HK40102925A - Anti-cd93 constructs and uses thereof - Google Patents

Description

Anti-CD93 constructs and their applications

Cross-references to related applications

This application claims priority to U.S. Provisional Application No. 63/084474, filed September 28, 2020; International Application No. PCT/US2021/035542, filed June 2, 2021; and International Application No. PCT/US2021/043784, filed July 29, 2021, the entire contents of which are incorporated herein by reference for all purposes.

Technical Field

This disclosure relates to anti-CD93 constructs (e.g., anti-CD93 antibodies) and their uses.

Sequence list submitted as an ASCII text file

The contents of the subsequent submissions in the form of an ASCII text file are incorporated into this article in their entirety by reference: Computer-readable form of a sequence list (CRF) (filename: 193852000246SEQLIST.TXT, date record: September 28, 2021, size: 196372 bytes).

Background Technology

CD93 (Cluster 93) is a protein encoded by the CD93 gene in humans. CD93 is a C-type lectin transmembrane receptor that plays a role not only in cell-cell adhesion but also in host defense. Initially thought to be a C1q receptor, CD93 is now believed to be involved in cell-cell adhesion and the clearance of apoptotic cells. The protein's intracellular cytoplasmic tail contains two highly conserved domains that may be involved in CD93 function. In fact, the highly charged juxtamembrane domain has been found to interact with membrane spike proteins, proteins known to play a role in linking transmembrane proteins to the cytoskeleton and in cytoskeleton remodeling. This process appears to be crucial for adhesion, migration, and phagocytosis.

All publications, patents, patent applications, and published patent applications mentioned herein are incorporated herein by reference in their entirety.

Invention Overview

The following overview is illustrative only and is not intended to be limiting in any way. That is, it is provided to highlight the strengths, benefits, and advantages of novel molecules and their uses. Therefore, this overview is not intended to identify essential features of the claimed subject matter, nor is it intended to determine the scope of the claimed subject matter.

On one hand, this application provides an anti-CD93 construct comprising an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for the binding epitope of CD93, wherein:

a) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:1, HC-CDR2 containing the amino acid sequence of SEQ ID NO:2, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:3, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:4, LC-CDR2 containing the amino acid sequence of SEQ ID NO:5, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:6;

b) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:17, HC-CDR2 containing the amino acid sequence of SEQ ID NO:18, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:19, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:20, LC-CDR2 containing the amino acid sequence of SEQ ID NO:21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:22;

c) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:33, HC-CDR2 containing the amino acid sequence of SEQ ID NO:34, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:35, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:36, LC-CDR2 containing the amino acid sequence of SEQ ID NO:37, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:38;

d) V _H-2 contains HC-CDR1 containing the amino acid sequence of SEQ ID NO:49, HC-CDR2 containing the amino acid sequence of SEQ ID NO:50, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:51, and V _L-2 contains LC-CDR1 containing the amino acid sequence of SEQ ID NO:52, LC-CDR2 containing the amino acid sequence of SEQ ID NO:53, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:54;

e) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:65, HC-CDR2 containing the amino acid sequence of SEQ ID NO:66, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:67, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:68, LC-CDR2 containing the amino acid sequence of SEQ ID NO:69, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:70;

f) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:81, HC-CDR2 containing the amino acid sequence of SEQ ID NO:82, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:83, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:84, LC-CDR2 containing the amino acid sequence of SEQ ID NO:85, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:86;

g) V _H-2 contains HC-CDR1 containing the amino acid sequence of SEQ ID NO:97, HC-CDR2 containing the amino acid sequence of SEQ ID NO:98, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:99, and V _L-2 contains LC-CDR1 containing the amino acid sequence of SEQ ID NO:100, LC-CDR2 containing the amino acid sequence of SEQ ID NO:101, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:102;

h) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:113, HC-CDR2 containing the amino acid sequence of SEQ ID NO:114, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:115, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:116, LC-CDR2 containing the amino acid sequence of SEQ ID NO:117, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:118;

i) V _H-2 contains HC-CDR1 containing the amino acid sequence of SEQ ID NO:129, HC-CDR2 containing the amino acid sequence of SEQ ID NO:130, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:131, and V _L-2 contains LC-CDR1 containing the amino acid sequence of SEQ ID NO:132, LC-CDR2 containing the amino acid sequence of SEQ ID NO:133, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:134;

j) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:145, HC-CDR2 containing the amino acid sequence of SEQ ID NO:146, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:147, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:148, 355, or 358, LC-CDR2 containing the amino acid sequence of SEQ ID NO:149 or 356, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:150, 357, or 359;

k)V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:161, HC-CDR2 containing the amino acid sequence of SEQ ID NO:162, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:163, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:164, LC-CDR2 containing the amino acid sequence of SEQ ID NO:165, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:166;

l) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:177, HC-CDR2 containing the amino acid sequence of SEQ ID NO:178, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:179, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:180 or 353, LC-CDR2 containing the amino acid sequence of SEQ ID NO:181 or 354, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:182;

m)V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:193, HC-CDR2 containing the amino acid sequence of SEQ ID NO:194, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:195, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:196, LC-CDR2 containing the amino acid sequence of SEQ ID NO:197, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:198;

n) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:209, HC-CDR2 containing the amino acid sequence of SEQ ID NO:210, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:211, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:212, LC-CDR2 containing the amino acid sequence of SEQ ID NO:213, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:214; or

o)V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:289, HC-CDR2 containing the amino acid sequence of SEQ ID NO:290, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:291, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:292, LC-CDR2 containing the amino acid sequence of SEQ ID NO:293, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:294;

p)V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:17 or 304, HC-CDR2 containing the amino acid sequence of SEQ ID NO:18 or 305, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:19, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:20, 301, 302, 303, or 306, LC-CDR2 containing the amino acid sequence of SEQ ID NO:21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:22.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:1, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:2, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:3, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:4, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:5, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:6, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:17 or 304, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:18 or 305, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, or variants thereof comprising up to 5, 4, 3, 2 or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:20, 301, 302, 303 or 306, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22, or variants thereof comprising up to 5, 4, 3, 2 or 1 amino acid substitutions in the LC-CDR.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:33, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:34, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:35, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:36, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:37, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:38, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:49, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:51, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:52, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:53, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:54, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:65, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:66, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:67, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:68, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:69, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:70, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:81, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:82, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:83, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:84, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:85, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:86, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:97, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:98, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:99, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:100, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:101, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:102, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:113, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:114, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:115, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:116, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:117, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:118, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:129, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:130, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:131, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:132, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:133, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:134, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:145, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:146, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:147, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:148, 355, or 358, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:149 or 356, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:150, 357, or 359, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:161, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:162, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:163, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:164, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:165, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:166, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:177, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:178, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:179, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:180 or 353, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:181 or 354, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:182, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:193, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:194, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:195, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:196, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:197, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:198, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:209, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:210, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:211, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:212, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:213, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:214, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:289, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:290, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:291, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:292, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:293, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:294, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

In some embodiments, V _H comprises: HC-CDR1 containing the amino acid sequence of SEQ ID NO:17 or 304, HC-CDR2 containing the amino acid sequence of SEQ ID NO:18 or 305, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:19, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR, and V _L comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:20, 301, 302, 303, or 306, LC-CDR2 containing the amino acid sequence of SEQ ID NO:21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:22, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

On the other hand, this application includes an anti-CD93 construct containing an antibody moiety that specifically binds to CD93, comprising:

a) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:13; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:14;

b) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequences shown in SEQ ID NO:29 and 307-312; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequences shown in SEQ ID NO:30 and 313-318;

c) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:45; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:46;

d) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:61; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:62;

e) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:77; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:78;

f) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:93; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:94;

g) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:109; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:110;

h) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:125; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:126;

i) HC-CDR1, HC-CDR2 and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2 and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:141, and LC-CDR1, LC-CDR2 and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2 and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:142;

j) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:157 and 360-362; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:158 and 363-365;

k) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:173; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:174;

l) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO: 189 and 347-349; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO: 190 and 350-352.

m)HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:205; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:206;

n) HC-CDR1, HC-CDR2 and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2 and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:221, and LC-CDR1, LC-CDR2 and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2 and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:222;

o) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:287 and 319-321; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:288 and 322-324;

p) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:307-312; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:313-318; or

q) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:319-321, and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:322-324.

In some embodiments of any of the anti-CD93 constructs described above, wherein V _H comprises any of the amino acid sequences of SEQ ID NO: 13, 29, 45, 61, 77, 93, 109, 125, 141, 157, 173, 189, 205, 221, 287, 307-312, and 319-321, or comprises a variant of an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and/or wherein V _{L comprises SEQ ID NO: 13, 29, 45, 61, 77, 93, 109, 125, 141, 157, 173, 189, 205, 221, 287, 307-312, and 319-321; and/or wherein V L} comprises any of the amino acid sequences of ... NOs: any one of the amino acid sequences of NOs 14, 30, 46, 62, 78, 94, 110, 126, 142, 158, 174, 190, 206, 222, 288, 313-318, and 322-324, or variants containing amino acid sequences having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V _H comprises the amino acid sequence of SEQ ID NO:13, or a variant thereof comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises the amino acid sequence of SEQ ID NO:14, or a variant thereof comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V _H comprises: an amino acid sequence of any one of SEQ ID NO:29 and 307-312 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: an amino acid sequence of any one of SEQ ID NO:30 and 313-318 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:45 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:46 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:61 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:62 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:77 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:78 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:93 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:94 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:109 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; V _L comprises: the amino acid sequence of SEQ ID NO:110 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:125 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:126 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:141 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:142 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, VH comprises: the amino acid sequence of SEQ ID NO:157 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and _VL comprises: the amino acid sequence of SEQ ID NO:158 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:173 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:174 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V _H comprises: an amino acid sequence of any one of SEQ ID NO:189 and 347-349 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: an amino acid sequence of any one of SEQ ID NO:190 and 350-352 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:205 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:206 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:221 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:222 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V _H comprises: an amino acid sequence of any one of SEQ ID NO:287 and 319-321 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: an amino acid sequence of any one of SEQ ID NO:288 and 322-324 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments of any of the anti-CD93 constructs described above, the antibody portion is an antibody or an antigen-binding fragment thereof selected from the group consisting of: full-length antibodies, bispecific antibodies, single-chain Fv (scFv) fragments, Fab fragments, Fab' fragments, F(ab')2, Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv)2, Fv-Fc fusions, scFv-Fc fusions, scFv-Fv fusions, diabody antibodies, trisomy antibodies, and tetrasomy antibodies. In some embodiments, the antibody portion is a full-length antibody.

In some embodiments of any of the anti-CD93 constructs described above, the antibody portion has an Fc fragment selected from the group consisting of Fc fragments from IgG, IgA, IgD, IgE, IgM, and combinations thereof and hybrids thereof. In some embodiments, the Fc fragment is selected from the group consisting of Fc fragments from IgG1, IgG2, IgG3, IgG4, and combinations thereof and hybrids thereof. In some embodiments, the Fc fragment has reduced effector function compared to the corresponding wild-type Fc fragment. In some embodiments, the Fc fragment has enhanced effector function compared to the corresponding wild-type Fc fragment. In some embodiments, the Fc fragment has a prolonged serum half-life. In some embodiments, the Fc fragment has a shortened serum half-life.

In some embodiments of any of the anti-CD93 constructs described above, the antibody partially blocks the binding of CD93 to IGFBP7 (e.g., human IGFBP7).

In some embodiments of any of the anti-CD93 constructs described above, the antibody partially blocks the binding of CD93 to MMRN2 (e.g., human MMRN2).

In some embodiments of any of the anti-CD93 constructs described above, the antibody partially blocks a) the binding of CD93 to IGFBP7 and/or b) the binding of CD93 to MMRN2.

In some embodiments of any of the anti-CD93 constructs described above, CD93 is human CD93.

In some embodiments, a fusion protein is provided comprising any of the above-described anti-CD93 constructs. In some embodiments, the anti-CD93 construct is fused to one or more cell signaling peptides or proteins. In some embodiments, the anti-CD93 construct is fused to one or more VEGF-binding moieties. In some embodiments, the anti-CD93 construct is fused to one or more VEGF-A-binding moieties. In some embodiments, the VEGF-A-binding moiety is aflibercept. In one embodiment, the fusion protein comprises: a heavy chain fusion polypeptide comprising the amino acid sequence shown in SEQ ID NO:366, or a variant comprising an amino acid sequence having at least about 80% (such as any one of at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a light chain polypeptide comprising the amino acid sequence shown in SEQ ID NO:367, or a variant comprising an amino acid sequence having at least about 80% (such as any one of at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

On the other hand, this application provides a pharmaceutical composition comprising any of the above-described anti-CD93 constructs and a pharmaceutically acceptable carrier.

On the other hand, this application provides an isolated nucleic acid that encodes any of the above-mentioned anti-CD93 constructs.

On the other hand, this application provides a vector containing any of the isolated nucleic acids described above.

On the other hand, this application provides an isolated host cell containing any of the isolated nucleic acids or vectors described above.

On the other hand, this application provides an immune conjugate comprising any of the above-described antiCD93 constructs linked to a therapeutic agent or a marker.

On the other hand, this application provides a method for generating an anti-CD93 construct, comprising: a) culturing the isolated host cells of claim 25 under conditions that effectively express the anti-CD93 construct; and b) obtaining the expressed anti-CD93 construct from the host cells.

On the other hand, this application provides a method for treating an individual's disease or condition, comprising administering to the individual an effective amount of any of the aforementioned anti-CD93 constructs or pharmaceutical compositions. In some embodiments, the disease or condition is associated with abnormal vascular structures. In some embodiments, the disease or condition is cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer comprises CD93+ endothelial cells. In some embodiments, the cancer comprises IGFBP7+ blood vessels. In some embodiments, the cancer is characterized by tumor hypoxia. In some embodiments, the cancer is locally advanced or metastatic cancer. In some embodiments, the cancer is selected from the group consisting of lymphoma, colon cancer, brain cancer, breast cancer, ovarian cancer, endometrial cancer, esophageal cancer, prostate cancer, cervical cancer, kidney cancer, bladder cancer, gastric cancer, non-small cell lung cancer, melanoma, and pancreatic cancer. In some embodiments, the anti-CD93 construct is administered to the individual parenterally. In some embodiments, the method further includes administering a second therapy. In some embodiments, the second therapy is selected from the group consisting of: surgery, radiation therapy, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormone therapy, targeted therapy, cryotherapy, ultrasound therapy, photodynamic therapy, and chemotherapy. In some embodiments, the second therapy is immunotherapy. In some embodiments, immunotherapy includes the administration of an immunomodulatory agent. In some embodiments, the immunomodulatory agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor includes an anti-PD-L1 antibody or an anti-PD-1 antibody. In some embodiments, the individual is a human being.

Attached Figure Description

Figure 1 shows the binding affinity of 16E4 and MM01 to human or cynomolgus monkey CD93.

Figure 2 shows the binding of various anti-CD93 antibodies to CHO cells expressing CD93.

Figures 3A-3D show the inhibition of the interaction between CD93 and IGFBP7 by 16E4 and MM01 at various concentrations compared to mIgG isotypes.

Figures 4A-4F show the inhibition of HUVEC tube formation by various anti-CD93 antibodies compared to the control.

Figures 5A-5B show the results of epitope binning of various anti-CD93 antibodies using Octet competition.

Figures 6A-6B show the cross-binding activity of various anti-CD93 antibodies against human and cynomolgus monkey CD93, as measured by biolayer interferometry (BLI) assays.

Figures 7A-7B show the alignment of V _H and V _L CDRs according to Kabat numbers. From top to bottom, the sequences in Figure 7A are SEQ ID NO:393-406, and the sequences in Figure 7B are SEQ ID NO:407-420.

Figures 8A-8B show the alignment of _VH and _VL CDRs determined by the VBASE2 tool. From top to bottom, the sequences in Figure 8A are SEQ ID NO:393-406, and the sequences in Figure 8B are SEQ ID NO:407-420.

Figure 9 shows the binding affinity of 10B1 and 7F3 to human CD93.

Figure 10 shows the binding of 16E4, 10B1, and 7F3 to CHO cells expressing human CD93 and the loss of binding to CHO-K1 cells.

Figures 11A-11B show the inhibition of the interaction between CD93 and MMRN2 by 16E4, 10B1, and 7F3 compared to the mIgG isotype at 50 μg/mL.

Figure 12 shows the inhibition of the interaction between CD93 and MMRN2 by 7F3 at different MMRN2 concentrations compared to the control (IgG2a).

Figure 13 shows the inhibition of the interaction between CD93 and MMRN2 by 7F3 compared to the control (IgG1).

Figure 14 shows the inhibition of the interaction between CD93 and IGFBP7 by 7F3 at various concentrations compared to the mIgG1 isotype.

Figures 15A-15B show the inhibition of HUVEC tube formation by 16E4 and 7F3 at both concentrations compared to the control.

Figure 16 shows an exemplary multispecific anti-CD93 construct that also recognizes VEGF.

Figure 17 shows tumor volume in mice treated with an exemplary anti-CD93 construct.

Figure 18 shows the tumor volume in mice treated with humanized 17B10 anti-CD93 antibody.

Figure 19 shows the binding of anti-CD93 antibody to primary HUVEC cells as determined by flow cytometry in the presence of human serum.

Figure 20 shows the binding of anti-CD93 antibody to primary HUVEC cells as determined by flow cytometry in the absence of human serum.

Figure 21 shows the binding of anti-CD93 antibody to hCD93 CHO cells as determined by flow cytometry in the presence of human serum.

Figure 22 shows the binding of anti-CD93 antibody to U937 cells as determined by flow cytometry.

Figures 23-24 show the inhibitory effect of an exemplary humanized 17B10 antibody on HUVEC tube formation.

Figures 25A-25B show the binding of an exemplary humanized 17B10 antibody to CHO cells overexpressing human CD93.

Figures 26A-26B show the binding of an exemplary humanized 17B10 antibody to KG1a and U937 cells.

Figure 27 shows the binding of humanized anti-CD93 antibody 17B10 to CHO cells expressing mouse CD93 on their cell surface, as determined by fluorescence activated cell sorting (FACS) assay.

Figure 28 shows the binding of an exemplary humanized 17B10 antibody to HEK cells expressing mouse CD93 on their cell surface, as determined by a fluorescence activated cell sorting (FACS) assay.

Figure 29 shows the SDS-PAGE analysis of exemplary humanized 16E4 antibody and humanized 7F3 antibody.

Figure 30 shows an ELISA analysis of exemplary humanized 16E4 and 7F3 antibodies binding to human CD93 (hCD93).

Figure 31 shows an ELISA analysis of the binding of an exemplary h7F3 (humanized 7F3) antibody to human CD93 (hCD93).

Figure 32 shows an ELISA analysis of exemplary hybridoma or humanized 16E4 antibody binding to hCD93.

Figure 33 shows an ELISA analysis of exemplary hybridoma or humanized 17B10 antibody binding to hCD93.

Figure 34 shows an exemplary ELISA analysis of humanized 17B10 combined with hCD93.

Figure 35 shows the FACS analysis of the binding of 16E4-hIgG1 and 7F3-hIgG1 antibodies to CHO-hCD93 cells.

Figure 36 shows the FACS analysis of the binding of humanized 7F3 to CHO-hCD93 cells.

Figure 37 shows the FACS analysis of the binding of h16E4 (humanized 16E4) to CHO-hCD93 cells.

Figure 38 shows the FACS analysis of humanized 7F3 binding to HUVEC cells.

Figure 39 shows the FACS analysis of binding to humanized 7F3 KG1a cells.

Figure 40 shows the FACS analysis of humanized 16E4 binding to KG1a cells.

Figure 41 shows the kinetic characterization of the binding of exemplary 16E4 and 7F3 antibodies to hCD93.

Figure 42 shows the kinetic characterization of the binding of an exemplary humanized 16E4 antibody to hCD93.

Figure 43 shows the binding affinity of exemplary 16E4 and 7F3 antibodies to human CD93 via Octet, and a summary of the binding affinity of exemplary 16E4 and 7F3 antibodies to CHO cells, HUVEC cells, or KG1a cells expressing human CD93, as measured by flow cytometry.

Figure 44 shows the FACS analysis of the blocking effect of humanized 7F3 on the binding of human MMRN2 to CHO-hCD93 cells.

Figure 45 shows the FACS analysis of the blocking effect of humanized 16E4 and 7F3 antibodies on the binding of MMRN2 to CHO-hCD93 cells.

Figure 46 shows the FACS analysis of the blocking effect of an exemplary humanized 7F3 antibody on the binding of human IGFBP7 to HUVEC cells.

Figure 47 shows Octet analysis of the blocking effect of exemplary 7F3 or 16E4 antibodies on the binding of human IGFBP7 to human CD93.

Figure 48 shows Octet analysis of the blocking effect of the exemplary 16E4 antibody on the binding of human IGFBP7 to human CD93.

Figures 49-50 show the effects of exemplary humanized 7F3 and 16E4 antibodies on HUVEC tube formation.

Figure 51 shows a summary of the characteristics of an exemplary anti-CD93 antibody.

Figure 52A shows the in vivo antitumor efficacy of 7F3, 16E4, and 17B10 chimeras in the B16F10 mouse model and the changes in body weight of the treated mice. Figure 52C shows the in vivo antitumor efficacy of 7F3, 16E4, 17B10, and 7F3/VEGFRFc in the B16F10 mouse model and the changes in body weight of the treated mice.

Figure 53A shows a schematic design of the 7h7F3/VEGFR construct.

Figure 53B shows the results of the FACS binding assay between CD93 and chimeric 7F3-hIgG1 or the exemplary chimeric 7F3/VEGFR construct (i.e., 7F3-aflibercept).

Figures 53C-53D show the results of the FACS blocking assay. Figure 53C shows that the original 7F3-mIgG1, humanized 7F3-hIgG1, and the exemplary 7F3/VEGFR construct humanized 7F3-aflibercept all block the interaction between CD93 and IGFBP7. Figure 53D shows that the original 7F3-mIgG1, humanized 7F3-hIgG1, and the exemplary 7F3/VEGFR construct humanized 7F3-aflibercept all block the interaction between CD93 and MMRN2.

Figures 53E-53F show the results of the ELISA binding assay. Figure 53E shows that chimeric 7F3-hIgG1 and humanized 7F3-afflibercept both bind to human CD93, while humanized 7F3-afflibercept and Avastin both bind to VEGFA. Figure 53F shows that chimeric 7F3-hIgG1, chimeric 7F3-afflibercept, and humanized 7F3-afflibercept bind to both human CD93 and cynomolgus monkey CD93. Avastin, chimeric 7F3-afflibercept, and humanized 7F3-afflibercept all bind to human VEGFA, while only chimeric 7F3-afflibercept and humanized 7F3-afflibercept bind to mouse VEGFA.

Figure 53G shows the results of an Octet binding assay that tested the binding of VEGFA to hFc-VEGF trap, h7F3-VEGF trap, or Avastin.

Detailed Implementation

This application provides novel anti-CD93 constructs that specifically bind to CD93 (e.g., anti-CD93 monoclonal antibodies or multispecific antibodies), methods for preparing anti-CD93 constructs, and methods for using the constructs (e.g., methods for treating diseases or conditions).

Anti-CD93 antibodies (e.g., anti-CD93 antibodies that block the interaction between CD93 and IGFBP7) can effectively treat tumors or cancers by blocking abnormal tumor angiogenesis, normalizing immature and leaky tumor blood vessels, promoting functional vascular networks in tumors, promoting vascular maturation, promoting a favorable tumor microenvironment, increasing immune cell infiltration in tumors, increasing tumor perfusion, reducing tumor proliferation, sensitizing tumors to second therapies, and/or facilitating the delivery of second agents. See, for example, WO2021062128A1, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the anti-CD93 constructs described herein reduce tumor size. In some embodiments, the anti-CD93 constructs described herein promote immune cell infiltration in tumors. In some embodiments, the anti-CD93 constructs described herein promote vascular maturation in tumors. In some embodiments, the anti-CD93 constructs described herein sensitize tumors to second therapies or facilitate the delivery of second agents.

I. Definition

The term "antibody" is used in its broadest sense and covers a wide range of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, and their antigen-binding fragments, provided they exhibit the desired antigen-binding activity. The term "antibody moiety" refers to a full-length antibody or its antigen-binding fragment.

Full-length antibodies consist of two heavy chains and two light chains. Variable regions of the light and heavy chains are responsible for antigen binding. These variable domains can be referred to as “ _VH ” and “ _VL ”, respectively. The variable regions in both chains typically contain three highly variable loops called complementarity-determining regions (CDRs) (light chain (LC) CDRs, including LC-CDR1, LC-CDR2, and LC-CDR3; heavy chain (HC) CDRs, including HC-CDR1, HC-CDR2, and HC-CDR3). The CDR boundaries of the antibody and antigen-binding fragments disclosed herein can be defined or identified according to the conventions of Kabat, Chothia, or Al-Lazikani (Al-Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991). The three core-residue junctions (CDRs) of either the heavy or light chain lie between flanking segments called framework regions (FRs). Framework regions are more conserved than CDRs and form a scaffold to support the hypervariable loop. The constant regions of the heavy and light chains do not participate in antigen binding but exhibit various effector functions. Antibodies are classified according to the amino acid sequence of their heavy chain constant regions. The five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, characterized by the presence of α, δ, ε, γ, and μ heavy chains, respectively. Several major antibody classes are further subdivided into subclasses, such as lgG1 (γ1 heavy chain), lgG2 (γ2 heavy chain), lgG3 (γ3 heavy chain), lgG4 (γ4 heavy chain), lgA1 (α1 heavy chain), or lgA2 (α2 heavy chain).

As used herein, the term "antigen-binding fragment" refers to an antibody fragment, including, for example, bispecific antibodies, Fab, Fab', F(ab')2, Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized bispecific antibodies (ds diabody), single-chain Fv (scFv), scFv dimers (bivalent bispecific antibodies), multispecific antibodies formed from a portion of an antibody containing one or more CDRs, camelidoid single-domain antibodies, nanobodies, domain antibodies, bivalent domain antibodies, or any other antibody fragment that binds to an antigen but does not contain the complete antibody structure. An antigen-binding fragment is capable of binding to the same antigen bound by a parent antibody or a parent antibody fragment (e.g., a parental scFv). In some embodiments, the antigen-binding fragment may contain one or more CDRs from a specific human antibody grafted into a frame region from one or more different human antibodies.

The “Fv” is the smallest antibody fragment containing a complete antigen recognition and binding site. This fragment consists of a dimer of a tightly, non-covalently bound heavy chain and a light chain variable region domain. Six hypervariable rings (three from the heavy chain and three from the light chain) are generated from the folding of these two domains, providing amino acid residues for antigen binding and conferring antibody antigen-binding specificity. However, even a single variable domain (or half of an Fv containing only the three antigen-specific CDRs) can recognize and bind antigens, although its affinity is generally lower than that of the entire binding site.

