaacttcggcggaaacttccgggataaagtgaccctgacccg
	ggacgtgtaccgcgagatcgcctacatggacatccggggcctgaagcccgatgacaccg
	ccgtgtactactgcgccagagacagaagctacggcgacagcagctgggctctggatgctt
	ggggccagggcacaaccgtggtggtgtctgccgataagacccacaccaccagcacaaa
	gggcccatcggttccctctggccccagcagcagaagcaccagcgaatctacagccgc
	cctgggctgcctcgtgaagaactacatcccaagcccatgaccatgtcctggaactaggc
	gctctgacaaacggcgtacacacctttccagccgtactccagaacaacggcctgtactct
	ctgagcagcgtcgtgacagtgcccagcagcagcctgggcaccaagacctacacctgtaa
	cgtggaccacaagcccagcaacaccaaggtggacaagcgggtggaatctaagtacggc
	cctccctgccctccttgcccagcccctgaatactgggcggaccctccgtgacctgttcccc
	ccaaagcccaaggacaccctgatgatcagccgaacccccgaagtgacctgcatggtggt
	ggatgtgtcccaggaagatcccgaggtacagttcaattggtacatggacggcgtgaaagt
	gcacaacgccaagaccaagcccagagaggaacagttcaacagcacctaccgggtggtg
	tccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgcaaggt
	gtccaacaagggcctgcccagctccatcgagaaaaccatcagcaaggccaagggccag
	ccccgcgagcctcaagtgtgtaccctgccccctagccaggaagaaataaccaagaacca
	ggtgtccctgagagtgccgtaaaaggatctaccccagcgacattgccgtggaatggga
	gagcaacggccaaccegaaaacaactacaaaaccaccccccctgtgaggacagegac
	ggctcattcttcctggtgtccaagctgaccgtggacaagagccggtggcaggaaggcaac
	gtgttcagctgaccgtgatgcacgaggccctgcacaaccactacacccagaagtccctgt
	ctctgtccctgggcaag

Light chain B	tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtgac	SEQ ID
	catcaactgccagacctctcagggcgtgggcagcgacctgcactggtatcagcacaagc	NO: 381
	ctggcagagcccccaaactactgatccaccacacaagcagcgtggaagatggcgtgcc
	cagcagattttccggcagcggcttccacaccagcttcaacctgaccatcagcgatctgcag
	gccgacgacattgccacctactattgtcaggtgctgcagttcttcggcagaggcagcagac
	tgcacatcaaggacaaaaacccataccgacatcgtgatgacccagacccccctgagcctga
	gcgtgacacctggacagcctgccagcatcagctgcaagagcagccagagcctggtgca
	caacaacgccaacacctacctgaactagtatagcagaagcccagccagagcccccagt
	ccctgatctacaaggtgtccaacagattcagcggcgtgcccgacagattctccggcagcg
	gctctggcaccgacttcaccctgaagatcagccgggtggaagccgaggacgtgggcgtg
	tactattgtggccagggcacccagtaccccttcacctttggcagcggcaccaaggtggaa
	atcaaggataagacccatacccgtacggtggccgctcccagcgtgttcatcttcccaccta
	gcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgagaacaacttctacc
	cccgcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagcc
	aggaaagcatgaccgagcaggacagcaaggactccacctacagcctgagcagcaccct
	gacactgagcaaggccgactacgagaagcacaagatgtacacctgcaaaatgacccac
	cagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 42 Amino Acid Sequences

Heavy chain A	Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv	SEQ ID
	ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv	NO: 382
	tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl
	qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg
	gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre
	eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp
	pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk
	ltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv	SEQ ID
	psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps	NO: 383
	deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl
	skadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikp	SEQ ID
	qygavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdssw	NO: 384
	aldawgqgttvvvsadkthtqvqlvesgggvvqpgrslrlscaasgftftkaw
	mhwvrqapgkqlewvaqikdksnsyatyyadsvkgrftisrddskntlylqm
	nslraedtavyycrgvyyalspfdywgqgtlvtvssdkthtastkgpsvfplapc
	srstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvt
	vpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfp
	pkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeq
	fnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvc
	tlppsqeemtknqvslscavkgfypsdiavewesngqpennykttppyldsd
	gsfflvskltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain B	Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgqspqsliykvsnr	SEQ ID
	fsgvpdrfsgsgsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveikdkthtyih	NO: 385
	vtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgvpsrfs
	gsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikdkthtrtvaapsvfifppsdeql
	ksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskad
	yekhkvyacevthqglsspvtksfnrgec

Binding Protein 42 Nucleotide Sequences

Heavy chain A	caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct	SEQ ID
	gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagc	NO: 386
	cacctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaacta
	caaccccagcctaaaatccagaaagaccatcagcaaggacaccagcaagaaccaggtg
	tccctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagaga
	caagggctacagctactactacagcatggactactggggccagggcaccaccgtgaccg
	tgtcatccgcgtcgaccaagggcccctcggtgttccctaggccccttgcagcagaagca
	ccagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtga
	ccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctcca
	gagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggca
	ccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcg
	ggtggaatctaagtacggccctccctgccaccttgcccagcccctgaatttctgggcgga
	ccctccgtgttcctgttccccccaaagcccaagaacaccctgatgatcagccggaccccc
	gaagtaacctgcgtaatggtggatgtatcccaggaagatcccaaggtgcagttcaattggt
	acgtggacggcgtgaaaatgcacaacgccaagaccaagcccagagaagaacagttca
	acagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggc
	aaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccat
	cagcaaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttgccag
	gaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagc
	gacattgccgtgaaatgggagagcaacgaccagcccaagaacaactacaagaccaccc
	cccctgtactggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagag
	ccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaacc
	actacacccagaagtccctgtctctgtccagggcaag

Light chain A	gacatccagatgacccagagccccagcagcctgtctgccgcgtgggcgacagagtga	SEQ ID
	ccatcacctgtcaggccagccagaacatctacgtatggctgaactggtatcaacagaagc	NO: 387
	ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc
	cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagcccctgcag
	cccgaggacattgccacctactactgccagcagggccagacctacccctacacattggc
	cagggcaccaagctggaaatcaagcgtacagtggccgctcccagcgtgttcatcttccca
	cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacnct
	acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca
	gccaggaaagcgtaaccgaacaggacagcaaggactccacctacaacctgaacaaca
	ccctgaccctgagcaaggccgactacgagaagcacaagatgtacgcctgcgaagtgac
	ccaccagggcctatctagccccgtgaccaagagatcaaccgggcgagtgt

Heavy chain B	agagcccacctggtgcagtctggcaccgccatgaagaaaccaagcgcctctgtgcgggt	SEQ ID
	gtcctgtcagacaagcagctacaccttcaccgcccacatcctgttctggttccggcagacc	NO: 388
	cctggcagaggactggaatgagtgggatggatcaagccccagtatggcgccgtgaactt
	cggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgagatcacct
	acatggacatccggggcctgaagcccgatgacaccgccgtggggctactgcgccagagac
	agaagctacggcgacagcagagggctctggatgcttggggccagggcacaaccgtgg
	tggtgtctgccgacaaaacccatacccaagtgcaactaatggaatctagcgacggagtg
	gtgcagcctgacaaaaacctgaaactgaactatgccgccagcgacttcaccttcaccaa
	ggcctggatgcactgggtgcgccaggcccctggaaagcagaggaatgggtggcccag
	atcaaggacaagagcaacagctacgccacctactacgccgacagcgtgaagggccagtt
	caccatcagccgggacgacagcaagaacaccagtacctgcagatgaacagcctgcag
	gccgagaacaccgccgtatactactgtcggggcgtgtactatgccctgaaccccttgatt
	actggggccaaagaaccctcgtaaccgtatctaatgataagacccacaccgcttcgacca
	agggcccatcggtgttccctctgacccatgcagcagaagcaccagcgaatctacagccg
	ccctgggctgcctcgtgaaggactactttcccgagcccgtgaccgtgtcctggaactctgg
	cgctctgacaagcggcgtgcacacctttccagccgtgctccagagcagcgacctgtactc
	tctgagcagcgtcgtgacagtgcccagcagcagcctgagcaccaaaacctacacctgta
	acgtggaccacaagcccagcaacaccaagatggacaagcgggtggaatctaagtacga
	ccctccctgccctccttgcccagcccctgaatactgagcgaaccctccgtgttcctattccc
	cccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtg
	gtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacgtggacggcgtggaa
	gtgcacaacgccaagaccaagcccagagaggaacagttcaacagcacctaccgggtgg
	tgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgcaag
	gtgtccaacaagggcctgcccagctccatcgagaaaaccatcagcaaggccaagggcc
	agccccgcgagcctcaagtgtgtaccctgccccctagccagaaaaagatgaccaagaac
	caggtgtccctaagctgtgccgtgaaaggcttctaccccagcaacattgccgtaaaatgg
	gagagcaacggccagcccgagaacaactacaagaccaccccccctgtgctggacagcg
	acggctcattcttcctggtgtccaagctgaccgtggacaagagccggtggcaggaaggca
	acgtattcagctgctccgtgatgcacgaggccctgcacaaccactacacccagaagtccc
	tgtctctgtccctagacaag

Light chain B	gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag	SEQ ID
	catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct	NO: 389
	ggtatctgcagaagcccggccagaacccccagtccctgatctacaagatgtccaacagat
	tcagcggcgtgcccaacagattctccggcagcggctaggcaccgacttcaccctaaaaa
	tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac
	cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccatacctacatc
	cacgtgacccagagccccagcagcctgtccgigtccatcggcgacagagtgaccatcaa
	ctgccagacctctcagagcgtgggcagcgacctgcactagtatcagcacaagcctggca
	gagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcccagcag
	attttccggcaacggcttccacaccagatcaacctgaccatcaacgatctgcaggccgac
	gacattgccacctactattgtcaggtgagcagttatcggcagaggcagcagactacacat
	caaggataagacccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagc
	gacgagcagctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttctaccccc
	gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccagg
	aaaacgtgaccgagcaggacaacaaggactccacctacagcctgagcagcaccctaac
	actgaacaaggccgactacgagaagcacaaggtatacgcctgcgaagtaacccaccag
	ggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 43 Amino Acid Sequences

Heavy chain A	Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwagggt	SEQ ID
	nynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysmdywgqgtt	NO: 390
	vtvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpav
	lqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapefl
	ggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkp
	reeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvyt
	lppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffly
	skltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Divltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnve	SEQ ID
	sgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleikrtvaapsv	NO: 391
	fifppsdeqlksgtasvvcllnnfypreakvqwkydnalqsgnsqesvteqdskdstys
	lsstltskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Rahlvqsgtamkkpgasvrvscqtsgytftahilfwfrqapgrglewvgwikp	SEQ ID
	qygavnfgggfrdrvtltrdvyreiaymdirglkpddtavyycardrsygdssw	NO: 392
	aldawgqgttvvvsadkthtqvqlvesgggvvqpgrslrlscaasgftftkaw
	mhwvrqapgkqlewvaqikdksnsyatyyadsvkgrftisrddskntlylqm
	nslraedtavyycrgvyyalspfdywgqgtlvtvssdkthtastkgpsvfplapc
	srstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvt
	vpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfp
	pkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeq
	fnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvc
	tlppsqeemtknqvslscavkgfypsdiavewesngqpennykttppyldsd
	gsfflvskltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain B	Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgqspqsliykvsnr	SEQ ID
	fsgvpdrfsgsgsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveikdkthtyih	NO: 393
	vtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgvpsrfs
	gsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikdkthtrtvaapsvfifppsdeql
	ksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltlskad
	yekhkvyacevthqglsspvtksfnrgec

Binding Protein 43 Nucleotide Sequences

Heavy chain A	caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct	SEQ ID
	gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagc	NO: 394
	cacctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaacta
	caaccccagcctaaaatccagaaagaccatcagcaaggacaccagcaagaaccaggtg
	tccctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagaga
	caagggctacagctactactacagcatggactactggggccagggcaccaccgtgaccg
	tgtcatccgcgtcgaccaagggcccctcggtgttccctaggccccttgcagcagaagca
	ccagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtga
	ccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctcca
	gagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggca
	ccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcg
	ggtggaatctaagtacggccctccctgccaccttgcccagcccctgaatttctgggcgga
	ccctccgtgttcctgttccccccaaagcccaagaacaccctgatgatcagccggaccccc
	gaagtaacctgcgtaatggtggatgtatcccaggaagatcccaaggtgcagttcaattggt
	acgtggacggcgtgaaaatgcacaacgccaagaccaagcccagagaagaacagttca
	acagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggc
	aaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccat
	cagcaaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttgccag
	gaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagc
	gacattgccgtgaaatgggagagcaacgaccagcccaagaacaactacaagaccaccc
	cccctgtactggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagag
	ccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaacc
	actacacccagaagtccctgtctctgtccagggcaag

Light chain A	gacatccagatgacccagagccccagcagcctgtctgccgcgtgggcgacagagtga	SEQ ID
	ccatcacctgtcaggccagccagaacatctacgtatggctgaactggtatcaacagaagc	NO: 395
	ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc
	cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagcccctgcag
	cccgaggacattgccacctactactgccagcagggccagacctacccctacacattggc
	cagggcaccaagctggaaatcaagcgtacagtggccgctcccagcgtgttcatcttccca
	cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacnct
	acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca
	gccaggaaagcgtaaccgaacaggacagcaaggactccacctacaacctgaacaaca
	ccctgaccctgagcaaggccgactacgagaagcacaagatgtacgcctgcgaagtgac
	ccaccagggcctatctagccccgtgaccaagagatcaaccgggcgagtgt

Heavy chain B	agagcccacctggtgcagtctggcaccgccatgaagaaaccaagcgcctctgtgcgggt	SEQ ID
	gtcctgtcagacaagcagctacaccttcaccgcccacatcctgttctggttccggcagacc	NO: 396
	cctggcagaggactggaatgagtgggatggatcaagccccagtatggcgccgtgaactt
	cggcggaggcttccgggatagagtgaccctgacccgggacgtgtaccgcgagatcacct
	acatggacatccggggcctgaagcccgatgacaccgccgtggggctactgcgccagagac
	agaagctacggcgacagcagagggctctggatgcttggggccagggcacaaccgtgg
	tggtgtctgccgacaaaacccatacccaagtgcaactaatggaatctagcgacggagtg
	gtgcagcctgacaaaaacctgaaactgaactatgccgccagcgacttcaccttcaccaa
	ggcctggatgcactgggtgcgccaggcccctggaaagcagaggaatgggtggcccag
	atcaaggacaagagcaacagctacgccacctactacgccgacagcgtgaagggccagtt
	caccatcagccgggacgacagcaagaacaccagtacctgcagatgaacagcctgcag
	gccgagaacaccgccgtatactactgtcggggcgtgtactatgccctgaaccccttgatt
	actggggccaaagaaccctcgtaaccgtatctaatgataagacccacaccgcttcgacca
	agggcccatcggtgttccctctgacccatgcagcagaagcaccagcgaatctacagccg
	ccctgggctgcctcgtgaaggactactttcccgagcccgtgaccgtgtcctggaactctgg
	cgctctgacaagcggcgtgcacacctttccagccgtgctccagagcagcgacctgtactc
	tctgagcagcgtcgtgacagtgcccagcagcagcctgagcaccaaaacctacacctgta
	acgtggaccacaagcccagcaacaccaagatggacaagcgggtggaatctaagtacga
	ccctccctgccctccttgcccagcccctgaatactgagcgaaccctccgtgttcctattccc
	cccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtggtg
	gtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacgtggacggcgtggaa
	gtgcacaacgccaagaccaagcccagagaggaacagttcaacagcacctaccgggtgg
	tgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaagagtacaagtgcaag
	gtgtccaacaagggcctgcccagctccatcgagaaaaccatcagcaaggccaagggcc
	agccccgcgagcctcaagtgtgtaccctgccccctagccagaaaaagatgaccaagaac
	caggtgtccctaagctgtgccgtgaaaggcttctaccccagcaacattgccgtaaaatgg
	gagagcaacggccagcccgagaacaactacaagaccaccccccctgtgctggacagcg
	acggctcattcttcctggtgtccaagctgaccgtggacaagagccggtggcaggaaggca
	acgtattcagctgctccgtgatgcacgaggccctgcacaaccactacacccagaagtccc
	tgtctctgtccctagacaag

Light chain B	gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag	SEQ ID
	catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct	NO: 397
	ggtatctgcagaagcccggccagaacccccagtccctgatctacaagatgtccaacagat
	tcagcggcgtgcccaacagattctccggcagcggctaggcaccgacttcaccctaaaaa
	tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac
	cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccatacctacatc
	cacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtgaccatcaa
	ctgccagacctctcagagcgtgggcagcgacctgcactagtatcagcacaagcctggca
	gagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcccagcag
	attttccggcaacggcttccacaccagatcaacctgaccatcaacgatctgcaggccgac
	gacattgccacctactattgtcaggtgagcagttatcggcagaggcagcagactacacat
	caaggataagacccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagc
	gacgagcagctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttctaccccc
	gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccagg
	aaaacgtgaccgagcaggacaacaaggactccacctacagcctgagcagcaccctaac
	actgaacaaggccgactacgagaagcacaaggtatacgcctgcgaagtaacccaccag
	ggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 44 Amino Acid Sequences