A "single-chain Fv," also abbreviated as "sFv" or "scFv," is an antibody fragment containing _VH and _VL antibody domains linked together to form a single polypeptide chain. In some embodiments, the scFv polypeptide also includes a polypeptide linker between the _VH and _VL domains, which allows the scFv to form the desired structure for antigen binding. For a review of scFv, see Plückthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

As used herein, the term “CDR” or “complementarity-determining region” refers to a discontinuous antigen-binding site found within the variable region of heavy and light chain polypeptides. These specific regions are described in Kabat et al., J. Biol. Chem. 252:6609-6616 (1977); Kabat et al., U.S. Dept. of Health and Human Services, “Sequences of proteins of immunological interest” (1991); Chothia et al., J. Mol. Biol. 196:901-917 (1987); Al-Lazikani B. et al., J. Mol. Biol. 273:927-94. 8 (1997); MacCallum et al., J. Mol. Biol. 262:732-745 (1996); Abhinandan and Martin, Mol. Immunol., 45:3832-3839 (2008); Lefranc M.P. et al., Dev. Comp. Immunol., 27:55-77 (2003); and Honegger and Plückthun, J. Mol. Biol., 309:657-670 (2001), where the definitions include overlap or subsets of amino acid residues when compared with each other. However, the application of any definition to refer to an antibody or transplanted antibody or its variants is intended to be within the scope of the terminology defined and used herein. The amino acid residues covering the CDRs defined in each of the references cited above are listed in Table 1 below for comparison. CDR prediction algorithms and interfaces are known in the art, including, for example, Abhinandan and Martin, Mol. Immunol., 45:3832-3839 (2008); Ehrenmann F. et al., Nucleic Acids Res., 38:D301-D307 (2010); and Adolf-Bryfogle J. et al., Nucleic Acids Res., 43:D432-D438 (2015). The contents of the references cited in this paragraph are incorporated herein by reference in their entirety for use in this application and may be included in one or more of the claims herein. In some embodiments, the CDR sequences provided herein are based on the IMGT definition. For example, CDR sequences can be determined using the VBASE2 tool (http://www.vbase2.org/vbase2.php, see also Retter I, Althaus HH, Münch R, Müller W: VBASE2, an integrative V gene database. NucleicAcids Res. 2005 Jan 1; 33 (Database issue): D671-4, which is incorporated herein by reference in its entirety).

Table 1: CDR Definition

^1. Residue numbering follows the nomenclature of Kabat et al. mentioned above.

^2. Residue numbering follows the nomenclature of Chothia et al. mentioned above.

^The residue numbering follows the nomenclature of MacCallum et al. mentioned above.

^4. Residue numbering follows the nomenclature of Lefranc et al. mentioned above.

The ^residue numbering follows the nomenclature of Honegger and Plückthun mentioned above.

The expressions “as in Kabat variable domain residue numbering” or “as in Kabat amino acid position numbering” and their variations refer to the numbering system used for the heavy chain or light chain variable domains in the antibody compilations by Kabat et al. mentioned above. Using this numbering system, the actual linear amino acid sequence can contain fewer or more amino acids, corresponding to the shortening or insertion of the FR or hypervariable region (HVR) of the variable domain. For example, the heavy chain variable domain may include a single amino acid insertion after residue 52 of H2 (according to residue 52a in Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c in Kabat). The Kabat number of a given antibody residue can be determined by comparing the homologous region of the antibody sequence with a “standard” Kabat numbered sequence.

Unless otherwise stated herein, the residue numbers in the immunoglobulin heavy chain are the same as the EU index numbers used by Kabat et al. above. "EU index as used by Kabat" refers to the residue numbers of human IgG1 EU antibodies.

“Frame” or “FR” residues are those variable domain residues other than the CDR residues defined in this paper.

The “humanized” form of non-human (e.g., rodent) antibodies is a chimeric antibody, which contains a minimal sequence derived from the non-human antibody. In most cases, humanized antibodies are human immunoglobulins (receptor antibodies), where residues from the hypervariable region (HVR) of the receptor are replaced by hypervariable region residues from a non-human species (donor antibody) (e.g., mouse, rat, rabbit, or non-human primate) with the desired antibody specificity, affinity, and ability. In some cases, frame region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may contain residues not found in the receptor or donor antibody. These modifications are made to further refine antibody performance. Generally, humanized antibodies will contain substantially at least one variable domain, typically both of the two variable domains, where all or substantially all of the hypervariable loops correspond to the hypervariable loops of the non-human immunoglobulin, and all or substantially all of the FRs are FRs of the human immunoglobulin sequence. Humanized antibodies will optionally also contain at least a portion of the immunoglobulin constant region (Fc), typically the constant region of the human immunoglobulin. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992).

"Human antibody" is an antibody having an amino acid sequence corresponding to that of human-produced antibodies and/or prepared using any of the techniques disclosed herein for preparing human antibodies. This definition of human antibody specifically excludes humanized antibodies containing non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Methods also used for preparing human monoclonal antibodies are described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5:368-74 (2001). Human antibodies can be prepared by administering antigens to transgenic animals that have been modified to produce such antibodies in response to antigen challenge, but whose endogenous loci have been disabled, such as immunized xenogeneic mice (see, for example, U.S. Patent Nos. 6,075,181 and 6,150,584 concerning XENOMOUSE ^™ technology). See also, for example, Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006) concerning human antibodies produced via human B-cell hybridoma technology.

The "percentage (%) amino acid sequence identity" or "homology" of the peptide and antibody sequences identified herein is defined as the percentage of amino acid residues in the candidate sequence that are identical to amino acid residues in the compared peptide, after sequence alignment, taking into account any conserved substitutions as part of sequence identity. For example, alignments for determining the percentage of amino acid sequence identity can be performed in various ways within the scope of the art using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), or MUSCLE software. Those skilled in the art can determine appropriate parameters for measuring alignments, including any algorithms required to achieve maximum alignment across the full length of the compared sequences. However, for the purposes of this document, the % amino acid sequence identity value is generated using the sequence comparison computer program MUSCLE (Edgar, R.C., Nucleic Acids Research 32(5):1792-1797, 2004; Edgar, R.C., BMC Bioinformatics 5(1):113, 2004).

"Homology" refers to the sequence similarity or identity between two polypeptides or two nucleic acid molecules. The molecules are homologous at that position when positions in two compared sequences are occupied by the same base or amino acid monomer subunit—for example, if each position in two protein molecules is occupied by a lysine, or if each position in two DNA molecules is occupied by an adenine. The percentage of homology between two sequences is a function of the number of shared matching or homologous positions divided by the number of compared positions and multiplied by 100. For example, if six out of ten positions in two sequences are matched or homologous, the two sequences have 60% homology. For instance, the protein sequences SGTSTD (SEQ ID NO:421) and TGTSDA (SEQ ID NO:422) have 50% homology. Typically, comparisons are performed when the two sequences are aligned to provide maximum homology.

The term "constant domain" refers to a portion of an immunoglobulin molecule that has a more conserved amino acid sequence relative to the other parts of the immunoglobulin containing the antigen-binding site (variable domains). Constant domains comprise the heavy chain _CH1 , _CH2 , and _CH3 domains (collectively referred to as _CH ) and the light chain CHL (or _CL ) domain.

The "light chain" of antibodies (immunoglobulins) in any mammalian species can be assigned to one of two distinct types, called "κ" and "λ," based on the amino acid sequence of their constant domains.

The “CH1 domain” (also known as the “C1” of the “H1” domain) typically extends from about amino acid 118 to about amino acid 215 (EU numbering system).

The "hinge region" is generally defined as the region in IgG corresponding to Glu216 to Pro230 of human IgG1 (Burton, Molec. Immunol. 22:161-206 (1985)). The hinge regions of other IgG isotypes can be aligned with the IgG1 sequence by placing the first and last cysteine residues that form the S-S bond between heavy chains in the same position.

The "CH2 domain" (also known as the "C2" domain) of the human IgG Fc region typically extends from about amino acid 231 to about amino acid 340. The unique feature of the CH2 domain is that it does not pair tightly with another domain. Instead, two N-linked branched carbohydrate chains are inserted between the two CH2 domains of the intact native IgG molecule. It is speculated that the carbohydrates provide an alternative to the domain-domain pairing and contribute to the stability of the CH2 domain. (Burton, Molec Immunol. 22:161-206 (1985)).

The “CH3 domain” (also known as the “C2 domain”) contains the extension of the Fc region from the C-terminus of the residues to the CH2 domain (i.e. from about amino acid residue 341 to the C-terminus of the antibody sequence, usually located at amino acid residues 446 or 447 of IgG).

The term "Fc region" or "fragment crystallizable region" used herein is used to define the C-terminal region of the immunoglobulin heavy chain, including the native sequence Fc region and variant Fc regions. Although the boundaries of the Fc region of the immunoglobulin heavy chain may vary, the human IgG heavy chain Fc region is generally defined as extending from the amino acid residue at Cys226 or from Pro230 to its carboxyl terminus. For example, during antibody production or purification, or by recombinant modification of the nucleic acid encoding the antibody heavy chain, the C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed. Therefore, compositions of complete antibodies may comprise antibody groups with all K447 residues removed, antibody groups with K447 residues not removed, and antibody groups containing a mixture of antibodies with and without K447 residues. Native sequence Fc regions suitable for the antibodies described herein include human IgG1, IgG2 (IgG2A, IgG2B), IgG3, and IgG4.

The term "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. Preferred FcRs are naturally occurring human FcRs. Furthermore, preferred FcRs are those that bind to IgG antibodies (γ receptors) and include subclasses of FcγRI, FcγRII, FcRN, and FcγRIII, including allelic variants and alternative splice forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibiting receptor"), which have similar amino acid sequences, differing primarily in their cytoplasmic domains. The activating receptor FcγRIIA contains an activation motif (ITAM) based on the immunoreceptor tyrosine residue in its cytoplasmic domain. The inhibiting receptor FcγRIIB contains an inhibitory motif (ITIM) based on the immunoreceptor tyrosine residue in its cytoplasmic domain. (See M. Annu. Rev. Immunol. 15:203-234 (1997)). FcRNs are essential for antibody circulation into the bloodstream and can prolong the serum half-life of antibodies. Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995) have reviewed FcR. Other FcRs, including those to be identified in the future, are included in the term "FcR" in this paper.

As used herein, the term "epitope" refers to a specific atom or amino acid group on an antigen that an antibody or antibody moiety binds to. If two antibodies or antibody moiety exhibit competitive binding to an antigen, they can bind to the same epitope within the antigen.

As used herein, in the presence of an equimolar concentration of a first antibody or a fragment thereof, when the first antibody or a fragment thereof inhibits the binding of a second antibody or a fragment thereof to the target antigen by at least about 50% (e.g., at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%), the first antibody or a fragment thereof “competes” with the second antibody or a fragment thereof to bind to the target antigen, and vice versa. A high-throughput process for “binding” antibodies based on their cross-competition is described in PCT Publication No. WO 03/48731.

As used herein, the terms “specific binding,” “specific recognition,” and “specific to” refer to measurable and reproducible interactions, such as the binding between a target and an antibody or antibody moiety, which determines the presence of the target in the presence of a heterogeneous group of molecules, including biomolecules. For example, an antibody or antibody moiety that specifically recognizes a target (which may be an epitope) is an antibody or antibody moiety that binds to the target with higher affinity, stronger affinity, easier binding, and/or longer duration compared to binding to other targets. In some embodiments, such as as measured by radioimmunoassay (RIA), the degree of antibody binding to an unrelated target is less than about 10% of the antibody binding to the target. In some embodiments, the antibody that specifically binds to the target has a dissociation constant (K_D) of ≤10 ^{^-5 M} , ≤10^{^-6} M, ≤10^-7 M, ≤10^{^-8 M} , ≤10^{^-9} M, ≤10^-10 M, ≤10^{^-11} M, or ≤10^{^-12} _M. In some embodiments, the antibody specifically binds to an epitope on a conserved protein from different species. In some embodiments, specific binding may include, but is not required to be, exclusive binding. The binding specificity of the antibody or antigen-binding domain can be determined experimentally using methods known in the art. Such methods include, but are not limited to, Western blotting, ELISA, BLI, RIA, ECL, IRMA, EIA, BIACORE™ assays, and peptide scanning.

As used herein, when molecule A (e.g., the anti-CD93 construct described herein) “blocks” the binding of molecule B (e.g., CD93) and molecule C (e.g., IGFBP7 or MMRN2), it refers to both direct and indirect blocking. For example, instead of directly blocking the binding of CD93 to IGFBP7 or MMRN2 by occupying at least a portion of the binding sites on CD93 responsible for IGFBP7 or MMRN2 binding, the anti-CD93 construct described herein can block the binding of CD93 to IGFBP7 or MMRN2 by altering the structure of CD93, thus preventing CD93 from binding to IGFBP7/MMRN2.

"Isolated" or "purified" antibodies (or constructs) are antibodies that have been identified, isolated, and/or recovered from components in their production environment (e.g., natural or recombinant). Preferably, the isolated peptide does not bind to any other components in its production environment.

An "isolated" nucleic acid molecule encoding the constructs, antibodies, or antigen-binding fragments thereof described herein is a nucleic acid molecule identified and isolated from at least one contaminated nucleic acid molecule that normally binds to it in the environment in which it is produced. Preferably, the isolated nucleic acid does not bind to any components associated with the production environment. The isolated nucleic acid molecules encoding the polypeptides and antibodies described herein are in a form different from their form or environment found in nature. Therefore, the isolated nucleic acid molecules are different from nucleic acids encoding the polypeptides and antibodies described herein that are naturally present in cells. Isolated nucleic acids include nucleic acid molecules that are normally contained in cells containing nucleic acid molecules, but which are present outside chromosomes or at chromosomal locations different from their natural chromosomal locations.

The term "control sequence" refers to the DNA sequence necessary for the expression of an operable coding sequence in a specific host organism. Control sequences applicable to prokaryotes include, for example, promoters, optional operon sequences, and ribosome binding sites. Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.

When a nucleic acid is placed in a functional relationship with another nucleic acid sequence, it is "operably ligated." For example, if the DNA of a pre-sequence or secretory leader sequence is expressed as a pre-protein involved in polypeptide secretion, the DNA of the pre-sequence or secretory leader sequence is operably ligated to the DNA of the polypeptide; if a promoter or enhancer affects the transcription of a sequence, the promoter or enhancer is operably ligated to the coding sequence; or if a ribosome binding site is located to facilitate translation, the ribosome binding site is operably ligated to the coding sequence. Generally, "operably ligated" means that the ligated DNA sequences are contiguous, and in the case of a secretory leader sequence, they are contiguous and contiguous within the reading frame. However, enhancers do not need to be contiguous. Ligation is accomplished by connecting to a convenient restriction site. If such a site is not available, synthetic oligonucleotide aptamers or adapters are used as a standard practice.

As used herein, the term "vector" refers to a nucleic acid molecule capable of replicating another nucleic acid linked to it. This term includes vectors as self-replicating nucleic acid structures as well as vectors integrated into the genome of a host cell that has been introduced therein. Some vectors are capable of directing the expression of nucleic acids operatively linked to them. Such vectors are referred to herein as "expression vectors."

As used herein, the terms “transfected,” “transformed,” or “transduced” refer to the process of transferring or introducing exogenous nucleic acids into host cells. “Transfected,” “transformed,” or “transduced” cells are cells that have been transfected, transformed, or transduced with exogenous nucleic acids. Cells include primary test cells and their progeny.

The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably to refer to cells in which exogenous nucleic acids have been introduced, including the progeny of such cells. Host cells include “transformers” and “transformed cells,” which include primary transformed cells and their derived progeny, regardless of passage number. The nucleic acid content of progeny cells may not be exactly the same as that of the parent cells, and they may contain mutations. This article includes mutant progeny cells with the same function or biological activity as those screened or selected in the initially transformed cells.

The term "immunoconjugate" includes references to the covalent linking of a therapeutic agent or detectable marker to an antibody (such as the antibody portion described herein). The linking can be direct or indirect, via a linker (such as a peptide linker).

As used herein, “treatment/treating” is a method of obtaining a beneficial or desired outcome (including clinical outcomes). For the purposes of this application, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: relief of one or more symptoms caused by the disease, reduction of the severity of the disease, stabilization of the disease (e.g., prevention or delay of disease progression), prevention or delay of disease spread (e.g., metastasis), prevention or delay of disease recurrence, delay or slowing of disease progression, improvement of disease status, provision of remission (partial or complete) of the disease, reduction of the dosage of one or more other medications required to treat the disease, delay of disease progression, increase or improvement of quality of life, weight gain, and/or prolongation of survival. “Treatment” also includes reduction of the pathological consequences of cancer (e.g., tumor volume). The methods of this application consider any one or more of these treatment aspects.

In the case of cancer, the term "treatment" includes any or all of the following: inhibiting the growth of cancer cells, inhibiting the replication of cancer cells, reducing the overall tumor burden, and improving one or more symptoms associated with the disease.

The term "inhibition" or "inhibit" refers to a reduction or cessation of any phenotypic trait, or a reduction or cessation of the occurrence, extent, or likelihood of that trait. "Reduction" or "inhibition" means a reduction, decrease, or prevention of activity, function, and/or quantity compared to a reference. In some embodiments, "reduction" or "inhibit" means the ability to result in an overall reduction of 20% or more. In another embodiment, "reduction" or "inhibit" means the ability to result in an overall reduction of 50% or more. In yet another embodiment, "reduction" or "inhibit" means the ability to result in an overall reduction of 75%, 85%, 90%, 95%, or more.

As used herein, “reference” means any sample, standard, or level used for comparative purposes. A reference may be obtained from healthy and/or disease-free samples. In some instances, a reference may be obtained from untreated samples. In some instances, a reference is obtained from a disease-free or untreated sample of an individual. In some instances, a reference is obtained from one or more healthy individuals who are not that individual or patient.

As used herein, “delaying disease progression” means slowing, hindering, mitigating, blocking, stabilizing, inhibiting, and/or delaying the development of a disease (e.g., cancer). Such delay can have varying durations, depending on the individual’s medical history and/or treatment received. As will be apparent to those skilled in the art, sufficient or significant delay can indeed include prevention, i.e., the individual does not develop the disease. For example, the development of advanced cancer, such as metastasis, can be delayed.

As used in this article, “prevention” includes providing prevention of the onset or recurrence of the disease in individuals who may be susceptible to the disease but have not yet been diagnosed with it.

As used herein, "inhibitory" function or activity refers to a reduction in function or activity when compared to the same conditions other than the target condition or parameter, or optionally, compared to another condition. For example, an antibody that inhibits tumor growth reduces the tumor growth rate compared to the tumor growth rate in the absence of the antibody.

The terms “subject,” “individual,” and “patient” are used interchangeably herein and refer to mammals, including but not limited to humans, cattle, horses, felines, canines, rodents, or primates. In some implementations, the individual is a human.

The “effective dose” of a drug refers to the amount that effectively achieves the desired therapeutic or preventative outcome within the necessary dosage and time period. The specific dosage may vary depending on one or more of the following: the particular drug selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to be imaged, and the physical delivery system carrying the drug.

The "therapeutic effective amount" of the substance/molecule, agonist, or antagonist of this application may vary depending on factors such as an individual's disease state, age, sex, and weight, as well as the ability of the substance/molecule, agonist, or antagonist to elicit the desired response in the individual. Therapeutic effective amount is also the amount by which any toxic or harmful effects of the substance/molecule, agonist, or antagonist are offset by the beneficial therapeutic effect. Therapeutic effective amounts may be delivered in one or more administrations.

"Prophylactic effective dose" refers to the amount that effectively achieves the desired preventive outcome within the necessary dosage and time period. It is usually, but not always, less necessary because the preventive dose is administered to the subject before or in the early stages of the disease; therefore, the preventive effective dose will be less than the therapeutic effective dose.

The terms "pharmaceutical formulation" and "pharmaceutical composition" refer to a formulation whose form allows for the effective biological activity of the active ingredient and which does not contain any additional ingredients that would have unacceptable toxicity to the individual to whom the formulation is administered. Such formulations may be sterile.

"Pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, formulation adjuvant, or carrier conventionally used in the art for use with therapeutic agents, which together constitute a "pharmaceutical composition" for individual administration. A pharmaceutically acceptable carrier is non-toxic to the recipient at the dosage and concentration used and is compatible with other components of the formulation. A pharmaceutically acceptable carrier is suitable for the formulation in which it is used.

"Sterile" preparations are sterile or substantially free of live microorganisms and their spores.

Administering in combination with one or more other therapeutic agents includes simultaneous (synchronous) and sequential or sequential administration in any order.

The term “synchronization” is used herein to refer to the administration of two or more therapeutic agents, wherein at least part of the administration overlaps in time, or the administration of one therapeutic agent falls within a short period of time relative to the administration of another therapeutic agent. For example, the time interval between the administration of two or more therapeutic agents does not exceed about 60 minutes, such as not exceeding any one of about 30, 15, 10, 5, or 1 minute.

The term “in sequence” is used in this document to refer to the administration of two or more therapeutic agents, wherein the administration of one or more agents continues after the administration of one or more other agents has been discontinued. For example, two or more therapeutic agents are administered at intervals of more than about 15 minutes, such as about 20, 30, 40, 50 or 60 minutes, 1 day, 2 days, 3 days, 1 week, 2 weeks or 1 month or longer.

As used in this article, “combination” means applying a treatment in addition to another treatment. Therefore, “combination” means applying a treatment before, during, or after applying another treatment to an individual.

The term "packaging insert" is used to refer to the instruction leaflet typically included in the commercial packaging of a therapeutic product, which contains information about the indications, usage, dosage, administration, combination therapy, contraindications, and/or warnings for using such a therapeutic product.

"Article" is any manufactured article (e.g., packaging or container) or kit that contains at least one pharmaceutical agent (e.g., a medicine for treating a disease or condition (e.g., cancer)) or a probe for specifically detecting the biomarkers described herein. In some embodiments, the manufactured article or kit is promoted, distributed, or sold as a unit for performing the methods described herein.

It should be understood that the embodiments of this application described herein include embodiments that are “composed of” and/or “substantially composed of”.

In this document, the reference to "about" a value or parameter includes (and describes) the variation with respect to that value or parameter itself. For example, a description involving "about X" includes a description of "X".

As used in this article, mentioning "not" a value or parameter usually means and describes a value "other than" that value or parameter. For example, "This method is not used to treat type X cancer" means that this method is used to treat types of cancer other than type X.

The term “about X-Y” used in this article has the same meaning as “about X to about Y”.

As used herein and in the appended claims, the singular forms “a/an” and “the” include plural references unless the context clearly specifies otherwise.

II. Anti-CD93 construct

This application provides an anti-CD93 construct comprising an anti-CD93 antibody portion that specifically binds to CD93 as described herein.

In some embodiments, the anti-CD93 construct comprises an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for the binding epitope of CD93, wherein VH _-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:1, HC-CDR2 containing the amino acid sequence of SEQ ID NO:2, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:3, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:4, LC-CDR2 containing the amino acid sequence of SEQ ID NO:5, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:6.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:1, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:2, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:3, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:4, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:5, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:6, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:7, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:8, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:9, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:10, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:11, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:12, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the above-described amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:1, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:2, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:3, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:4, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:5, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:6.

In some embodiments, the antibody portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:13, and LC-CDR1, LC-CDR2, and LC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:14.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:13 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:14 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the anti-CD93 construct comprises an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for the binding epitope of CD93, wherein VH _-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:17, HC-CDR2 containing the amino acid sequence of SEQ ID NO:18, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:19, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:20, LC-CDR2 containing the amino acid sequence of SEQ ID NO:21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:22.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:17, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:18, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:20, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:23, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:24, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:25, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:26, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:27, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:28, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the above-described amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:17, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:18, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:20, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22.

In some embodiments, the antibody portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which respectively comprise the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:29 and 307-312, and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively comprise the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:30 and 313-318.

In some embodiments, V _H comprises: an amino acid sequence of any one of SEQ ID NO:29 and 307-312 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: an amino acid sequence of any one of SEQ ID NO:30 and 313-318 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the anti-CD93 construct comprises an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for the binding epitope of CD93, wherein VH _-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:33, HC-CDR2 containing the amino acid sequence of SEQ ID NO:34, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:35, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:36, LC-CDR2 containing the amino acid sequence of SEQ ID NO:37, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:38.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:33, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:34, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:35, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:36, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:37, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:38, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:39, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:40, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:41, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:42, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:43, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:44, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the above-described amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:33, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:34, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:35, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:36, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:37, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:38.

In some embodiments, the antibody portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:45, and LC-CDR1, LC-CDR2, and LC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:46.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:45 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:46 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the anti-CD93 construct comprises an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for the binding epitope of CD93, wherein VH _-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:49, HC-CDR2 containing the amino acid sequence of SEQ ID NO:50, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:51, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:52, LC-CDR2 containing the amino acid sequence of SEQ ID NO:53, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:54.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:49, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:51, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:52, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:53, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:54, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:55, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:56, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:57, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:58, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:59, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:60, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the above-described amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:49, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:51, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:52, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:53, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:54.

In some embodiments, the antibody portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:61, and LC-CDR1, LC-CDR2, and LC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:62.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:61 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:62 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the anti-CD93 construct comprises an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for the binding epitope of CD93, wherein VH _-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:65, HC-CDR2 containing the amino acid sequence of SEQ ID NO:66, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:67, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:68, LC-CDR2 containing the amino acid sequence of SEQ ID NO:69, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:70.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:65, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:66, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:67, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:68, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:69, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:70, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:71, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:72, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:73, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:74, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:75, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:76, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the above-described amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:65, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:66, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:67, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:68, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:69, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:70.

In some embodiments, the antibody portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:77, and LC-CDR1, LC-CDR2, and LC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:78.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:77 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:78 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the anti-CD93 construct comprises an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for the binding epitope of CD93, wherein VH _-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:81, HC-CDR2 containing the amino acid sequence of SEQ ID NO:82, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:83, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:84, LC-CDR2 containing the amino acid sequence of SEQ ID NO:85, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:86.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:81, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:82, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:83, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:84, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:85, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:86, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:87, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:88, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:89, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:90, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:91, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:92, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the above-described amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:81, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:82, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:83, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:84, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:85, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:86.

In some embodiments, the antibody portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:93, and LC-CDR1, LC-CDR2, and LC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:94.

In some embodiments, V _H comprises the amino acid sequence of SEQ ID NO:93, or a variant thereof comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises the amino acid sequence of SEQ ID NO:94, or a variant thereof comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the anti-CD93 construct comprises an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for the binding epitope of CD93, wherein VH _-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:97, HC-CDR2 containing the amino acid sequence of SEQ ID NO:98, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:99, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:100, LC-CDR2 containing the amino acid sequence of SEQ ID NO:101, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:102.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:97, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:98, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:99, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:100, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:101, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:102, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 103, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 104, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 105, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 106, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 107, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 108, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the above-described amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:97, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:98, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:99, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:100, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:101, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:102.

In some embodiments, the antibody portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:109, and LC-CDR1, LC-CDR2, and LC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:110.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:109 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:110 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the anti-CD93 construct comprises an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for the binding epitope of CD93, wherein VH _-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:113, HC-CDR2 containing the amino acid sequence of SEQ ID NO:114, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:115, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:116, LC-CDR2 containing the amino acid sequence of SEQ ID NO:117, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:118.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:113, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:114, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:115, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:116, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:117, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:118, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 119, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 120, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 121, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 122, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 123, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 124, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the above-described amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:113, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:114, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:115, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:116, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:117, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:118.

In some embodiments, the antibody portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:125, and LC-CDR1, LC-CDR2, and LC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:126.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:125 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:126 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the anti-CD93 construct comprises an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for the binding epitope of CD93, wherein VH _-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:129, HC-CDR2 containing the amino acid sequence of SEQ ID NO:130, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:131, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:132, LC-CDR2 containing the amino acid sequence of SEQ ID NO:133, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:134.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:129, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:130, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:131, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:132, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:133, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:134, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 135, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 136, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 137, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 138, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 139, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 140, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the above-described amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:129, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:130, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:131, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:132, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:133, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:134.

In some embodiments, the antibody portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:141, and LC-CDR1, LC-CDR2, and LC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:142.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:141 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:142 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the anti-CD93 construct comprises an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for the binding epitope of CD93, wherein _VH-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:145, HC-CDR2 containing the amino acid sequence of SEQ ID NO:146, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:147, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:148, 355, or 358, LC-CDR2 containing the amino acid sequence of SEQ ID NO:149 or 356, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:150, 357, or 359.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:145, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:146, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:147, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:148, 355, or 358, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:149 or 356, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:150, 357, or 359, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:151, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:152, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:153, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:154, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:155, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:156, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the above-described amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:145, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:146, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:147, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:148, 355, or 358, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:149 or 356, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:150, 357, or 359.

In some embodiments, the antibody portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which respectively comprise the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:157 and 360-362, and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively comprise the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:158 and 363-365.

In some embodiments, V _H comprises: an amino acid sequence of any one of SEQ ID NO:157 and 360-362 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: an amino acid sequence of any one of SEQ ID NO:158 and 363-365 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:157 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:158 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:360 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:363 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:360 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:364 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:360 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:365 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:361 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:363 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:361 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:364 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:361 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:365 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:362 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:363 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:362 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:364 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:362 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:365 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the anti-CD93 construct comprises an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for the binding epitope of CD93, wherein VH _-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:161, HC-CDR2 containing the amino acid sequence of SEQ ID NO:162, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:163, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:164, LC-CDR2 containing the amino acid sequence of SEQ ID NO:165, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:166.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:161, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:162, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:163, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:164, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:165, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:166, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:167, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:168, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:169, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:170, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:171, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:172, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the above-described amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:161, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:162, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:163, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:164, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:165, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:166.

In some embodiments, the antibody portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:173, and LC-CDR1, LC-CDR2, and LC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:174.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:173 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:174 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the anti-CD93 construct comprises an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for the binding epitope of CD93, wherein VH _-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:177, HC-CDR2 containing the amino acid sequence of SEQ ID NO:178, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:179, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:180 or 353, LC-CDR2 containing the amino acid sequence of SEQ ID NO:181 or 354, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:182.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:177, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:178, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:179, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:180 or 353, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:181 or 354, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:182, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:177, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:178, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:179, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:180, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:181, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:182. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:183, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:184, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:185, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:186, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:187, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:188, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the above-described amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:177, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:178, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:179, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:180 or 353, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:181 or 354, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:182.

In some embodiments, the antibody portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:189 and 347-349, and LC-CDR1, LC-CDR2, and LC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:190 and 350-352.

In some embodiments, V _H comprises the amino acid sequence of any one of SEQ ID NO:189 and 347-349, or a variant of an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises the amino acid sequence of any one of SEQ ID NO:190 and 350-352, or a variant of an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:189 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:190 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:347 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:350 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:347 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:351 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: an amino acid sequence of any one of SEQ ID NO:347 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: an amino acid sequence of any one of SEQ ID NO:352 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:348 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:350 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:348 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:351 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:348 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:352 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:349 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:350 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises the amino acid sequence of SEQ ID NO:349, or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:351, or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:349 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:352 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the anti-CD93 construct comprises an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for the binding epitope of CD93, wherein VH _-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:193, HC-CDR2 containing the amino acid sequence of SEQ ID NO:194, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:195, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:196, LC-CDR2 containing the amino acid sequence of SEQ ID NO:197, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:198.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:193, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:194, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:195, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:196, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:197, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:198, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:199, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:200, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:201, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:202, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:203, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:204, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the above-described amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:193, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:194, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:195, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:196, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:197, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:198.

In some embodiments, the antibody portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:205, and LC-CDR1, LC-CDR2, and LC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:206.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:205 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:206 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the anti-CD93 construct comprises an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for the binding epitope of CD93, wherein VH _-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:209, HC-CDR2 containing the amino acid sequence of SEQ ID NO:210, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:211, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:212, LC-CDR2 containing the amino acid sequence of SEQ ID NO:213, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:214.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:209, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:210, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:211, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:212, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:213, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:214, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:215, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:216, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:217, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:218, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:219, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:220, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the above-described amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:209, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:210, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:211, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:212, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:213, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:214.

In some embodiments, the antibody portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:221, and LC-CDR1, LC-CDR2, and LC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:222.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:221 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:222 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the anti-CD93 construct comprises an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for the binding epitope of CD93, wherein VH _-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:289, HC-CDR2 containing the amino acid sequence of SEQ ID NO:290, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:291, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:292, LC-CDR2 containing the amino acid sequence of SEQ ID NO:293, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:294.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:289, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:290, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:291, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:292, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:293, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:294, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:295, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:296, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:297, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:298, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:299, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:300, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the above-described amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:289, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:290, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:291, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:292, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:293, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:294.

In some embodiments, the antibody portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which respectively comprise the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:287 and 319-321, and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively comprise the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:288 and 322-324.

In some embodiments, V _H comprises: an amino acid sequence of any one of SEQ ID NO:287 and 319-321 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: an amino acid sequence of any one of SEQ ID NO:288 and 322-324 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the antibody portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which respectively comprise the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:287 and 319-321, and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively comprise the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:288 and 322-324.

In some embodiments, V _H comprises: an amino acid sequence of any one of SEQ ID NO:319-321 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: an amino acid sequence of any one of SEQ ID NO:322-324 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:319 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:322 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:319 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:323 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:319 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:324 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:320 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:322 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:320 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:323 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:320 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:324 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:321 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:322 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:321 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:323 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:321 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:324 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the anti-CD93 construct comprises an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for the binding epitope of CD93, wherein _VH-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:17 or 304, HC-CDR2 containing the amino acid sequence of SEQ ID NO:18 or 305, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:19, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:20, 301, 302, 303, or 306, LC-CDR2 containing the amino acid sequence of SEQ ID NO:21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:22.

In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17 or 304, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18 or 305, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, 301, 302, 303, or 306, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the above-described amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, anti-CD93 V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:17, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:18, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, and anti-CD93 V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:20, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22.

In some embodiments, anti-CD93 V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:17, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:18, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, and anti-CD93 V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:301, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22.

In some embodiments, anti-CD93 V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:17, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:18, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, and anti-CD93 V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:302, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22.

In some embodiments, anti-CD93 V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:17, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:18, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, and anti-CD93 V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:303, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22.

In some embodiments, anti-CD93 V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:17, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:18, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, and anti-CD93 V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:306, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22.

In some embodiments, anti-CD93 V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:304, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:305, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, and anti-CD93 V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:20, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22.

In some embodiments, anti-CD93 V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:304, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:305, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, and anti-CD93 V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:301, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22.

In some embodiments, anti-CD93 V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:304, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:305, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, and anti-CD93 V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:302, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22.

In some embodiments, anti-CD93 V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:304, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:305, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, and anti-CD93 V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:303, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22.

In some embodiments, anti-CD93 V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:304, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:305, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, and anti-CD93 V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:306, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22.

In some embodiments, the antibody portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which respectively comprise the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:29 and 307-312, and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively comprise the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:30 and 313-318.

In some embodiments, V _H comprises the amino acid sequence of any one of SEQ ID NO:307-312, or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises the amino acid sequence of any one of SEQ ID NO:313-318, or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:307 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:313 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:307 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:314 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:307 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:315 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:307 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:316 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:307 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:317 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:307 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:318 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:308 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:313 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:308 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:314 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:308 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:315 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:308 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:316 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:308 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:317 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:308 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:318 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:309 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:313 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:309 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:314 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:309 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:315 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:309 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:316 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:309 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:317 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:309 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:318 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:310 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:313 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:310 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:314 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:310 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:315 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:310 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:316 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, VH comprises: the amino acid sequence of SEQ ID NO:310 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and _VL comprises: the amino acid sequence of SEQ ID NO:317 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:310 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:318 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:311 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:313 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:311 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:314 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:311 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:315 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:311 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:316 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:311 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:317 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:311 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:318 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:312 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:313 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:312 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:314 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:312 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:315 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:312 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:316 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:312 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:317 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:312 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:318 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the antibody portion comprises a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:33, ii) HC-CDR2 comprising the amino acid sequence _{RIFPGDGDX1X2YX3GKFKG} (SEQ ID NO: ₂₃₃ ), wherein X1X2 is AN _or TD, and/or _X3 is N or D, and iii) HC-CDR3 comprising the amino acid sequence TGAAYX1FDPFPY (SEQ ID NO:234), wherein _X1 is D or E; and VL comprises: i) LC-CDR1 comprising the amino acid sequence _{SSX1KSLLHSX2GX3TYLY} (SEQ ID NO:235), wherein X1 is S or T, X2 is N or S, and/or _X3 is V or I, ii) comprising SEQ ID NO:33, wherein _X1 is S or T, X2 is N or _S , and/or X3 is V or I, and iii) HC-CDR2 comprising the amino acid sequence _{RIFPGDGDX1X2YX3GKFKG} (SEQ ID NO:233), wherein X1 is AN or TD, and/or _X3 is N or I, and iii) HC-CDR2 comprising the amino acid sequence _{RIFPGDGDX1X2YX3GKFKG} (SEQ ID NO:233), wherein X1 is AN or TD, and/or X3 is N or I, and iii) HC- _CDR2 comprising the amino acid sequence RIFPGDGDX1X2YX3GKFKG (SEQ ID NO:233), wherein _X1 is AN or TD, and/or _X3 is N or I, and iv ... LC-CDR2 containing the amino acid sequence of SEQ ID NO:37, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:38.

In some embodiments, the antibody portion comprises a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) an HC-CDR1 comprising the amino acid sequence _{X1 YWX2} N (SEQ ID NO:236), wherein _X1 is S or T, and/or _X2 is L or M; ii) an HC-CDR2 comprising the amino acid sequence _{RIX1 PGDGDX2 X3 YX4} GKFKG (SEQ ID NO:237), wherein _X1 is Y or F, _{X2 X3} is TD or AN, and/or _X4 is N or D; and iii) an HC-CDR3 comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:35, ₁₆₃ , and 179; and _VL comprises: i) an LC-CDR1 comprising the amino acid sequence _{X1 X2 X3} KSLLHSX4 _GX5 TYLY (SEQ ID NO:238 ₎ , wherein _{... X3} is SSS, SST, or RFS, _X4 is N or S, and/or _X5 = V or I, ii) LC-CDR2 comprising the amino acid sequence _X1 MSNLAS (SEQ ID NO: 239), wherein _X1 is R or Q, and iii) LC-CDR3 comprising the amino acid sequence _{AQX1 LEX2 PX3} T (SEQ ID NO: 240), wherein _X1 is M or N, _X2 is R or L, and/or _X3 is F or W. In some embodiments, LC-CDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 38, 166, and 182.

In some embodiments, the antibody portion comprises a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC- _CDR1 comprising the amino acid sequence _X1YVX2H (SEQ ID NO:241), wherein _X1 is A or S, and/or _X2 is M or I; ii) HC-CDR2 comprising the amino acid sequence _{YIX1PYX2DX3TX4YNEKFKG} (SEQ ID NO: ₂₄₂ ), wherein _X1 is _F or _N , _X2 is N or S, _X3 is G or Y, and/or _X4 is E or Q; and iii) HC- _CDR3 comprising the amino acid sequence _{RX1DGNPYX2MDY} (SEQ ID NO:243), wherein _X1 is T or A, and/or _X2 is T or A; and _VL comprises: i) comprising KASQDVSTAVX1 (SEQ ID NO: ₂₄₁ ). LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 244, wherein _X1 is A or V; ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 117; and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 118. In some embodiments, LC-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 115 or 221.

In some embodiments, the antibody portion comprises a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:1, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:2, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:3, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions; and wherein _VL comprises: i) LC-CDR1 comprising the amino acid sequence KASQX1 _VX2 TX3 _VX4 (SEQ ID NO:245), wherein X1 is N or D, X2 is G or S, X3 is N or _A, and/or _X4 is A or V, ii) LC-CDR2 comprising the amino acid sequence SASYRX1 X2 (SEQ ID NO:246), wherein a _{) X1} is F or Y, X2 is I or T, or b _{) X1} is F or Y, _X2 is I or T, or X1 is F or Y, X2 is I or T, or X1 is F or Y, _X2 is I or T, or X1 is F or Y, X2 is _I or T, or X1 is F or Y, _X2 is I or T, _X1 is F or Y, X2 is I or T, X1 is I or Y, _X2 is I or T, X2 is I or Y _{... X2} is FI or YT, and iii) is an LC-CDR3 comprising the amino acid sequence _{QQX1X2X3X4PX5T} ( _{SEQ ID} NO: ₂₄₇ ), wherein _X1X2X3X4 is YNRN _or HYST, and/or _X5 is _I or _F. In some embodiments, LC-CDR3 comprises the amino acid sequence shown in SEQ ID NO:6 _, 118, or 214. In some embodiments, LC-CDR3 comprises the amino acid sequence shown in SEQ ID NO:6.

In some embodiments, the antibody portion comprises a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:113, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:114, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:115, or variants thereof comprising up to 5, 4, ₃ , 2, or 1 amino acid substitutions; and wherein _VL comprises: i) LC-CDR1 comprising the amino acid sequence KASQX1 _{VX2 TX3 VX4} (SEQ ID NO:245 ₎ , wherein _X1 is N or D, _X2 is G or S, _X3 is N or A, and/or _X4 is A or V, ii) LC-CDR2 comprising the amino acid sequence SASYRX1 _X2 (SEQ ID NO:246), wherein a) _X1 is F or Y, X ₂ is I or T, or b) X ₁ X ₂ is FI or YT, and iii) LC-CDR3 comprising the amino acid sequence QQX ₁ X ₂ X ₃ X ₄ PX ₅ T (SEQ ID NO: 247), wherein X ₁ X ₂ X ₃ X ₄ is YNRN or HYST, and/or X ₅ is I or F. In some embodiments, LC-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 6, 118, or 214. In some embodiments, LC-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 118.

In some embodiments, the antibody portion comprises a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:209, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:210, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:211, or variants thereof comprising up to 5, 4, ₃ , 2, or 1 amino acid substitutions; and wherein _VL comprises: i) LC-CDR1 comprising the amino acid sequence KASQX1 _{VX2 TX3 VX4} (SEQ ID NO:245 ₎ , wherein _X1 is N or D, _X2 is G or S, _X3 is N or A, and/or _X4 is A or V, ii) LC-CDR2 comprising the amino acid sequence SASYRX1 _X2 (SEQ ID NO:246), wherein a) _X1 is F or Y, X ₂ is I or T, or b) X ₁ X ₂ is FI or YT, and iii) LC-CDR3 comprising the amino acid sequence QQX ₁ X ₂ X ₃ X ₄ PX ₅ T (SEQ ID NO: 247), wherein X ₁ X ₂ X ₃ X ₄ is YNRN or HYST, and/or X ₅ is I or F. In some embodiments, LC-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 6, 118, or 214. In some embodiments, LC-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 214.

In some embodiments, the antibody portion comprises a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:17, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:18, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions; and wherein _VL comprises: i) LC-CDR1 comprising the amino acid sequence _X1 ASQSVX2 _X3 X4 X5 _X6 SYMX7 (SEQ ID NO:248), wherein _{X1 is K or R, X2 X3 X4 X5 X6 is DYAGD or STSSY, and/or X7 is N or H, ii) LC-CDR2 comprising the amino acid sequence X1 ASNLES (SEQ ID NO:249), wherein X1 is K or R , X2 X3 X4 X5 X6} is DYAGD or STSSY, and/or _X7 is N or H, and ... ₁ is A or Y, and iii) is an LC-CDR3 comprising the amino acid sequence _{QX1 X2 X3 X4 X5 PX6} T (SEQ ID NO:250), wherein _{X1 X2 X3 X4 X5} is QTNED or HSWEI, and/or _X6 is R or F. In some embodiments, LC-CDR3 comprises the amino acid sequence shown in SEQ ID NO:22 or 54. In some embodiments, LC-CDR3 comprises the amino acid sequence shown in SEQ ID NO:22.

In some embodiments, the antibody portion comprises a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:49, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:51, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions; and wherein _VL comprises: i) LC-CDR1 comprising the amino acid sequence _X1 ASQSVX2 _X3 X4 X5 _X6 SYMX7 (SEQ ID NO:248), wherein _{X1 is K or R, X2 X3 X4 X5 X6 is DYAGD or STSSY, and/or X7 is N or H, ii) LC-CDR2 comprising the amino acid sequence X1 ASNLES (SEQ ID NO:249), wherein X1 is K or R , X2 X3 X4 X5 X6} is DYAGD or STSSY, and/or _X7 is N or H, and ... ₁ is A or Y, and iii) is an LC-CDR3 comprising the amino acid sequence _{QX1 X2 X3 X4 X5 PX6} T (SEQ ID NO: 250), wherein _{X1 X2 X3 X4 X5} is QTNED or HSWEI, and/or _X6 is R or F. In some embodiments, LC-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 22 or 54. In some embodiments, LC-CDR3 comprises the amino acid sequence shown in SEQ ID NO: 54.

In some implementations, the construct comprises or is selected from the group consisting of an antibody or an antigen-binding fragment thereof: full-length antibody, bispecific antibody, single-chain Fv (scFv) fragment, Fab fragment, Fab' fragment, F(ab')2, Fv fragment, disulfide-stabilized Fv fragment (dsFv), (dsFv)2, _VHH , Fv-Fc fusion, scFv-Fc fusion, scFv-Fv fusion, bisomatic antibody, trisomatic antibody, and tetrasomatic antibody.

In some implementations, the anti-CD93 antibody is a full-length antibody.

In some implementations, the anti-CD93 antibody portion is scFv.

In some embodiments, the anti-CD93 antibody portion comprises an Fc fragment of an immunoglobulin selected from the group consisting of IgG, IgA, IgD, IgE, IgM, and combinations thereof and hybrids thereof. In some embodiments, the anti-CD93 antibody portion or full-length antibody comprises an Fc fragment of an immunoglobulin selected from the group consisting of IgG1, IgG2, IgG3, IgG4, and combinations thereof and hybrids thereof. In some embodiments, the Fc fragment has reduced effector function compared to the corresponding wild-type Fc fragment. In some embodiments, the Fc fragment has enhanced effector function compared to the corresponding wild-type Fc fragment. In some embodiments, the Fc fragment has been modified to increase the serum half-life compared to the corresponding wild-type Fc fragment. In some embodiments, the Fc fragment has been modified to shorten the serum half-life compared to the corresponding wild-type Fc fragment.

In some implementations, the antibody portion comprises a humanized antibody of any of the antibody portions described herein.

In some implementations, the anti-CD93 construct contains or is an anti-CD93 fusion protein.

In some implementations, the anti-CD93 construct comprises or is a multispecific anti-CD93 construct (e.g., a bispecific antibody).

In some implementations, the anti-CD93 construct comprises or is an anti-CD93 immunoconjugate.

In some embodiments, the anti-CD93 construct blocks the binding of CD93 and IGFBP7. In some embodiments, the IGFBP7 is human IGFBP7. In some embodiments, after pre-incubation of the anti-CD93 antibody with CD93 or CD93-expressing cells, the binding of CD93 to IGFBP7 is blocked by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more. In some embodiments, the dose ratio of the anti-CD93 antibody to CD93 is about 1:10, 1:6, 1:3, 1:1.5, 1:1, 4:3, 2:1, or 5:1. In some embodiments, after pre-incubating the anti-CD93 antibody at concentrations of approximately 50 μg/ml, 25 μg/ml, 10 μg/ml, 5 μg/ml, 2 μg/ml, 1 μg/ml, 0.8 μg/ml, 0.6 μg/ml, or 0.4 μg/ml, the binding of CD93 to IGFBP7 is blocked by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more.

In some embodiments, the anti-CD93 construct blocks the binding of CD93 and MMRN2. In some embodiments, MMRN2 is human MMRN2. In some embodiments, MMRN2 is the MMRN2 ^495-674 fragment. In some embodiments, after pre-incubation of the anti-CD93 antibody with CD93 or CD93-expressing cells, the binding of CD93 to MMRN2 is blocked by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more. In some embodiments, the anti-CD93 construct does not block the binding of CD93 and MMRN2.

In some implementations, the anti-CD93 construct blocks the binding of CD93 to IGFBP7 and MMRN2.

In some embodiments, the anti-CD93 construct does not block the interaction between CD93 and IGFBP7. In some embodiments, the anti-CD93 construct does not block the interaction between CD93 and MMRN2. In some embodiments, the anti-CD93 construct does not block the interaction between IGFBP7 or MMRN2.

In some implementations, CD93 is human CD93.

a) Antibody affinity

The binding specificity of the antibody moiety can be determined experimentally using methods known in the art. Such methods include, but are not limited to, Western blotting, ELISA, RIA, ECL, IRMA, EIA, BLI, BIACORE ^™ assays, flow cytometry, and peptide scanning.

In some embodiments, the _KD between the antibody moiety and CD93 is about ^10⁻⁷ M to about ^10⁻¹² M, about ^10⁻⁷ M to about ^10⁻⁸ M, about ^10⁻⁸ M to about ^10⁻⁹ M, about 10⁻⁹ M to about ^10⁻¹⁰ M, about ^10⁻¹⁰ M to about ^10⁻¹¹ M, about ^10⁻¹¹ M to about ^10⁻¹² M, about ^10⁻⁷ M to about ^10⁻¹² M, about ^10⁻⁸ M to about ^10⁻¹² M, about ^10⁻⁹ M to about ^10⁻¹² M, about ^10⁻¹⁰ M to about ^10⁻¹² M, about ^10⁻⁷ M to about ^10⁻¹¹ M, about ^10⁻⁹ M to about ^{10⁻¹¹ M} , about ^10⁻⁷ M to about ^10⁻¹⁰ M, about ^10⁻⁸ M to about ^10⁻¹⁰ M ^{, or about 10⁻⁷ M to about 10⁻⁹} M. In some embodiments, the _KD binding strength between the antibody moiety and CD93 is stronger than any one of about ^10⁻⁷ M, ^10⁻⁸ M, ^10⁻⁹ M, ^10⁻¹⁰ M, ^10⁻¹¹ M, or ^10⁻¹² M. In some embodiments, CD93 is human CD93.

In some embodiments, the _Kon of the antibody moiety binding to CD93 is about ^{103 M⁻¹ s⁻¹} to about ^{108 M⁻¹ s⁻¹} , about ¹⁰³ M⁻¹ ^s⁻¹ to about 104 M⁻¹ ^s⁻¹ , about ^{104 M⁻¹ s⁻¹} to about ^{105 M⁻¹ s⁻¹} , about ^{105 M⁻¹ s⁻¹} to about ^{106 M⁻¹ s⁻¹} , about ^{106 M⁻¹ s⁻¹} to about ^{107 M⁻¹ s⁻¹} , or about ^{107 M⁻¹ s⁻¹ to about 108 M⁻¹ s⁻¹ .} In some implementations, the _Kon of the antibody moiety binding to CD93 is about ^{103 M⁻¹ s⁻¹} to about ^10⁵ M⁻¹ ^s⁻¹ , about ^{10⁴ M⁻¹ s⁻¹} to about 10⁶ ^{M⁻¹ s⁻¹} , about ^{10⁵ M⁻¹ s⁻¹} to about ^{10⁷ M⁻¹ s⁻¹} , about ^10⁶ M⁻¹ ^s⁻¹ to about ^{10⁸ M⁻¹ s⁻¹} , about ^{10⁴ M⁻¹ s⁻¹} to about ^{10⁷ M⁻¹ s⁻¹ ,} or ^{about 10⁵ M⁻¹ s⁻¹ to} about ^{10⁸ M⁻¹ s⁻¹} . In some embodiments, the K _{_on} between the antibody moiety and CD93 does not exceed any one of about 10 ^³ M ^{^-1} s^{^-1} , ¹⁰ ^⁵ M ^{^-1}s^-1, 10 ^⁶ M ^{^-1}s^-1, 10 ^⁷M^-1s^{^-1} , or 10^⁸ M ^{^-1} s ^{^-1} . In some embodiments, CD93 is human CD93.

In some implementations, the _Koff for binding between the antibody moiety and CD93 is about 1 ^s⁻¹ to about ^{10⁻⁶ s⁻¹} , about 1 ^s⁻¹ to about ^{10⁻² s⁻¹} , about ^10⁻² s⁻¹ to about ^{10⁻³ s⁻¹} , about ^{10⁻³ s⁻¹} to about ^{10⁻⁴ s⁻¹} , about ^{10⁻⁴ s⁻¹} to about ^{10⁻⁵ s⁻¹} , about ^{10⁻⁵ s⁻¹} to about ^{10⁻⁶ s⁻¹} , about ^{1 s⁻¹} to about ^{10⁻⁵ s⁻¹} , about ^{10⁻² s⁻¹} to about ^{10⁻⁶ s⁻¹} , about ^{10⁻⁴ s⁻¹} to about ^{10⁻⁶ s⁻¹} , about ^{10⁻² s⁻¹ to} about ^{10⁻⁵ s⁻¹} , or ^{about 10⁻³ s⁻¹ to} about ^{10⁻⁵ s⁻¹ .} In some embodiments, the _Koff for binding between the antibody moiety and CD93 is at least any one of about 1 ^s⁻¹ , ^{10⁻² s⁻¹} , ^{10⁻³ s⁻¹} , ^{10⁻⁴ s⁻¹} , ^{10⁻⁵ s⁻¹} , or ^{10⁻⁶ s⁻¹} . In some embodiments, CD93 is human CD93.

In some implementations, the binding affinity of the anti-CD93 antibody portion or the anti-CD93 construct is higher than (e.g., having a smaller _KD value) than that of existing anti-CD93 antibodies (e.g., anti-human CD93 antibodies, such as MM01).

b) Chimeric or humanized antibodies

In some embodiments, the anti-CD93 antibody portion is a chimeric antibody. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984). In some embodiments, the chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse) and a human constant region. In some embodiments, the chimeric antibody is a "class-switching" antibody, wherein the class or subclass has been changed from that of the parent antibody. A chimeric antibody includes its antigen-binding fragment.

In some embodiments, the anti-CD93 antibody is a humanized antibody. Typically, non-human antibodies are humanized to reduce immunogenicity in humans while retaining the specificity and affinity of the parent non-human antibody. Typically, humanized antibodies contain one or more variable domains, where the HVR, such as CDR, (or a portion thereof) is derived from the non-human antibody, and the FR (or a portion thereof) is derived from the human antibody sequence. Optionally, the humanized antibody will also contain at least a portion of the human constant region. In some embodiments, some FR residues in the humanized antibody are substituted with corresponding residues from the non-human antibody (e.g., an antibody from which the HVR residues are derived), for example, to restore or enhance antibody specificity or affinity.