Heavy chain A	Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwagggt	SEQ ID
	nynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysmdywgqgtt	NO: 398
	vtvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpav
	lqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapefl
	ggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkp
	reeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvyt
	lppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffly
	skltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Divltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnve	SEQ ID
	sgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleikrtvaapsv	NO: 399
	fifppsdeqlksgtasvvcllnnfypreakvqwkydnalqsgnsqesvteqdskdstys
	lsstltskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvqlvesgggvvqpgrslrlscaasgftftkawmhwvrqapgkqlewvaqi	SEQ ID
	kdksnsyatyyadsvkgrftisrddskntlylqmnslraedtavvycrgvyyal	NO: 400
	spfdywgqgtlvtvsssrahlvqsgtamkkpgasvrvscqtsgytftahilfwfr
	qapgrglewvgwikpqygavnfgggfrdrvtltrdvyreiaymdirglkpddt
	avyycardrsygdsswaldawgqgttvvvsartastkgpsvfplapcsrstsest
	aalgclvkdyfpepvtvswnsgaltsgvhtfpaviqssglysissvvtvpssslgt
	ktytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflfppkpkdtl
	misrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrv
	vsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvctlppsq
	eemtknqvslscavkgfypsdiavewesngqpennykttppvldsdgsfflvs
	kltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain B	Yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgvp	SEQ ID
	srfsgsgthtsfnltisdlqaddiatyycqvlqffgrgsrlhikgqpkaapdivmtqtplsl	NO: 401
	svtpgqpasiscksaqslvhnnantylswylqkpggspqsliykvsnrfsgvpdrfsgs
	gsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveiktkgpsrtvaapsvfifpps
	deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl
	skadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 44 Nucleotide Sequences

Heavy chain A	caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct	SEQ ID
	gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagc	NO: 402
	cacctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaacta
	caaccccagcctaaaatccagaaagaccatcagcaaggacaccagcaagaaccaggtg
	tccctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagaga
	caagggctacagctactactacagcatggactactggggccagggcaccaccgtgaccg
	tgtcatccgcgtcgaccaagggcccctcggtgttccctaggccccttgcagcagaagca
	ccagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtga
	ccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctcca
	gagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggca
	ccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcg
	ggtggaatctaagtacggccctccctgccaccttgcccagcccctgaatttctgggcgga
	ccctccgtgttcctgttccccccaaagcccaagaacaccctgatgatcagccggaccccc
	gaagtaacctgcgtaatggtggatgtatcccaggaagatcccaaggtgcagttcaattggt
	acgtggacggcgtgaaaatgcacaacgccaagaccaagcccagagaagaacagttca
	acagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggc
	aaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccat
	cagcaaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttgccag
	gaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagc
	gacattgccgtgaaatgggagagcaacgaccagcccaagaacaactacaagaccaccc
	cccctgtactggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagag
	ccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaacc
	actacacccagaagtccctgtctctgtccagggcaag

Light chain A	gacatccagatgacccagagccccagcagcctgtctgccgcgtgggcgacagagtga	SEQ ID
	ccatcacctgtcaggccagccagaacatctacgtatggctgaactggtatcaacagaagc	NO: 403
	ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc
	cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagcccctgcag
	cccgaggacattgccacctactactgccagcagggccagacctacccctacacattggc
	cagggcaccaagctggaaatcaagcgtacagtggccgctcccagcgtgttcatcttccca
	cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacnct
	acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca
	gccaggaaagcgtaaccgaacaggacagcaaggactccacctacaacctgaacaaca
	ccctgaccctgagcaaggccgactacgagaagcacaagatgtacgcctgcgaagtgac
	ccaccagggcctatctagccccgtgaccaagagatcaaccgggcgagtgt

Heavy chain B	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc	NO: 404
	ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact
	acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt
	cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg
	tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa
	gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg
	tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa
	cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac
	gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg
	tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac
	cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc
	cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca
	cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc
	cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac
	accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc
	cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga
	tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc
	gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc
	cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc
	aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag
	ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta
	ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg
	aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga
	acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa
	gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc
	acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag

Light chain B	tacatccacgtgacccagagccccagcagcctgtccgtgtccatcggcsacaga	SEQ ID
	gtgaccatcaactgccagacctctcaggctgggcagegacctgcactggtatc	NO: 405
	agcacaagcctggcagagcceccaagagctgatccaccacacaagcagcgtg
	gaagatggcgtgcccagcagattaccggcagcggcttccacaccagcttcaacc
	tgaccatcagcgatagcaggccgacgacattgccacctactattgtcaggtgctg
	cagttcttcggcagaggcagcagactgcacatcaagggccagcccaaggccgc
	ccccgacatcgtgatgacccaacccccagagcctgagcgtgacacctggaca
	gcctgccagcatcagctgcaagagcagccagagcctggtgcacaacaacgcca
	acacctacctgagctggtatctgcagaagcccggccagagcccccagtccctgat
	ctacaaggtgtccaacagattcagcgcgtgcccgacagattctccggcagcgg
	ctctggcaccgacttcaccctgaagatcagccgggtggaagccgaggacgtggg
	cgtgtactattgtggccagggcacccagtaccccttcacattggcagcggcacca
	aggtggaaatcaagaccaagggccccagccgtacggtggccgctcccagcgtg
	ttcatcttcccacctagcgacgagcagctgaagtccggcacagcactgtcgtgtg
	cctgctgaaacttctacccccgcgaggccaaagtgcagtggaaggtggacaa
	cgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaag
	gactccacctacagcctgagcagcaccctgacactgacaaggccgactacga
	aagcacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtg
	accaagagcttcaaccggggcgagtgt

Binding Protein 45 Amino Acid Sequences

Heavy chain A	Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwagggt	SEQ ID
	nynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysmdywgqgtt	NO: 406
	vtvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpav
	lqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapefl
	ggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkp
	reeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvyt
	lppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffly
	skltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Divltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnve	SEQ ID
	sgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleikrtvaapsv	NO: 407
	fifppsdeqlksgtasvvcllnnfypreakvqwkydnalqsgnsqesvteqdskdstys
	lsstltskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	qvqlvesgggvvqpgrslrlscaasgftftkawmhwvrqapgkqlewvaqik	SEQ ID
	dksnsyatyyadsvkgrftisrddskntlylqmnslraedtavyycrgvyyals	NO: 408
	pfdywgqgtlvtvssdkthtrahlvqsgtamkkpgasvrvscqtsgytftahilf
	wfrqapgrglewvgwikpqygavnfgggfrdrvtltrdvyreiaymdirglkp
	ddtavyycardrsygdsswaldawgggttvvvsadkthtastkgpsvfplapc
	srstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavlqssgtyslssvvt
	vpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflggpsvflf
	ppkpkdtimisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpree
	qfnstyrvvsvltvlhqdwllgkeykckvsnkglpssiektiskakgqprepq
	vctlppsqeemtknqvslscavkgfypsdiavewesngqpennykttppvld
	sdgsfflvskltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain B	Yihvtqspsslsvsigdrvtincqtsqgvgsdlhwyqhkpgrapkllihhtssvedgvp	SEQ ID
	srfsgsgfhtsfnltisdlqaddiatyycqvlqffgrgsrlhikdkthtdivmtqtpl	NO: 409
	slsvtpgqpasisckssqslvhnnantylswylqkpgqspqsliykvsnrfsgvpdrf
	sgsgsgtdftlkisrveaedvgvyycgqgtqypftfgsgtkveikdkthtrtvaaps
	vfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskd
	styslsstltlskadyekhkvyacevthqglsspvtksfnrgec

Binding Protein 45 Nucleotide Sequences

Heavy chain A	caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct	SEQ ID
	gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagc	NO: 410
	cacctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaacta
	caaccccagcctaaaatccagaaagaccatcagcaaggacaccagcaagaaccaggtg
	tccctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagaga
	caagggctacagctactactacagcatggactactggggccagggcaccaccgtgaccg
	tgtcatccgcgtcgaccaagggcccctcggtgttccctaggccccttgcagcagaagca
	ccagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtga
	ccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctcca
	gagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggca
	ccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcg
	ggtggaatctaagtacggccctccctgccaccttgcccagcccctgaatttctgggcgga
	ccctccgtgttcctgttccccccaaagcccaagaacaccctgatgatcagccggaccccc
	gaagtaacctgcgtaatggtggatgtatcccaggaagatcccaaggtgcagttcaattggt
	acgtggacggcgtgaaaatgcacaacgccaagaccaagcccagagaagaacagttca
	acagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggc
	aaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccat
	cagcaaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttgccag
	gaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagc
	gacattgccgtgaaatgggagagcaacgaccagcccaagaacaactacaagaccaccc
	cccctgtactggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagag
	ccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaacc
	actacacccagaagtccctgtctctgtccagggcaag

Light chain A	gacatcgtgctgacacagagccctgctagcctggccgtgtctcctggacagagggccac	SEQ ID
	catcacctgtagagccagcgagagcgtggaatattacgtgaccagcctgatgcagtggta	NO: 411
	tcagcagaagcccggccaaccccccaagctgctgattttcgccgccaacaacatggaaa
	gcggcgtgccagccagattttccgacagcggctctggcaccgacttcaccctgaccatca
	accccgtggaagccaacgacgtggccaactactactgccagcagagccggaaggtacc
	ctacacctttggccagggcaccaagctggaaatcaagcgtacggtggccgctcccagcg
	tgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcct
	gctgaacaacttctacccccgcgaggccaaggtgcagtggaaggtggacaatgccctgc
	agagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactccacctaca
	gcctgagcagcaccagaccctgagcaaggccaactacgagaaacacaaggtatacgc
	ctgcgaagtaacccaccaggacctgtctagccccgtgaccaagagcttcaaccgggacg
	agtgt

Heavy chain B	caggtgcagctggtggaatctagcgacggagtgatgcagcctagcagaagcctgagac	SEQ ID
	tgagctgtgccgccaacggcttcaccttcaccaaggcctagatgcactaggtacgccaa	NO: 412
	gcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaacagctacg
	ccacctactacgccgacagcgtgaagggccggacaccatcagccgggacgacagcaa
	gaacaccagtacctacaaataaacagcctgcaggccgaagacaccgccgtatactact
	gtcggggcgtgtactatgccctgagccccttcgattactggggccagggaaccctcgtga
	ccgtgtctagtgacaaaacccataccagagcccacctggtgcagtctggcaccgccatga
	agaaaccaggcgcactgtgcgggtgtcctgtcagacaagcggctacaccacaccgccc
	acatcagttaggttccggcaggcccctggcagaagactggaatgggtaggatggatca
	agccccagtatggcgccgtgaacttcggcagaggcttccgggatagagtgaccctgacc
	cgggacgtgtaccgcgagatcgcctacatggacatccggggcctgaagcccgataaca
	ccgccgtgtactactgcgccagagacagaagctacggcgacagcagctgggctctggat
	gcttggggccagggcacaaccgtggtggtgtctgccgataagacccacaccgccagca
	caaagggcccatcggtgttccctctggccccttgcagcagaagcaccagcgaatctacag
	ccgccctgggctgcctcgtgaaggactactttcccgagcccgtgaccgtgtcctggaactc
	tggcgctctgacaagcggcgtgacacctttccagccgtgaccagagcagggcctgta
	ctctctgagcagcgtcgtgacagtgcccagcagcagcctgagcaccaagacctacacct
	gtaacgtgaaccacaagcccagcaacaccaaggtggacaagcgagtggaatctaaata
	cggccctccctgccctccttgcccagcccctgaatttctgggcggaccctccgtgttcctgt
	tccccccaaagcccaaggacaccctgatgatcagccggacccccgaagtgacctgcgtg
	gtggtggatgtgtcccaggaagatcccgaggtgcagacaatggtacgtggacggcgtg
	gaagtgcacaacgccaagaccaagcccagagaggaacagttcaacagcacctaccgg
	gtggtgtccatgctgaccatgctgcaccaggactggctgaacggcaaagagtacaagta
	caaggtgtccaacaaggacctgcccagaccatcgagaaaaccatcagcaaggccaag
	ggccagccccgcgagcctcaagttgtaccctgccccctagccaggaagagatgacca
	agaaccaggtgtccctgagctgtgccgtgaaaggcttctaccccagcgacattgccgtgg
	aatgggagagcaacggccagcccgagaacaactacaagaccaccccccctgtgagga
	cagcgacggctcattcacctggtgtccaagagaccgtggacaagagccggtggcagg
	aaggcaacgtgacagagaccgtgatgcacgagaccctgcacaaccactacacccag
	aagtccctgtctctgtccagggcaag

Light chain B	tacatccacgtgacccagancccagcagcctgtccgtgtccatcggcgacagagtgac	SEQ ID
	catcaactgccagacctctcagggcgtaggcagcgacctgcactgatatcagcacaagc	NO: 413
	ctggcagagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcc
	cagcagattttccggcagcggcttccacaccagatcaacctgaccatcagcgatctgcag
	gccgacgacattgccacctactattgtcaggtgagcagacttcggcagaggcagcagac
	tgcacatcaaggacaaaacccataccgacatcgtgatgacccagacccccctgagcctg
	agcgtgacacctggacagcctgccagcatcagagcaagagcagccagagcctggtgc
	acaacaacgccaacacctacctgagaggtatctgagaagcccggccagagccccca
	gtccagatctacaaggtgtccaacagattcagcggcgtacccgacagattctccggcag
	cggctctggcaccgacttcaccctgaagatcagccgggtggaagccgaggacgtgggc
	gtgtactattgtggccagggcacccagtaccccttcacctttggcagcggcaccaaggtg
	gaaatcaaggataagacccatacccgtacggtggccgctcccagcgtgacatcttcccac
	ctagcgacgagcagctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttcta
	cccccacgaggccaaagtgcagtagaaggtgaacaacgccagcagagcggcaacag
	ccaggaaagcatgaccgagcaggacagcaaggactccacctacagcctgagcagcac
	cctgacactgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgacc
	caccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 46 Amino Acid Sequences

Heavy chain A	Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv	SEQ ID
	ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv	NO: 414
	tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl
	qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg
	gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre
	eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp
	pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk
	ltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv	SEQ ID
	psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps	NO: 415
	deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl
	skadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwi	SEQ ID
	shegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrd	NO: 416
	yalydddgalnwavdvdylsnlefwgqgtavtvsssqvqlvesgggvvqpgr
	slrlscaasgftftkawmhwvrqapgkqlewvaqikdksnsyatyyadsvkg
	rftisrddskntlylqmnslraedtavyycrgvyyalspfdywgqgtlvtvssrta
	stkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl
	qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpa
	peflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgve
	vhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektis
	kakgqprepqvctlppsqeemtknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsdgsfflvskltvdksrwqegnvfscsvmhealhnhytqksls
	lslgk

Light chain B	Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgspqsliykvsnr	SEQ ID
	fsgvpdrfsgsgsgtdftikisrveaccivgvyycgqgtqypftfgsgtkveikgqpkaa	NO: 417
	pdfvitqsphslsvtpaesasiscksshsiihgdrnnylawyvqkparspqiiiylassra
	sgvpdrfsgsgsdkdftikisrvetethigtyycniggrespvirtfmtkvdiktkgpsrt
	vaapsvfifppsdeciiksgtasvvcllnnfypreakvqwkvdnalcisgnsciesvteqd
	skdsiyslsstitlskadyekhkvyacehqgisspvtksfnrgec

Binding Protein 46 Nucleotide Sequences

Heavy chain A	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc	NO: 418
	ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact
	acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt
	cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg
	tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa
	gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg
	tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa
	cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac
	gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg
	tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac
	cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc
	cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca
	cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc
	cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac
	accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc
	cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga
	tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc
	gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc
	cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc
	aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag
	ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta
	ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg
	aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga
	acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa
	gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc
	acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag

Light chain A	gacatccagatgacccagagccccagcagcctgtctgccgcgtgggcgacagagtga	SEQ ID
	ccatcacctgtcaggccagccagaacatctacgtatggctgaactggtatcaacagaagc	NO: 419
	ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc
	cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagcccctgcag
	cccgaggacattgccacctactactgccagcagggccagacctacccctacacattggc
	cagggcaccaagctggaaatcaagcgtacagtggccgctcccagcgtgttcatcttccca
	cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacnct
	acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca
	gccaggaaagcgtaaccgaacaggacagcaaggactccacctacaacctgaacaaca
	ccctgaccctgagcaaggccgactacgagaagcacaagatgtacgcctgcgaagtgac
	ccaccagggcctatctagccccgtgaccaagagatcaaccgggcgagtgt