Humanized antibodies and their manufacturing methods have been reviewed, for example, in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and further described, for example, in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat’l Acad. Sci. USA 86:10029-10033 (1989); US patents 5,821,337, 7,527,791, 6,982,321 and 7,087,409; Kashmir i et al., Methods 36:25-34 (2005) (describes SDR(a-CDR) transplantation); Padlan, Mol. Immunol. 28:489-498 (1991) (describes “repairing surfaces”); Dall’Acqua et al., Methods 36:43-60 (2005) (describes “FR shuffling”); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describes the “guided selection” approach to FR shuffling).

Human frame regions that can be used for humanization include, but are not limited to: frame regions selected using a “best fit” method (see, for example, Sims et al., J. Immunol. 151:2296 (1993)); frame regions derived from the common sequences of human antibodies from specific subgroups of the light or heavy chain variable regions (see, for example, Carter et al., Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al., J. Immunol., 151:2623 (1993)). ); human mature (somatic mutation) framework region or human germline framework region (see, for example, Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and framework regions derived from screening FR libraries (see, for example, Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271:22611-22618 (1996)).

It should be understood that humanization of mouse-derived antibodies is a common and routinely used technique. Therefore, it should be understood that any and all humanized forms of anti-CD93 antibodies disclosed in the sequence listing may be used in preclinical or clinical settings. In the event that any reference anti-CD93 antibody or a humanized form of its antigen-binding region is used in such a preclinical or clinical setting, the humanized form at that time is expected to have the same or similar biological activity and characteristics as the original unhumanized form.

c) Human antibodies

In some embodiments, the anti-CD93 antibody portion is a human antibody (referred to as a human domain antibody or human DAb). Human antibodies can be generated using various techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001), Lonberg, Curr. Opin. Immunol. 20:450-459 (2008), and Chen, Mol. Immunol. 47(4):912-21 (2010). Transgenic mice or rats capable of generating fully human single-domain antibodies (or DAbs) are known in the art. See, for example, US20090307787A1, US Patent No. 8,754,287, US20150289489A1, US20100122358A1, and WO2004049794.

Human antibodies (e.g., human DAbs) can be prepared by administering immunogens to transgenic animals that have been modified to produce complete human antibodies or complete antibodies with human variable regions in response to antigen challenge. These animals typically contain all or part of the human immunoglobulin loci, which replace endogenous immunoglobulin loci, or are present extrachromosomally or randomly integrated into the animal's chromosome. In such transgenic mice, endogenous immunoglobulin loci are typically inactivated. For a review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, for example, U.S. Patent Nos. 6,075,181 and 6,150,584 describing the XENOMOUSE ^™ technology; U.S. Patent No. 5,770,429 describing the technology; U.S. Patent No. 7,041,870 describing the technology; and U.S. Patent Application Publication No. US2007/0061900 describing the technology. Human variable regions derived from complete antibodies produced by such animals can be further modified, for example, by combining them with different human constant regions.

Human antibodies (e.g., human DAb) can also be prepared using hybridoma-based methods. Human myeloma and mouse-human heterologous myeloma cell lines used for the production of human monoclonal antibodies have been described (see, e.g., Kozbor J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp.51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147:86 (1991)). Human antibodies produced via human B-cell hybridoma technology have also been described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Other methods include, for example, U.S. Patent No. 7,189,826 (describing the production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridoma). Human hybridoma technology (Trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).

Human antibodies (e.g., human DAbs) can also be generated by isolating variable domain sequences of Fv clones selected from human phage display libraries. Such variable domain sequences can then be combined with desired human constant domains. The technique for selecting human antibodies from antibody libraries is described below.

d) Antibodies derived from library

The anti-CD93 antibody described herein can be isolated by screening a combinatorial library of antibodies with the desired activity. For example, various methods in the art are known for generating phage display libraries and screening such libraries to obtain antibodies with the desired binding characteristics. Such methods are reviewed, for example, in Hoogenboom et al.'s Methods in Molecular Biology 178:1-37 (O’Brien et al., ed., Human Press, Totowa, NJ, 2001), and further described, for example, in McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352:624-628 (1991); Marks et al., J. Mol. Biol. 222:581-597 (1992); Marks and Bradbury, Methods in Mo Lecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2):299-310 (2004); Lee et al., J. Mol. Biol. 340(5):1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34):12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132 (2004). Methods for constructing single-domain antibody libraries have been described, for example, see U.S. Patent No. 7371849.

In some phage display methods, libraries of the _VH and _VL genes are cloned separately by polymerase chain reaction (PCR) and randomly recombined in a phage library, allowing for screening of antigen-binding phages, as described in Winter et al., Ann. Rev. Immunol., 12:433-455 (1994). Phages typically display antibody fragments, either as scFv fragments or as Fab fragments. Libraries derived from immunogenic sources provide high-affinity antibodies against immunogens without the need for hybridoma construction. Alternatively, original libraries (e.g., from humans) can be cloned to provide a single source of antibodies against a wide range of non-self and self antigens without any immunization, as described by Griffiths et al., EMBO J, 12:725-734 (1993). Finally, the original library encoding the highly variable CDR3 region can also be synthesized by cloning an unrearranged V gene fragment from stem cells and using PCR primers containing random sequences, and rearrangement can be performed in vitro, as described in Hoogenboom and Winter, J. Mol. Biol., 227:381-388 (1992). Patent publications describing human antibody phage libraries include, for example, U.S. Patent No. 5,750,373 and U.S. Patent Publications Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360.

Antibodies or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments in this paper.

e) Substitution, insertion, deletion, and variants

In some embodiments, antibody variants with one or more amino acid substitutions are provided. Mutagenic sites associated with the substitutions include HVR (or CDR) and FR. Conservative substitutions are shown under the “Preferred Substitutions” heading in Table 2. More substantial variations are provided under the “Exemplary Substitutions” heading in Table 2 and are further described below with reference to the amino acid side chain categories. Amino acid substitutions can be introduced into the relevant antibodies, and products can be screened for desired activities (e.g., retained/improved antigen binding, reduced immunogenicity, or improved ADCC or CDC).

Table 2 Amino Acid Substitution

initial residues Exemplary replacement Preferred replacement Ala(A) Val; Leu; Ile Val Arg(R) Lys；Gln；Asn Lys Asn(N) Gln; His; Asp, Lys; Arg Gln Asp(D) Glu;Asn Glu Cys(C) Ser；Ala Ser Gln(Q) Asn; Glu Asn Glu(E) Asp; Gln Asp Gly(G) Ala Ala His(H) Asn; Gln; Lys; Arg Arg Ile(I) Leu; Val; Met; Ala; Phe; Leucine Leu Leu(L) Leucine; Ile; Val; Met; Ala; Phe Ile Lys(K) Arg；Gln；Asn Arg Met(M) Leu; Phe; Ile Leu Phe(F) Trp; Leu; Val; Ile; Ala; Tyr Tyr Pro(P) Ala Ala Ser(S) Thr Thr Thr(T) Val; Ser Ser Trp(W) Tyr; Phe Tyr Tyr(Y) Trp; Phe; Thr; Ser Phe Val(V) Ile; Leu; Met; Phe; Ala; Leucine Leu

Amino acids can be grouped according to common side chain characteristics: (1) hydrophobic: leucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that affect chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe.

Non-conservative substitution would require replacing one type of member with another.

One type of substitution variant involves replacing one or more hypervariable residues of a parent antibody (e.g., a humanized antibody or a human antibody). Typically, the resulting variant selected for further research will have modifications (e.g., improvements) in certain biological properties (e.g., increased affinity, decreased immunogenicity) relative to the parent antibody, and/or will substantially retain some of the biological properties of the parent antibody. An exemplary substitution variant is an affinity-matured antibody, which can be conveniently generated, for example, using phage display-based affinity maturation techniques, such as those described herein. In short, one or more HVR residues are mutated to display the variant antibody on a phage and screen for specific biological activities (e.g., binding affinity).

Alterations (e.g., substitutions) can be made in the HVR to, for example, to improve antibody affinity. Such alterations can be made in HVR “hotspots” (i.e., residues encoded by codons that mutate at high frequencies during somatic maturation) and (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)) and/or SDR (a-CDR), testing the binding affinity of the resulting variant _VH or _VL . Affinity maturation by constructing secondary libraries and reselecting from them has been described, for example, Hoogenboom et al. Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some embodiments of affinity maturation, diversity is introduced into the variant gene selected for maturation via any of a variety of methods (e.g., error-prone PCR, strand shuffling, or oligonucleotide directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity or molecular behavior. Another approach to introducing diversity involves HVR-directed methods, where several HVR residues are randomized (e.g., 4-6 residues at a time). HVR residues involved in antigen binding can be specifically identified, for example, by mutagenesis or modeling using alanine or histidine scans. HC-CDR3 and LC-CDR3 are typically targeted in particular.

In some implementations, substitution, insertion, or deletion may occur within one or more HVRs, as long as such changes do not substantially reduce the antibody's ability to bind to the antigen. For example, conserved changes that do not substantially reduce binding affinity (e.g., conserved substitutions as described herein) may be made in the HVR outside of HVR "hotspots" or CDRs.

A useful method for identifying target residues or regions of an antibody that can be targeted for mutagenesis is known as “alanine scan mutagenesis,” as described by Cunningham and Wells (1989) Science, 244:1081-1085. In this method, a target residue or group of target residues (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) is identified and replaced with a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to determine whether the antibody-antigen interaction is affected. Further substitutions can be introduced at amino acid positions that show functional sensitivity to the initial substitution. Alternatively, or additionally, the crystal structure of the antigen-antibody complex can be used to identify contact points between the antibody and antigen. Such contact residues and adjacent residues can be targeted or eliminated as substitution candidates. Variants can be screened to determine whether they contain the desired properties of the antibody.

Amino acid sequence insertions include amino and/or carboxyl-terminal fusions of polypeptides ranging in length from one residue to one hundred or more residues, as well as intra-sequence insertions of single or multiple amino acid residues. Examples of terminal insertions include antibodies having an N-terminal methionine residue. Other insertion variants of antibody molecules include fusions of the N-terminus or C-terminus of the antibody with an enzyme (e.g., for ADEPT) or a polypeptide that increases the antibody's serum half-life.

f) Glycosylation variants

In some implementations, the anti-CD93 antibody moiety is modified to increase or decrease the degree of glycosylation of the construct. The addition or deletion of antibody glycosylation sites can be conveniently achieved by altering the amino acid sequence to create or remove one or more glycosylation sites.

In cases where the antibody moiety contains an Fc region, the carbohydrates linked to it can be modified. Natural antibodies produced by mammalian cells typically contain branched bitennary oligosaccharides, which are usually linked to Asn297 of the _CH2 domain of the Fc region via N-linking. See, for example, Wright et al., TIBTECH 15:26-32 (1997). Oligosaccharides can include various carbohydrates such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose linked to GlcNAc in the “stem” of the bitennary oligosaccharide structure. In some embodiments, the oligosaccharides in the antibody moiety can be modified to produce antibody variants with certain improved properties.

In some embodiments, the anti-CD93 antibody moiety has a carbohydrate structure lacking fucose linked (directly or indirectly) to the Fc region. For example, the amount of fucose in such antibodies can be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain of Asn297 relative to the sum of all sugar structures linked to Asn297 (e.g., complex, heterozygous, and high-mannose structures), as described, for example, in WO 2008/077546. Asn297 refers to the asparagine residue (EU number of Fc region residues) located at approximately position 297 in the Fc region; however, due to minor sequence variations in the antibody, Asn297 may also be located approximately ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300. Such fucoidylated variants may have improved ADCC function. See, for example, U.S. Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (KyowaHakko Kogyo Co., Ltd.). Examples of publications related to “defucosylated” or “fucosylated” antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US2004/ 0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; WO2005/053742; WO2002/0 31140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells with protein fucosylation defects (Ripka et al., Arch. Biochem. Biophys. 249:533-545 (1986); US Patent Application No. US 2003/0157108 A1, Presta, L; and WO2004/056312A1, Adams et al., especially in Example 11), and knockout cell lines, such as α-1,6-fucosylation gene, FUT8, knockout CHO cells (see, for example, Yamane-Ohnuki et al. Biotech. Bioeng. 87:614 (2004); Kanda, Y. et al. Biotechnol. Bioeng. 94(4):680-688 (2006); and WO2003/085107).

In some embodiments, the anti-CD93 antibody portion has a bimeric oligosaccharide, for example, wherein the biantennary oligosaccharide linked to the Fc region of the antibody is bimeric by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, for example, WO 2003/011878 (Jean-Mairet et al.); U.S. Patent No. 6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al.). Antibody variants having at least one galactose residue in the oligosaccharide linked to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).

g) Fc region variant

In some implementations, the anti-CD93 antibody portion includes an Fc fragment.

The terms “Fc region,” “Fc domain,” “Fc fragment,” or “Fc” refer to the C-terminal non-antigen-binding region of an immunoglobulin heavy chain, which comprises at least a portion of a constant region. This term includes both native and variant Fc regions. In some embodiments, the human IgG heavy chain Fc region extends from Cys226 to the C-terminus of the heavy chain. However, the C-terminal lysine residue (Lys447) of the Fc region may or may not be present without affecting the structure or stability of the Fc region. Unless otherwise specified herein, the amino acid residues in the IgG or Fc region are numbered according to the antibody’s EU numbering system, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

In some embodiments, the Fc fragment is derived from immunoglobulins selected from the group consisting of IgG, IgA, IgD, IgE, IgM, and combinations thereof and hybrids thereof. In some embodiments, the Fc fragment is derived from immunoglobulins selected from the group consisting of IgG1, IgG2, IgG3, IgG4, and combinations thereof and hybrids thereof.

In some implementations, the Fc fragment has reduced effector function (e.g., at least about 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, or 95% reduced effector function, as measured by antibody-dependent cytotoxicity (ADCC) levels) compared to the corresponding wild-type Fc fragment.

In some embodiments, the Fc fragment is an IgG1 Fc fragment. In some embodiments, the IgG1 Fc fragment contains an L234A mutation and/or an L235A mutation. In some embodiments, the Fc fragment is an IgG2 or IgG4 Fc fragment. In some embodiments, the Fc fragment is an IgG4 Fc fragment containing S228P, F234A, and/or L235A mutations. In some embodiments, the Fc fragment contains an N297A mutation. In some embodiments, the Fc fragment contains an N297G mutation.

In some embodiments, one or more amino acid modifications may be introduced into the Fc region of the antibody moiety to create an Fc region variant. The Fc region variant may contain a human Fc region sequence (e.g., human IgG1, IgG2, IgG3, or IgG4 Fc region) containing amino acid modifications (e.g., substitutions) at one or more amino acid positions.

In some implementations, the Fc fragment possesses some, but not all, effector functions, making it an ideal candidate for applications where the in vivo half-life of the antibody moiety is important, but certain effector functions (e.g., complement and ADCC) are not essential or detrimental. In vitro and/or in vivo cytotoxicity assays can be performed to confirm a reduction/depletion of CDC and/or ADCC activity. For example, an Fc receptor (FcR) binding assay can be performed to ensure that the antibody lacks FcγR binding (and therefore may lack ADCC activity), but retains FcRn binding capacity. The primary cells mediating ADCC, NK cells, express only FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 2 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays for assessing ADCC activity of target molecules are described in U.S. Patent Nos. 5,500,362 (see, for example, Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985)); 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assays can be used (see, for example, the ACTI ^™ non-radioactive cytotoxicity assay for flow cytometry (Cell Technology, Inc. Mountain View, CA; and the CytoTox non-radioactive cytotoxicity assay (Promega, Madison, WI)). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively, or additionally, the ADCC activity of the target molecule can be assessed in vivo, for example in animal models, such as those disclosed by Clynes et al., Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). A C1q binding assay can also be performed to confirm that the antibody cannot bind C1q and therefore lacks CDC activity. See, for example, WO 2006/029879 and WO C1q and C3c binding ELISA in 2005/100402. To assess complement activation, a CDC assay can be performed (see, e.g., Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and M.J. Glennie, Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance/half-life assays can also be performed using methods known in the art (see, e.g., Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006)).

Antibodies with reduced effector function include antibodies with one or more substituted residues 238, 265, 269, 270, 297, 327, and 329 in the Fc region (US Patent No. 6,737,056). Such Fc mutants include Fc mutants with substitutions at two or more positions of amino acid positions 265, 269, 270, 297, and 327, including the so-called “DANA” Fc mutant where residues 265 and 297 are substituted with alanine (US Patent No. 7,332,581). In some embodiments, the Fc fragment contains the N297A mutation. In some embodiments, the Fc fragment contains the N297G mutation.

Certain antibody variants that improve or reduce FcR binding are described. (See, for example, U.S. Patent No. 6,737,056; WO 2004/056312 and Shields et al., J. Biol. Chem. 9(2):6591-6604(2001)).

In some embodiments, the Fc fragment is an IgG1 Fc fragment. In some embodiments, the IgG1 Fc fragment contains an L234A mutation and/or an L235A mutation. In some embodiments, the IgG1 Fc fragment contains an L235A mutation and/or a G237A mutation. In some embodiments, the Fc fragment is an IgG2 or IgG4 Fc fragment. In some embodiments, the Fc fragment is an IgG4 Fc fragment containing S228P, F234A, and/or L235A mutations.

In some embodiments, the antibody portion comprises an Fc region with one or more amino acid substitutions that improve ADCC, such as substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbers of the residues).

In some implementations, alterations are made in the Fc region that result in altered (i.e., improved or reduced) Clq binding and/or complement-dependent cytotoxicity (CDC), for example, as described in U.S. Patent Nos. 6,194,551, WO 99/51642, and Idusogie et al. J. Immunol. 164:4178-4184 (2000).

In some embodiments, antibody variants containing a variant Fc region include one or more amino acid substitutions that alter the half-life and/or alter the binding to the neonatal Fc receptor (FcRn). Antibodies with increased half-life and improved binding to the neonatal Fc receptor (FcRn) are described in US2005/0014934A1 (Hinton et al.), where the neonatal Fc receptor is responsible for transferring maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)). Those antibodies contain an Fc region having one or more substitutions that alter the binding of the Fc region to the FcRn. Such Fc variants include those with substitutions at one or more Fc region residues (e.g., substitution at Fc region residue 434 (US Patent No. 7,371,826)).

For other examples of Fc region variants, see also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821; and WO 94/29351.

h) Cysteine-engineered antibody variants

In some embodiments, it may be necessary to generate cysteine-engineered antibody moieties, such as "thioMAb," in which one or more residues of the antibody are substituted with cysteine residues. In specific embodiments, the substituted residues are located at accessible sites on the antibody. By substituting those residues with cysteine, reactive thiol groups are thus located at accessible sites on the antibody and can be used to conjugate the antibody to other moieties, such as pharmaceutical or linker-pharmaceutical moieties, to produce immunoconjugates, as further described herein. In some embodiments, any one or more of the following residues may be substituted with cysteine: A118 (EU number) of the heavy chain; and S400 (EU number) of the Fc region of the heavy chain. Cysteine-engineered antibody moieties can be generated as described, for example, in U.S. Patent No. 7,521,541.

i) Antibody derivatives

In some embodiments, the antibody portion described herein may be further modified to include other non-protein portions known in the art and readily available. Suitable portions for antibody derivatization include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymers, polyamino acids (homopolymers or random copolymers) and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may be advantageous in manufacturing due to its stability in water. The polymer can have any molecular weight and can be branched or unbranched. The number of polymers attached to the antibody can vary, and if more than one polymer is attached, they can be the same or different molecules. Typically, the quantity and/or type of polymer used for derivatization can be determined based on considerations including, but not limited to, the specific properties or functions of the antibody to be improved, and whether the antibody derivative will be used for diagnostics under defined conditions.

In some embodiments, the antibody portion may be further modified to include one or more bioactive proteins, peptides, or fragments thereof. As used interchangeably herein, “bioactive” or “biologically active” means exhibiting biological activity in vivo to perform a specific function. For example, it can refer to binding to a specific biomolecule such as a protein, DNA, etc., and then promoting or inhibiting the activity of that biomolecule. In some embodiments, bioactive proteins or fragments thereof include proteins and peptides administered to patients as active pharmaceutical substances to prevent or treat diseases or conditions, proteins and peptides for diagnostic purposes, such as enzymes for diagnostic tests or in vitro assays, and proteins and peptides administered to patients to prevent diseases, such as vaccines.

Multispecific anti-CD93 construct

In some embodiments, the anti-CD93 construct comprises a multispecific (e.g., bispecific) anti-CD93 construct comprising an anti-CD93 antibody portion of any of the anti-CD93 antibody portions described herein, and a second binding portion (e.g., a second antibody portion) that specifically recognizes a second antigen.

In some implementations, the multispecific anti-CD93 molecule comprises an anti-CD93 antibody portion and a second portion (e.g., a second antibody portion) that specifically recognizes a second antigen.

In some implementations, the second antigen is an immune checkpoint molecule. In some implementations, the second antigen is PD-1 or PD-L1.

In some implementations, the second part is the extracellular domain (ECD) of PD-1 or PD-L1. In some implementations, the second part is a PD-L1 trap or PD-1 trap. See, for example, Nat Commun. 2018 Jun 8; 9(1):2237.

In some implementations, the second antigen is a tumor antigen.

In some embodiments, the second antigen is an angiogenic agent. In some embodiments, the angiogenic agent is a VEGF (e.g., human VEGF) antibody. In some embodiments, the angiogenic agent is a VEGF receptor. In some embodiments, the angiogenic agent is VEGFR1 (e.g., human VEGFR1). In some embodiments, the angiogenic agent is VEGFR2 (e.g., human VEGFR2).

In some embodiments, the second portion comprises the extracellular domain (ECD) of the VEGF receptor. In some embodiments, the second portion comprises the ECD of VEGFR1 and/or VEGFR2. In some embodiments, the second portion comprises a VEGF trap. See, for example, Proc Natl Acad Sci USA. 2002 Aug 20; 99(17):11393-8.

In some embodiments, the second antibody portion and the anti-CD93 antibody portion are fused to each other via a adapter (e.g., any adapter of any operable form permitted by the present invention to allow the binding portion to function properly). In some embodiments, the adapter is a GS adapter. In some embodiments, the adapter is selected from the group consisting of SEQ ID NO: 225-232 and 338.

In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising: a) an anti-CD93 antibody portion according to any of the anti-CD93 antibody portions described herein; and b) a second antibody portion (anti-PD-L1 antibody portion) that specifically recognizes PD-L1.

In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising a) a full-length anti-CD93 antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains comprises a heavy chain variable region (V_{_H} ) and each of the two light chains comprises a light chain variable region (V_{_L} ), and b) an anti-PD-L1 antibody moiety (e.g., any antibody moiety described herein) fused to at least one or both heavy chains of the full-length anti-CD93 antibody. In some embodiments, the anti-PD-L1 antibody moiety is fused to the N-terminus of the two heavy chains. In some embodiments, the anti-PD-L1 antibody moiety is fused to the C-terminus of the two heavy chains.

In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising a) an anti-PD-L1 antibody moiety comprising a full-length antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains comprises a heavy chain variable region (V_{_H} ) and each of the two light chains comprises a light chain variable region (V_{_L} ), and b) an anti-CD93 antibody moiety fused to at least one or both heavy chains of the anti-PD-L1 full-length antibody (e.g., any anti-CD93 antibody moiety described herein). In some embodiments, the anti-CD93 antibody moiety is fused to the N-terminus of the two heavy chains. In some embodiments, the anti-CD93 antibody moiety is fused to the C-terminus of the two heavy chains.

In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising a) a full-length anti-CD93 antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains comprises a heavy chain variable region (V_{_H} ) and each of the two light chains comprises a light chain variable region (V_{_L} ), and b) an anti-PD-L1 antibody moiety (e.g., any antibody moiety described herein) fused to at least one or both light chains of the full-length anti-CD93 antibody. In some embodiments, the anti-PD-L1 antibody moiety is fused to the N-terminus of the two light chains. In some embodiments, the anti-PD-L1 antibody moiety is fused to the C-terminus of the two light chains.

In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising a) an anti-PD-L1 antibody moiety comprising a full-length antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains comprises a heavy chain variable region (V_{_H} ) and each of the two light chains comprises a light chain variable region (V _{_L} ), and b) an anti-CD93 antibody moiety (e.g., any antibody moiety described herein) fused to at least one or both light chains of the anti-PD-L1 full-length antibody. In some embodiments, the anti-CD93 antibody moiety is fused to the N-terminus of the two light chains. In some embodiments, the anti-CD93 antibody moiety is fused to the C-terminus of the two light chains.

In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising: a) an anti-CD93 antibody portion according to any of the anti-CD93 antibody portions described herein; and b) a second antibody portion (anti-PD-1 antibody portion) that specifically recognizes PD-1.

In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising a) a full-length anti-CD93 antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains comprises a heavy chain variable region (V_{_H} ) and each of the two light chains comprises a light chain variable region (V_{_L} ), and b) an anti-PD-1 antibody moiety (e.g., any antibody moiety described herein) fused to one or both heavy chains of the full-length anti-CD93 antibody. In some embodiments, the anti-PD-1 antibody moiety is fused to the N-terminus of the two heavy chains. In some embodiments, the anti-PD-1 antibody moiety is fused to the C-terminus of the two heavy chains.

In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising a) an anti-PD-1 antibody moiety comprising a full-length antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains comprises a heavy chain variable region (V_{_H} ) and each of the two light chains comprises a light chain variable region (V_{_L} ), and b) an anti-CD93 antibody moiety fused to at least one or both heavy chains of the full-length anti-PD-1 antibody (e.g., any anti-CD93 antibody moiety described herein). In some embodiments, the anti-CD93 antibody moiety is fused to the N-terminus of the two heavy chains. In some embodiments, the anti-CD93 antibody moiety is fused to the C-terminus of the two heavy chains.

In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising a) a full-length anti-CD93 antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains comprises a heavy chain variable region (V_{_H} ) and each of the two light chains comprises a light chain variable region (V_{_L} ), and b) an anti-PD-1 antibody moiety (e.g., any antibody moiety described herein) fused to at least one or both light chains of the full-length anti-CD93 antibody. In some embodiments, the anti-PD-1 antibody moiety is fused to the N-terminus of the two light chains. In some embodiments, the anti-PD-1 antibody moiety is fused to the C-terminus of the two light chains.

In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising a) an anti-PD-1 antibody moiety comprising a full-length antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains comprises a heavy chain variable region (V_{_H} ) and each of the two light chains comprises a light chain variable region (V_{_L} ), and b) an anti-CD93 antibody moiety (e.g., any antibody moiety described herein) fused to at least one or both light chains of the full-length anti-PD-1 antibody. In some embodiments, the anti-CD93 antibody moiety is fused to the N-terminus of the two light chains. In some embodiments, the anti-CD93 antibody moiety is fused to the C-terminus of the two light chains.

In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising: a) an anti-CD93 antibody portion according to any of the anti-CD93 antibody portions described herein; and b) a second binding portion that specifically recognizes VEGF.

In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising a) a full-length anti-CD93 antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains comprises a heavy chain variable region (V_{_H} ) and each of the two light chains comprises a light chain variable region (V_{_L} ), and b) a second binding moiety that specifically recognizes VEGF, said VEGF being fused to at least one or both heavy chains of the full-length anti-CD93 antibody. In some embodiments, the second binding moiety is fused to the N-terminus of the two heavy chains. In some embodiments, the second binding moiety is fused to the C-terminus of the two heavy chains.

In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising a) an anti-VEGF antibody moiety comprising a full-length antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains comprises a heavy chain variable region (V_{_H} ) and each of the two light chains comprises a light chain variable region (V_{_L} ), and b) an anti-CD93 antibody moiety fused to at least one or both heavy chains of the full-length anti-VEGF antibody (e.g., any anti-CD93 antibody moiety described herein). In some embodiments, the anti-CD93 antibody moiety is fused to the N-terminus of the two heavy chains. In some embodiments, the anti-CD93 antibody moiety is fused to the C-terminus of the two heavy chains.

In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising a) a full-length anti-CD93 antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains comprises a heavy chain variable region (V_{_H} ) and each of the two light chains comprises a light chain variable region (V_{_L} ), and b) a second binding moiety that specifically recognizes VEGF, said VEGF being fused to at least one or both light chains of the full-length anti-CD93 antibody. In some embodiments, the second binding moiety is fused to the N-terminus of the two light chains. In some embodiments, the second binding moiety that specifically recognizes VEGF is fused to the C-terminus of the two light chains.

In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising a) an anti-VEGF antibody moiety comprising a full-length antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains comprises a heavy chain variable region (V_{_H} ) and each of the two light chains comprises a light chain variable region (V_{_L} ), and b) an anti-CD93 antibody moiety (e.g., any antibody moiety described herein) fused to at least one or both light chains of the full-length anti-VEGF antibody. In some embodiments, the anti-CD93 antibody moiety is fused to the N-terminus of the two light chains. In some embodiments, the anti-CD93 antibody moiety is fused to the C-terminus of the two light chains.

In some embodiments, an anti-CD93 construct is provided comprising a) a full-length antibody that specifically recognizes CD93 comprising two heavy chains and two light chains, wherein each of the two heavy chains comprises a heavy chain variable region (V_{_H}) containing the amino acid sequence HC-CDR1 of SEQ ID NO:289, the amino acid sequence HC-CDR2 of SEQ ID NO:290, and the amino acid sequence HC-CDR3 of SEQ ID NO:291, and wherein each of the two light chains comprises a light chain variable region (V_{_L} ) containing the amino acid sequence LC-CDR1 of SEQ ID NO:292, the amino acid sequence LC-CDR2 of SEQ ID NO:293, and the amino acid sequence LC-CDR3 of SEQ ID NO:294, and b) a VEGF-binding moiety comprising the amino acid sequence of SEQ ID NO:325, wherein the VEGF-binding moiety is fused to one or both heavy chains of the full-length antibody. In some embodiments, the VEGF-binding moiety is fused to the C-terminus of the two heavy chains of the full-length antibody. In some embodiments, the VEGF-binding portion is fused to the full-length antibody without a linker. In some embodiments, the VEGF-binding portion is fused to the full-length antibody via a linker. In some embodiments, the linker is a GS linker selected from the group consisting of SEQ ID NO:225-232 and 338. In some embodiments, the linker comprises the amino acid sequence of SEQ ID NO:338. In some embodiments, anti-CD93 V _H comprises the amino acid sequence of any one of SEQ ID NO:287 and 319-321 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises the amino acid sequence of any one of SEQ ID NO:288 and 322-324 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the full-length antibody has an IgG1 isotype (e.g., human IgG1 isotype). In some embodiments, the heavy chain comprises: the amino acid sequence of SEQ ID NO:342 or a variant comprising an amino acid sequence having at least about 80% (e.g., any one of at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the light chain comprises: the amino acid sequence of SEQ ID NO:343 or a variant comprising an amino acid sequence having at least about 80% (e.g., any one of at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, an anti-CD93 construct is provided comprising a heavy chain fusion polypeptide comprising: the amino acid sequence shown in SEQ ID NO:366 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a light chain comprising: the amino acid sequence shown in SEQ ID NO:367 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, anti-CD93 V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:1, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:2, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:3, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and anti-CD93 V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:4, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:5, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:6, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

In some embodiments, anti-CD93 V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:17 or 304, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:18 or 305, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, or variants thereof comprising up to 5, 4, 3, 2 or 1 amino acid substitutions in the HC-CDR, and anti-CD93 V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:20, 301, 302, 303 or 306, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22, or variants thereof comprising up to 5, 4, 3, 2 or 1 amino acid substitutions in the LC-CDR.

In some embodiments, anti-CD93 V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:289, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:290, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:291, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and anti-CD93 V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:292, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:293, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:294, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, anti-CD93 V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:295, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:296, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:297, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and anti-CD93 V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:298, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:299, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:300, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

In some embodiments, the amino acid substitutions described above are limited to the "exemplary substitutions" shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of this application.

Exemplary anti-PD-L1 antibody portion

Exemplary anti-PD-L1 antibody portions include, but are not limited to, those described in WO2019228514A1, WO2019227490A1, and WO2020019232A1.

In some embodiments, the anti-PD-L1 antibody portion (e.g., scFv) for a multispecific anti-CD93 construct comprises an antibody portion containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody portion competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region (VL _-2 ) for the binding epitope of PD-L1, wherein _VH-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:251, HC-CDR2 containing the amino acid sequence of SEQ ID NO:252, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:253, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:254, LC-CDR2 containing the amino acid sequence of SEQ ID NO:255, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:256.

In some embodiments, the anti-PD-L1 portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:281, 282, or 283; and LC-CDR1, LC-CDR2, and LC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:284, 285, or 286.

In some embodiments, the anti-PD-L1 antibody portion (e.g., scFv) for the multispecific anti-CD93 construct comprises a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein: a) _VH comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:251, HC-CDR2 containing the amino acid sequence of SEQ ID NO:252, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:253, or variants thereof containing up to about 5, 4, 3, 2, or 1 amino acid substitutions in total in HC-CDR; and b) _VL comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:254, LC-CDR2 containing the amino acid sequence of SEQ ID NO:255, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:256, or variants thereof containing up to about 5, 4, 3, 2, or 1 amino acid substitutions in total in LC-CDR.

In some embodiments, the amino acid substitutions described above are limited to the "exemplary substitutions" shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of this application.

In some embodiments, V _H comprises: an amino acid sequence of SEQ ID NO:281, 282 or 283 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity; and V _L comprises: an amino acid sequence of SEQ ID NO:284, 285 or 286 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99%) sequence identity. In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:281 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:284 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:282 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:285 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:283 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:286 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some implementations, the second antibody portion and the anti-CD93 antibody portion are fused together via a linker (e.g., any linker of any operable form that allows the binding portion to function properly, as described herein).

Exemplary anti-PD-1 antibody portion

Exemplary anti-PD-1 antibody portions include, but are not limited to, those described in WO2018133842 and WO2018133837.

In some embodiments, the anti-PD-1 antibody portion (e.g., scFv) for a multispecific anti-CD93 construct comprises an antibody portion containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody portion competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region (VL _-2 ) for the binding epitope of PD-1, wherein _VH-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:257, HC-CDR2 containing the amino acid sequence of SEQ ID NO:258, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:259, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:260, LC-CDR2 containing the amino acid sequence of SEQ ID NO:261, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:262.

In some embodiments, the anti-PD-1 portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:275; and LC-CDR1, LC-CDR2, and LC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:276.

In some embodiments, the anti-PD-1 antibody portion (e.g., scFv) for a multispecific anti-CD93 construct comprises a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein: a) _VH comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:257, HC-CDR2 containing the amino acid sequence of SEQ ID NO:258, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:259, or a variant thereof containing up to about 5, 4, 3, 2, or 1 amino acid substitutions in total in the HC-CDR; and b) _VL comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:260, LC-CDR2 containing the amino acid sequence of any one of SEQ ID NO:261, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:262, or a variant thereof containing up to about 5, 4, 3, 2, or 1 amino acid substitutions in total in the LC-CDR. In some embodiments, the above-mentioned amino acid substitutions are limited to the “exemplary substitutions” shown in Table 2 of this application. In some embodiments, the amino acid substitution is limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the second antibody portion comprises a humanized antibody portion derived from a mouse antibody, said mouse antibody comprising a heavy chain variable region ( _VH ) containing the amino acid sequence shown in SEQ ID NO:275 and a light chain variable region ( _VL ) containing the amino acid sequence shown in SEQ ID NO:276.

In some embodiments, the anti-PD-1 antibody portion (e.g., scFv) for a multispecific anti-CD93 construct comprises an antibody portion containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody portion competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region (VL _-2 ) for the binding epitope of PD-1, wherein _VH-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:263, HC-CDR2 containing the amino acid sequence of SEQ ID NO:264, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:265, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:266, LC-CDR2 containing the amino acid sequence of SEQ ID NO:267, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:268.

In some embodiments, the anti-PD-1 portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:277; and LC-CDR1, LC-CDR2, and LC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:278.

In some embodiments, the anti-PD-1 antibody portion (e.g., scFv) for a multispecific anti-CD93 construct comprises a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein: a) _VH comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:263, HC-CDR2 containing the amino acid sequence of SEQ ID NO:264, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:265, or a variant thereof containing up to about 5, 4, 3, 2, or 1 amino acid substitutions in total in the HC-CDR; and b) _VL comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:266, LC-CDR2 containing the amino acid sequence of any one of SEQ ID NO:267, and LC-CDR3 containing the amino acid sequence of any one of SEQ ID NO:268, or a variant thereof containing up to about 5, 4, 3, 2, or 1 amino acid substitutions in total in the LC-CDR. In some embodiments, the above-mentioned amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of this application. In some embodiments, the amino acid substitution is limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the anti-PD-1 antibody portion comprises a humanized antibody portion derived from a mouse antibody, said mouse antibody comprising a heavy chain variable region ( _VH ) containing the amino acid sequence shown in SEQ ID NO:277 and a light chain variable region ( _VL ) containing the amino acid sequence shown in SEQ ID NO:278.

In some embodiments, the anti-PD-1 antibody portion (e.g., scFv) for a multispecific anti-CD93 construct comprises an antibody portion containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody portion competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region (VL _-2 ) for the binding epitope of PD-1, wherein _VH-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:269, HC-CDR2 containing the amino acid sequence of SEQ ID NO:270, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:271, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:272, LC-CDR2 containing the amino acid sequence of SEQ ID NO:273, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:274.

In some embodiments, the anti-PD-1 portion comprises HC-CDR1, HC-CDR2, and HC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:279; and LC-CDR1, LC-CDR2, and LC-CDR3, which are respectively contained in the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:280.

In some embodiments, the anti-PD-1 antibody portion (e.g., scFv) for a multispecific anti-CD93 construct comprises a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein: a) _VH comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:269, HC-CDR2 containing the amino acid sequence of SEQ ID NO:270, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:271, or variants thereof containing up to about 5, 4, 3, 2, or 1 amino acid substitutions in total in the HC-CDR; and b) _VL comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:272, LC-CDR2 containing the amino acid sequence of SEQ ID NO:273, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:274, or variants thereof containing up to about 5, 4, 3, 2, or 1 amino acid substitutions in total in the LC-CDR. In some embodiments, the above-mentioned amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of this application. In some embodiments, the amino acid substitution is limited to the “preferred substitutions” shown in Table 2 of this application.

In some embodiments, the second antibody portion comprises a humanized antibody portion derived from a mouse antibody, said mouse antibody comprising a heavy chain variable region ( _VH ) containing the amino acid sequence shown in SEQ ID NO:279 and a light chain variable region ( _VL ) containing the amino acid sequence shown in SEQ ID NO:280.

In some implementations, the second antibody portion and the anti-CD93 antibody portion are fused together via a linker (e.g., any linker of any operable form that allows the binding portion to function properly, as described herein).

Exemplary binding portions that specifically recognize VEGF

Exemplary binding portions that specifically recognize VEGF include, but are not limited to, Avastin, Ramucirumab, or VEGF-trap (aflibercept), or variants or functional portions thereof.

In some embodiments, the binding portion for specifically recognizing VEGF in the multispecific anti-CD93 construct is an antibody portion (e.g., scFv) comprising an antibody portion containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:326, HC-CDR2 containing the amino acid sequence of SEQ ID NO:327, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:328, and _VL comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:329, HC-CDR2 containing the amino acid sequence of SEQ ID NO:330, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:331.

In some embodiments, the binding portion for the specific recognition of VEGF in the multispecific anti-CD93 construct is an antibody portion (e.g., scFv) comprising an antibody portion containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:332, HC-CDR2 containing the amino acid sequence of SEQ ID NO:333, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:334, and _VL comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:335, HC-CDR2 containing the amino acid sequence of SEQ ID NO:336, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:337.

In some embodiments, the binding moiety for specifically recognizing VEGF in the multispecific anti-CD93 construct is an antibody moiety (e.g., scFv) comprising an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:289, HC-CDR2 containing the amino acid sequence of SEQ ID NO:290, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:291, and _VL comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:292, LC-CDR2 containing the amino acid sequence of SEQ ID NO:293, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:294. In some embodiments, the binding moiety for specifically recognizing VEGF in the multispecific anti-CD93 construct comprises the amino acid sequence of SEQ ID NO:325.

In some embodiments, the anti-CD93 construct is a multispecific (e.g., bispecific) anti-CD93 construct comprising: a) a full-length anti-CD93 antibody comprising two heavy chains and two light chains, wherein each of the two heavy chains comprises a heavy chain variable region ( _VH ) and each of the two light chains comprises a light chain variable region ( _VL ), wherein the _VH comprises: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:289, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:290, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:291, and the _VL comprises: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:292, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:293, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:294; and b) a binding portion that specifically recognizes VEGF, which is fused to the C-terminus of the two heavy chains of the full-length anti-CD93 antibody. In some embodiments, the binding portion for the specific recognition of VEGF in the multispecific anti-CD93 construct comprises: the amino acid sequence of SEQ ID NO:325, or a variant comprising an amino acid sequence having at least about 80% (such as at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, an anti-CD93 construct is provided, comprising: a heavy chain fusion polypeptide comprising the amino acid sequence shown in SEQ ID NO:366, or a variant comprising an amino acid sequence having at least about 80% (such as any one of at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a light chain comprising the amino acid sequence shown in SEQ ID NO:367, or a variant comprising an amino acid sequence having at least about 80% (such as any one of at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, the multispecific anti-CD93 construct is capable of blocking the interaction between CD93 and IGFBP7. In some embodiments, the multispecific anti-CD93 construct is capable of blocking the interaction between CD93 and IGFBP7 by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

In some embodiments, the multispecific anti-CD93 construct is capable of blocking the interaction between CD93 and MMRN2. In some embodiments, the multispecific anti-CD93 construct is capable of blocking the interaction between CD93 and MMRN2 by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

In some embodiments, the multispecific anti-CD93 construct is capable of binding to VEGFA with dissociation constants less than 1 nM, about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, or greater than about 50 nM, as measured by biolayer interferometry. In some embodiments, the multispecific anti-CD93 construct is capable of binding to VEGFA with a dissociation constant of about 2 nM, as measured by biolayer interferometry.

Additional anti-CD93 fusion protein

In some implementations, the anti-CD93 construct comprises an anti-CD93 antibody portion (e.g., anti-CD93scFv) and a second portion.

In some embodiments, the second portion includes a half-life extension portion. In some embodiments, the half-life extension portion is an albumin-binding portion (e.g., an albumin-binding antibody portion). In some embodiments, the anti-CD93 antibody portion and the half-life extension portion are connected by a adapter (e.g., any adapter described in the “Adapter” section).

In some embodiments, the second part comprises the extracellular domain of the receptor. In some embodiments, the second part is the extracellular domain (ECD) of PD-1 or PD-L1. In some embodiments, the second part is a PD-L1 trap or a PD-1 trap. See, for example, Nat Commun. 2018 Jun 8; 9(1):2237. In some embodiments, the second part comprises the extracellular domain (ECD) of the VEGF receptor. In some embodiments, the second part comprises the ECD of VEGFR1 and/or VEGFR2. In some embodiments, the second part comprises a VEGF trap. See, for example, Proc Natl Acad Sci USA. 2002 Aug 20; 99(17):11393-8.

Anti-CD93 Immunoconjugate

This application also provides an anti-CD93 immunoconjugate comprising an anti-CD93 antibody moiety (such as any CD93 antibody moiety described herein) and a second agent. In some embodiments, the second agent is a therapeutic agent. In some embodiments, the second agent is a label.

connector

In some embodiments, the anti-CD93 constructs described herein include one or more linkers between two parts (e.g., an anti-CD93 antibody part and a half-life extension part, or, in the multispecific constructs described above, an anti-CD93 antibody part and a second binding part). The length, flexibility, and/or other characteristics of the linkers used in the anti-CD93 constructs may have some influence on properties (including, but not limited to, affinity, specificity, or affinity for one or more specific antigens or epitopes). For example, longer linkers may be chosen to ensure that two adjacent domains do not spatially interfere with each other. In some embodiments, the linker (e.g., a peptide linker) includes flexible residues (e.g., glycine and serine) such that adjacent domains can move freely relative to each other. For example, a glycine-serine duplex may be a suitable peptide linker. In some embodiments, the linker is a non-peptide linker. In some embodiments, the linker is a peptide linker. In some embodiments, the linker is a non-cleavable linker. In some embodiments, the linker is a cleavable linker.

Other connector considerations include the impact on the physical or pharmacokinetic properties of the resulting compound, such as solubility, lipophilicity, hydrophilicity, hydrophobicity, stability (more or less stable and planned degradation), rigidity, flexibility, immunogenicity, regulation of antibody binding, and ability to be incorporated into micelles or liposomes.

peptide linkers

Peptide linkers can have naturally occurring or non-natural sequences. For example, sequences derived from the hinge region of heavy-chain-only antibodies can be used as linkers. See, for example, WO1996/34103.

The peptide linker can have any suitable length. In some embodiments, the length of the peptide linker is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 75, 100 or more amino acids. In some embodiments, the length of the peptide linker is no more than about 100, 75, 50, 40, 35, 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5 or fewer amino acids. In some embodiments, the length of the peptide linker is any one of the following: about 1 amino acid to about 10 amino acids, about 1 amino acid to about 20 amino acids, about 1 amino acid to about 30 amino acids, about 5 amino acids to about 15 amino acids, about 10 amino acids to about 25 amino acids, about 5 amino acids to about 30 amino acids, about 10 amino acids to about 30 amino acids, about 30 amino acids to about 50 amino acids, about 50 amino acids to about 100 amino acids, or about 1 amino acid to about 100 amino acids.

The fundamental technical characteristic of this peptide linker is that it does not contain any polymerization activity. Features of peptide linkers (including the absence of secondary structure promotion) are known in the art and described, for example, by Dall’Acqua et al. (Biochem. (1998) 37, 9266-9273), Cheadle et al. (Mol Immunol (1992) 29, 21-30) and Raag and Whitlow (FASEB (1995) 9(1), 73-80). In the case of a “peptide linker,” a particularly preferred amino acid is Gly. Furthermore, peptide linkers that do not promote any secondary structure are preferred. The connection between these domains can be provided, for example, through genetic engineering. Methods for preparing fusion- and operablely linked bispecific single-stranded constructs and expressing them in mammalian cells or bacteria are well known in the art (e.g., WO 99/54440, Ausubel, Current Protocols in Molecular Biology, Green Publishing Associates and Wiley Interscience, N.Y. 1989 and 1994, or Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. 2001).

Peptide linkers can be stable linkers that cannot be cleaved by proteases, especially matrix metalloproteinases (MMPs).

The connector can also be a flexible connector. Exemplary flexible connectors include glycine polymers (G) _n (SEQ ID NO:225), glycine-serine polymers (including, for example, (GS) _n (SEQ ID NO:226), (GSGGS) _n (SEQ ID NO:227), (GGGGS) _n (SEQ ID NO:228), and (GGGS) _n (SEQ ID NO:229), where n is an integer of at least 1), glycine-alanine polymers, alanine-serine polymers, and other flexible connectors known in the art. Glycine and glycine-serine polymers are relatively unstructured and therefore may be able to act as neutral tethers between components. Glycine enters even more phi-psi spaces than alanine and is less restricted than residues with longer side chains (see Scheraga, Rev. Computational Chem. 11 173-142 (1992)). Those skilled in the art will recognize that the design of antibody fusion proteins can include wholly or partially flexible connectors, such that the connectors can include flexible connector portions as well as one or more portions that impart less flexible structures to provide the desired antibody fusion protein structure.

In addition, exemplary linkers also include, for example, an amino acid sequence of (GGGGS) _n (SEQ ID NO:228), where n is an integer between 1 and 8, such as (GGGGS) ₃ (SEQ ID NO:230; hereinafter referred to as "(G4S)3" or "GS3"), or (GGGGS) ₆ (SEQ ID NO:231; hereinafter referred to as "(G4S)6" or "GS6"). In some embodiments, the peptide linker comprises an amino acid sequence of (GSTSGSGKPGSGEGS) _n (SEQ ID NO:232), where n is an integer between 1 and 3.

Non-peptide linkers

The coupling of two parts can be achieved through any chemical reaction that binds the two molecules, as long as both components retain their respective activities, such as binding a second agent in CD93 and an anti-CD93 multispecific antibody, respectively. This connection can include many chemical mechanisms, such as covalent binding, affinity binding, intercalation, coordination binding, and complexation. In some embodiments, the binding is covalent. Covalent binding can be achieved through the direct condensation of existing side chains or by incorporating an external bridging molecule. In this case, many divalent or multivalent linkers can be used to couple protein molecules. Representative coupling agents may include organic compounds such as thioesters, carbodiimides, succinimides, diisocyanates, glutaraldehyde, diazobenzene, and hexamethylenediamine. This list is not intended to exhaust all known classes of coupling agents in the art, but rather to provide examples of more common coupling agents (see Killen and Lindstrom, Jour. Immun. 133:1335-2549 (1984); Jansen et al., Immunological Reviews 62:185-216 (1982); and Vitetta et al., Science 238:1098 (1987)).

Connectors that can be used in this application are described in the literature (see, for example, Ramakrishnan, S. et al., Cancer Res. 44:201-208 (1984), which describes the use of MBS (M-maleimide benzoyl-N-hydroxysuccinimide ester). In some embodiments, the non-peptide connectors used herein include: (i) EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; (ii) SMPT (4-succinimide-oxycarbonyl-α-methyl-α-(2-pyridyl-dithio)-toluene (Pierce Chem. Co., Cat. (21558G)); (iii) SPDP (succinimide-6-[3-(2-pyridyl-dithio)propionylamino]hexanoate (Pierce Chem. Co., Cat. (21558G)). (iv) Sulfo-LC-SPDP (sulfosuccinimide-6-[3-(2-pyridyldithio)propionamide]hexanoate (Pierce Chem.Co.Cat.#2165-G); and (v) Sulfo-NHS (N-hydroxysulfosuccinimide: Pierce Chem.Co.Cat.#24510) conjugated with EDC. In some embodiments, the connector is a PEG-containing connector.

The aforementioned linkers contain components with different properties, thus potentially leading to bispecific antibodies with varying physicochemical properties. For example, sulfo-NHS esters of alkyl carboxylic acids are more stable than sulfo-NHS esters of aromatic carboxylic acids. Linkers containing NHS esters have lower solubility than sulfo-NHS esters. Furthermore, the linker SMPT contains sterically hindered disulfide bonds, which can form antibody fusion proteins with enhanced stability. Disulfide bonds are generally less stable than other bonds because they cleave in vitro, resulting in fewer usable antibody fusion proteins. In particular, Sulfo-NHS can enhance the stability of carbodiimide conjugates. When used in combination with Sulfo-NHS, carbodiimide conjugates (such as EDC) form esters that are more resistant to hydrolysis than carbodiimide conjugates alone.

III. Preparation Method

In some embodiments, a method is provided for preparing an anti-CD93 construct or antibody moiety that specifically binds to CD93, and compositions, such as polynucleotides, nucleic acid constructs, vectors, host cells, or culture media, generated during the preparation of the anti-CD93 construct or antibody moiety. The anti-CD93 construct or antibody moiety or composition described herein can be prepared by a number of methods generally described below, and more specifically in the examples.

Antibody expression and production

The antibodies described herein (including anti-CD93 monoclonal antibodies, anti-CD93 bispecific antibodies, and anti-CD93 antibody portions) can be prepared using any method known in the art, including the methods described below and in the examples.

Monoclonal antibodies

Monoclonal antibodies are obtained from a substantially homogeneous population of antibodies, meaning that individual antibodies comprising this population are identical, except for the possible presence of small amounts of naturally occurring mutations and/or post-translational modifications (e.g., isomerization, amidation). Therefore, the modifier “monoclonal” indicates that the antibody is not a mixture of discrete antibodies. For example, monoclonal antibodies can be prepared using the hybridoma method first described by Kohler et al., Nature, 256:495 (1975), or by a recombinant DNA method (US Patent No. 4,816,567). In the hybridoma method, mice or other suitable host animals, such as hamsters or llamas, are immunized as described above to induce lymphocytes that produce or are capable of producing antibodies that specifically bind to proteins used for immunization. Alternatively, lymphocytes can be immunized in vitro. The lymphocytes are then fused with myeloma cells using a suitable fusion agent (e.g., polyethylene glycol) to form hybridoma cells (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986)). For information on the immunity of camels, see Example 1.

Immunosuppressants typically consist of an antigenic protein or a fusion variant thereof. Peripheral blood lymphocytes (“PBLs”) are usually used if human cells are required, or spleen cells or lymph node cells are used if non-human mammalian cells are required. The lymphocytes are then fused with an immortalized cell line using a suitable fusion agent (such as polyethylene glycol) to form hybridoma cells. (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press (1986), pp. 59-103.)

Immortalized cell lines are typically transformed mammalian cells, particularly rodent, bovine, and human myeloma cells. Rat or mouse myeloma cell lines are commonly used. These hybridoma cells are seeded and grown in a suitable culture medium, preferably containing one or more substances that inhibit the growth or survival of unfused parental myeloma cells. For example, if the parental myeloma cells lack hypoxanthine-guanine phosphoribosyltransferase (HGPRT or HPRT), the hybridoma culture medium typically contains hypoxanthine, aminopterin, and thymidine (HAT medium), which inhibit the growth of HGPRT-deficient cells.

Preferred immortalized myeloma cells are those that can fuse efficiently, support stable high-level antibody production by selected antibody-producing cells, and are sensitive to culture media (such as HAT medium). Among these, preferred are mouse myeloma cell lines, such as those derived from MOPC-21 and MPC-11 mouse tumors, available from Salk Institute Cell Distribution Center, San Diego, Calif., USA, and USA and SP-2 cells (and their derivatives, e.g., X63-Ag8-653), available from American Type Culture Collection, Manassas, Va., USA. Human myeloma and mouse-human allogeneic myeloma cell lines have also been described for the production of human monoclonal antibodies (Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp.51-63 (Marcel Dekker, Inc., New York, 1987)).