Heavy chain B	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc	NO: 420
	ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact
	acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt
	cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg
	tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa
	gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg
	tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa
	cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac
	gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg
	tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac
	cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc
	cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca
	cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc
	cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac
	accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc
	cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga
	tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc
	gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc
	cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc
	aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag
	ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta
	ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg
	aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga
	acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa
	gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc
	acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag

Light chain B	gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag	SEQ ID
	catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct	NO: 421
	ggtatctgcagaagcccggccagaacccccagtccctgatctacaagatgtccaacagat
	tcagcggcgtgcccaacagattctccggcagcggctaggcaccgacttcaccctaaaaa
	tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac
	cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccatacctacatc
	cacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtgaccatcaa
	ctgccagacctctcagagcgtgggcagcgacctgcactagtatcagcacaagcctggca
	gagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcccagcag
	attttccggcaacggcttccacaccagatcaacctgaccatcaacgatctgcaggccgac
	gacattgccacctactattgtcaggtgagcagttatcggcagaggcagcagactacacat
	caaggataagacccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagc
	gacgagcagctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttctaccccc
	gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccagg
	aaaacgtgaccgagcaggacaacaaggactccacctacagcctgagcagcaccctaac
	actgaacaaggccgactacgagaagcacaaggtatacgcctgcgaagtaacccaccag
	ggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 47 Amino Acid Sequences

Heavy chain A	Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv	SEQ ID
	ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv	NO: 422
	tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl
	qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg
	gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre
	eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp
	pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk
	ltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv	SEQ ID
	psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps	NO: 423
	deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl
	skadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwi	SEQ ID
	shegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrd	NO: 424
	yalydddgalnwavdvdylsnlefwgqgtavtvsssqvqlvesgggvvqpgr
	slrlscaasgftftkawmhwvrqapgkqlewvaqikdksnsyatyyadsvkg
	rftisrddskntlylqmnslraedtavyycrgvyyalspfdywgqgtlvtvssrta
	stkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl
	qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpa
	peflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgve
	vhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektis
	kakgqprepqvctlppsqeemtknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsdgsfflvskltvdksrwqegnvfscsvmhealhnhytqksls
	lslgk

Light chain B	Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgspqsliykvsnr	SEQ ID
	fsgvpdrfsgsgsgtdftikisrveaccivgvyycgqgtqypftfgsgtkveikgqpkaa	NO: 425
	pdfvitqsphslsvtpaesasiscksshsiihgdrnnylawyvqkparspqiiiylassra
	sgvpdrfsgsgsdkdftikisrvetethigtyycniggrespvirtfmtkvdiktkgpsrt
	vaapsvfifppsdeciiksgtasvvcllnnfypreakvqwkvdnalcisgnsciesvteqd
	skdsiyslsstitlskadyekhkvyacehqgisspvtksfnrgec

Binding Protein 47 Nucleotide Sequences

Heavy chain A	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc	NO: 426
	ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact
	acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt
	cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg
	tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa
	gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg
	tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa
	cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac
	gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg
	tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac
	cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc
	cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca
	cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc
	cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac
	accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc
	cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga
	tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc
	gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc
	cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc
	aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag
	ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta
	ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg
	aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga
	acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa
	gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc
	acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag

Light chain A	gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag	SEQ ID
	catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct	NO: 427
	ggtatctgcagaagcccggccagaacccccagtccctgatctacaagatgtccaacagat
	tcagcggcgtgcccaacagattctccggcagcggctaggcaccgacttcaccctaaaaa
	tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac
	cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccatacctacatc
	cacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtgaccatcaa
	ctgccagacctctcagagcgtgggcagcgacctgcactagtatcagcacaagcctggca
	gagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcccagcag
	attttccggcaacggcttccacaccagatcaacctgaccatcaacgatctgcaggccgac
	gacattgccacctactattgtcaggtgagcagttatcggcagaggcagcagactacacat
	caaggataagacccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagc
	gacgagcagctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttctaccccc
	gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccagg
	aaaacgtgaccgagcaggacaacaaggactccacctacagcctgagcagcaccctaac
	actgaacaaggccgactacgagaagcacaaggtatacgcctgcgaagtaacccaccag
	ggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc	NO: 428
	ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact
	acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt
	cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg
	tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa
	gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg
	tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa
	cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac
	gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg
	tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac
	cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc
	cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca
	cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc
	cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac
	accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc
	cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga
	tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc
	gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc
	cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc
	aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag
	ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta
	ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg
	aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga
	acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa
	gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc
	acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag

Light chain B	gacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccag	SEQ ID
	catcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctgagct	NO: 429
	ggtatctgcagaagcccggccagaacccccagtccctgatctacaagatgtccaacagat
	tcagcggcgtgcccaacagattctccggcagcggctaggcaccgacttcaccctaaaaa
	tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac
	cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccatacctacatc
	cacgtgacccagagccccagcagcctgtccgtgtccatcggcgacagagtgaccatcaa
	ctgccagacctctcagagcgtgggcagcgacctgcactagtatcagcacaagcctggca
	gagcccccaagctgctgatccaccacacaagcagcgtggaagatggcgtgcccagcag
	attttccggcaacggcttccacaccagatcaacctgaccatcaacgatctgcaggccgac
	gacattgccacctactattgtcaggtgagcagttatcggcagaggcagcagactacacat
	caaggataagacccatacccgtacggtggccgctcccagcgtgttcatcttcccacctagc
	gacgagcagctgaagtccggcacagcctagtcgtgtgcctgctgaacaacttctaccccc
	gcgaggccaaagtgcagtggaaggtggacaacgccctgcagagcggcaacagccagg
	aaaacgtgaccgagcaggacaacaaggactccacctacagcctgagcagcaccctaac
	actgaacaaggccgactacgagaagcacaaggtatacgcctgcgaagtaacccaccag
	ggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Binding Protein 48 Amino Acid Sequences

Heavy chain A	Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv	SEQ ID
	ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv	NO: 430
	tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl
	qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg
	gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre
	eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp
	pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk
	ltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv	SEQ ID
	psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps	NO: 431
	deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl
	skadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvqlvesgggvvqpgrslrlscaasgftftkawmhwyrqapgkqlewvaqi	SEQ ID
	kdksnsyatyyadsvkgrftisrddskntlykynnsiraedtavyycrgvyyals	NO: 432
	pfdywgqgtlytysssqvhitqsgpevrkpgtsykysckapgntiktydlhwv
	rsvpg1glqwmgwishegdkkvivertkakvtidwdrstntayiqlsgitsgd
	tavyycakgskhrirdyalydddgainwaydvdylsniefwgqgtaytyssrt
	astkgpsvfplapcsrstsestaalgelykdyfpepmswnsgaitsgvhtfpay
	lgssglyslssyytypssslgtktytcnvdhkpsntkvdkrveskygppcppcp
	apeflggpsvfifppkpkdtimisapeytcyvydvsqedpevqfimyydgy
	evhnaktkpreeqfnstyrvvsvitvlhqdvvingkeykekvsnkgipssiekti
	skakgqprepqvctIppscieemtknqvstscavkgfypsdiavewesnme
	nnykttppvldsdgsfflvsldtvdksrwqegnvfscsvrnhealhnhytqksls
	lslgk

Light chain B	Dfvltqsphslsvtpgesasiscksshslihgdmnylawyvqkpgrspqllassras	SEQ ID
	gvpdrfsgsgsdkdfilkisrvetedvgtyycatqgrespvirtfgqtttkvdikgqpkaap	NO: 433
	divmtqtplsisvtpggpasisckssgslvlitmantylswykikpggspcisitykvsnrf
	sgvpdrfsgsgsgtdfilkisneacdvgvyycgqgttpftfgsgtkveiktkgpsrtv
	aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalgsgnsqcsvtecids
	kdstystssthiskadyckhkvyaccvthqgisspvtksfargec

Binding Protein 48 Nucleotide Sequences

Heavy chain A	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc	NO: 434
	ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact
	acgcccagaagaccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgaaccagctgagaagcgacgacaccaccatgtactactgcacccagt
	cccactacgacctggattagaacttcgacatgtagggcaagagcaccaccgtgacagtgt
	ctagcgcgtcgaccaagggcccctcggtgttccctctggccccttgcagcagaagcacca
	gcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgaccg
	tgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctccagag
	cagcggcagtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggcacca
	agacctacacctgtaacatggaccacaaacccagcaacaccaaggtagacaagcgagt
	ggaatctaagtacggccctccctgccctccttgcccagcccctgaatttctgggcggaccc
	tccgtgttcctgttccccccaaagcccaaggacaccctgatgatcagccggacccccgaa
	gtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacg
	tggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagttcaacag
	cacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaag
	agtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccatcagc
	aaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttgccaggaaga
	gatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggatctaccccagcgacatt
	gccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccct
	gtgctggacagcgacggctcattcacctgtactccaaactgaccgtggacaagaaccaat
	ggcaggaaggcaacgtgttcagctgaccgtgatacacgaggccagcacaaccactac
	acccagaagtccctgtctctgtccctgggcaag

Light chain A	gacatccagatgacccagcagccccagcagcctgtctgccagcgtgggcgacagagtga	SEQ ID
	ccatcacctgtcaggccagccagaacatctacgtgtggctgaactggtatcagcagaagc	NO: 435
	ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc
	cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagctccctgcag
	cccgaggacattgccacctactactgccagcagggccagacctacccctacacctttggc
	cagggcaccaagctggaaatcaagcgtacggtggccgctcccagcgtgttcatcttccca
	cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttct
	acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca
	gccaggaaagcgtaaccgagcaggacagcaaggactccacctacaacctgagcagca
	ccctgaccctgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgac
	ccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	caggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaagcctgagact	SEQ ID
	gagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactgggtgcgccagg	NO: 436
	cccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaacagctacgc
	cacctactacgccgacagcgtgaagggccggttcaccatcagccgggacgacagcaag
	aacaccagtacctgcagatgaacagcctgcgggccgaggacaccgccgtgtactactgt
	cggggcgtgtactatgccagaacccatcgattactgaggccagagaaccctcgtaacc
	gtgtctagtagccaggtgcacctgacacagagcggacccgaagtgcggaagcctggca
	cctctgtgaaggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcact
	gggtgcgcagcgtgccaggacagggactgcagtggatgggctggatcagccacgagg
	gcgacaagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacaga
	agcaccaacaccgcctacctacagagagcggcctaacctctggcgataccgccgtgta
	ctactgcaccaaaggcagcaagcaccgactgagagactacgccagtacgacgatgac
	ggcgccagaactgggccgtggatgtgaactacctgagcaacctggaattaggggcca
	gggcacagccgtgaccgtgtcatctcggaccgccagcacaaagggcccatcggtgttcc
	ctctggccccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtga
	aggactactttcccgagcccgtgaccgtgtcctggaactctggcgctagacaagcggcgt
	gcacacctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgac
	agtgcccagcagcagcagggcaccaagacctacacctataacgtggaccacaagccc
	agcaacaccaagatggacaagcgggtagaatctaagtacgaccctccctgccctccttgc
	ccagcccctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggaca
	ccctgatgatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaa
	gatcccgaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagac
	caagcccagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgc
	tgcaccaggactggctgaacggcaaagagtacaagtgcaaggtatccaacaagagcctg
	cccagctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaag
	tgtgtaccctgccccctagccaggaagagatgaccaagaaccaggtgtccctgagctgtg
	ccgtgaaaggatctaccccagcgacattgccgtggaatgggagagcaacggccagccc
	gagaacaactacaagaccaccccccctgtgaggacagcgacggctcattcacctggtgt
	ccaagctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtg
	atgcacgaggccctgcacaaccactacacccagaagtccctatactgtccctggacaag

Light chain B	gacttcgtgagacccagagccctcacagcctgagcgtgacacctggcgagagcgccag	SEQ ID
	catcagagcaagagcagccactccctgatccacggcgaccgaaacaactacctagatg	NO: 437
	gtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcagag
	ccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttcaccctgaag
	atcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcagagaga
	gcccctggacctttggccagggcaccaaggtggacatcaagggccagcccaaggccgc
	ccccgacatcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctg
	ccagcatcagctgcaagagcagccagagcctggtgcacaacaacgccaacacctacctg
	agctggtatctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaac
	agattcagcggctttgcccgacagattctccggcagcggctctggcaccgacttcacccta
	aagatcaaccaggtaaaaaccgaggacatgggcgtgtactattatggccagggcaccc
	agtacccatcaccatgacaacggcaccaaggtggaaatcaagaccaaaggccccagc
	cgtacggtggccgctcccagcgtgttcatcttcccacctagcgacgagcagctgaagtcc
	ggcacagcctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcag
	tggaaggtggacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcag
	gacagcaaggactccacctacagcctgagcagcaccctgacactgagcaaggccgact
	acgagaagcacaaggtgtacgcctgcgaagtgacccaccagggcctatctagccccgtg
	ctccaagaacttcaaccgaagcgagtgt

Binding Protein 49 Amino Acid Sequences

Heavy chain A	Qvqlvqsgaevvkpgasvkvsckasgytftsyyihwvrqapgqglewigsiypgnv	SEQ ID
	ntnyaqkfqgratltvdtsistaymelsrlrsddtavyyctshygldwnfdvwgkgttv	NO: 438
	tvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl
	qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapeflg
	gpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpre
	eqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlp
	pcqeemtkmnqvslwclvkgfypsdiavewesngqpennykttppvldsdgsfflysk
	ltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Diqmtqspsslsasvgdrvtitcqasqniyvwlnwyqqkpgkapklliykasnlhtgv	SEQ ID
	psrfsgsgsgtdffitisslqpediatyycqqgqtypytfqqgtkleikrtvaapsvfifpps	NO: 439
	deqlksgtasvvcllnnfypreakvqwkvdnalqsgnsqesvteqdskdstyslsstltl
	skadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvqlvesgggvvqpgrslrlscaasgftftkawmhwyrqapgkqlewvaqi	SEQ ID
	kdksnsyatyyadsvkgrftisrddskntlykynnsiraedtavyycrgvyyals	NO: 440
	pfdywgqgtlytysssqvhitqsgpevrkpgtsykysckapgntiktydlhwv
	rsvpg1glqwmgwishegdkkvivertkakvtidwdrstntayiqlsgitsgd
	tavyycakgskhrirdyalydddgainwaydvdylsniefwgqgtaytyssrt
	astkgpsvfplapcsrstsestaalgelykdyfpepmswnsgaitsgvhtfpay
	lgssglyslssyytypssslgtktytcnvdhkpsntkvdkrveskygppcppcp
	apeflggpsvfifppkpkdtimisapeytcyvydvsqedpevqfimyydgy
	evhnaktkpreeqfnstyrvvsvitvlhqdvvingkeykekvsnkgipssiekti
	skakgqprepqvcttppscieemtknqvstscavkgfypsdiavewesnme
	nnykttppvldsdgsfflvsldtvdksrwqegnvfscsvrnhealhnhytqksls
	lslgk

Light chain B	Dfvltqsphslsvtpgesasiscksshslihgdmnylawyvqkpgrspqllassras	SEQ ID
	gvpdrfsgsgsdkdfilkisrvetedvgtyycatqgrespvirtfgqtttkvdikgqpkaap	NO: 441
	divmtqtplsisvtpggpasisckssgslvlitmantylswykikpggspcisitykvsnrf
	sgvpdrfsgsgsgtdfilkisneacdvgvyycgqgttpftfgsgtkveiktkgpsrtv
	aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalgsgnsqcsvtecids
	kdstystssthiskadyckhkvyaccvthqgisspvtksfargec

Binding Protein 49 Nucleotide Sequences

Heavy chain A	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc	NO: 442
	ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact
	acgcccagaagaccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgaaccagctgagaagcgacgacaccaccatgtactactgcacccagt
	cccactacgacctggattagaacttcgacatgtagggcaagagcaccaccgtgacagtgt
	ctagcgcgtcgaccaagggcccctcggtgttccctctggccccttgcagcagaagcacca
	gcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgaccg
	tgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctccagag
	cagcggcagtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggcacca
	agacctacacctgtaacatggaccacaaacccagcaacaccaaggtagacaagcgagt
	ggaatctaagtacggccctccctgccctccttgcccagcccctgaatttctgggcggaccc
	tccgtgttcctgttccccccaaagcccaaggacaccctgatgatcagccggacccccgaa
	gtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattggtacg
	tggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagttcaacag
	cacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaag
	agtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccatcagc
	aaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttgccaggaaga
	gatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggatctaccccagcgacatt
	gccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccct
	gtgctggacagcgacggctcattcacctgtactccaaactgaccgtggacaagaaccaat
	ggcaggaaggcaacgtgttcagctgaccgtgatacacgaggccagcacaaccactac
	acccagaagtccctgtctctgtccctgggcaag