The production of monoclonal antibodies against antigens in the culture medium for hybridoma cell growth is measured. Preferably, the binding specificity of the monoclonal antibodies produced by hybridoma cells is determined by immunoprecipitation or by in vitro binding assays, such as flow cytometry, radioimmunoassay (RIA), or enzyme-linked immunosorbent assay (ELISA).

The presence of monoclonal antibodies against desired antigens in the culture medium for hybridoma cells can be determined. Preferably, the binding affinity and specificity of the monoclonal antibody can be determined by immunoprecipitation or by in vitro binding assays, such as radioimmunoassay (RIA), enzyme-linked assay (ELISA), or BLI. Such techniques and assays are known in the art. For example, binding affinity can be determined by the Skachard analysis described in Munson et al., Anal. Biochem., 107:220 (1980).

Once hybridoma cells that produce antibodies with the desired specificity, affinity, and/or activity are identified, the clones can be subcloned using a limiting dilution procedure and grown using standard methods (Goding, ibid.). Suitable media for this purpose include, for example, D-MEM or RPMI-1640 media. Furthermore, hybridoma cells can be grown as tumors in mammals.

Subclonal secreted monoclonal antibodies can be appropriately isolated from culture medium, ascites, or serum using conventional immunoglobulin purification procedures, such as protein A-agarose, hydroxyapatite chromatography, ion exchange chromatography, gel electrophoresis, dialysis, or affinity chromatography.

Monoclonal antibodies can also be prepared using recombinant DNA methods, such as those described in U.S. Patent No. 4,816,567 and those described above. The mRNA encoding the monoclonal antibody is readily isolated and sequenced using standard procedures, e.g., by using oligonucleotide probes capable of specifically binding to cDNA encoding both the heavy and light chains of mouse antibodies. Hybridoma cells are a preferred source of this mRNA. After isolation, the cDNA can be placed in an expression vector and then transfected into host cells, such as *E. coli* cells, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells (which otherwise do not produce immunoglobulins), to synthesize the monoclonal antibody in these recombinant host cells. Review articles on the recombinant expression of antibody-encoding DNA in bacteria include Skerra et al., *Curr. Opinion in Immunol.*, 5:256-262 (1993) and Plückthun, *Immunol. Revs.*, 130:151-188 (1992).

In a further implementation, antibodies can be isolated from the generated antibody phage library using the techniques described in McCafferty et al., Nature, 348:552-554 (1990). Clackson et al., Nature, 352:624-628 (1991) and Marks et al., J. Mol. Biol., 222:581-597 (1991) describe the isolation of mouse and human antibodies using phage libraries, respectively. Subsequent publications describe the production of high-affinity (nM range) human antibodies via chain tamponade (Marks et al., Bio/Technology, 10:779-783 (1992)), as well as combined infection and in vivo recombination as a strategy for constructing very large phage libraries (Waterhouse et al., Nucl. Acids Res., 21:2265-2266 (1993)). Therefore, these techniques are viable alternatives to traditional monoclonal antibody hybridoma techniques for isolating monoclonal antibodies.

For example, DNA can be modified by replacing homologous mouse sequences with coding sequences of constant domains of the human heavy and light chains (US Patent No. 4,816,567; Morrison et al., Proc. Natl Acad. Sci. USA, 81:6851 (1984)), or by covalently linking all or part of the coding sequence of a non-immunoglobulin polypeptide to an immunoglobulin coding sequence. Typically, such non-immunoglobulin polypeptides replace constant domains of antibodies, or they replace variable domains of an antigen-binding site of an antibody, to produce chimeric bivalent antibodies containing an antigen-specific antigen-binding site and an antigen-combining site specific to different antigens.

The monoclonal antibodies described herein can be monovalent, and their preparation is well known in the art. For example, one method involves the recombinant expression of immunoglobulin light chains and modified heavy chains. The heavy chains are typically truncated at any point in the Fc region to prevent heavy chain cross-linking. Alternatively, the associated cysteine residues can be substituted with another amino acid residue or deleted to prevent cross-linking. In vitro methods are also suitable for preparing monovalent antibodies. Digesting the antibody to produce its fragments, particularly Fab fragments, can be accomplished using conventional techniques known in the art.

Chimeric or hybrid antibodies can also be prepared in vitro using methods known in synthetic protein chemistry, including those involving cross-linking agents. For example, immunotoxins can be constructed using disulfide exchange reactions or by forming thioether bonds. Examples of suitable reagents for this purpose include iminothiolates and methyl-4-mercaptobutyrimidate.

Nucleic acid molecules encoding antibody portions

In some embodiments, a polynucleotide encoding any of the anti-CD93 constructs or antibody moieties described herein is provided. In some embodiments, a polynucleotide prepared using any of the methods described herein is provided. In some embodiments, the nucleic acid molecule comprises a heavy chain or light chain polynucleotide encoding an antibody moiety (e.g., an anti-CD93 antibody moiety). In some embodiments, the nucleic acid molecule comprises a heavy chain polynucleotide encoding an antibody moiety (e.g., an anti-CD93 antibody moiety) and a light chain polynucleotide encoding an antibody moiety. In some embodiments, a first nucleic acid molecule comprises a first polynucleotide encoding a heavy chain, and a second nucleic acid molecule comprises a second polynucleotide encoding a light chain.

In some such embodiments, the heavy and light chains are expressed as two separate polypeptides from one nucleic acid molecule or from two separate nucleic acid molecules. In some embodiments, such as when the antibody is scFv, a single polynucleotide encodes a single polypeptide comprising a heavy and light chain linked together.

In some embodiments, the polynucleotide encoding the heavy or light chain of the antibody moiety (e.g., the anti-CD93 antibody moiety) includes a nucleotide sequence encoding a leader sequence located at the N-terminus of the heavy or light chain during translation. As discussed above, the leader sequence can be a natural heavy or light chain leader sequence or another heterologous leader sequence.

In some embodiments, the polynucleotide is DNA. In some embodiments, the polynucleotide is RNA. In some embodiments, the RNA is mRNA.

Nucleic acid molecules can be constructed using recombinant DNA techniques conventional in the art. In some embodiments, the nucleic acid molecule is an expression vector suitable for expression in a selected host cell.

Nucleic acid constructs

In some embodiments, nucleic acid constructs comprising any of the polynucleotides described herein are provided. In some embodiments, nucleic acid constructs prepared using any of the methods described herein are provided.

In some embodiments, the nucleic acid construct further includes a promoter operatively linked to a polynucleotide. In some embodiments, the polynucleotide corresponds to a gene, wherein the promoter is a wild-type promoter of that gene.

carrier

In some embodiments, a vector comprising any polynucleotide encoding the heavy and/or light chains of any antibody moiety described herein (e.g., an anti-CD93 antibody moiety) or a nucleic acid construct described herein is provided. In some embodiments, a vector prepared using any of the methods described herein is provided. Vectors comprising polynucleotides encoding any anti-CD93 construct described herein, such as antibodies, scFvs, fusion proteins, or other forms of constructs (e.g., anti-CD93scFv) are also provided. Such vectors include, but are not limited to, DNA vectors, phage vectors, viral vectors, retroviral vectors, etc. In some embodiments, the vector comprises a first polynucleotide sequence encoding the heavy chain and a second polynucleotide sequence encoding the light chain. In some embodiments, the heavy and light chains are expressed from the vector as two separate polypeptides. In some embodiments, the heavy and light chains are expressed as part of a single polypeptide, for example, when the antibody is an scFv.

In some embodiments, the first vector contains a polynucleotide encoding the heavy chain, and the second vector contains a polynucleotide encoding the light chain. In some embodiments, the first and second vectors are transfected into host cells in similar amounts (e.g., similar molar amounts or similar mass amounts). In some embodiments, the first and second vectors are transfected into host cells in a molar ratio or mass ratio between 1:1 and 1:5. In some embodiments, the vector encoding the heavy chain and the vector encoding the light chain are transfected in a mass ratio between 1:1 and 1:5. In some embodiments, the vector encoding the heavy chain and the vector encoding the light chain are transfected in a mass ratio of 1:2.

In some implementations, a vector optimized for expressing the peptide in CHO or CHO-derived cells or NSO cells is selected. Exemplary such vectors are described in Running Deer et al., Biotechnol. Prog. 20:880-889 (2004).

host cells

In some embodiments, a host cell comprising any of the peptides, nucleic acid constructs, and/or vectors described herein is provided. In some embodiments, a host cell prepared using any of the methods described herein is provided. In some embodiments, the host cell is capable of producing any of the antibody moieties described herein under fermentation conditions.

In some embodiments, the antibody moiety described herein (e.g., the anti-CD93 antibody moiety) may be expressed in prokaryotic cells such as bacterial cells; or in eukaryotic cells such as fungal cells (e.g., yeast), plant cells, insect cells, and mammalian cells. Such expression may be performed, for example, according to procedures known in the art. Exemplary eukaryotic cells that can be used to express the polypeptide include, but are not limited to, COS cells, including COS 7 cells; 293 cells, including 293-6E cells; CHO cells, including CHO-S, DG44; Lec13 CHO cells, and FUT8 CHO cells; Crucell cells; and NSO cells. In some embodiments, the antibody moiety described herein (e.g., the anti-CD93 antibody moiety) may be expressed in yeast. See, for example, U.S. Publication No. US 2006/0270045A1. In some embodiments, a particular eukaryotic host cell is selected based on its ability to perform desired post-translational modifications to the heavy and/or light chains of the antibody moiety. For example, in some embodiments, the polypeptide produced by CHO cells has a higher level of sialylation than the same polypeptide produced by 293 cells.

One or more nucleic acids can be introduced into desired host cells by any method, including but not limited to calcium phosphate transfection, DEAE-dextran-mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, etc. Non-limiting exemplary methods are described, for example, in Sambrook et al., Molecular Cloning, A Laboratory Manual, ^3rd ed. Cold Spring Harbor Laboratory Press (2001). Nucleic acids can be transiently or stably transfected into desired host cells according to any suitable method.

This application also provides host cells comprising any of the polynucleotides or vectors described herein. In some embodiments, the invention provides host cells comprising anti-CD93 antibodies. Any host cell capable of overexpressing heterologous DNA can be used for the purpose of isolating genes encoding target antibodies, peptides, or proteins. Non-limiting examples of mammalian host cells include, but are not limited to, COS, HeLa, and CHO cells. See also PCT Publication WO 87/04462. Suitable non-mammalian host cells include prokaryotes (e.g., Escherichia coli or Bacillus subtilis) and yeasts (e.g., Saccharomyces cerevisiae, S. pombe; or Kluyveromyces lactis).

In some implementations, the antibody portion is generated in a cell-free system. Non-limiting exemplary cell-free systems are described, for example, in Sitaraman et al., Methods Mol. Biol. 498:229-44 (2009); Spirin, Trends Biotechnol. 22:538-45 (2004); and Endo et al., Biotechnol. Adv. 21:695-713 (2003).

culture medium

In some embodiments, a culture medium comprising any antibody moiety, polynucleotide, nucleic acid construct, vector, and/or host cell described herein is provided. In some embodiments, a culture medium prepared using any of the methods described herein is provided.

In some embodiments, the culture medium contains hypoxanthine, aminopterin, and/or thymidine (e.g., HAT medium). In some embodiments, the culture medium does not contain serum. In some embodiments, the culture medium contains serum. In some embodiments, the culture medium is D-MEM or RPMI-1640 medium. In some embodiments, the culture medium is a chemically defined medium. In some embodiments, the chemically defined medium is optimized for the host cell line.

Purification of the antibody portion

Anti-CD93 constructs (e.g., anti-CD93 monoclonal antibodies or multispecific antibodies) can be purified by any suitable method. Such methods include, but are not limited to, the use of affinity matrices or hydrophobic interaction chromatography. Suitable affinity ligands include ROR1 ECD and ligands that bind to the antibody constant region. For example, protein A, protein G, protein A/G, or antibody affinity columns can be used to bind the constant region and purify anti-CD93 constructs containing the Fc fragment. Hydrophobic interaction chromatography, such as butyl or phenyl columns, can also be used to purify some peptides, such as antibodies. Ion exchange chromatography (e.g., anion exchange chromatography and/or cation exchange chromatography) can also be used to purify some peptides, such as antibodies. Mixed-mode chromatography (e.g., reversed-phase/anion exchange, reversed-phase/cation exchange, hydrophilic interaction/anion exchange, hydrophilic interaction/cation exchange, etc.) can also be used to purify some peptides, such as antibodies. Many methods for purifying peptides are known in the art.

V. Treatment Methods

This document also provides methods for treating an individual's disease or condition or modulating an individual's immune response. These methods include administering the anti-CD93 construct described herein to an individual (e.g., a mammal such as a human). It should be understood that the discussion of anti-CD93 constructs in this section applies to any anti-CD93 construct described in this application, such as multispecific anti-CD93 constructs, such as anti-CD93 fusion proteins, such as anti-CD93/VEGFR fusion proteins including anti-CD93/aflibercept fusion proteins. In some embodiments, methods for treating an individual's disease or condition or modulating an immune response are provided, comprising administering to the individual an effective amount of the anti-CD93 construct described herein. Exemplary diseases or conditions include, but are not limited to, age-related macular degeneration (AMD), diabetic macular edema (DME), choroidal neovascularization (CNV), and cancer.

In some embodiments, a method of treating an individual disease or condition (e.g., AMD, DME, CNV, or cancer) is provided, comprising administering to the individual an effective amount of an anti-CD93 construct comprising an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region (VL _-2 ) for a CD93 binding epitope, wherein _VH-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:1, HC-CDR2 containing the amino acid sequence of SEQ ID NO:2, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:3, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:4, LC-CDR2 containing the amino acid sequence of SEQ ID NO:5, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:6. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:1, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:2, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:3, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:4, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:5, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:6, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution. In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:1, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:2, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:3, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:4, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:5, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:6. In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:13 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:14 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, a method of treating an individual disease or condition (e.g., AMD, DME, CNV, or cancer) is provided, comprising administering to the individual an effective amount of an anti-CD93 construct comprising an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region (VL _-2 ) for a CD93 binding epitope, wherein _VH-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:17, HC-CDR2 containing the amino acid sequence of SEQ ID NO:18, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:19, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:20, LC-CDR2 containing the amino acid sequence of SEQ ID NO:21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:22. In some embodiments, anti-CD93 V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:17 or 304, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:18 or 305, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, or variants thereof comprising up to 5, 4, 3, 2 or 1 amino acid substitutions in the HC-CDR, and anti-CD93 V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:20, 301, 302, 303 or 306, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22, or variants thereof comprising up to 5, 4, 3, 2 or 1 amino acid substitutions in the LC-CDR.

In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:17, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:18, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:20, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22. In some embodiments, V _H comprises: an amino acid sequence of any one of SEQ ID NO:29 and 307-312 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: an amino acid sequence of any one of SEQ ID NO:30 and 313-318 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, a method of treating an individual disease or condition (e.g., AMD, DME, CNV, or cancer) is provided, comprising administering to the individual an effective amount of an anti-CD93 construct comprising an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region (VL _-2 ) for a CD93 binding epitope, wherein _VH-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:33, HC-CDR2 containing the amino acid sequence of SEQ ID NO:34, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:35, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:36, LC-CDR2 containing the amino acid sequence of SEQ ID NO:37, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:38. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:33, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:34, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:35, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:36, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:37, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:38, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:33, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:34, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:35, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:36, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:37, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:38. In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:45 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:46 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, a method of treating an individual disease or condition (e.g., AMD, DME, CNV, or cancer) is provided, comprising administering to the individual an effective amount of an anti-CD93 construct comprising an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region (VL _-2 ) for a CD93 binding epitope, wherein _VH-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:65, HC-CDR2 containing the amino acid sequence of SEQ ID NO:66, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:67, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:68, LC-CDR2 containing the amino acid sequence of SEQ ID NO:69, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:70. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:65, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:66, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:67, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:68, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:69, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:70, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:65, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:66, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:67, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:68, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:69, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:70. In some embodiments, V _H comprises: the amino acid sequence of SEQ ID NO:77 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:78 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, a method of treating an individual disease or condition (e.g., AMD, DME, CNV, or cancer) is provided, comprising administering to the individual an effective amount of an anti-CD93 construct comprising an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region (VL _-2 ) for a CD93 binding epitope, wherein _VH-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:289, HC-CDR2 containing the amino acid sequence of SEQ ID NO:290, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:291, and VL _-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:292, LC-CDR2 containing the amino acid sequence of SEQ ID NO:293, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:294. In some embodiments, V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:289, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:290, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:291, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:292, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:293, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:294, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. In some embodiments, the anti-CD93 antibody portion is a humanized antibody derived from an anti-CD93 antibody comprising a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein _VH comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:289, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:290, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:291, and _VL comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:292, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:293, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:294. In some embodiments, V _H comprises: an amino acid sequence of any one of SEQ ID NO:287 and 319-321 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises: an amino acid sequence of any one of SEQ ID NO:288 and 322-324 or a variant comprising an amino acid sequence having at least about 80% (e.g., at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

In some embodiments, a method of treating an individual disease or condition (such as AMD, DME, CNV, or cancer) is provided, comprising administering to the individual an effective amount of an anti-CD93 construct, the anti-CD93 construct comprising: a) a full-length antibody specifically recognizing CD93 comprising two heavy chains and two light chains, wherein each of the two heavy chains comprises a heavy chain variable region ( _VH ), the _VH comprising: HC-CDR1 comprising the amino acid sequence of SEQ ID NO:289, HC-CDR2 comprising the amino acid sequence of SEQ ID NO:290, and HC-CDR3 comprising the amino acid sequence of SEQ ID NO:291, and wherein each of the two light chains comprises a light chain variable region ( _VL ), the _VL comprising: LC-CDR1 comprising the amino acid sequence of SEQ ID NO:292, LC-CDR2 comprising the amino acid sequence of SEQ ID NO:293, and LC-CDR3 comprising the amino acid sequence of SEQ ID NO:294; and b) comprising SEQ ID NO:293, and HC-CDR2 comprising the amino acid sequence of SEQ ID NO:293; and b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:293; and c ... The VEGF-binding portion of the amino acid sequence NO:325 is fused to one or both heavy chains of the full-length antibody. In some embodiments, the VEGF-binding portion is fused to the C-terminus of both heavy chains of the full-length antibody. In some embodiments, the VEGF-binding portion is fused to the full-length antibody via a linker. In some embodiments, the linker is a GS linker or selected from SEQ ID NO:225-232 and 338. In some embodiments, the linker comprises the amino acid sequence of SEQ ID NO:338. In some embodiments, the anti-CD93 V _H comprises the amino acid sequence of any one of SEQ ID NO:287 and 319-321, or a variant comprising an amino acid sequence having at least about 80% (such as at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and V _L comprises the amino acid sequence of any one of SEQ ID NO:288 and 322-324, or a variant comprising an amino acid sequence having at least about 80% (such as at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the full-length antibody has an IgG1 isotype (such as human IgG1 isotype). In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO:342, or a variant comprising an amino acid sequence having at least about 80% (such as at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the light chain comprises the amino acid sequence of SEQ ID NO:343, or a variant comprising an amino acid sequence having at least about 80% (such as at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, a method of treating an individual's disease or condition (such as AMD, DME, CNV, or cancer) is provided, comprising administering to the individual an effective amount of an anti-CD93 construct comprising: a heavy chain fusion polypeptide comprising the amino acid sequence shown in SEQ ID NO:366, or a variant comprising an amino acid sequence having at least about 80% (such as any one of at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a light chain polypeptide comprising the amino acid sequence shown in SEQ ID NO:367, or a variant comprising an amino acid sequence having at least about 80% (such as any one of at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the amino acid substitutions are limited to the "exemplary substitutions" shown in Table 2 of this application. In some embodiments, the amino acid substitutions are limited to the "preferred substitutions" shown in Table 2 of this application.

In some embodiments, a method of treating a tumor is provided, comprising administering to a subject any of the anti-CD93 constructs described herein. In some embodiments, the method delays tumor growth by at least about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more than 90% compared to tumor growth in the absence of an anti-CD93 construct.

In some embodiments, a method for reducing tumor size in a subject is provided, comprising administering to the subject any of the anti-CD93 constructs described herein. In some embodiments, reducing tumor size refers to reducing the volume of the tumor in the subject. In some embodiments, reducing tumor size refers to reducing the size (e.g., diameter) of the tumor in the subject. In some embodiments, the tumor size is reduced by at least about 2%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more than about 90% compared to the size of the corresponding tumor in a subject who has not received the anti-CD93 construct. In some embodiments, the tumor size is reduced by about 50%, about 60%, about 70%, about 80%, or about 90% compared to the size of the corresponding tumor in a subject who has not received the anti-CD93 construct. In some embodiments, a method for eliminating one or more tumors in a subject is provided, comprising administering to the subject any of the anti-CD93 constructs described herein. In some implementations, tumor elimination occurs approximately 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or more than 8 weeks after the anti-CD93 construct.

In some embodiments, a method for promoting the infiltration of immune cells into a subject's tumor is provided, comprising administering to the subject any of the anti-CD93 constructs described herein. In some embodiments, the method increases immune cell penetration into the tumor by at least about 2%, about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more than about 90% compared to a subject who has not received an anti-CD93 construct.

In some embodiments, a method is provided to eliminate one or more tumors in a subject, reduce the size of tumors in a subject, and/or promote the infiltration of immune cells into the subject's tumors, comprising administering an anti-CD93 construct, wherein the anti-CD93 construct comprises: a heavy chain fusion polypeptide comprising the amino acid sequence shown in SEQ ID NO:366, or a variant comprising an amino acid sequence having at least about 80% (such as at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity; and a light chain polypeptide comprising the amino acid sequence shown in SEQ ID NO:367.

In some embodiments, a method is provided to eliminate one or more tumors in a subject, reduce the size of tumors in a subject, and/or promote the infiltration of immune cells into the subject's tumors, comprising administering an anti-CD93 construct (such as any of the multispecific anti-CD93 constructs described herein), wherein the anti-CD93 construct is capable of blocking the interaction between CD93 and IGFBP7. In some embodiments, the multispecific anti-CD93 construct is capable of blocking the interaction between CD93 and IGFBP7 by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the anti-CD93 construct is capable of blocking the interaction between CD93 and MMRN2. In some embodiments, the multispecific anti-CD93 construct is capable of blocking the interaction between CD93 and MMRN2 by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

In some embodiments, a method is provided to eliminate one or more tumors in a subject, reduce the size of tumors in a subject, and/or promote the infiltration of immune cells into the subject's tumors, comprising administering any of the multispecific anti-CD93 constructs described herein, wherein the multispecific anti-CD93 construct is capable of blocking the interaction between CD93 and MMRN2. In some embodiments, the multispecific anti-CD93 construct is capable of blocking the interaction between CD93 and MMRN2 by at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

In some embodiments, a method is provided to eliminate one or more tumors, reduce the size of tumors in a subject, and/or promote the infiltration of immune cells into the subject's tumors, comprising administering any of the multispecific anti-CD93 constructs described herein, wherein the multispecific anti-CD93 construct is capable of binding to VEGFA with a dissociation constant less than 1 nM, about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 10 nM, about 20 nM, about 30 nM, about 40 nM, about 50 nM, or greater than about 50 nM as measured by biolayer interferometry. In some embodiments, the multispecific anti-CD93 construct is capable of binding to VEGFA with a dissociation constant of about 2 nM as measured by biolayer interferometry.

Disease or ailment

The methods described herein are applicable to any disease or condition associated with abnormal vascular structures. In some embodiments, the disease or condition is related to new blood vessel formation. In some embodiments, the disease or condition is psoriasis. In some embodiments, the disease or condition is a benign tumor. In some embodiments, the disease or condition is cancer.

Diseases related to angiogenesis

In some implementations, the disease or condition is associated with neovascularization. The term "neovascularization" as used herein refers to the phenomenon of the development of new vascular systems from existing ones.

In some implementations, the disease or condition is associated with the formation of new blood vessels in the eye.

In some embodiments, the disease or condition is choroidal neovascularization (CNV), also known as wet AMD. Choroidal neovascularization may involve the growth of new blood vessels originating from the choroid and extending through a Bruch's membrane tear into the sub-RPE or subretinal space, which can be a major cause of vision loss. CNV can cause a sudden deterioration in central vision, becoming noticeable within weeks. Other possible symptoms include color blindness and metamorphopsia (distorted straight lines appear as wavy lines). Bleeding from the new blood vessels can accelerate the onset of CNV symptoms. CNV can also include a feeling of pressure at the back of the eye. In some embodiments, the methods and pharmaceutical compositions disclosed herein are used to treat CNV or ocular conditions associated with neovascularization.

Late-stage “wet” forms of AMD (neovascular or exudative) are less common but can frequently cause rapid and often severe loss of central vision. In the wet form of AMD, choroidal neovascularization forms and develops into a network of blood vessels that can grow beneath and through the retinal pigment epithelium. Because this is accompanied by plasma leakage and/or hemorrhage into the subretinal space, severe and sudden loss of central vision can occur if this occurs in the macula. Unless otherwise stated, the term “AMD” can refer to dry AMD or wet AMD. This application relates to the treatment or prevention of AMD, wet AMD, and/or dry AMD.

In some implementations, the disease or condition is macular edema following retinal vein occlusion (RVO).

In some implementations, the disease or condition is diabetic macular edema (DME). Diabetic macular edema (DME) is swelling of the diabetic retina caused by fluid leakage from blood vessels within the macula. The macula is the central part of the retina, a small area rich in cone cells, which are specialized nerve endings that detect color and are essential for daytime vision. As macular edema progresses, blurring occurs in the central or only lateral areas of the central visual field. Vision loss caused by diabetic macular edema can last for months and result in an inability to focus clearly. Common symptoms of DME include blurred vision, floaters, and diplopia, and if left untreated, it can eventually lead to blindness. In some implementations, the methods and pharmaceutical compositions disclosed herein are used to treat DME.

In some embodiments, the disease or condition is retinal vein occlusion. Retinal vein occlusion refers to the blockage of small veins that carry blood out of the retina. The retina is a layer of tissue at the back of the inner eye that converts light images into nerve signals and sends them to the brain. The most common causes of retinal vein occlusion are arteriosclerosis (atherosclerosis) and blood clot formation. Blockage of smaller veins in the retina (branching veins or BRVOs) usually occurs where retinal arteries cross due to thickening or hardening caused by atherosclerosis and put pressure on the retinal veins. Symptoms of retinal vein occlusion can include sudden blurred vision or loss of vision in all or part of one eye. In some embodiments, the methods and pharmaceutical compositions disclosed herein are used to treat retinal vein occlusion.

In some implementations, the disease or condition is diabetic retinopathy (DR) in patients with DME.

cancer

In some implementations, the disease or condition described herein is cancer. Cancers that can be treated using any of the methods described herein include any type of cancer. Types of cancers that can be treated with the agents described in this application include, but are not limited to, carcinomas, blastomas, sarcomas, benign and malignant tumors such as sarcomas, carcinomas, and melanomas. Adult tumors/cancers and childhood tumors/cancers are also included.

In various implementation schemes, cancer is early-stage cancer, non-metastatic cancer, primary cancer, advanced cancer, locally advanced cancer, metastatic cancer, remission cancer, recurrent cancer, cancer in a supportive environment, cancer in a neo-supportive environment, or cancer that is essentially difficult to treat.