Light chain A	gacatccagatgacccagcagccccagcagcctgtctgccagcgtgggcgacagagtga	SEQ ID
	ccatcacctgtcaggccagccagaacatctacgtgtggctgaactggtatcagcagaagc	NO: 443
	ccggcaaggcccccaagctgctgatctacaaggccagcaacctgcacaccggcgtgcc
	cagcagattttctggcagcggctccggcaccgacttcaccctgacaatcagctccctgcag
	cccgaggacattgccacctactactgccagcagggccagacctacccctacacctttggc
	cagggcaccaagctggaaatcaagcgtacggtggccgctcccagcgtgttcatcttccca
	cctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctgctgaacaacttct
	acccccacgaggccaaggtacaatggaaggtggacaatgccctgcagagcagcaaca
	gccaggaaagcgtaaccgagcaggacagcaaggactccacctacaacctgagcagca
	ccctgaccctgagcaaggccgactacgagaagcacaaggtgtacgcctgcgaagtgac
	ccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcgagtgt

Heavy chain B	caggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaagcctgagact	SEQ ID
	gagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactgggtgcgccagg	NO: 444
	cccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaacagctacgc
	cacctactacgccgacagcgtgaagggccggttcaccatcagccgggacgacagcaag
	aacaccagtacctgcagatgaacagcctgcgggccgaggacaccgccgtgtactactgt
	cggggcgtgtactatgccagaacccatcgattactgaggccagagaaccctcgtaacc
	gtgtctagtagccaggtgcacctgacacagagcggacccgaagtgcggaagcctggca
	cctctgtgaaggtgtcctgcaaggcccctggcaacaccctgaaaacctacgacctgcact
	gggtgcgcagcgtgccaggacagggactgcagtggatgggctggatcagccacgagg
	gcgacaagaaagtgatcgtggaacggttcaaggccaaagtgaccatcgactgggacaga
	agcaccaacaccgcctacctacagagagcggcctaacctctggcgataccgccgtgta
	ctactgcaccaaaggcagcaagcaccgactgagagactacgccagtacgacgatgac
	ggcgccagaactgggccgtggatgtgaactacctgagcaacctggaattaggggcca
	gggcacagccgtgaccgtgtcatctcggaccgccagcacaaagggcccatcggtgttcc
	ctctggccccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtga
	aggactactttcccgagcccgtgaccgtgtcctggaactctggcgctagacaagcggcgt
	gcacacctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgac
	agtgcccagcagcagcagggcaccaagacctacacctataacgtggaccacaagccc
	agcaacaccaagatggacaagcgggtagaatctaagtacgaccctccctgccctccttgc
	ccagcccctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggaca
	ccctgatgatcagccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaa
	gatcccgaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagac
	caagcccagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgc
	tgcaccaggactggctgaacggcaaagagtacaagtgcaaggtatccaacaagagcctg
	cccagctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaag
	tgtgtaccctgccccctagccaggaagagatgaccaagaaccaggtgtccctgagctgtg
	ccgtgaaaggatctaccccagcgacattgccgtggaatgggagagcaacggccagccc
	gagaacaactacaagaccaccccccctgtgaggacagcgacggctcattcacctggtgt
	ccaagctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtg
	atgcacgaggccctgcacaaccactacacccagaagtccctatactgtccctggacaag

Light chain B	gacttcgtgctgacccagagccctcacagcctgagcgtgacactggcgagagcgccag	SEQ ID
	catcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctggcttg	NO: 445
	gtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcagag
	ccagcggcgtgcccgatagattactggcagcggcagcgacaaggacttcaccctgaag
	atcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcagagaga
	gcccctggacctttggccagggcaccaaggtggacatcaaggacaaaacccataccgac
	atcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccagcat
	cagctacaagagcagccagagcctgatgcacaacaacgccaacacctacctgagaggt
	atctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagattca
	gcggcgtgcccgacagattctccggcagcggctctggcaccgacttcaccctgaagatca
	gccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtaccc
	cttcacctttggcagcggcaccaaggtggaaatcaaggataagacccatacccgtacggt
	ggccgctcccagcgtgttcatatcccacctagcaacgagcagctgaagtccggcacagc
	ctctgtcgtatgcctactaaacaacttctacccccgcaaggccaaaatgcagtggaaggta
	gacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaa
	ggactccacctacagcctgagcagcaccctgacactgagcaaggccgactacgagaag
	cacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagag
	cttcaaccggggcgagtgt

Binding Protein 50 Amino Acid Sequences

Heavy chain A	Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwagggt	SEQ ID
	nynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysmdywgqgtt	NO: 446
	vtvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpav
	lqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapefl
	ggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkp
	reeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvyt
	lppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffly
	skltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Divltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnve	SEQ ID
	sgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleikrtvaapsv	NO: 447
	fifppsdeqlksgtasvvcllnnfypreakvqwkydnalqsgnsqesvteqdskdstys
	lsstltskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwi	SEQ ID
	shegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrd	NO: 448
	yalydddgalnwavdvdylsnlefwgqgtavtvsssqvqlvesgggvvqpgr
	slrlscaasgftftkawmhwvrqapgkqlewvaqikdksnsyatyyadsvkg
	rftisrddskntlylqmnslraedtavyycrgvyyalspfdywgqgtlvtvssrta
	stkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl
	qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpa
	peflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgve
	vhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektis
	kakgqprepqvctlppsqeemtknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsdgsfflvskltvdksrwqegnvfscsvmhealhnhytqksls
	lslgk

Light chain B	Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgspqsliykvsnr	SEQ ID
	fsgvpdrfsgsgsgtdftikisrveaccivgvyycgqgtqypftfgsgtkveikgqpkaa	NO: 449
	pdfvitqsphslsvtpaesasiscksshsiihgdrnnylawyvqkparspqiiiylassra
	sgvpdrfsgsgsdkdftikisrvetethigtyycniggrespvirtfmtkvdiktkgpsrt
	vaapsvfifppsdeciiksgtasvvcllnnfypreakvqwkvdnalcisgnsciesvteqd
	skdsiyslsstitlskadyekhkvyacehqgisspvtksfnrgec

Binding Protein 50 Nucleotide Sequences

Heavy chain A	caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct	SEQ ID
	gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagc	NO: 450
	cacctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaacta
	caaccccagcctaaaatccagaaagaccatcagcaaggacaccagcaagaaccaggtg
	tccctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagaga
	caagggctacagctactactacagcatggactactggggccagggcaccaccgtgaccg
	tgtcatccgcgtcgaccaagggcccctcggtgttccctaggccccttgcagcagaagca
	ccagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtga
	ccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctcca
	gagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggca
	ccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcg
	ggtggaatctaagtacggccctccctgccaccttgcccagcccctgaatttctgggcgga
	ccctccgtgttcctgttccccccaaagcccaagaacaccctgatgatcagccggaccccc
	gaagtaacctgcgtaatggtggatgtatcccaggaagatcccaaggtgcagttcaattggt
	acgtggacggcgtgaaaatgcacaacgccaagaccaagcccagagaagaacagttca
	acagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggc
	aaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccat
	cagcaaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttgccag
	gaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagc
	gacattgccgtgaaatgggagagcaacgaccagcccaagaacaactacaagaccaccc
	cccctgtactggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagag
	ccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaacc
	actacacccagaagtccctgtctctgtccagggcaag

Light chain A	gacatcgtgctgacacagagccctgctagcctggccgtgtctcctggacagagggccac	SEQ ID
	catcacctgtagagccagcgagagcgtggaatattacgtgaccagcctgatgcagtggta	NO: 451
	tcagcagaagcccggccaaccccccaagctgctgattttcgccgccaacaacatggaaa
	gcggcgtgccagccagattttccgacagcggctctggcaccgacttcaccctgaccatca
	accccgtggaagccaacgacgtggccaactactactgccagcagagccggaaggtacc
	ctacacctttggccagggcaccaagctggaaatcaagcgtacggtggccgctcccagcg
	tgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcct
	gctgaacaacttctacccccgcgaggccaaggtgcagtggaaggtggacaatgccctgc
	agagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactccacctaca
	gcctgagcagcaccagaccctgagcaaggccaactacgagaaacacaaggtatacgc
	ctgcgaagtaacccaccaggacctgtctagccccgtgaccaagagcttcaaccgggacg
	agtgt

Heavy chain B	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc	NO: 452
	ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact
	acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt
	cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg
	tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa
	gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg
	tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa
	cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac
	gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg
	tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac
	cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc
	cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca
	cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc
	cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac
	accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc
	cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga
	tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc
	gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc
	cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc
	aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag
	ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta
	ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg
	aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga
	acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa
	gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc
	acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag

Light chain B	gacttcgtgctgacccagagccctcacagcctgagcgtgacactggcgagagcgccag	SEQ ID
	catcagctgcaagagcagccactccctgatccacggcgaccggaacaactacctggcttg	NO: 453
	gtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcagag
	ccagcggcgtgcccgatagattactggcagcggcagcgacaaggacttcaccctgaag
	atcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcagagaga
	gcccctggacctttggccagggcaccaaggtggacatcaaggacaaaacccataccgac
	atcgtgatgacccagacccccctgagcctgagcgtgacacctggacagcctgccagcat
	cagctacaagagcagccagagcctgatgcacaacaacgccaacacctacctgagaggt
	atctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagattca
	gcggcgtgcccgacagattctccggcagcggctctggcaccgacttcaccctgaagatca
	gccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtaccc
	cttcacctttggcagcggcaccaaggtggaaatcaaggataagacccatacccgtacggt
	ggccgctcccagcgtgttcatatcccacctagcaacgagcagctgaagtccggcacagc
	ctctgtcgtatgcctactaaacaacttctacccccgcaaggccaaaatgcagtggaaggta
	gacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaa
	ggactccacctacagcctgagcagcaccctgacactgagcaaggccgactacgagaag
	cacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagag
	cttcaaccggggcgagtgt

Binding Protein 51 Amino Acid Sequences

Heavy chain A	Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwagggt	SEQ ID
	nynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysmdywgqgtt	NO: 454
	vtvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpav
	lqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapefl
	ggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkp
	reeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvyt
	lppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffly
	skltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Divltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnve	SEQ ID
	sgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleikrtvaapsv	NO: 455
	fifppsdeqlksgtasvvcllnnfypreakvqwkydnalqsgnsqesvteqdskdstys
	lsstltskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvhltqsgpevrkpgtsvkvsckapgntlktydlhwvrsvpgqglqwmgwi	SEQ ID
	shegdkkviverfkakvtidwdrstntaylqlsgltsgdtavyycakgskhrlrd	NO: 456
	yalydddgalnwavdvdylsnlefwgqgtavtvsssqvqlvesgggvvqpgr
	slrlscaasgftftkawmhwvrqapgkqlewvaqikdksnsyatyyadsvkg
	rftisrddskntlylqmnslraedtavyycrgvyyalspfdywgqgtlvtvssrta
	stkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpavl
	qssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpa
	peflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgve
	vhnaktkpreeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektis
	kakgqprepqvctlppsqeemtknqvslscavkgfypsdiavewesngqpe
	nnykttppvldsdgsfflvskltvdksrwqegnvfscsvmhealhnhytqksls
	lslgk

Light chain B	Divmtqtplslsvtpgqpasisckssqslvhnnantylswylqkpgspqsliykvsnr	SEQ ID
	fsgvpdrfsgsgsgtdftikisrveaccivgvyycgqgtqypftfgsgtkveikgqpkaa	NO: 457
	pdfvitqsphslsvtpaesasiscksshsiihgdrnnylawyvqkparspqiiiylassra
	sgvpdrfsgsgsdkdftikisrvetethigtyycniggrespvirtfmtkvdiktkgpsrt
	vaapsvfifppsdeciiksgtasvvcllnnfypreakvqwkvdnalcisgnsciesvteqd
	skdsiyslsstitlskadyekhkvyacehqgisspvtksfnrgec

Binding Protein 51 Nucleotide Sequences

Heavy chain A	caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct	SEQ ID
	gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagc	NO: 458
	cacctggaaaaggcctggaatggctgggcgtgatctgggctggcggaggcaccaacta
	caaccccagcctaaaatccagaaagaccatcagcaaggacaccagcaagaaccaggtg
	tccctgaagctgagcagcgtgacagccgccgataccgccgtgtactactgcgccagaga
	caagggctacagctactactacagcatggactactggggccagggcaccaccgtgaccg
	tgtcatccgcgtcgaccaagggcccctcggtgttccctaggccccttgcagcagaagca
	ccagcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtga
	ccgtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctcca
	gagcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggca
	ccaagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcg
	ggtggaatctaagtacggccctccctgccaccttgcccagcccctgaatttctgggcgga
	ccctccgtgttcctgttccccccaaagcccaagaacaccctgatgatcagccggaccccc
	gaagtaacctgcgtaatggtggatgtatcccaggaagatcccaaggtgcagttcaattggt
	acgtggacggcgtgaaaatgcacaacgccaagaccaagcccagagaagaacagttca
	acagcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggc
	aaagagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccat
	cagcaaggccaagggccagccccgcgagcctcaagtgtataccctgcccccttgccag
	gaagagatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagc
	gacattgccgtgaaatgggagagcaacgaccagcccaagaacaactacaagaccaccc
	cccctgtactggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagag
	ccggtggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaacc
	actacacccagaagtccctgtctctgtccagggcaag

Light chain A	gacatcgtgctgacacagagccctgctagcctggccgtgtctcctggacagagggccac	SEQ ID
	catcacctgtagagccagcgagagcgtggaatattacgtgaccagcctgatgcagtggta	NO: 459
	tcagcagaagcccggccaaccccccaagctgctgattttcgccgccaacaacatggaaa
	gcggcgtgccagccagattttccgacagcggctctggcaccgacttcaccctgaccatca
	accccgtggaagccaacgacgtggccaactactactgccagcagagccggaaggtacc
	ctacacctttggccagggcaccaagctggaaatcaagcgtacggtggccgctcccagcg
	tgttcatcttcccacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcct
	gctgaacaacttctacccccgcgaggccaaggtgcagtggaaggtggacaatgccctgc
	agagcggcaacagccaggaaagcgtgaccgagcaggacagcaaggactccacctaca
	gcctgagcagcaccagaccctgagcaaggccaactacgagaaacacaaggtatacgc
	ctgcgaagtaacccaccaggacctgtctagccccgtgaccaagagcttcaaccgggacg
	agtgt

Heavy chain B	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc	NO: 460
	ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact
	acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt
	cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg
	tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa
	gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg
	tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa
	cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac
	gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg
	tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac
	cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc
	cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca
	cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc
	cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac
	accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc
	cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga
	tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc
	gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc
	cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc
	aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag
	ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta
	ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg
	aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga
	acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa
	gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc
	acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag

Light chain B	gacatcgtgatgacccagacccccctgagcctgagcgtgacacaggacagcctgccag	SEQ ID
	catcagctgcaaaagcagccagagcctggtgcacaacaacaccaacacctacctgagct	NO: 461
	ggtatctgcagaagcccggccagaacccccagtccagatctacaagatgtccaacagat
	tcagcggcgtgcccaacagattaccggcagcggctaggcaccgacttcaccctaaaaa
	tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac
	cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccataccgacttc
	gtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgccagcatca
	gctgcaagagcagccactccctgatccacggcgaccggaacaactacctggcttggtac
	gtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcagagcca
	gcggcgtgcccgatagattttaggcagcggcagcgacaaggacttcaccctgaagatca
	gccgggtggaaaccgaggacgtaagcacctactactgtatgcaggacaaagagagccc
	ctggacctttggccagggcaccaaggtggacatcaaggataagacccatacccgtacggt
	ggccgctcccagcgtgttcatcacccacctagcgacgagcagagaagtccggcacagc
	ctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtagaaggtg
	gacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacaacaa
	ggactccacctacagcctgaacaacaccctgacactgagcaaggccgactacgagaag
	cacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaaaag
	cttcaaccggggcgagtgt

Binding Protein 52 Amino Acid Sequences

Heavy chain A	Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwagggt	SEQ ID
	nynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysmdywgqgtt	NO: 462
	vtvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpav
	lqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapefl
	ggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkp
	reeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvyt
	lppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffly
	skltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Divltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnve	SEQ ID
	sgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleikrtvaapsv	NO: 463
	fifppsdeqlksgtasvvcllnnfypreakvqwkydnalqsgnsqesvteqdskdstys
	lsstltskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvqlvesgggvvqpgrslrlscaasgftftkawmhwyrqapgkqlewvaqi	SEQ ID
	kdksnsyatyyadsvkgrftisrddskntlykynnsiraedtavyycrgvyyals	NO: 464
	pfdywgqgtlytysssqvhitqsgpevrkpgtsykysckapgntiktydlhwv
	rsvpg1glqwmgwishegdkkvivertkakvtidwdrstntayiqlsgitsgd
	tavyycakgskhrirdyalydddgainwaydvdylsniefwgqgtaytyssrt
	astkgpsvfplapcsrstsestaalgelykdyfpepmswnsgaitsgvhtfpay
	lgssglyslssyytypssslgtktytcnvdhkpsntkvdkrveskygppcppcp
	apeflggpsvfifppkpkdtimisapeytcyvydvsqedpevqfimyydgy
	evhnaktkpreeqfnstyrvvsvitvlhqdvvingkeykekvsnkgipssiekti
	skakgqprepqvcttppscieemtknqvstscavkgfypsdiavewesnme
	nnykttppvldsdgsfflvsldtvdksrwqegnvfscsvrnhealhnhytqksls
	lslgk

Light chain B	Dfvltqsphslsvtpgesasiscksshslihgdmnylawyvqkpgrspqllassras	SEQ ID
	gvpdrfsgsgsdkdfilkisrvetedvgtyycatqgrespvirtfgqtttkvdikgqpkaap	NO: 465
	divmtqtplsisvtpggpasisckssgslvlitmantylswykikpggspcisitykvsnrf
	sgvpdrfsgsgsgtdfilkisneacdvgvyycgqgttpftfgsgtkveiktkgpsrtv
	aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalgsgnsqcsvtecids
	kdstystssthiskadyckhkvyaccvthqgisspvtksfargec

Binding Protein 52 Nucleotide Sequences

Heavy chain A	caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct	SEQ ID
	gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagcc	NO: 466
	acctggaaaaggcctggaatggagggcgtgatctgggctggcggaggcaccaactaca
	accccagcctgaagtccagaaagaccatcagcaaggacaccagcaagaaccaggtgtc
	cctgaagctgagcagcgtgacagccaccgataccgccgtatactactacgccagagaca
	agggctacagctactactacagcatggactactggggccagggcaccaccgtgaccgtg
	tcatccgcgtcgaccaagggcccctcggtgttccctctggccccttgcagcagaagcacc
	agcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgacc
	gtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctccaga
	gcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggcacc
	aagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcggg
	tggaatctaagtacggccctccctgccctccttacccaacccctgaatttagggcggacc
	ctccgtgttcctgttccccccaaagcccaaggacaccagatgatcaaccggacccccga
	agtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattggtac
	gtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagttcaaca
	gcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaa
	gagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccatcag
	caaggccaagggccaaccccacgagcctcaaatgtataccctaccccatgccaggaaa
	agatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagcgacat
	tgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccct
	gtgctggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagagccggt
	ggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccactac
	acccagaagtccctgtctctgtccctgggcaag

Light chain A	gacatcgtgctgacacagagccctgctagcctggccgtgtctcctggacagagggccac	SEQ ID
	catcacctgtagagccagcgagagcgtgaatattacgtgaccagcctgatgcagtggtat	NO: 467
	cagcagaagcccggccagccccccaagctgctgatatcgccgccaacaacgtggaaaa
	cggcgtgccagccagattttccggcagcggctctggcaccaacttcaccctgaccatcaa
	ccccgtggaagccaacgacgtggccaactactactgccagcagagccggaaggtgccc
	tacacctttggccagggcaccaagaggaaatcaagcgtacggtggccgctcccagcgt
	gttcatcttcccacctagcgacgagcagctgaagtccggcacagcctctgtcgtgtgcctg
	ctgaacaacttctacccccgcgaggccaaggtgcagtggaaggtggacaatgccctgca
	gagcggcaacagccaggaaaacgtgaccgagcaggacagcaaggactccacctacag
	cctgagcagcaccctgaccctgagcaaggccgactacgagaagcacaaggtgtacgcct
	gcgaagtgacccaccagggcctgtctagccccgtgaccaagagcttcaaccggggcga
	gtgt

Heavy chain B	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc	NO: 468
	ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact
	acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt
	cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg
	tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa
	gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg
	tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa
	cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac
	gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg
	tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac
	cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc
	cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca
	cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc
	cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac
	accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc
	cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga
	tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc
	gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc
	cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc
	aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag
	ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta
	ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg
	aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga
	acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa
	gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc
	acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag

Light chain B	gacatcgtgatgacccagacccccctgagcctgagcgtgacacaggacagcctgccag	SEQ ID
	catcagctgcaaaagcagccagagcctggtgcacaacaacaccaacacctacctgagct	NO: 469
	ggtatctgcagaagcccggccagaacccccagtccagatctacaagatgtccaacagat
	tcagcggcgtgcccaacagattaccggcagcggctaggcaccgacttcaccctaaaaa
	tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac
	cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccataccgacttc
	gtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgccagcatca
	gctgcaagagcagccactccctgatccacggcgaccggaacaactacctggcttggtac
	gtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcagagcca
	gcggcgtgcccgatagattttaggcagcggcagcgacaaggacttcaccctgaagatca
	gccgggtggaaaccgaggacgtaagcacctactactgtatgcaggacaaagagagccc
	ctggacctttggccagggcaccaaggtggacatcaaggataagacccatacccgtacggt
	ggccgctcccagcgtgttcatcacccacctagcgacgagcagagaagtccggcacagc
	ctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtagaaggtg
	gacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacaacaa
	ggactccacctacagcctgaacaacaccctgacactgagcaaggccgactacgagaag
	cacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaaaag
	cttcaaccggggcgagtgt

Binding Protein 53 Amino Acid Sequences

Heavy chain A	Qvqlqesgpglvkpsqtlsltctvsgfslsdygvhwvrqppgkglewlgviwagggt	SEQ ID
	nynpslksrktiskdtsknqvslklssvtaadtavyycardkgysyyysmdywgqgtt	NO: 470
	vtvssastkgpsvfplapcsrstsestaalgclvkdyfpepvtvswnsgaltsgvhtfpav
	lqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppcpapefl
	ggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkp
	reeqfnstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvyt
	lppcqeemtknqvslwclvkgfypsdiavewesngqpennykttppvldsdgsffly
	skltvdksrwqegnvfscsvmhealhnhytqkslslslgk

Light chain A	Divltqspaslavspgqratitcrasesveyyvtslmqwyqqkpgqppkllifaasnve	SEQ ID
	sgvparfsgsgsgtdftltinpveandvanyycqqsrkvpytfgqgtkleikrtvaapsv	NO: 471
	fifppsdeqlksgtasvvcllnnfypreakvqwkydnalqsgnsqesvteqdskdstys
	lsstltskadyekhkvyacevthqglsspvtksfnrgec

Heavy chain B	Qvqlvesgggvvqpgrslrlscaasgftftkawmhwyrqapgkqlewvaqi	SEQ ID
	kdksnsyatyyadsvkgrftisrddskntlykynnsiraedtavyycrgvyyals	NO: 472
	pfdywgqgtlytysssqvhitqsgpevrkpgtsykysckapgntiktydlhwv
	rsvpg1glqwmgwishegdkkvivertkakvtidwdrstntayiqlsgitsgd
	tavyycakgskhrirdyalydddgainwaydvdylsniefwgqgtaytyssrt
	astkgpsvfplapcsrstsestaalgelykdyfpepmswnsgaitsgvhtfpay
	lgssglyslssyytypssslgtktytcnvdhkpsntkvdkrveskygppcppcp
	apeflggpsvfifppkpkdtimisapeytcyvydvsqedpevqfimyydgy
	evhnaktkpreeqfnstyrvvsvitvlhqdvvingkeykekvsnkgipssiekti
	skakgqprepqvcttppscieemtknqvstscavkgfypsdiavewesnme
	nnykttppvldsdgsfflvsldtvdksrwqegnvfscsvrnhealhnhytqksls
	lslgk

Light chain B	Dfvltqsphslsvtpgesasiscksshslihgdmnylawyvqkpgrspqllassras	SEQ ID
	gvpdrfsgsgsdkdfilkisrvetedvgtyycatqgrespvirtfgqtttkvdikgqpkaap	NO: 473
	divmtqtplsisvtpggpasisckssgslvlitmantylswykikpggspcisitykvsnrf
	sgvpdrfsgsgsgtdfilkisneacdvgvyycgqgttpftfgsgtkveiktkgpsrtv
	aapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalgsgnsqcsvtecids
	kdstystssthiskadyckhkvyaccvthqgisspvtksfnrgec

Binding Protein 53 Nucleotide Sequences

Heavy chain A	caggtgcagctgcaggaatctggccctggcctcgtgaagcctagccagaccctgagcct	SEQ ID
	gacctgtaccgtgtccggcttcagcctgagcgactacggcgtgcactgggtgcgccagcc	NO: 474
	acctggaaaaggcctggaatggagggcgtgatctgggctggcggaggcaccaactaca
	accccagcctgaagtccagaaagaccatcagcaaggacaccagcaagaaccaggtgtc
	cctgaagctgagcagcgtgacagccaccgataccgccgtatactactacgccagagaca
	agggctacagctactactacagcatggactactggggccagggcaccaccgtgaccgtg
	tcatccgcgtcgaccaagggcccctcggtgttccctctggccccttgcagcagaagcacc
	agcgaatctacagccgccctgggctgcctcgtgaaggactactttcccgagcccgtgacc
	gtgtcctggaactctggcgctctgacaagcggcgtgcacacctttccagccgtgctccaga
	gcagcggcctgtactctctgagcagcgtcgtgacagtgcccagcagcagcctgggcacc
	aagacctacacctgtaacgtggaccacaagcccagcaacaccaaggtggacaagcggg
	tggaatctaagtacggccctccctgccctccttacccaacccctgaatttagggcggacc
	ctccgtgttcctgttccccccaaagcccaaggacaccagatgatcaaccggacccccga
	agtgacctgcgtggtggtggatgtgtcccaggaagatcccgaggtgcagttcaattggtac
	gtggacggcgtggaagtgcacaacgccaagaccaagcccagagaggaacagttcaaca
	gcacctaccgggtggtgtccgtgctgaccgtgctgcaccaggactggctgaacggcaaa
	gagtacaagtgcaaggtgtccaacaagggcctgcccagctccatcgagaaaaccatcag
	caaggccaagggccaaccccacgagcctcaaatgtataccctaccccatgccaggaaa
	agatgaccaagaaccaggtgtccctgtggtgtctcgtgaaaggcttctaccccagcgacat
	tgccgtggaatgggagagcaacggccagcccgagaacaactacaagaccaccccccct
	gtgctggacagcgacggctcattcttcctgtactccaagctgaccgtggacaagagccggt
	ggcaggaaggcaacgtgttcagctgctccgtgatgcacgaggccctgcacaaccactac
	acccagaagtccctgtctctgtccctgggcaag

Light chain A	gacatcgtgatgacccagacccccctgagcctgagcgtgacacaggacagcctgccag	SEQ ID
	catcagctgcaaaagcagccagagcctggtgcacaacaacaccaacacctacctgagct	NO: 475
	ggtatctgcagaagcccggccagaacccccagtccagatctacaagatgtccaacagat
	tcagcggcgtgcccaacagattaccggcagcggctaggcaccgacttcaccctaaaaa
	tcagccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtac
	cccttcacctttggcagcggcaccaaggtggaaatcaaggacaaaacccataccgacttc
	gtgctgacccagagccctcacagcctgagcgtgacacctggcgagagcgccagcatca
	gctgcaagagcagccactccctgatccacggcgaccggaacaactacctggcttggtac
	gtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcagagcca
	gcggcgtgcccgatagattttaggcagcggcagcgacaaggacttcaccctgaagatca
	gccgggtggaaaccgaggacgtaagcacctactactgtatgcaggacaaagagagccc
	ctggacctttggccagggcaccaaggtggacatcaaggataagacccatacccgtacggt
	ggccgctcccagcgtgttcatcacccacctagcgacgagcagagaagtccggcacagc
	ctctgtcgtgtgcctgctgaacaacttctacccccgcgaggccaaagtgcagtagaaggtg
	gacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacaacaa
	ggactccacctacagcctgaacaacaccctgacactgagcaaggccgactacgagaag
	cacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaaaag
	cttcaaccggggcgagtgt

Heavy chain B	caggtgcagctggtgcagtctggcgccgaggtcgtgaaacctggcgcctctgtgaaggt	SEQ ID
	gtcctgcaaggccagcggctacacctttaccagctactacatccactgggtgcgccaggc	NO: 476
	ccctggacagggactggaatggatcggcagcatctaccccggcaacgtgaacaccaact
	acgcccagaagttccagggcagagccaccctgaccgtggacaccagcatcagcaccgc
	ctacatggaactgagccggctgagaagcgacgacaccgccgtgtactactgcacccggt
	cccactacggcctggattggaacttcgacgtgtggggcaagggcaccaccgtgacagtg
	tctagcagccaggtgcagctggtggaatctggcggcggagtggtgcagcctggcagaa
	gcctgagactgagctgtgccgccagcggcttcaccttcaccaaggcctggatgcactggg
	tgcgccaggcccctggaaagcagctggaatgggtggcccagatcaaggacaagagcaa
	cagctacgccacctactacgccgacagcgtgaagggccggttcaccatcagccgggac
	gacagcaagaacaccctgtacctgcagatgaacagcctgcgggccgaggacaccgccg
	tgtactactgtcggggcgtgtactatgccctgagccccttcgattactggggccagggaac
	cctcgtgaccgtgtctagtcggaccgccagcacaaagggcccatcggtgttccctctggc
	cccttgcagcagaagcaccagcgaatctacagccgccctgggctgcctcgtgaaggact
	actttcccgagcccgtgaccgtgtcctggaactctggcgctctgacaagcggcgtgcaca
	cctttccagccgtgctccagagcagcggcctgtactctctgagcagcgtcgtgacagtgcc
	cagcagcagcctgggcaccaagacctacacctgtaacgtggaccacaagcccagcaac
	accaaggtggacaagcgggtggaatctaagtacggccctccctgccctccttgcccagcc
	cctgaatttctgggcggaccctccgtgttcctgttccccccaaagcccaaggacaccctga
	tgatcaaccggacccccgaagtgacctgcgtggtggtggatgtgtcccaggaagatccc
	gaggtgcagttcaattggtacgtggacggcgtggaagtgcacaacgccaagaccaagcc
	cagagaggaacagttcaacagcacctaccgggtggtgtccgtgctgaccgtgctgcacc
	aggactggctgaacggcaaagagtacaagtgcaaggtgtccaacaagggcctgcccag
	ctccatcgagaaaaccatcagcaaggccaagggccagccccgcgagcctcaagtgtgta
	ccctgccccctagccaggaagagatgaccaagaaccaagtgtccctgagctgtgccgtg
	aaaggcttctaccccagcgacattgccgtggaatgggagagcaacggccagcccgaga
	acaactacaagaccaccccccctgtgctggacaacgacggctcattcttcctggtatccaa
	gctgaccgtggacaagagccggtggcaggaaggcaacgtgttcagctgctccgtgatgc
	acgaggccctgcacaaccactacacccagaagtccctgtctctgtccctgggcaag

Light chain B	gacttcgtgagacccaaagccctcacagcctgagcatgacacctggcgagagcgccag	SEQ ID
	catcagctgcaaaagcagccactccctgatccacggcgaccgaaacaactacctagcttg	NO: 477
	gtacgtgcagaagcccggcagatccccccagctgctgatctacctggccagcagcagag
	ccagcggcgtgcccgatagattttctggcagcggcagcgacaaggacttcaccctgaag
	atcagccgggtggaaaccgaggacgtgggcacctactactgtatgcagggcagagaga
	gcccctggacctttagccagggcaccaagatggacatcaagaacaaaacccataccgac
	atcgtgatgacccagacccccagagcctgaacgtgacacctgaacagcctaccagcat
	cagctgcaagagcagccagagcctggtacacaacaacgccaacacctacctgagctggt
	atctgcagaagcccggccagagcccccagtccctgatctacaaggtgtccaacagattca
	gcggcgtgcccgacagattctccggcagcggctctggcaccgacttcaccctgaagatca
	gccgggtggaagccgaggacgtgggcgtgtactattgtggccagggcacccagtaccc
	cttcacctttggcagcggcaccaaggtggaaatcaaggataagacccatacccgtacggt
	ggccactcccagcgtgttcatcttcccacctaacgacgagcagctgaagtccgacacagc
	ctctgtcgtgtgcctgctgaacaacttctacccccgcgagaccaaagtacagtggaagatg
	gacaacgccctgcagagcggcaacagccaggaaagcgtgaccgagcaggacagcaa
	ggactccacctacagcctgagcagcaccctgacactgagcaaggccgactacgagaag
	cacaaggtgtacgcctgcgaagtgacccaccagggcctgtctagccccgtgaccaagag
	cttcaaccggggcgagtgt

TABLE A

CDR sequences of binding proteins

Ab	CDRH1	CDRH2	CDRH3	CDRL1	CDRL2	CDRL3

CD4BS ″a″	dctln	wikprggavnyarplqg	gkncdynwdfeh	rtsqyglsa	sgstraa	qqyef
	(SEQ ID NO: 248)	(SEQ ID NO: 249)	(SEQ ID NO: 250)	(SEQ ID NO: 266)	(SEQ ID NO: 267)	(SEQ ID NO: 268)