In some implementations, cancer is a solid tumor.

In some embodiments, the cancer comprises CD93+ tumor endothelial cells. In some embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the endothelial cells in the tumor are CD93-positive. In some embodiments, the cancer contains at least 20%, 40%, 60%, 80%, or 100% more CD93+ endothelial cells than the subject's normal tissue. In some embodiments, the cancer contains at least 20%, 40%, 60%, 80%, or 100% more CD93+ endothelial cells than the corresponding organs of a subject or a group of subjects without cancer.

In some implementations, the cancer contains IGFBP7+ blood vessels. In some implementations, the cancer contains at least 20%, 40%, 60%, 80%, or 100% more IGFBP7+ blood vessels than normal tissue in the subject. In some implementations, the cancer contains at least 20%, 40%, 60%, 80%, or 100% more IGFBP7+ blood vessels than the corresponding organs in subjects or groups of subjects without cancer.

In some implementations, the cancer (e.g., a solid tumor) is characterized by tumor hypoxia. In some implementations, the cancer is characterized by at least about 1%, 2%, 3%, 4%, or 5% of a permonidazole-positive percentage (i.e., permonidazole-positive area divided by the total tumor area).

Examples of cancers treatable by the methods described in this application include, but are not limited to, anal cancer, astrocytoma (e.g., cerebellum and cerebrum), basal cell carcinoma, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain tumors (e.g., glioma, brainstem glioma, cerebellar or cerebral astrocytoma (e.g., astrocytoma, malignant glioma, medulloblastoma, and glioblastoma), breast cancer, cervical cancer, colon cancer, brain cancer, colorectal cancer, endometrial cancer (e.g., uterine cancer), esophageal cancer, and eye cancer (e.g., intraocular melanoma and retina). Hemoblastoma, gastric cancer, gastrointestinal stromal tumor (GIST), head and neck cancer, hepatocellular carcinoma (hepatoma), liver cancer, lung cancer (small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma), medulloblastoma, melanoma, mesothelioma, myelodysplastic syndrome, nasopharyngeal carcinoma, neuroblastoma, ovarian cancer, pancreatic cancer, parathyroid carcinoma, peritoneal cancer, pituitary adenoma, rectal cancer, kidney cancer, renal pelvis and ureter cancer (transitional cell carcinoma), rhabdomyosarcoma, skin cancer (e.g., non-melanoma, squamous cell carcinoma) Melanoma and Merkel cell carcinoma), small bowel cancer, squamous cell carcinoma, testicular cancer, thyroid cancer, and tuberous sclerosis. Other examples of cancer can be found in The Merck Manual of Diagnosis and Therapy, 19th Edition, § on Hematology and Oncology, 2011 (ISBN 978-0-911910-19-3); The Merck Manual of Diagnosis and Therapy, 20th Edition, § on Hematology and Oncology, 2018 (ISBN 978-0-911-91042-1) (2018 digital online version on the Merck Manual's website); and SEER Program Coding and Staging Manual 2016, each of which is incorporated in its entirety by reference for all purposes.

Subjects

In some implementations, the subjects are mammals (e.g., humans).

In some embodiments, the subject has tissue containing abnormal blood vessels, said abnormal blood vessels containing CD93+ endothelial cells. In some embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the endothelial cells in the tissue containing abnormal blood vessels are CD93 positive. In some embodiments, the tissue containing abnormal blood vessels contains at least 20%, 40%, 60%, 80%, or 100% more CD93+ endothelial cells than normal tissue in the subject. In some embodiments, the tissue containing abnormal blood vessels contains at least 20%, 40%, 60%, 80%, or 100% more CD93+ endothelial cells than the corresponding organs in subjects or a group of subjects without abnormal blood vessels.

In some embodiments, the subject has tissue containing abnormal blood vessels, said abnormal blood vessels being IGFBP7+ vessels. In some embodiments, the tissue contains at least 20%, 40%, 60%, 80%, or 100% more IGFBP7+ vessels than normal tissue in the subject. In some embodiments, the tissue contains at least 20%, 40%, 60%, 80%, or 100% more IGFBP7+ vessels than the corresponding organs in subjects without abnormal blood vessels or in a group of subjects.

In some embodiments, subjects are selected for treatment based on abnormal vascular structures. In some embodiments, the abnormal vascular structure is characterized by CD93+ endothelial cells (e.g., by measuring CD93+CD31+ cells). In some embodiments, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the endothelial cells in the tissue with abnormal vessels are CD93-positive. In some embodiments, the tissue with abnormal vessels contains at least 20%, 40%, 60%, 80%, or 100% more CD93+ endothelial cells than normal tissue in the subject. In some embodiments, the tissue with abnormal vessels contains at least 20%, 40%, 60%, 80%, or 100% more CD93+ endothelial cells in the corresponding organ than in subjects without abnormal vessels or in a group of subjects.

In some embodiments, the abnormal vascular structure is characterized by an abnormal level of IGFBP7+ vessels. In some embodiments, the tissue contains at least 20%, 40%, 60%, 80%, or 100% more IGFBP7+ vessels than normal tissue in the subject. In some embodiments, the tissue contains at least 20%, 40%, 60%, 80%, or 100% more IGFBP7+ vessels than the corresponding organ in a subject or a group of subjects without abnormal vessels.

In some implementations, the subject receives at least one prior therapy. In some implementations, the prior therapy includes radiation therapy, chemotherapy, and/or immunotherapy. In some implementations, the subject is resistant, refractory, or relapsed to the prior therapy.

Dosage and method of administering the anti-CD93 construct

The dosing regimen (e.g., specific dose and frequency) of the anti-CD93 construct administered to an individual for the treatment of a disease or condition as described herein can vary depending on the specific anti-CD93 construct (e.g., an anti-CD93 monoclonal antibody or multispecific antibody, such as an anti-CD93 fusion protein), the method of administration, and the type of disease or condition being treated. In some embodiments, the type of disease or condition is cancer. In some embodiments, the effective amount of the anti-CD93 construct (e.g., an anti-CD93 monoclonal or multispecific antibody) is an amount that effectively elicits an objective response (e.g., a partial or complete response). In some embodiments, the effective amount of the anti-CD93 construct (e.g., an anti-CD93 monoclonal or multispecific antibody) is an amount sufficient to elicit a complete response in an individual. In some embodiments, the effective amount of the anti-CD93 construct (e.g., an anti-CD93 monoclonal or multispecific antibody) is an amount sufficient to elicit a partial response in an individual. In some implementations, an effective amount of the anti-CD93 construct (e.g., an anti-CD93 monoclonal or multispecific antibody) is an amount sufficient to produce an overall response rate exceeding any one of about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, 80%, 85%, or 90% in a population of individuals treated with the anti-CD93 construct (e.g., an anti-CD93 monoclonal or multispecific antibody). For example, an individual's response to treatment using the methods described herein can be determined based on RECIST levels.

In some embodiments, the effective amount of the anti-CD93 construct (e.g., anti-CD93 monoclonal or multispecific antibody) is an amount sufficient to prolong an individual's progression-free survival. In some embodiments, the effective amount of the anti-CD93 construct (e.g., anti-CD93 monoclonal or multispecific antibody) is an amount sufficient to prolong an individual's overall survival. In some embodiments, the effective amount of the anti-CD93 construct (e.g., anti-CD93 monoclonal or multispecific antibody) is an amount sufficient to produce a clinical benefit of more than about 50%, 60%, 70%, 80%, or 90% in a population of individuals treated with the anti-CD93 construct (e.g., anti-CD93 monoclonal or multispecific antibody).

In some implementations, the effective amount of an anti-CD93 construct (e.g., an anti-CD93 monoclonal or multispecific antibody), alone or in combination with a second, third, and/or fourth agent, is sufficient to reduce at least one of the following tumor size, cancer cell number, or tumor growth rate by a factor of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% compared to the corresponding tumor size, cancer cell number, or tumor growth rate in the same subject prior to treatment, or compared to the corresponding activity in other untreated subjects (e.g., those receiving placebo): 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%. Standard methods can be used to measure the magnitude of this effect, such as in vitro assays using purified enzymes, cell-based assays, animal models, or human tests.

In some implementations, the effective amount of the anti-CD93 construct (e.g., an anti-CD93 monoclonal or multispecific antibody) is below the level that induces a toxicological effect (i.e., an effect above the clinically acceptable level of toxicity) or is at a level that can be controlled or tolerated when the composition is administered to an individual.

In some embodiments, the effective amount of the anti-CD93 construct (e.g., an anti-CD93 monoclonal antibody or a multispecific antibody) is an amount close to the maximum tolerated dose (MTD) of the composition after the same dosing regimen. In some embodiments, the effective amount of the anti-CD93 construct (e.g., an anti-CD93 monoclonal antibody or a multispecific antibody) is greater than any one of about 80%, 90%, 95%, or 98% of the MTD.

In some embodiments, an effective amount of the anti-CD93 construct (e.g., an anti-CD93 monoclonal or multispecific antibody) is an amount that slows or inhibits the progression of disease or condition (e.g., at least about 5%, 10%, 15%, 20%, 30%, 40%, or 50%) compared to an untreated individual. In some embodiments, the disease or condition is an autoimmune disease. In some embodiments, the disease or condition is an infection.

In some implementations, the effective amount of an anti-CD93 construct (e.g., an anti-CD93 monoclonal or multispecific antibody) is the amount that reduces the side effects (autoimmune response) of the disease (e.g., transplantation) by at least about 5%, 10%, 15%, 20%, 30%, 40%, or 50% compared to an untreated individual.

In some embodiments of any of the foregoing aspects, the effective amount of the anti-CD93 construct (e.g., anti-CD93 monoclonal or multispecific antibody) is in the range of about 0.001 μg/kg to about 100 mg/kg of total weight, for example, about 0.005 μg/kg to about 50 mg/kg, about 0.01 μg/kg to about 10 mg/kg, or about 0.01 μg/kg to about 1 mg/kg.

In some embodiments, treatment includes more than one administration of the anti-CD93 construct (e.g., about two, three, four, five, six, seven, eight, nine, or ten administrations of the anti-CD93 construct). In some embodiments, two administrations are performed over approximately one week. In some embodiments, the second administration is performed at least about 1, 2, 3, 4, 5, 6, or 7 days after the first administration. In some embodiments, the second administration is performed about 1–14 days, 1–10 days, 1–7 days, 2–6 days, or 3–5 days after the first administration. In some embodiments, the anti-CD93 construct is administered about 1–3 times per week (e.g., about once a week, about twice a week, or about three times a week).

The anti-CD93 construct can be administered to an individual (e.g., a human) via various routes, including, for example, intravenous, intra-arterial, intraperitoneal, intrapulmonary, oral, inhalation, intravesical, intramuscular, intratracheal, subcutaneous, intraocular, intrathecal, transmucosal, and transdermal. In some embodiments, the anti-CD93 construct is contained in a pharmaceutical composition administered to the individual. In some embodiments, a sustained-release formulation of the composition may be used. In some embodiments, the composition is administered intravenously. In some embodiments, the composition is administered intraperitoneally. In some embodiments, the composition is administered intraperitoneally. In some embodiments, the composition is administered intramuscularly. In some embodiments, the composition is administered subcutaneously. In some embodiments, the composition is administered intravenously. In some embodiments, the composition is administered orally.

combination therapy

This application also provides a method of administering an anti-CD93 construct to an individual to treat a disease or condition (e.g., cancer), wherein the method further includes administering a second agent or therapy. In some embodiments, the second agent or therapy is a standard or commonly used agent or therapy for treating a disease or condition. In some embodiments, the second agent or therapy includes a chemotherapy agent. In some embodiments, the second agent or therapy includes surgery. In some embodiments, the second agent or therapy includes radiation therapy. In some embodiments, the second agent or therapy includes immunotherapy. In some embodiments, the second agent or therapy includes cell therapy (e.g., cell therapy comprising immune cells (e.g., CAR T cells)). In some embodiments, the second agent or therapy includes angiogenesis inhibitors.

In some embodiments, the second agent is a chemotherapeutic agent. In some embodiments, the second agent is an antimetabolite. In some embodiments, the antimetabolite is 5-FU.

In some embodiments, the second agent is an immune checkpoint modulator. In some embodiments, the immune checkpoint modulator is an inhibitor of an immune checkpoint protein selected from the group consisting of PD-L1, PD-L2, CTLA4, PD-L2, PD-1, CD47, TIGIT, GITR, TIM3, LAG3, CD27, 4-1BB, and B7H4. In some embodiments, the immune checkpoint protein is PD-1. In some embodiments, the second agent is an anti-PD-1 antibody or a fragment thereof.

In some embodiments, the second therapy is immunotherapy. In some embodiments, immunotherapy includes administration of immune cells expressing a chimeric antigen receptor. In some embodiments, the immune cells are T cells (e.g., CD4+ T cells or CD8+ T cells). In some embodiments, the chimeric antigen receptor binds to a tumor antigen.

In some embodiments, the anti-CD93 construct is administered concurrently with a second agent or therapy. In some embodiments, the anti-CD93 construct is administered simultaneously with a second agent or therapy. In some embodiments, the anti-CD93 construct is administered sequentially with a second agent or therapy. In some embodiments, the anti-CD93 construct is administered before a second agent or therapy. In some embodiments, the anti-CD93 construct is administered after a second agent or therapy. In some embodiments, the anti-CD93 construct is administered in the same unit dosage form as the second agent or therapy. In some embodiments, the anti-CD93 construct is administered in a different unit dosage form than the second agent or therapy. In some embodiments, the anti-CD93 construct is administered in the same unit dosage form as the second agent or therapy. In some embodiments, the anti-CD93 construct is administered in a different unit dosage form than the second agent or therapy.

VI. Compositions, kits and products

This document also provides compositions (e.g., formulations) comprising any of the anti-CD93 constructs or anti-CD93 antibody portions described herein, nucleic acids encoding the antibody portion, vectors containing nucleic acids encoding the antibody portion, or host cells containing nucleic acids or vectors.

Suitable formulations of the anti-CD93 construct described herein can be obtained by mixing an anti-CD93 construct or anti-CD93 antibody moiety of desired purity with an optional pharmaceutically acceptable carrier, excipient, or stabilizer (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. Ed. (1980)), in the form of a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients, or stabilizers are non-toxic to the recipient at the dose and concentration used and include buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (e.g., octadecyl dimethyl benzyl ammonium chloride; hexamethyl ammonium chloride; benzalkonium chloride, benzyl chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10). (Residues) Peptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., zinc-protein complexes); and/or nonionic surfactants, such as TWEEN ^™ , PLURONICS ^™ , or polyethylene glycol (PEG). Lyophilized formulations suitable for subcutaneous administration are described in WO97/04801. Such lyophilized formulations can be reconstituted to high protein concentrations with suitable diluents, and the reconstituted formulations can be subcutaneously administered to individuals to be imaged, diagnosed, or treated herein.

Preparations intended for internal administration must be sterile. This can be easily achieved, for example, by filtration through a sterile filter membrane.

Kits containing any of the anti-CD93 constructs or anti-CD93 antibody motifs described herein are also provided. These kits can be used with any of the methods described herein for modulating cellular composition or for therapeutic purposes.

In some implementations, kits containing anti-CD93 constructs that specifically bind to CD93 are provided.

In some embodiments, the kit further includes a device capable of delivering the anti-CD93 construct into an individual. One type of device used for applications such as parenteral delivery is a syringe for injecting the composition into the subject. Inhalation devices may also be used for certain applications.

In some implementations, the kit also contains therapeutic agents for treating diseases or conditions such as cancer, infectious diseases, autoimmune diseases, or transplantation.

The kit described in this application is packaged in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, wide-mouth flasks, flexible packaging (e.g., sealed Mylar or plastic bags), etc. The kit may optionally include additional components such as buffer solutions and explanatory information.

Therefore, this application also provides articles of manufacture. Articles of manufacture may include a container and a label or packaging insert affixed to or attached to the container. Suitable containers include vials (e.g., sealed vials), bottles, wide-mouth bottles, flexible packaging, etc. Typically, the container contains the composition and may have a sterile inlet (e.g., the container may be an intravenous solution bag or a vial with a stopper that can be punctured by a hypodermic needle). The label or packaging insert indicates that the composition is intended for imaging, diagnosis, or treatment of a specific condition in an individual. The label or packaging insert will further contain instructions for administering the composition to the individual and for imaging the individual. The label may indicate instructions for reconstitution and/or use. The container containing the composition may be a multi-purpose vial that allows for repeated administration (e.g., from 2-6 doses) of the reconstituted formulation. The packaging insert refers to instructions typically included in the commercial packaging of diagnostic products, containing information on the indications, usage, dosage, administration, contraindications, and/or warnings for using such diagnostic products. Additionally, the product may include a second container containing pharmaceutically acceptable buffer solutions, such as bactericidal water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and glucose solution. It may further include other materials required from a commercial and user perspective, including additional buffer solutions, diluents, filters, needles, and syringes.

The kit or product may include a composition of multiple unit doses and instructions for use, and is packaged in a quantity sufficient for storage and use in pharmacies such as hospital pharmacies and compound preparation pharmacies.

Those skilled in the art will recognize that several embodiments are possible within the scope and spirit of the invention. The invention will now be described in more detail with reference to the following non-limiting embodiments. These embodiments further illustrate the invention, but should not be construed as limiting the scope of the invention in any way.

Exemplary Implementation

Implementation Scheme 1. An anti-CD93 construct comprising an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region ( _VL-2 ) for a CD93 binding epitope, wherein:

a) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:1, HC-CDR2 containing the amino acid sequence of SEQ ID NO:2, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:3, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:4, LC-CDR2 containing the amino acid sequence of SEQ ID NO:5, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:6;

b) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:17, HC-CDR2 containing the amino acid sequence of SEQ ID NO:18, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:19, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:20, LC-CDR2 containing the amino acid sequence of SEQ ID NO:21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:22;

c) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:33, HC-CDR2 containing the amino acid sequence of SEQ ID NO:34, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:35, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:36, LC-CDR2 containing the amino acid sequence of SEQ ID NO:37, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:38;

d) V _H-2 contains HC-CDR1 containing the amino acid sequence of SEQ ID NO:49, HC-CDR2 containing the amino acid sequence of SEQ ID NO:50, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:51, and V _L-2 contains LC-CDR1 containing the amino acid sequence of SEQ ID NO:52, LC-CDR2 containing the amino acid sequence of SEQ ID NO:53, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:54;

e) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:65, HC-CDR2 containing the amino acid sequence of SEQ ID NO:66, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:67, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:68, LC-CDR2 containing the amino acid sequence of SEQ ID NO:69, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:70;

f) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:81, HC-CDR2 containing the amino acid sequence of SEQ ID NO:82, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:83, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:84, LC-CDR2 containing the amino acid sequence of SEQ ID NO:85, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:86;

g) V _H-2 contains HC-CDR1 containing the amino acid sequence of SEQ ID NO:97, HC-CDR2 containing the amino acid sequence of SEQ ID NO:98, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:99, and V _L-2 contains LC-CDR1 containing the amino acid sequence of SEQ ID NO:100, LC-CDR2 containing the amino acid sequence of SEQ ID NO:101, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:102;

h) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:113, HC-CDR2 containing the amino acid sequence of SEQ ID NO:114, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:115, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:116, LC-CDR2 containing the amino acid sequence of SEQ ID NO:117, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:118;

i) V _H-2 contains HC-CDR1 containing the amino acid sequence of SEQ ID NO:129, HC-CDR2 containing the amino acid sequence of SEQ ID NO:130, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:131, and V _L-2 contains LC-CDR1 containing the amino acid sequence of SEQ ID NO:132, LC-CDR2 containing the amino acid sequence of SEQ ID NO:133, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:134;

j) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:145, HC-CDR2 containing the amino acid sequence of SEQ ID NO:146, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:147, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:148, 355, or 358, LC-CDR2 containing the amino acid sequence of SEQ ID NO:149 or 356, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:150, 357, or 359;

k)V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:161, HC-CDR2 containing the amino acid sequence of SEQ ID NO:162, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:163, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:164, LC-CDR2 containing the amino acid sequence of SEQ ID NO:165, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:166;

l) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:177, HC-CDR2 containing the amino acid sequence of SEQ ID NO:178, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:179, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:180 or 353, LC-CDR2 containing the amino acid sequence of SEQ ID NO:181 or 354, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:182;

m)V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:193, HC-CDR2 containing the amino acid sequence of SEQ ID NO:194, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:195, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:196, LC-CDR2 containing the amino acid sequence of SEQ ID NO:197, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:198;

n)V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:209, HC-CDR2 containing the amino acid sequence of SEQ ID NO:210, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:211, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:212, LC-CDR2 containing the amino acid sequence of SEQ ID NO:213, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:214;

o) V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:289, HC-CDR2 containing the amino acid sequence of SEQ ID NO:290, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:291, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:292, LC-CDR2 containing the amino acid sequence of SEQ ID NO:293, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:294; or

p)V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:17 or 304, HC-CDR2 containing the amino acid sequence of SEQ ID NO:18 or 305, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:19, and V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:20, 301, 302, 303, or 306, LC-CDR2 containing the amino acid sequence of SEQ ID NO:21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:22.

Implementation Scheme 2. The anti-CD93 construct of Implementation Scheme 1, wherein:

a) V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:1, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:2, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:3, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:4, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:5, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:6, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

b) V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:17, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:18, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:20, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

c) V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:33, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:34, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:35, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:36, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:37, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:38, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

d) V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:49, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:51, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:52, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:53, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:54, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

e) V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:65, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:66, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:67, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:68, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:69, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:70, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

f) V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:81, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:82, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:83, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:84, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:85, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:86, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

g) V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:97, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:98, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:99, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:100, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:101, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:102, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

h) V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:113, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:114, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:115, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:116, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:117, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:118, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

i) V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:129, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:130, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:131, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:132, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:133, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:134, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

j) V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:145, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:146, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:147, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:148, 355, or 358, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:149 or 356, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:150, 357, or 359, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

k) V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:161, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:162, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:163, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:164, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:165, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:166, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

l) V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:177, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:178, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:179, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:180 or 353, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:181 or 354, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:182, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

m) V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:193, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:194, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:195, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:196, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:197, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:198, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

n) V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:209, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:210, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:211, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:212, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:213, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:214, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

o) V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:289, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:290, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:291, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:292, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:293, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:294, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR, or

p)V _H comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:17 or 304, HC-CDR2 containing the amino acid sequence of SEQ ID NO:18 or 305, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:19, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in HC-CDR; and V _L comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:20, 301, 302, 303, or 306, LC-CDR2 containing the amino acid sequence of SEQ ID NO:21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:22, or variants thereof containing up to 5, 4, 3, 2, or 1 amino acid substitution in LC-CDR.

Implementation Scheme 3. The anti-CD93 construct of Implementation Scheme 2, wherein V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:1, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:2, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:3, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:4, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:5, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:6, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

Implementation Scheme 4. The anti-CD93 construct of Implementation Scheme 2, wherein V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17 or 304, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18 or 305, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, or variants thereof comprising up to 5, 4, 3, 2 or 1 amino acid substitutions in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, 301, 302, 303 or 306, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22, or variants thereof comprising up to 5, 4, 3, 2 or 1 amino acid substitutions in the LC-CDR.

Implementation Scheme 5. The anti-CD93 construct of Implementation Scheme 2, wherein V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:33, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:34, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:35, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the HC-CDR; and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:36, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:37, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:38, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitution in the LC-CDR.

Implementation Scheme 6. The anti-CD93 construct of Implementation Scheme 2, wherein V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:49, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:51, or variants thereof comprising up to 5, 4, 3, 2 or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:52, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:53, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:54, or variants thereof comprising up to 5, 4, 3, 2 or 1 amino acid substitutions in the LC-CDR.

Implementation Scheme 7. The anti-CD93 construct of Implementation Scheme 2, wherein V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 65, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 66, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 67, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 68, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 69, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 70, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

Implementation Scheme 8. The anti-CD93 construct of Implementation Scheme 2, wherein V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 83, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 84, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 85, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 86, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

Implementation Scheme 9. The anti-CD93 construct of Implementation Scheme 2, wherein V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 97, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 99, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 100, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 101, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 102, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

Implementation Scheme 10. The anti-CD93 construct of Implementation Scheme 2, wherein V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 113, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 114, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 115, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 116, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 117, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 118, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

Implementation Scheme 11. The anti-CD93 construct of Implementation Scheme 2, wherein V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 129, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 131, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 132, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 133, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 134, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

Implementation Scheme 12. The anti-CD93 construct of Implementation Scheme 2, wherein V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 145, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 148, 355, or 358, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 149 or 356, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 150, 357, or 359, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

Implementation Scheme 13. The anti-CD93 construct of Implementation Scheme 2, wherein V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 161, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 162, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 163, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 164, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 165, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 166, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

Implementation Scheme 14. The anti-CD93 construct of Implementation Scheme 2, wherein V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 177, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 178, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 179, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) CDR1 comprising the amino acid sequence of SEQ ID NO: 180 or 353, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 181 or 354, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

Implementation Scheme 15. The anti-CD93 construct of Implementation Scheme 2, wherein V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:193, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:194, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:195, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:196, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:197, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:198, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

Implementation Scheme 16. The anti-CD93 construct of Implementation Scheme 2, wherein V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:209, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:210, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:211, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:212, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:213, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:214, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

Implementation Scheme 17. The anti-CD93 construct of Implementation Scheme 2, wherein V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:289, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:290, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:291, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:292, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:293, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:294, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR.

Implementation Scheme 18. An anti-CD93 construct comprising an antibody moiety that specifically binds to CD93, comprising:

a) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:13; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:14;

b) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:29 and 307-312; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:30 and 313-318;

c) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:45; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:46;

d) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:61; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:62;

e) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:77; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:78;

f) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:93; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:94;

g) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:109; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:110;

h) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:125; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:126;

i) HC-CDR1, HC-CDR2 and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2 and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:141, and LC-CDR1, LC-CDR2 and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2 and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:142;

j) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:157 and 360-362; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:158 and 363-365;

k) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:173; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:174;

l) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO: 189 and 347-349; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO: 190 and 350-352.

m)HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:205; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:206;

n) HC-CDR1, HC-CDR2 and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2 and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:221, and LC-CDR1, LC-CDR2 and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2 and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:222;

o) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:287 and 319-321; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:288 and 322-324;

p) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:307-312; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:313-318; or

q) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:319-321, and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:322-324.

Implementation Scheme 19. An anti-CD93 construct of any one of Implementation Schemes 1-18, wherein V _H comprises: an amino acid sequence of any one of SEQ ID NO: 13, 29, 45, 61, 77, 93, 109, 125, 141, 157, 173, 189, 205, 221, 287, 307-312 and 319-321 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and/or wherein V _L comprises: an amino acid sequence of any one of SEQ ID NO: 14, 30, 46, 62, 78, 94, 110, 126, 142, 158, 174, 190, 206, 222, 288, 313-318 and 322-324 or a variant comprising an amino acid sequence having at least about 80% sequence identity.