CD4BS ″b″	GYTFTAHI	IKPQYGAV	drsygdsswalda	QGVGSD	HTS	qvlqf
	(SEQ ID NO: 251)	(SEQ ID NO: 252)	(SEQ ID NO: 253)	(SEQ ID NO: 269)	(SEQ ID NO: 270)	(SEQ ID NO: 271)

MPER	gfdfdnaw	itgpggwssv	tgkyydfwsgyppgeeyfqd	rgdslrshyas	gknnrps	ssrdksgsrlsv
	(SEQ ID NO: 254)	(SEQ ID NO: 255)	(SEQ ID NO: 256)	(SEQ ID NO: 272)	(SEQ ID NO: 273)	(SEQ ID NO: 274)

V1/V2 dir.	GNTLKTYD	ISHEGDKK	cakgskhrlrdyalyddd	hslihgdrnny	las	cmqgrespwtf
″a″	(SEQ ID NO: 257)	(SEQ ID NO: 258)	galnwavdvdylsnlefw	(SEQ ID NO: 275)	(SEQ ID NO: 276)	(SEQ ID NO: 277)
			(SEQ ID NO: 259)

V3 dir.	SGASISDSY	VHKSGDT	ARTLHGRRIYGIVAFNEWF	SLGSRA	NNQ	HIWDSRVPTKWV
	(SEQ ID NO: 260)	(SEQ ID NO: 261)	TYFYMDV	(SEQ ID NO: 278)	(SEQ ID NO: 279)	(SEQ ID NO: 280)
			(SEQ ID NO: 262)

V1/V dir.	QFRFDGYG	ISHDGIKK	CAKDLREDECEEWWSDYY	TSNIGNNF	ETD	atwaaslssarv
″b″	(SEQ ID NO: 263)	(SEQ ID NO: 264)	DFGKQLPCAKSRGGLVGIA	(SEQ ID NO: 281)	(SEQ ID NO: 282)	(SEQ ID NO: 283)
			DNW
			(SEQ ID NO: 265)

Ab	CDRH1	CDRH2	CDRH3	CDRL1	CDRL2	CDRL3

Anti-CD28	GYTFTSYY	IYPGNVNT	trshygldwnfdv	QNIYVW	KAS	qqgqtypyt
	(SEQ ID NO: 479)	(SEQ ID NO: 480)	(SEQ ID NO: 481)	(SEQ ID NO: 488)	(SEQ ID NO: 489)	(SEQ ID NO: 490)

Anti-CD28	GFSLSDYG	IWAGGGT	ardkgysyyysmd	ESVEYYVTSL	AAS	qqsrkvpyt
	(SEQ ID NO: 482)	(SEQ ID NO: 483)	(SEQ ID NO: 484)	(SEQ ID NO: 491)	(SEQ ID NO: 492)	(SEQ ID NO: 493)

Anti-CD3	GFTFTKAW	IKDKSNS	rgvyyalspfdy	QSLVHNNANTY	KVS	gqgtqyp
	(SEQ ID NO: 485)	(SEQ ID NO: 486)	(SEQ ID NO: 487)	(SEQ ID NO: 494)	(SEQ ID NO: 495)	(SEQ ID NO: 496)

TABLE B

CDR sequences of parental antibodies

Ab	CDR_H1	CDR_H2	CDR_H3	CDR_L1	CDR_L2	CDR_L3

CD4BS ″a″	DCTLN	LKPRGGAVNYARP	GKNCDYNWDFEH	RTSQYGLSA	SGSTRAA	QQYEF
	(SEQ ID NO: 248)	LQ	(SEQ ID NO: 250)	(SEQ ID NO: 266)	(SEQ ID NO: 267)	(SEQ ID NO: 268)
		(SEQ ID NO: 497)

CD4BS ″b″	GYTFTAHI	IKPQYGAV	DRSYGDSSWALDA	QGVGSD	HTS	QVLQF
	(SEQ ID NO: 251)	(SEQ ID NO: 252)	(SEQ ID NO: 253)	(SEQ ID NO: 269)	(SEQ ID NO: 270)	(SEQ ID NO: 271)

MPER	GFDFDNAW	ITGPGGWSSV	TGKYYDFWSGYPPGEEYFQ	SLRSHY	GKN	SSRDKSGSRLSV
	(SEQ ID NO: 254)	(SEQ ID NO: 255)	D	(SEQ ID NO: 500)	(SEQ ID NO: 501)	(SEQ ID NO: 274)
			(SEQ ID NO: 256)

MPER_100W	GFDFDNAW	ITGPGGWSSV	TGKYYDFWWGYPPGEEYF	SLRSHY	GKN	SSRDKSGSRLSV
	(SEQ ID NO: 254)	(SEQ ID NO: 255)	QD	(SEQ ID NO: 500)	(SEQ ID NO: 501)	(SEQ ID NO: 274)
			(SEQ ID NO: 259)

V1/V2	GNTLKTYD	ISHEGDKK	CAKGSKHRLRDYALYDDD	HSLIHGDRNNY	LAS	CMQGRESPWTF
directed ″a″	(SEQ ID NO: 257)	(SEQ ID NO: 258)	GALNWAVDVDYLSNLEFW	(SEQ ID NO: 275)	(SEQ ID NO: 276)	(SEQ ID NO: 277)
			(SEQ ID NO: 259)

V1/V2	QFRFDGYG	ISHDGIKK	CAKDLREDECEEWWSDYY	TSNIGNNF	ETD	ATWAASLSSAR
directed ″b″	(SEQ ID NO: 263)	(SEQ ID NO: 264)	DFGKQLPCAKSRGGLVGIA	(SEQ ID NO: 281)	(SEQ ID NO: 282)	V
			DNW			(SEQ ID NO: 283)
			(SEQ ID NO: 265)

V3	GASISDSY	VHKSGDT	ARTLHGRRIYGIVAFNEWF	SLGSRA	NNQ	HIWDSRVPTKW
directed	(SEQ ID NO: 499)	(SEQ ID NO: 261)	TYFYMDV	(SEQ ID NO: 278)	(SEQ ID NO: 279)	V
			(SEQ ID NO: 262)			(SEQ ID NO: 280)

CD28	GYTFTSYY	IYPGNVNT	TRSHYGLDWNFDV	QNIYVW	KAS	QQGQTYPYT
	(SEQ ID NO: 479)	(SEQ ID NO: 480)	(SEQ ID NO: 481)	(SEQ ID NO: 488)	(SEQ ID NO: 489)	(SEQ ID NO: 490)

CD28_2	GFSLSDYG	IWAGGGT	ARDKGYSYYYSMD	ESVEYYVTSL	AAS	QQSRKVPYT
	(SEQ ID NO: 482)	(SEQ ID NO: 483)	(SEQ ID NO: 484)	(SEQ ID NO: 491)	(SEQ ID NO: 492)	(SEQ ID NO: 493)

CD3	GFTFTKAW	IKDKSNS	RGVYYALSPFDY	QSLVHNNANTY	KVS	GQGTQYP
	(SEQ ID NO: 485)	(SEQ ID NO: 486)	(SEQ ID NO: 487)	(SEQ ID NO: 494)	(SEQ ID NO: 495)	(SEQ ID NO: 496)

TABLE C

Variable domain sequences of parental antibodies

Ab Name	V_H	V_L

CD4BS ″a″	QVQLVQSGGQMKKPGESMRISCRASGYEFIDCTLNWIRLAP	EIVLTQSPGTLSLSPGETAIISCRTSQYGSLAWYQQ
	GKRPEWMGWLKPRGGAVNYARPLQGRVTMTRDVYSDTAF	RPGQAPRLVIYSGSTRAAGIPDRFSGSRWGPDYNL
	LELRSLTVDDTAVYFCTRGKNCDYNWDFEHWGRGTPVIV	TISNLESGDFGVYYCQQYEFFGQGTKVQVDIK
	S	(SEQ ID NO: 512)
	(SEQ ID NO: 502)

CD4BS ″b″	RAHLVQSGTAMKKPGASVRVSCQTGYTFTAHILFWFRQAP	YIHVTQSPSSLSVSIGDRVTINCQTSQGVGSDLHW
	GRGLEWVGWIKPQYGAVNFGGGFRDRVTLTRDVYREIAY	YQHKPGRAPKLLIHHTSSVEDGVPSRFSGSGFHTS
	MDIRGLKPDDTAVYYCARDRSYGDSSWALDAWGQGTTVV	FNLTISDLQADDIATYYCQVLQFFGRGSRLHIK
	VSA	(SEQ ID NO: 513)
	(SEQ ID NO: 503)

CD4BS ″b″	RAHLVQSGTAMKKPGASVRVSCQTSGYTFTAHILFWFRQAP	YIHVTQSPSSLSVSIGDRVTINCQTSQGVGSDLHW
(Δglycan)	GRGLEWVGWIKPQYGAVNFGGGFRDRVTLTRDVYREIAY	YQHKPGRAPKLLIHHTSSVEDGVPSRFSGSGFHTS
	MDIRGLKPDDTAVYYCARDRSYGDSSWALDAWGQGTTVV	F LTISDLQADDIATYYCQVLQFFGRGSRLHIK
	VSA	(SEQ ID NO: 514)
	(SEQ ID NO: 503)

CD4BS ″b″	RAHLVQSGTAMKKPGASVRVSCQTSGYTFTAHILFWFRQAP	YIHVTQSPSSLSVSIGDRVTINCQTSQGVGSDLHW
(Δisomerization	GRGLEWVGWIKPQYGAVNFGGGFRDRVTLTRDVYREIAY	YQHKPGRAPKLLIHHTSSVE GVPSRFSGSGFHTS
D55E)	MDIRGLKPDDTAVYYCARDRSYGDSSWALDAWGQGTTVV	FNLTISDLQADDIATYYCQVLQFFGRGSRLHIK
	VSA	(SEQ ID NO: 515)
	(SEQ ID NO: 503)

CD4BS ″b″	RAHLVQSGTAMKKPGASVRVSCQTSGYTFTAHILFWFRQAP	YIHVTQSPSSLSVSIGDRVTINCQTSQGVGSDLWH
(Δisomerization	GRGLEWVGWIKPQYGAVNFGGGFRDRVTLTRDVYREIAY	YQHKPGRAPKLLIHHTSSVED VPSRFSGSGFHTS
G56A)	MDIRGLKPDDTAVYYCARDRSYGDSSWALDAWGQGTTVV	FNLTISDLQADDIATYYCQVLQFFGRGSRLHIK
	VSA	(SEQ ID NO: 516)
	(SEQ ID NO: 503)

CD4BS ″b″	RAHLVQSGTAMKKPGASVRVSCQTSGYTFTAHILFWFRQAP	YIHVTQSPSSLSVSIGDRVTINCQTSQGVGSDLHW
(Δglycan/	GRGLEWVGWIKPQYGAVNFGGGFRDRVTLTRDVYREIAY	YQHKPGRAPKLLIHHTSSVE GVPSRFSGSGFHTS
Δisomerization	MDIRGLKPDDTAVYYCARDRSYGDSSWALDAWGQGTTVV	F LTISDLQADDIATYYCQVLQFFGRGSRLHIK
D55E)	VSA	(SEQ ID NO: 517)
	(SEQ ID NO: 503)

MPER	EVRLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQP	ASELTQDPAVSVALKQTVTITCRGDSLRSHYASW
	PGKGLEWVGRITGPGEGWSVDYAESVKGRFTISRDNTKNTL	YQKKPGQAPVLLFYGKNNRPSGIPDRFSGSASGN
	YLEMNNVRTEDTGYYFCARTGKYYDFWSGYPPGEEYFQD	RASLTITGAQAEDEADYYCSSRDKSGSRLSVFGG
	WGQGTLVIVSS	GTKLTVL
	(SEQ ID NO: 504)	(SEQ ID NO: 518)

MPER_100W	EVRLVESGGGLVKPGGSLRLSCSASGFDFDNAWMTWVRQP	ASELTQDPAVSVALKQTVTITCRGDSLRSHYASW
	PGKGLEWVGRITGPGEGWSVDYAESVKGRFTISRDNTKNTL	YQKKPGQAPVLLFYGKNNRPSGIPDRFSGSASGN
	YLEMNNVRTEDTGYYFCARTGKYYDFW GYPPGEEYFQD	RASLTITGAQAEDEADYYCSSRDKSGSRLSVFGG
	WGQGTLVIVSS	GTKLTVL
	(SEQ ID NO: 505)	(SEQ ID NO: 518)

V1/V2	QVHLTQSGPEVRKPGTSVKVSCKAPGNTLKTYDLHWVRSV	DFVLTQSPHSLSVTPGESASISCKSSHSLIHGDRNN
directed ″a″	PGQGLQWMGWISHEGDKKVIVERFKAKVTIDWDRSTNTAY	YLAWYVQKPGRSPQLLIYLASSRASGVPDRFSGS
	LQLSGLTSGDTAVYYCAKGSKHRLRDYALYDDDGALNWA	GSDKDFTLKISRVETEDVGTYYCMQGRESPWTFG
	VDVDYLSNLEFWGQGTAVTVSS	QGTKVDIK
	(SEQ ID NO: 506)	(SEQ ID NO: 519)

V1/V2	QVQLVESGGGVVQPGTSLRLSCAASQFRFGDYGMHWVRQ	QSVLTQPPSVSAAPGQKVTISCSGNTSNIGNNFVS
directed ″b″	APGKGLEWVASISHDGIKKYHAEKVWGRFTISRDNSKNTLY	WYQQRPGRAPQLLIYETDKRPSGIPDRFSASKSGT
	LQMNSLRPEDTALYYCAKDLREDECEEWWSDYYDFGKQLP	SGTLAITGLQTGDEADYYCATWAASLSSARVFGT
	CAKSRGGLVGIADNWGQGTMVTVSS	GTKVIVL
	(SEQ ID NO: 507)	(SEQ ID NO: 520)

V3	QMQLQESGPGLVKPSETLSLTCSVSGASISDSYWSWIRRSPG	SDISVAPGETARISCGEKSLGSRAVQWYQHRAGQ
directed	KGLEWIGYVHKSGDTNYSPSLKSRVNLSLDTSKNQVSLSLV	APSLIIYNNQDRPSGIPERFSGSPDSPFGTTATLTIT
	AATAADSGKYYCARTLHGRRIYGIVAFNEWFTYFYMDVW	SVEAGDEADYYCHIWDSRVPTKWVFGGGTTLTV
	GNGTQVTVSS	G
	(SEQ ID NO: 508)	(SEQ ID NO: 521)

CD28	QVQLVQSGAEVVKPGASVKVSCKASGYTFTSYYIHWVRQA	DIQMTQSPSSLSASVGDRVTITCQASQNIYVWLN
	PGQGLEWIGSIYPGNVNTNYAQKRQGRATLTVDTSISTAYM	WYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSG
	ELSRLRSDDTAVYYCTRSHYGLDWNFDVWGKGTTVTVSS	TDFTLTISSLQPEIATYYCCQQGQTYPYTFGQGTK
	(SEQ ID NO: 509)	LEIK
		(SEQ ID NO: 522)

CD28_2	QVQLQESGPGLVKPSQTLSLTCTVSGFSLSDYGVHWVRQPP	DIVLTTQSPASLAVSPGQRATITCRASESVEYYVTS
	GKGLEWLGVIWAGGGTNYNPSLKSRKTISKDTSKNQVSLKL	LMQWYQQKPGQPPKLLIFAASNVESGVPARFSGS
	SSVTAADTAVYYCARDKGYSYYYSMDYWGQGTTVTVSS	GSGTDFTLTINPVEANDVANYYCQQSRKVPYTFG
	(SEQ ID NO: 510)	QGTKLEIK
		(SEQ ID NO: 523)

CD3	QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQ	DIVMTQTPLSLSVTPGQPASISCKSSQSLVHNNAN
	APGKQLEWVAQIKDKSNSYATYYADSVKGRFTISRDDSKNT	TYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGS
	LYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTV	GSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFG
	SS	SGTKVEIK
	(SEQ ID NO: 511)	(SEQ ID NO: 524)

CDR sequences are underlined.
Variable domain modifications are shown in bold and italicized.

Claims

What is claimed is:

1. A binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:

V_L2-L₁-V_L1-L₂-C_L [I];

a second polypeptide chain comprises a structure represented by the formula:

V_H1-L₃-V_H2-L₄-C_H1 [II];

a third polypeptide chain comprises a structure represented by the formula:

V_H3-C_H1 [III],

and a fourth polypeptide chain comprises a structure represented by the formula:

V_L3-C_L [IV];

wherein

V_L1is a first immunoglobulin light chain variable domain;

V_L2is a second immunoglobulin light chain variable domain;

V_L3is a third immunoglobulin light chain variable domain;

V_H1is a first immunoglobulin heavy chain variable domain;

V_H2is a second immunoglobulin heavy chain variable domain;

V_H3is a third immunoglobulin heavy chain variable domain;

C_Lis an immunoglobulin light chain constant domain;

C_H1is an immunoglobulin C_H1heavy chain constant domain; and

L₁, L₂, L₃, and L₄are amino acid linkers;

and wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair.

2. A binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:

V_L2-L₁-V_L1-L₂-C_L [I]

and a second polypeptide chain comprises a structure represented by the formula:

V_H1-L₃-V_H2-L₄-C_H1-hinge-C_H2-C_H3 [II]

and a third polypeptide chain comprises a structure represented by the formula:

V_H3-C_H1-hinge-C_H2-C_H3 [III]

V_L3-C_L [IV]

wherein:

V_L1is a first immunoglobulin light chain variable domain;

V_L2is a second immunoglobulin light chain variable domain;

V_L3is a third immunoglobulin light chain variable domain;

V_H1is a first immunoglobulin heavy chain variable domain;

V_H2is a second immunoglobulin heavy chain variable domain;

V_H3is a third immunoglobulin heavy chain variable domain;

C_Lis an immunoglobulin light chain constant domain;

C_H1is an immunoglobulin C_H1heavy chain constant domain;

C_H2is an immunoglobulin C_H2heavy chain constant domain;

C_H3is an immunoglobulin C_H3heavy chain constant domain;

hinge is an immunoglobulin hinge region connecting the C_H1and C_H2domains; and

L₁, L₂, L₃and L₄are amino acid linkers;

3. The binding protein of claim 1 or claim 2, wherein the one or more HIV target protein is selected from the group consisting of glycoprotein 120, glycoprotein 41 and glycoprotein 160.

4. The binding protein of claim 1 or claim 2, wherein the binding protein is trispecific and capable of specifically binding three different epitopes on a single HIV target protein.

5. The binding protein of claim 1 or claim 2, wherein the binding protein is trispecific and capable of specifically binding two different epitopes on a first HIV target protein, and one epitope on a second HIV target protein, wherein the first and second HIV target proteins are different.

6. The binding protein of claim 1 or claim 2, wherein the binding protein is trispecific and capable of specifically binding three different antigen targets.

7. The binding protein of claim 1 or claim 2, wherein the binding protein is capable of inhibiting the function of one or more HIV target proteins.

8. The binding protein of any one of claims 1-7, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively.

9. The binding protein of any one of claims 1-7, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.

10. The binding protein of any one of claims 1-9, wherein V_L1comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.

11. The binding protein of any one of claims 1-10, wherein V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively.

12. The binding protein of any one of claims 1-10, wherein V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.

13. The binding protein of any one of claims 1-12, wherein V_L2comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.

14. The binding protein of any one of claims 1-13, wherein V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; or a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively.

15. The binding protein of any one of claims 1-13, wherein V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.

16. The binding protein of any one of claims 1-15, wherein V_L3comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, and 521.

17. The binding protein of any one of claims 1-16, wherein V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively.

18. The binding protein of any one of claims 1-16, wherein V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.

19. The binding protein of any one of claims 1-18, wherein V_H1comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.

20. The binding protein of any one of claims 1-19, wherein V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively.

21. The binding protein of any one of claims 1-19, wherein V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.

22. The binding protein of any one of claims 1-21, wherein V_H2comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.

23. The binding protein of any one of claims 1-22, wherein V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; or a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively.

24. The binding protein of any one of claims 1-22, wherein V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.

25. The binding protein of any one of claims 1-24, wherein V_H3comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, and 508.

26. The binding protein of any one of claims 1-25, wherein V_L1comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; V_L2comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; V_L3comprises a CDR-L1 comprising the sequence of SEQ ID NO: 266, a CDR-L2 comprising the sequence of SEQ ID NO: 267, and a CDR-L3 comprising the sequence of SEQ ID NO: 268; V_H1comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; V_H2comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; and V_H3comprises a CDR-H1 comprising the sequence of SEQ ID NO: 248, a CDR-H2 comprising the sequence of SEQ ID NO: 497, and a CDR-H3 comprising the sequence of SEQ ID NO: 250.

27. The binding protein of any one of claims 1-25, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 512, V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 502.

28. The binding protein of any one of claims 1-27, wherein V_L1comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; V_L2comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; V_L3comprises a light chain variable domain comprising the sequence of SEQ ID NO: 512; V_H1comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; V_H2comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; and V_H3comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 502.

29. The binding protein of any one of claims 1-25, wherein V_L1comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; V_L2comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; V_L3comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; V_H1comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; V_H2comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; and V_H3comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253.

30. The binding protein of any one of claims 1-25, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503.

31. The binding protein of any one of claims 1-25 and 29-30, wherein V_L1comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; V_L2comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; V_L3comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; V_H1comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; V_H2comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; and V_H3comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503.

32. The binding protein of any one of claims 1-25, wherein V_L1comprises a CDR-L1 comprising the sequence of SEQ ID NO: 275, a CDR-L2 comprising the sequence of SEQ ID NO: 276, and a CDR-L3 comprising the sequence of SEQ ID NO: 277; V_L2comprises a CDR-L1 comprising the sequence of SEQ ID NO: 500, a CDR-L2 comprising the sequence of SEQ ID NO: 501, and a CDR-L3 comprising the sequence of SEQ ID NO: 274; V_L3comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; V_H1comprises a CDR-H1 comprising the sequence of SEQ ID NO: 257, a CDR-H2 comprising the sequence of SEQ ID NO: 258, and a CDR-H3 comprising the sequence of SEQ ID NO: 259; V_H2comprises a CDR-H1 comprising the sequence of SEQ ID NO: 254, a CDR-H2 comprising the sequence of SEQ ID NO: 255, and a CDR-H3 comprising the sequence of SEQ ID NO: 256; and V_H3comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253.

33. The binding protein of any one of claims 1-25, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 519; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 518; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 506; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 504; and V_H3 comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503.

34. The binding protein of any one of claims 1-25 and 32-33, wherein V_L1comprises a light chain variable domain comprising the sequence of SEQ ID NO: 519; V_L2comprises a light chain variable domain comprising the sequence of SEQ ID NO: 518; V_L3comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513, V_H1comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 506; V_H2comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 504; and V_H3comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503.

35. The binding protein of claim 1, wherein the second polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains.

36. The binding protein of claim 1, wherein the third polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains.

37. The binding protein of claim 1, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.

38. The binding protein of claim 1, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.

39. The binding protein of claim 1, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H1immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.

40. The binding protein of claim 2, wherein the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.

41. The binding protein of claim 2, wherein the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.

42. The binding protein of claim 2, wherein the C_H3domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.

43. The binding protein of claim 1 or claim 2, wherein at least one of L₁, L₂, L₃, or L₄is independently 0 amino acids in length.

44. The binding protein of claim 1 or claim 2, wherein L₁, L₂, L₃, or L₄are each independently at least one amino acid in length.

45. The binding protein of any one of claims 1-44, wherein L₁comprises Asp-Lys-Thr-His-Thr (SEQ ID NO: 525).

46. A binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:

V_L2-L₁-V_L1-L₂-C_L [I]

V_H1-L₃-V_H2-L₄-C_H1 [II]

and a third polypeptide chain comprises a structure represented by the formula:

V_H3-C_H1 [III]

V_L3-C_L [IV]

wherein:

V_L1is a first immunoglobulin light chain variable domain;

V_L2is a second immunoglobulin light chain variable domain;

V_L3is a third immunoglobulin light chain variable domain;

V_H1is a first immunoglobulin heavy chain variable domain;

V_H2is a second immunoglobulin heavy chain variable domain;

V_H3is a third immunoglobulin heavy chain variable domain;

C_Lis an immunoglobulin light chain constant domain;

C_H1is the immunoglobulin C_H1heavy chain constant domain; and

L₁, L₂, L₃, and L₄are amino acid linkers;

wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair;

wherein:

(a) V_L1, V_L2and V_L3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 2, 4, 10, 12, 18, 20, 26, 28, 34, 36, 42, 44, 50, 52, 58, 60, 66, 68, 74, 76, 82, 84, 90, 92, 98, 100, 106, 108, 114, 116, 122, 124, 130, 132, 138, 140, 146, 148, 154, 156, 162, 164, 170, 172, 178, 180, 186, 188, 194, 196, 202, 204, 210, 212, 218, 220, 226, 228, 233, 235, 241, 243; or

(b) V_L1, V_L2and V_L3each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs:266-283; and

wherein:

(a) V_H1, V_H2, and V_H3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 1, 3, 9, 11, 17, 10, 25, 27, 33, 35, 41, 43, 49, 51, 57, 59, 65, 67, 73, 75, 81, 83, 89, 91, 97, 99, 105, 107, 113, 115, 121, 123, 129, 131, 137, 139, 145, 147, 153, 155, 161, 163, 169, 171, 177, 179, 185, 187, 193, 195, 201, 203, 209, 211, 217, 219, 225, 227, 232, 234, 240, 242; or

(b) V_H1, V_H2, and V_H3each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-265.

47. A binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:

V_L2-L₁-V_L1-L₂-C_L [I]

V_H1-L₃-V_H2-L₄-C_H1-hinge-C_H2-C_H3 [II]

and a third polypeptide chain comprises a structure represented by the formula:

V_H3-C_H1-hinge-C_H2-C_H3 [III]

V_L3-C_L [IV]

wherein:

V_L1is a first immunoglobulin light chain variable domain;

V_L2is a second immunoglobulin light chain variable domain;

V_L3is a third immunoglobulin light chain variable domain;

V_H1is a first immunoglobulin heavy chain variable domain;

V_H2is a second immunoglobulin heavy chain variable domain;

V_H3is a third immunoglobulin heavy chain variable domain;

C_Lis an immunoglobulin light chain constant domain;

C_H1is the immunoglobulin C_H1heavy chain constant domain;

C_H2is an immunoglobulin C_H2heavy chain constant domain;

C_H3is an immunoglobulin C_H3heavy chain constant domain;

hinge is an immunoglobulin hinge region connecting the C_H1and C_H2domains; and

L₁, L₂, L₃, and L₄are amino acid linkers;

wherein:

48. The binding protein of claim 46, wherein the second polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains.

49. The binding protein of claim 46, wherein the third polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains.

50. The binding protein of claim 46, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.

51. The binding protein of claim 46, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.

52. The binding protein of claim 46, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.

53. The binding protein of claim 47, wherein the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.

54. The binding protein of claim 47, wherein the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.

55. The binding protein of claim 47, wherein the C_H3domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.

56. The binding protein of claim 46 or claim 47, wherein at least one of L₁, L₂, L₃, or L₄is independently 0 amino acids in length.

57. The binding protein of claim 46 or claim 47, wherein L₁, L₂, L₃, or L₄are each independently at least one amino acid in length.

58. The binding protein of any one of claims 46-57, wherein L₁comprises Asp-Lys-Thr-His-Thr (SEQ ID NO: 525).

59. A binding protein comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain wherein:

(a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 4; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2;

(b) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 12 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 12; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 11 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 11; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 9 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 9; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10;

(c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 20 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 20; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 19 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 17 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 17; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 18 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18;

(d) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 28 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 28; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 27 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 27; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 25 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 25; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 26 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 26;

(e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 36; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 35 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 35; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 33 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 33; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 34 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 34;

(f) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 44 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 44; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 43 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 43; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 41 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 41; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 42 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 42;

(g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 52 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 52; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 51 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 51; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 49 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 49; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 50 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 50;

(h) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 60 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 60; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 59 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 59; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 57; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 58 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 58;

(i) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 68; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 67; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 65 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 65; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 66 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 66;

(j) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 76; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 75; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 73; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 74 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 74;

(k) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 84 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 84; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 83 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 83; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 81 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 81; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 82 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 82;

(l) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 92 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:92; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 91 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 91; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 89 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 89; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 90 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 90;

(m) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 100 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 100; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 99 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 99; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 97 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 97; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 98 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 98;

(n) the first polypeptide comprises the amino acid sequence of SEQ ID NO: 108 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 108; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 107 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 107; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 105 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 105; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 106 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 106;

(o) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 116 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 116; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 115 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 115; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 113 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 113; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 114;

(p) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 124 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 124; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 123 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 123; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 121 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 121; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 122 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 122;

(q) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 132 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 132; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 131; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 129 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 129; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 130 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 130;

(r) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 140 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 140; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 139 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 139; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 137 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 137; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 138;

(s) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 148 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 148; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 147 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 147; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 145 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 145; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 146 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 146;

(t) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 156 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 156; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 155 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 155; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 153 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 153; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 154 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 154;

(u) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 164 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 164; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 163 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 163; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 161 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 161; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 162 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 162;

(v) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 172 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 172; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 171 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 171; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 169 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 169; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 170 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 170;

(w) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 180 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 180; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 179; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 177 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 177; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 178 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 178;

(x) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 188 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 188; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 187 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 187; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 185 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 185; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 186 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 186;

(y) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 196 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 196; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 195 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 195; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 193 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 193; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 194 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 194;

(z) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 204 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 204; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 203 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 203; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 201 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 201; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 202 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 202;

(aa) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 212 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 212; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 211 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 211; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 209 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 209; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 210 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 210;

(bb) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 220 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 220; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 219 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 219; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 217 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 217; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 218 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 218;

(cc) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 228 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 228; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 227 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 227; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 225 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 225; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 226 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 226;

(dd) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 235 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 235; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 234 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 234; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 232 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 232; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 233 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 233; or

(ee) first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 243 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 243; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 242 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 242; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 240 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 240; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 241 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 241.

60. A binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins and one or more T cell target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:

V_L2-L₁-V_L1-L₂-C_L [I];

a second polypeptide chain comprises a structure represented by the formula:

V_H1-L₃-V_H2-L₄-C_H1 [II];

a third polypeptide chain comprises a structure represented by the formula:

V_H3-C_H1 [III];

V_L3-C_L [IV];

wherein

V_L1is a first immunoglobulin light chain variable domain;

V_L2is a second immunoglobulin light chain variable domain;

V_L3is a third immunoglobulin light chain variable domain;

V_H1is a first immunoglobulin heavy chain variable domain;

V_H2is a second immunoglobulin heavy chain variable domain;

V_H3is a third immunoglobulin heavy chain variable domain;

C_Lis an immunoglobulin light chain constant domain;

C_H1is the immunoglobulin C_H1heavy chain constant domain; and

L₁, L₂, L₃, and L₄are amino acid linkers;

61. A binding protein comprising four polypeptide chains that form three antigen binding sites that specifically bind one or more HIV target proteins and one or more T cell target proteins, wherein a first polypeptide chain comprises a structure represented by the formula:

V_L2-L₁-V_L1-L₂-C_L [I];

a second polypeptide chain comprises a structure represented by the formula:

V_H1-L₃-V_H2-L₄-C_H1-hinge-C_H2-C_H3 [II];

a third polypeptide chain comprises a structure represented by the formula:

V_H3-C_H1-hinge-C_H2-C_H3 [III];

V_L3-C_L [IV];

wherein

V_L1is a first immunoglobulin light chain variable domain;

V_L2is a second immunoglobulin light chain variable domain;

V_L3is a third immunoglobulin light chain variable domain;

V_H1is a first immunoglobulin heavy chain variable domain;

V_H2is a second immunoglobulin heavy chain variable domain;

V_H3is a third immunoglobulin heavy chain variable domain;

C_Lis an immunoglobulin light chain constant domain;

C_H1is the immunoglobulin C_H1heavy chain constant domain;

C_H2is an immunoglobulin C_H2heavy chain constant domain;

C_H3is an immunoglobulin C_H3heavy chain constant domain;

hinge is an immunoglobulin hinge region connecting the C_H1and C_H2domains; and

L₁, L₂, L₃, and L₄are amino acid linkers;

62. The binding protein of claim 60 or claim 61, wherein the one or more HIV target proteins are selected from the group consisting of glycoprotein 120, glycoprotein 41 and glycoprotein 160.

63. The binding protein of claim 60 or claim 61, wherein the one or more T cell target proteins are CD3 or CD28.

64. The binding protein of claim 60 or claim 61, wherein the binding protein is trispecific and capable of specifically binding an HIV target protein and two different epitopes on a single T cell target protein.

65. The binding protein of claim 60 or claim 61, wherein the binding protein is trispecific and capable of specifically binding an HIV target protein and two different T cell target proteins.

66. The binding protein of claim 60 or claim 61, wherein the binding protein is trispecific and capable of specifically binding a T cell target protein and two different epitopes on a single HIV target protein.

67. The binding protein of claim 60 or claim 61, wherein the binding protein is trispecific and capable of specifically binding a T cell target protein and two different HIV target proteins.

68. The binding protein of claim 60 or claim 61, wherein the first and second polypeptide chains form two antigen binding sites that specifically target two T cell target proteins, and the third and fourth polypeptide chains form an antigen binding site that specifically binds an HIV target protein.

69. The binding protein of any one of claims 60-68, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively.

70. The binding protein of any one of claims 60-68, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.

71. The binding protein of any one of claims 60-70, wherein V_L1comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.

72. The binding protein of any one of claims 60-71, wherein V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively.

73. The binding protein of any one of claims 60-71, wherein V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.

74. The binding protein of any one of claims 60-73, wherein V_L2comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.

75. The binding protein of any one of claims 60-74, wherein V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 comprising a sequence as set forth in SEQ ID NOs: 266, 267, and 268, respectively; a sequence as set forth in SEQ ID NOs: 269, 270, and 271, respectively; a sequence as set forth in SEQ ID NOs: 500, 501, and 274, respectively; a sequence as set forth in SEQ ID NOs: 275, 276, and 277, respectively; a sequence as set forth in SEQ ID NOs: 281, 282, and 283, respectively; a sequence as set forth in SEQ ID NOs: 278, 279, and 280, respectively; a sequence as set forth in SEQ ID NOs: 488, 489, and 490, respectively; a sequence as set forth in SEQ ID NOs: 491, 492, and 493, respectively; or a sequence as set forth in SEQ ID NOs: 494, 495, and 496, respectively.

76. The binding protein of any one of claims 60-74, wherein V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.

77. The binding protein of any one of claims 60-76, wherein V_L3comprises a light chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, and 524.

78. The binding protein of any one of claims 60-77, wherein V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively.

79. The binding protein of any one of claims 60-77, wherein V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.

80. The binding protein of any one of claims 60-79, wherein V_H1comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.

81. The binding protein of any one of claims 60-80, wherein V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively.

82. The binding protein of any one of claims 60-80, wherein V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.

83. The binding protein of any one of claims 60-82, wherein V_H2comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.

84. The binding protein of any one of claims 60-83, wherein V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 comprising a sequence as set forth in SEQ ID NOs: 248, 497, and 250, respectively; a sequence as set forth in SEQ ID NOs: 251, 252, and 253, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 256, respectively; a sequence as set forth in SEQ ID NOs: 254, 255, and 498, respectively; a sequence as set forth in SEQ ID NOs: 257, 258, and 259, respectively; a sequence as set forth in SEQ ID NOs: 263, 264, and 265, respectively; a sequence as set forth in SEQ ID NOs: 499, 261, and 262, respectively; a sequence as set forth in SEQ ID NOs: 479, 480, and 481, respectively; a sequence as set forth in SEQ ID NOs: 482, 483, and 484, respectively; or a sequence as set forth in SEQ ID NOs: 485, 486, and 487, respectively.

85. The binding protein of any one of claims 60-83, wherein V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.

86. The binding protein of any one of claims 60-85, wherein V_H3comprises a heavy chain variable domain comprising a sequence selected from the group consisting of SEQ ID NOs: 502, 503, 504, 505, 506, 507, 508, 509, 510, and 511.

87. The binding protein of any one of claims 60-86, wherein V_L1comprises a CDR-L1 comprising the sequence of SEQ ID NO: 488, a CDR-L2 comprising the sequence of SEQ ID NO: 489, and a CDR-L3 comprising the sequence of SEQ ID NO: 490; V_L2comprises a CDR-L1 comprising the sequence of SEQ ID NO: 494, a CDR-L2 comprising the sequence of SEQ ID NO: 495, and a CDR-L3 comprising the sequence of SEQ ID NO: 496; V_L3comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; V_H1comprises a CDR-H1 comprising the sequence of SEQ ID NO: 479, a CDR-H2 comprising the sequence of SEQ ID NO: 480, and a CDR-H3 comprising the sequence of SEQ ID NO: 481; V_H2comprises a CDR-H1 comprising the sequence of SEQ ID NO: 485, a CDR-H2 comprising the sequence of SEQ ID NO: 486, and a CDR-H3 comprising the sequence of SEQ ID NO: 487; and V_H3comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253.

88. The binding protein of any one of claims 60-86, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 522; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 524; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 509; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 511; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503.

89. The binding protein of any one of claims 60-88, wherein V_L1comprises a light chain variable domain comprising the sequence of SEQ ID NO: 522; V_L2comprises a light chain variable domain comprising the sequence of SEQ ID NO: 524; V_L3comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; V_H1comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 509; V_H2comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 511; and V_H3comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503.

90. The binding protein of any one of claims 60-86, wherein V_L1comprises a CDR-L1 comprising the sequence of SEQ ID NO: 494, a CDR-L2 comprising the sequence of SEQ ID NO: 495, and a CDR-L3 comprising the sequence of SEQ ID NO: 496; V_L2comprises a CDR-L1 comprising the sequence of SEQ ID NO: 488, a CDR-L2 comprising the sequence of SEQ ID NO: 489, and a CDR-L3 comprising the sequence of SEQ ID NO: 490; V_L3comprises a CDR-L1 comprising the sequence of SEQ ID NO: 269, a CDR-L2 comprising the sequence of SEQ ID NO: 270, and a CDR-L3 comprising the sequence of SEQ ID NO: 271; V_H1comprises a CDR-H1 comprising the sequence of SEQ ID NO: 485, a CDR-H2 comprising the sequence of SEQ ID NO: 486, and a CDR-H3 comprising the sequence of SEQ ID NO: 487; V_H2comprises a CDR-H1 comprising the sequence of SEQ ID NO: 479, a CDR-H2 comprising the sequence of SEQ ID NO: 480, and a CDR-H3 comprising the sequence of SEQ ID NO: 481; and V_H3comprises a CDR-H1 comprising the sequence of SEQ ID NO: 251, a CDR-H2 comprising the sequence of SEQ ID NO: 252, and a CDR-H3 comprising the sequence of SEQ ID NO: 253.

91. The binding protein of any one of claims 60-86, wherein V_L1comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 524; V_L2comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 522; V_L3comprises a CDR-L1, CDR-L2, and CDR-L3 of a light chain variable domain comprising the light chain variable domain sequence of SEQ ID NO: 513; V_H1comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 511; V_H2comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 509; and V_H3comprises a CDR-H1, CDR-H2, and CDR-H3 of a heavy chain variable domain comprising the heavy chain variable domain sequence of SEQ ID NO: 503.

92. The binding protein of any one of claims 60-86 and 90-91, wherein V_L1comprises a light chain variable domain comprising the sequence of SEQ ID NO: 524; V_L2comprises a light chain variable domain comprising the sequence of SEQ ID NO: 522; V_L3comprises a light chain variable domain comprising the sequence of SEQ ID NO: 513; V_H1comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 511; V_H2comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 509; and V_H3comprises a heavy chain variable domain comprising the sequence of SEQ ID NO: 503.

93. The binding protein of claim 60, wherein the second polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains.

94. The binding protein of claim 60, wherein the third polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains.

95. The binding protein of claim 60, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.

96. The binding protein of claim 60, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.

97. The binding protein of claim 60, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.

98. The binding protein of claim 61, wherein the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.

99. The binding protein of claim 61, wherein the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.

100. The binding protein of claim 61, wherein the C_H3domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.

101. The binding protein of claim 60 or claim 61, wherein at least one of L₁, L₂, L₃, or L₄is independently 0 amino acids in length.

102. The binding protein of claim 60 or claim 61, wherein L₁, L₂, L3, or L₄are each independently at least one amino acid in length.

103. The binding protein of any one of claims 60-102, wherein L₁is Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299).

104. A binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:

V_L2-L₁-V_L1-L₂-C_L [I]

V_H1-L₃-V_H2-L₄-C_H1 [II]

and a third polypeptide chain comprises a structure represented by the formula:

V_H3-C_H1 [III]

V_L3-C_L [IV]

wherein:

V_L1is a first immunoglobulin light chain variable domain;

V_L2is a second immunoglobulin light chain variable domain;

V_L3is a third immunoglobulin light chain variable domain;

V_H1is a first immunoglobulin heavy chain variable domain;

V_H2is a second immunoglobulin heavy chain variable domain;

V_H3is a third immunoglobulin heavy chain variable domain;

C_Lis an immunoglobulin light chain constant domain;

C_H1is the immunoglobulin C_H1heavy chain constant domain; and

L₁, L₂, L₃, and L₄are amino acid linkers;

wherein:

(a) V_L1, V_L2and V_L3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 303, 305, 311, 313, 319, 321, 327, 329, 335, 337, 343, 345, 351, 353, 359, 361, 367, 369, 375, 377, 383, 385, 391, 393, 399, 401, 407, 409, 415, 417, 423, 425, 431, 433, 439, 441, 447, 449, 455, 457, 463, 465, 471, 473; or

(b) V_L1, V_L2and V_L3each independently comprise light chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 266-271, 275-277, 488-496; and

wherein:

(a) V_H1, V_H2, and V_H3are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 302, 304, 310, 312, 318, 320, 326, 328, 334, 336, 342, 344, 350, 352, 358, 360, 366, 368, 374, 376, 382, 384, 390, 392, 398, 400, 406, 408, 414, 416, 422, 424, 430, 432, 438, 440, 446, 448, 454, 456, 462, 464, 470, 472; or

(b) V_H1, V_H2, and V_H3each independently comprise heavy chain complementarity determining regions of a variable domain comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 248-253, 257-259, 479-487.

105. A binding protein comprising four polypeptide chains that form three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula:

V_L2-L₁-V_L1-L₂-C_L [I]

V_H1-L₃-V_H2-L₄-C_H1-hinge-C_H2-C_H3 [II]

and a third polypeptide chain comprises a structure represented by the formula:

V_H3-C_H1-hinge-C_H2-C_H3 [III]

V_L3-C_L [IV]

wherein:

V_L1is a first immunoglobulin light chain variable domain;

V_L2is a second immunoglobulin light chain variable domain;

V_L3is a third immunoglobulin light chain variable domain;

V_H1is a first immunoglobulin heavy chain variable domain;

V_H2is a second immunoglobulin heavy chain variable domain;

V_H3is a third immunoglobulin heavy chain variable domain;

C_Lis an immunoglobulin light chain constant domain;

C_H1is the immunoglobulin C_H1heavy chain constant domain;

C_H2is an immunoglobulin C_H2heavy chain constant domain;

C_H3is an immunoglobulin C_H3heavy chain constant domain;

hinge is an immunoglobulin hinge region connecting the C_H1and C_H2domains; and

L₁, L₂, L₃, and L₄are amino acid linkers;

wherein:

(a) V_H1, V_H2, and V_H3 are each independently a variable domain derived from an amino acid sequence as set forth in any one of SEQ ID NOs: 302, 304, 310, 312, 318, 320, 326, 328, 334, 336, 342, 344, 350, 352, 358, 360, 366, 368, 374, 376, 382, 384, 390, 392, 398, 400, 406, 408, 414, 416, 422, 424, 430, 432, 438, 440, 446, 448, 454, 456, 462, 464, 470, 472; or

106. The binding protein of claim 104, wherein the second polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains.

107. The binding protein of claim 104, wherein the third polypeptide chain further comprises an Fc region linked to C_H1, the Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains.

108. The binding protein of claim 104, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.

109. The binding protein of claim 104, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.

110. The binding protein of claim 104, wherein the second polypeptide chain further comprises a first Fc region linked to C_H1, the first Fc region comprising an immunoglobulin hinge region and C_H2and C_H3immunoglobulin heavy chain constant domains, and wherein the third polypeptide chain further comprises a second Fc region linked to C_H1, the second Fc region comprising an immunoglobulin hinge region and C_H2and C_H1immunoglobulin heavy chain constant domains; wherein the first and second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.

111. The binding protein of claim 105, wherein the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.

112. The binding protein of claim 105, wherein the C_H3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the C_H3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 according to EU Index, wherein the amino acid substitutions are S354C and T366W.

113. The binding protein of claim 105, wherein the C_H3domains of the second and the third polypeptide chains both comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 according to EU Index, wherein the amino acid substitutions are M428L and N434S.

114. The binding protein of claim 104 or claim 105, wherein at least one of L₁, L₂, L₃, or L₄is independently 0 amino acids in length.

115. The binding protein of claim 104 or claim 105, wherein L₁, L₂, L₃, or L₄are each independently at least one amino acid in length.

116. The binding protein of any one of claims 104-115, wherein L₁is Gly-Gln-Pro-Lys-Ala-Ala-Pro (SEQ ID NO: 299).

117. A binding protein comprising a first polypeptide chain, a second polypeptide chain, a third polypeptide chain and a fourth polypeptide chain wherein:

(a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 305 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 305; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 304 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 304; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 302 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 302; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 303 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 303;

(b) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 313 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 313; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 312 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 312; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 310 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 310; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 311 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 311;

(c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 321 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 321; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 320 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 320; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 318 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 318; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 319 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 319;

(d) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 329 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 329; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 328 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 328; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 326 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 326; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 327 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 327;

(e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 337 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 337; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 336 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 336; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 334 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 334; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 335 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 335;

(f) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 345 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 345; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 344 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 344; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 342 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 342; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 343 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 343;

(g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 353 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 353; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 352 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:352; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 350 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 350; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 351 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 351;

(h) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 361 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 361; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 360 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 360; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 358 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 358; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 359 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 359;

(i) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 369 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 369; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 368 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 368; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 366 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 366; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 367 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 367;

(j) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 377 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 377; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 376 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 376; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 374 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 374; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 375 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 375;

(k) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 385 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 385; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 384 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 384; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 382 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 382; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 383 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 383;

(l) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 393 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 393; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 392 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 392; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 390 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 390; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 391 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 391;

(m) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 401 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 401; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 400 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 400; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 398 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 398; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 399 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 399;

(n) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 409 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 409; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 408 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 408; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 406 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 406; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 407 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 407;

(p) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 417 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 417; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 416 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 416; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 414 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 414; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 415 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 415;

(q) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 425 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 425; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 424 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 424; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 422 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 422; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 423 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 423;

(r) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 433 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:433; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 432 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 432; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 430 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 430; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 431 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 431;

(s) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 441 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 441; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 440 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 440; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 438 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 438; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 439 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 439;

(t) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 449 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 449; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 448 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 448; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 446 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 446; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 447 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 447,

(u) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 457 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 457; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 456 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 456; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 454 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 454; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 455 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 455;

(v) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 465 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 465; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 464 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 464; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 462 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 462; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 463 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 463; or

(w) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO: 473 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 473; the second polypeptide chain comprises the amino acid sequence of SEQ ID NO: 472 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 472; the third polypeptide chain comprises the amino acid sequence of SEQ ID NO: 470 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 470; and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO: 471 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 471.

118. An isolated nucleic acid molecule comprising a nucleotide sequence encoding the binding protein of any one of claims 1-117.

119. An expression vector comprising the nucleic acid molecule of claim 118.

120. An isolated host cell comprising the nucleic acid molecule of claim 118.

121. An isolated host cell comprising the expression vector of claim 119.

122. The isolated host cell of claim 120 or claim 121, wherein the host cell is a mammalian cell or an insect cell.

123. A vector system comprising one or more vectors encoding a first, second, third, and fourth polypeptide chain of a binding protein of any one of claims 1-117.

124. The vector system of claim 123, wherein the vector system comprises a first vector encoding the first polypeptide chain of the binding protein, a second vector encoding the second polypeptide chain of the binding protein, a third vector encoding the third polypeptide chain of the binding protein, and a fourth vector encoding the fourth polypeptide chain of the binding protein.

125. The vector system of claim 123, wherein the vector system comprises a first vector encoding the first and second polypeptide chains of the binding protein, and a second vector encoding the third and fourth polypeptide chains of the binding protein.

126. The vector system of any one of claims 123-125, wherein the one or more vectors are expression vectors.

127. An isolated host cell comprising the vector system of any one of claims 123-126.

128. The isolated host cell of claim 127, wherein the host cell is a mammalian cell or an insect cell.

129. A method of producing a binding protein, the method comprising:

a) culturing a host cell of any one of claims 120-122 and claims 127-128 under conditions such that the host cell expresses the binding protein; and

b) isolating the binding protein from the host cell.

130. A method of preventing and/or treating HIV infection in a patient comprising administering to the patient a therapeutically effective amount of at least one binding protein of any one of claims 1-117.

131. The method of claim 130, wherein the binding protein is co-administered with standard anti-retroviral therapy.

132. The method of claim 130 or claim 131, wherein administration of the at least one binding protein results in the neutralization of one or more HIV virions.

133. The method of any one of claims 130-132, wherein administration of the at least one binding protein results in the elimination of one or more latently and/or chronically HIV-infected cells in the patient.

134. The method of any one of claims 130-133, wherein the patient is a human.

135. The binding protein of any one of claims 1-117 for the prevention or treatment of an HIV infection in a patient.

136. The binding protein of claim 135, wherein the binding protein is co-administered with standard anti-retroviral therapy.

137. The binding protein of claim 135 or claim 136, wherein the binding protein causes the neutralization of one or more HIV virions in the patient.

138. The binding protein of any one of claims 135-137, wherein the binding protein causes the elimination of one or more latently and/or chronically HIV-infected cells in the patient.

139. The binding protein of any one of claims 135-138, wherein the patient is a human.