Implementation Scheme 20. The anti-CD93 construct of Implementation Scheme 19, wherein:

a) V _H comprises: the amino acid sequence of SEQ ID NO:13 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:14 or a variant comprising an amino acid sequence having at least about 80% sequence identity.

b) V _H comprises: the amino acid sequence of any one of SEQ ID NO:29 and 307-312 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and V _L comprises: the amino acid sequence of any one of SEQ ID NO:30 and 313-318 or a variant comprising an amino acid sequence having at least about 80% sequence identity.

c) V _H comprises: the amino acid sequence of SEQ ID NO:45 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:46 or a variant comprising an amino acid sequence having at least about 80% sequence identity.

d) V _H comprises: the amino acid sequence of SEQ ID NO:61 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:62 or a variant comprising an amino acid sequence having at least about 80% sequence identity.

e) V _H comprises: the amino acid sequence of SEQ ID NO:77 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:78 or a variant comprising an amino acid sequence having at least about 80% sequence identity.

f) V _H comprises: the amino acid sequence of SEQ ID NO:93 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:94 or a variant comprising an amino acid sequence having at least about 80% sequence identity.

g) V _H comprises: the amino acid sequence of SEQ ID NO:109 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:110 or a variant comprising an amino acid sequence having at least about 80% sequence identity.

h) V _H comprises: the amino acid sequence of SEQ ID NO:125 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:126 or a variant comprising an amino acid sequence having at least about 80% sequence identity.

i) V _H contains: the amino acid sequence of SEQ ID NO:141 or a variant containing an amino acid sequence having at least about 80% sequence identity; and V _L contains: the amino acid sequence of SEQ ID NO:142 or a variant containing an amino acid sequence having at least about 80% sequence identity.

j) V _H contains: the amino acid sequence of SEQ ID NO:157 or a variant containing an amino acid sequence having at least about 80% sequence identity; and V _L contains: the amino acid sequence of SEQ ID NO:158 or a variant containing an amino acid sequence having at least about 80% sequence identity.

k)V _H comprises: the amino acid sequence of SEQ ID NO:173 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:174 or a variant comprising an amino acid sequence having at least about 80% sequence identity.

l) V _H comprises: the amino acid sequence of any one of SEQ ID NO: 189 and 347-349 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and V _L comprises: the amino acid sequence of any one of SEQ ID NO: 190 and 350-352 or a variant comprising an amino acid sequence having at least about 80% sequence identity.

m)V _H comprises: the amino acid sequence of SEQ ID NO:205 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:206 or a variant comprising an amino acid sequence having at least about 80% sequence identity.

n) V _H comprises: the amino acid sequence of SEQ ID NO:221 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and V _L comprises: the amino acid sequence of SEQ ID NO:222 or a variant comprising an amino acid sequence having at least about 80% sequence identity.

o) V _H comprises: the amino acid sequence of any one of SEQ ID NO:287 and 319-321 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and V _L comprises: the amino acid sequence of any one of SEQ ID NO:288 and 322-324 or a variant comprising an amino acid sequence having at least about 80% sequence identity.

p) V _H comprises: the amino acid sequence of any one of SEQ ID NO:307-312 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and V _L comprises: the amino acid sequence of any one of SEQ ID NO:313-318 or a variant comprising an amino acid sequence having at least about 80% sequence identity, or

q) V _H comprises: an amino acid sequence of any one of SEQ ID NO:319-321 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and V _L comprises: an amino acid sequence of any one of SEQ ID NO:322-324 or a variant comprising an amino acid sequence having at least about 80% sequence identity.

Implementation Scheme 21. An anti-CD93 construct of any one of Implementation Schemes 1-20, wherein the antibody portion is an antibody or an antigen-binding fragment selected from the group consisting of: full-length antibody, bispecific antibody, single-chain Fv (scFv) fragment, Fab fragment, Fab' fragment, F(ab')2, Fv fragment, disulfide-stabilized Fv fragment (dsFv), (dsFv)2, Fv-Fc fusion, scFv-Fc fusion, scFv-Fv fusion, bisomatic antibody, trisomatic antibody, and tetrasomatic antibody.

Implementation scheme 22. The anti-CD93 construct of implementation scheme 21, wherein the antibody portion is a full-length antibody.

Implementation Scheme 23. An anti-CD93 construct of any one of Implementation Schemes 1-22, wherein the antibody portion has an Fc fragment selected from the group consisting of Fc fragments from IgG, IgA, IgD, IgE, IgM, and combinations thereof and hybrids thereof.

Implementation Scheme 24. The anti-CD93 construct of Implementation Scheme 23, wherein the Fc fragment is selected from the group consisting of Fc fragments from IgG1, IgG2, IgG3, IgG4, and combinations thereof and hybrids thereof.

Implementation scheme 25. The anti-CD93 construct of implementation scheme 23 or implementation scheme 24, wherein the Fc fragment has reduced effector functionality compared with the corresponding wild-type Fc fragment.

Implementation Scheme 26. The anti-CD93 construct of Implementation Scheme 23 or Implementation Scheme 24, wherein the Fc fragment has enhanced effector functionality compared to the corresponding wild-type Fc fragment.

Implementation Scheme 27. An anti-CD93 construct of any one of Implementation Schemes 1-26, wherein the antibody partially blocks the binding of CD93 to IGFBP7.

Implementation Scheme 28. An anti-CD93 construct of any one of Implementation Schemes 1-26, wherein the antibody partially blocks the binding of CD93 to MMRN2.

Implementation scheme 29. An anti-CD93 construct of any one of implementation schemes 1-22, wherein CD93 is human CD93.

Implementation Scheme 30. A pharmaceutical composition comprising an anti-CD93 construct of any one of Implementation Schemes 1-29 and a pharmaceutically acceptable carrier.

Implementation Scheme 31. An isolated nucleic acid encoding an anti-CD93 construct of any one of Implementation Schemes 1-28.

Implementation Scheme 32. A vector comprising the isolated nucleic acid of Implementation Scheme 31.

Implementation Scheme 33. An isolated host cell comprising the isolated nucleic acid of Implementation Scheme 31 or the vector of Implementation Scheme 32.

Implementation Scheme 34. An immune conjugate comprising an antiCD93 construct linked to any one of Implementation Schemes 1-29 of a therapeutic agent or marker.

Implementation Scheme 35. A method for generating an anti-CD93 construct, comprising:

a) Culture the isolated host cells described in Implementation Scheme 33 under conditions that effectively express the anti-CD93 construct; and

b) Obtain the expressed anti-CD93 construct from the host cells.

Implementation Scheme 36. A method of treating an individual disease or ailment, comprising administering to the individual an effective amount of the anti-CD93 construct of any one of Implementation Schemes 1-29 or the pharmaceutical composition of Implementation Scheme 30.

Implementation Scheme 37. The method of Implementation Scheme 36, wherein the disease or symptom is associated with abnormal vascular structure.

Implementation scheme 38. The method of implementation scheme 36 or implementation scheme 37, wherein the disease or condition is cancer.

Implementation scheme 39. The method of implementation scheme 38, wherein the cancer is a solid tumor.

Implementation scheme 40. The method of implementation scheme 38 or implementation scheme 39, wherein the cancer includes CD93+ endothelial cells.

Implementation Scheme 41. The method of any one of Implementation Schemes 38-40, wherein the cancer includes IGFBP7+ vessels.

Implementation Scheme 42. The method of any one of Implementation Schemes 38-41, wherein the cancer includes MMRN2+ blood vessels.

Implementation Scheme 43. The method of any one of Implementation Schemes 38-42, wherein the cancer is characterized by tumor hypoxia.

Implementation Scheme 44. The method of any one of Implementation Schemes 38-43, wherein the cancer is locally advanced or metastatic cancer.

Implementation Scheme 45. The method of any one of Implementation Schemes 38-44, wherein the cancer is selected from the group consisting of: lymphoma, colon cancer, brain cancer, breast cancer, ovarian cancer, endometrial cancer, esophageal cancer, prostate cancer, cervical cancer, kidney cancer, bladder cancer, gastric cancer, non-small cell lung cancer, melanoma, and pancreatic cancer.

Implementation Scheme 46. The method of any one of Implementation Schemes 36-45, wherein the anti-CD93 construct is administered to an individual via parenteral administration.

Implementation Scheme 47. The method of any one of Implementation Schemes 36-46, wherein the method further comprises administering a second therapy.

Implementation scheme 48. The method of implementation scheme 47, wherein the second therapy is selected from the group consisting of: surgery, radiotherapy, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormone therapy, targeted therapy, cryotherapy, ultrasound therapy, photodynamic therapy, and chemotherapy.

Implementation scheme 49. The method of implementation scheme 48, wherein the second therapy is immunotherapy.

Implementation scheme 50. The method of implementation scheme 49, wherein the immunotherapy includes the administration of an immunomodulator.

Implementation Scheme 51. The method of Implementation Scheme 50, wherein the immunomodulator is an immune checkpoint inhibitor.

Implementation Scheme 52. The method of Implementation Scheme 51, wherein the immune checkpoint inhibitor comprises an anti-PD-L1 antibody or an anti-PD-1 antibody.

Example 53. The method of any one of Examples 36-52, wherein the individual is a person.

Example

The following embodiments are intended to illustrate this application only and should not be considered as limiting this application in any way. The following embodiments and detailed descriptions are provided by way of illustration rather than limitation.

Example 1. Production of mouse anti-human CD93 monoclonal antibody

Four NZBWF1 mice were immunized with recombinant human CD93 protein (Sino Biologicals). Mice received a primary immunization intraperitoneally with a mixture of 100 μg antigen and 100 μL of complete Freund's adjuvant, followed by two booster immunizations intraperitoneally with a mixture of 100 μg antigen and 100 μL of incomplete Freund's adjuvant. Serum titers were tested and confirmed by ELISA and FACS assays. Five days prior to spleen harvest, a final IP booster immunization with 80 μg antigen was delivered to the mice. Single-cell suspensions of spleen cells from immunized mice were fused with mouse myeloma cell lines. The fused hybridoma supernatants were screened by ELISA for specific binding to human CD93 protein, followed by FACS screening with CD93-expressing CHO cells. Briefly, for FACS screening, the presence of CD93-binding antibodies in the hybridoma supernatant was revealed by PE-labeled goat anti-mouse polyclonal antibodies. Subclonal FACS-positive CD93-specific hybridomas were further confirmed by ELISA and FACS assays. The purified monoclonal antibodies were characterized by functional IGFBP7/CD93 blocking and HUVEC tube formation assays. The resulting hybridomas 16E4, 17B10, and 7F3 were identified as representative antibody clones.

Example 2. Cloning and sequencing of CD93 monoclonal antibody

Sample preparation

Total RNA was isolated from hybridoma cell line cultures (2 x ^10⁶ cells). RNA was processed to remove aberrant transcripts and reverse transcribed using oligonucleotide (dT) primers. Samples of the resulting cDNA were amplified in separate PCRs using frame 1 primer pairs specific to either the heavy or light chain. Reaction products were isolated, size-assessed, and recovered on agarose gels. In some cases, secondary nested PCR was performed to increase the yield of desired fragments. Amplicon was cloned into a 4-TOPO vector using a TA cloning strategy. Fifteen colonies were selected, and plasmid DNA was amplified using primers specific to the vector DNA sequence. The size of the PCR product for each clone insertion was assessed by gel electrophoresis, and six reactions were prepared for sequencing using a PCR cleanup kit and cyclic sequencing with fluorescent dye terminators and capillary-based electrophoresis. Sanger sequencing was performed on the PCR products and the multiplasmid DNA of the TA clones.

Sequence Analysis

DNA sequence data from all constructs were analyzed to identify common sequences for the heavy and light chains. _VH and _VL CDR alignments based on Kabat numbering or VBASE2 tool are shown in Figures 7A-7B and 8A-8B. Tables 3 and 4 list the _VH and _VL CDRs for various antibodies and common sequences.

Table 3. V _H CDRs of various antibodies and common sequences.

Table 4. V _L CDRs of various antibodies and common sequences.

The shared sequences were compared with known variable region sequences to rule out human error and/or process contamination. The shared sequences were then analyzed using online tools to verify that they encode productive immunoglobulins.

Example 3. Measurement of the binding affinity of anti-CD93 antibody to human and cynomolgus monkey CD93 by biolayer interferometry (BLI) assay.

The binding affinity of the anti-CD93 antibody was determined using Octet QKe (Fortebio) via biolayer interferometry. Human recombinant CD93 protein (SinoBiological Inc., catalog number 12589-H08H) or cynomolgus monkey CD93 protein (homemade) was biotinylated using EZ-LINK NHS-PEG4 biotin (Thermo Fisher Scientific). A streptavidin biosensor (Fortebio) was used to load the biotinylated CD93 protein (300 s, 5 μg/ml). The baseline was stabilized for 60 s in 1X kinetic buffer (Fortebio) before allowing serially diluted anti-CD93 antibody to bind to the captured protein for 300 s. The sensor was dissociated in 1X kinetic buffer for 600 s. Data analysis was performed using ForteBio Data Analysis HT 11.1 software.

As shown in Figures 1 and 9, 16E4, 10B1, 7F3, and the reference antibody MM01 all effectively bind to human CD93. 16E4 and MM01 also bind to cynomolgus monkey CD93 (Figure 1). 10B1 and 7F3 also bind to cynomolgus monkey CD93 (data not shown).

Example 4. Determining the binding of anti-CD93 antibody to CHO cells expressing human CD93 on their cell surface by fluorescence activated cell sorting (FACS) assay.

CHO cells expressing human CD93 were isolated by incubation with TrypLE reagent (Thermos Fisher), which maintained the integrity of CD93 on the cell surface. Cells were then incubated with 10 μg/ml anti-CD93 antibody and reference antibody MM01 (SinoBiological Inc., catalog number 12589-MMO1) at 4°C for 30 min. After washing with FACS buffer, cells were incubated with Alexa Fluor 488-conjugated anti-human IgG or anti-mouse IgG antibody (Jackson ImmunoResearch) at 4°C for 30 min. After washing twice with FACS buffer, samples were collected in a NovoCyte flow cytometer and analyzed using NovoExpress software. Similarly, the binding of antibodies 16E4, 10B1, and 7F3 to CHO-K1 cells was tested.

As shown in Figures 2 and 10, all 15 hybridoma clones, as well as the commercially available antibody MM01, bound to CHO cells expressing hCD93 (as evidenced by the separation of peaks corresponding to anti-CD93mAb and control), while there was no binding between CHO-K1 cells and 16E4, 10B1, or 7F3 (as evidenced by the lack of peak separation).

Example 5. IGFBP7/CD93 blocking assay in CHO cells expressing human CD93 by treatment with anti-CD93 antibody.

CHO cells expressing human CD93 ( ¹ x 10⁵ cells per well) were treated with consecutive concentrations of anti-CD93 antibody or an allotype control at 4°C for 30 min. Cells were then incubated with His-tagged human IGFBP7 recombinant protein (0.1 μg/ml) at 4°C for another 30 min. Cells were then washed with FACS buffer and incubated with 1 μg/ml rabbit anti-IGFBP7 antibody (Sino Biological Inc., catalog number 13100-R003) at 4°C for 30 min. After incubation, cells were washed with FACS buffer and incubated with PE-conjugated anti-rabbit IgG antibody (Biolegend) at 4°C for 30 min. After washing twice with FACS buffer, samples were analyzed and data acquired in NovoCyteFlow.

As shown in Figures 3A-3D, 16E4 mAb effectively blocked the interaction between CD93 and IGFBP7 at various concentrations (including the lowest concentration of 0.4 μg/ml) (as evidenced by the reduced separation between the peaks corresponding to anti-CD93 mAb and the negative control). Figure 14 shows that 7F3 effectively blocked the interaction between CD93 and IGFBP7 at 50 μg/ml (as evidenced by the disappearance of the “shoulder” of the control peak).

Example 6. MMRN2/CD93 blocking assay in CHO cells expressing human CD93 by treatment with anti-CD93 antibody.

CHO cells expressing human CD93 (1 x ^10⁵ /well) were treated with 50 μg/ml anti-CD93 antibody (16E4, 10B1, and 7F3) or an allotype control at 4°C for 30 min. Cells were then incubated for another 30 min at 4°C with His-tagged recombinant MMRN2 protein or biotinylated MMRN2 protein (0.1–0.5 μg/ml). After incubation, cells were washed with FACS buffer and incubated at 4°C for 30 min at a 1:500 ratio with anti-His conjugated APC or streptavidin conjugated APC. After washing twice with FACS buffer, samples were analyzed and data acquired in NovoCyte Flow.

As shown in Figures 11A-11B, 7F3 mAb effectively blocked the interaction between MMRN2 and CD93 (as evidenced by the reduced separation between the peaks corresponding to 7F3 mAb and the control; Figure 11A: 0.5 μg/ml MMRN2; Figure 11B: 0.1 μg/ml). 16E4 and 10B1 did not show significant blocking of the interaction between MMRN2 and CD93.

As described above, the blocking effect of 7F3 mIgG1, 5H9 mIgG2a and 16E4 mIgG2a on CD93/MMRN2 was further tested at 0.1 μg/ml MMRN2 ^495-674 and 0.5 μg/ml MMRN2 ^495-674 (self-made), with IgG2a as a negative control.

As shown in Figure 12, 7F3 effectively blocks the CD93/MMRN2 interaction at both 0.1 μg/ml MMRN2 ^(495-674) and up to 0.5 μg/ml MMRN2 ^(495-674 ) (as evidenced by the left shift of the 7F3 peak). 7F3 also effectively blocks the CD93/MMRN2 interaction at 0.1 μg/ml MMRN2, as shown in Figure 13 (as evidenced by the left shift of the 7F3 peak).

Example 7. HUVEC tube formation inhibition test

Human umbilical vein endothelial cells (HUVECs, Thermo Fisher Scientific, Waltham, MA) were cultured in 200 mL of medium supplemented with low serum growth supplement (LSGS, Thermo Fisher Scientific, Waltham, MA) at 37°C and 5% _CO2 . 96-well plates were coated with 50 μL of Geltrex reduced growth factor basement membrane matrix (Thermo Fisher Scientific) and incubated at 37°C for 30 min. To investigate the effect of hybridoma antibody on tube formation, ² x 10⁴ HUVEC cells were seeded onto the matrix-coated plates and incubated at 37°C and 5% _CO2 for 18 h with or without purified hybridoma antibody. Avastin-IL10 fusion protein was used as a control. Images were obtained using an optical microscope.

As shown in Figures 4A-4F and 15A-15B, hybridoma antibodies including 10B1, 16E4, 5H9, 16G9, 19E12, and 7F3 effectively inhibited tube formation at concentrations of 4 μg/ml and/or 8 μg/ml. Specifically, compared to the negative control, the total tube length of HUVECs treated with 10B1 or 16E4 was reduced to 45% and 61.5%, respectively. Compared to the negative control, the total tube length of HUVECs treated with 8 μg/ml of 7F3 was reduced to 71.7%, and to 73.5% at 4 μg/ml. 10B1 achieved inhibitory effects comparable to Avastin at the same dosage.

Example 8. Epitope binning assay of anti-CD93 antibody by Octet competition

The anti-CD93 antibody epitope binning was determined using Octet QKe (Fortebio). Human recombinant CD93 protein (Sino Biological Inc., catalog number 12589-H08H) was biotinylated using EZ-LINK NHS-PEG4 biotin (Thermo Fisher Scientific). A streptavidin biosensor tip (Fortebio) was used to capture the biotinylated human CD93 protein (300 s, 5 μg/ml). The baseline was stabilized in 1X kinetic buffer (Fortebio) for 60 s, followed by allowing the primary anti-CD93 antibody (10 μg/ml) to bind to the captured protein for 300 s. A set of secondary CD93 antibodies (10 μg/ml) was then allowed to rebind to the antigen and primary antibody complex for 300 s. The signal for each binding event was recorded, and data analysis was performed on ForteBio DataAnalysis HT 11.1 software.

As shown in Figures 5A-5B, 5H9, 10B1, 16E4, 16G9, 19E12, 16B6 and MM01 are binding pairs between them, indicating that they bind to different epitopes on CD93.

Example 9. Measurement of cross-binding activity of anti-CD93 mAb in humans and cynomolgus monkeys using biolayer interferometry (BLI) assay.

The binding affinity of the anti-CD93 antibody was determined using Octet QKe (Fortebio) via biolayer interferometry. Human recombinant CD93 protein (SinoBiological Inc., catalog number 12589-H08H) or cynomolgus monkey CD93 protein (homemade) was biotinylated using EZ-LINK NHS-PEG4 biotin (Thermo Fisher Scientific). A streptavidin biosensor (Fortebio) was used to load the biotinylated CD93 protein (300 s, 5 μg/ml). The baseline was stabilized in 1X kinetic buffer (Fortebio) for 60 s before allowing serially diluted anti-CD93 antibody to associate with the captured protein for 300 s. The sensor was then dissociated in 1X kinetic buffer for 600 s. Data analysis was performed using ForteBio Data Analysis HT 11.1 software.

As shown in Figures 6A-6B, 5H9, 12H4, 16B6, 16E4, 16G9, 17A7, 17B10, 17E6, 19B5, 19E12, 20C7, and MM01 cross-react with cynomolgus monkey CD93, while 7C10, 16A1, and 17G11 do not cross-react with cynomolgus monkey CD93.

Table 5 summarizes the characteristics of various anti-CD93 antibodies.

Table 5. Summary of the characteristics of various anti-CD93 antibodies.

Example 10. Humanization of anti-CD93 antibody and generation of VEGF-inhibiting anti-CD93 construct

Exemplary humanized anti-CD93 heavy chain variable sequences and light chain variable sequences were generated. See SEQ ID NO: 307-324 and 347-365 in the sequence listing. The CDR sequences of the humanized heavy chain variable region sequences and light chain variable region sequences of 16E4, 17B10, 16A1, and 7F3 were analyzed, as shown in Tables 6-7.

Table 6. Heavy chain CDR and humanized sequence of anti-CD93 antibody.

Table 7. Light chain CDR and humanized sequence of anti-CD93 antibody.

Various humanized 16E4, 17B10, 16A1 and 7F3 are generated by pairing a humanized heavy chain variable region sequence with a humanized light chain variable region sequence, as shown in Tables 6 and 7.

SDS-PAGE stability analysis of humanized 16E4 and 7F3 is shown in Figure 29. SDS-PAGE was performed under both reducing and non-reducing conditions to assess the stability of the humanized 16E4 and 7F3 antibodies. The humanized 16E4 and 7F3 antibodies were incubated in the dark at 40°C for 2 and 4 weeks. Final samples were run on SDS-PAGE and stained with Coomassie blue to assess any visual changes in the antibodies that may have occurred during incubation. Parental hybridoma 16E4 was run as a positive control. By this SDS-PAGE analysis, no significant changes in recombinant humanized 16E4 and 7F3 were observed at day 0, week 2, or week 4 post-incubation.

An anti-CD93 construct that also targets VEGF was designed and generated. See Figure 16. For example, a VEGF-trap (aflibercept, e.g., SEQ ID NO: 325) is fused to the C-terminus of both heavy chains of a full-length human IgG1 antibody via the linker GSDKTHT (SEQ ID NO: 338), wherein the antibody contains any 7F3 heavy chain variable region and light chain variable region and their humanized sequences (e.g., SEQ ID NO: 287, 288, and 319-324). Exemplary heavy chain and light chain sequences are shown in SEQ ID NOs: 342 and 343. In some embodiments, the heavy chain or light chain further has a signal peptide fused to the N-terminus of the heavy chain or light chain (e.g., SEQ ID NO: 344, 345, or 346).

Example 11. Animal studies using 17B10 antibody

1. Syngeneic B16F10 model

The antitumor activity of the anti-CD93 17B10 antibody was evaluated in a Biocytogen B16F10 melanoma syngeneic mouse model. Octet and FACS analyses showed that the 17B10 antibody did not exhibit strong cross-reactivity with mouse CD93, but did show some binding to CD93-HEK cells at high protein concentrations.

For the syngeneic mouse model, a mouse cell line of B16F10 tumor cells (0.2 x ^10⁶ ) was implanted into female C57BL/6J mice in serum-free medium. When the tumor reached 40–50 ^mm³ , mice (n = 8/test sample) were randomly assigned to groups. Anti-CD93 antibody (and isotype control) was administered intraperitoneally at 0.3 mg/mice on days 0, 3, 7, and 10. Efficacy was assessed based on total tumor volume. Body weight was measured to ensure that the overall health of the animals was not affected by the test sample. 17B10 used in this study was expressed in hybridoma cells and purified by a Protein G column. 16G9 and 16A1 were used for comparison. Tumor volumes for each group are shown in Figure 17. Mice in the 17B10 and 16G9 groups exhibited smaller tumor volumes compared to mice in the 16A1 group and the IgG1 control group, indicating better antitumor efficacy.

2. Lewis lung cancer

The antitumor activity of a humanized anti-CD93 17B10 antibody was evaluated in an endogeneic mouse model of Lewis lung cancer (LLC). Humanized 17B10 containing mouse IgG1 Fc was recombinantly generated in ExpiHEK cells. The antibody was purified using a Protein G column, then concentrated and buffer-exchanged for 1×PBS. Based on Octet and FACS analyses, the humanized 17B10 antibody did not exhibit strong cross-reactivity with mouse CD93, but showed binding at high protein concentrations.

For the syngeneic mouse model, a mouse cell line of LLC tumor cells (0.2 × ^10⁶ ) in serum-free medium was implanted into female C57BL/6J mice. When the tumor reached 40–50 ^mm³ , mice (n = 7/test sample) were randomly assigned to groups. Anti-CD93 antibody (and isotype control) was administered intraperitoneally at 0.3 mg/mice on days 0, 3, 7, and 10. Efficacy was assessed based on total tumor volume. Body weight was measured to ensure that the overall health of the animals was not affected by the test sample.

Figure 18 shows the tumor volume plus/minus SEM from baseline. Figure 18 demonstrates that mice in the 17B10 group exhibited smaller tumor volumes compared to mice in the isotype control group.

3. Development of knock-in mouse models

Two methods were used to develop knock-in mouse models. The knock-in model was designed to replace mouse CD93 protein with human CD93 protein.

Two cuts were performed using CRISPR/Cas9, with guide RNA #1 targeting the ATG region of the 5' UTR of mouse CD93 and guide RNA #2 targeting the beginning of the 3' UTR. Homologous-directed repair fused the mouse 5' UTR to the human CD93 cDNA frame using donor DNA, enabling expression of the endogenous CD93 promoter. Repair downstream of the stop codon ensured that the CD93 hybrid transcript contained the mouse 3' UTR. Pure C57BL/6N mice were used as the background for the knock-in model. Embryonic stem cell clones were generated and expanded using the knock-in human CD93 gene. After sequence confirmation, blastocyst injection was performed to establish a chimeric founder. From there, the embryos were cultured, and heterozygous and homozygous pups were identified by genotyping.

Alternatively, CRISPR/Cas9 was used to remove mouse exon 1 of CD93, which corresponds to the extracellular domain of CD93 (S25-N572). In homology-directed repair, the donor DNA contained the human CD93 sequence from T26-K580. The resulting construct expressed proteins containing the humanized extracellular domain of CD93, as well as mouse transmembrane and intracellular domains. After sequence confirmation, C57BL/6 mouse embryonic stem cells were used for the knock-in model. Ozgene used its proprietary Go-Germiline blastocysts for injection to establish a chimeric basis. Genotyping and phenotyping were performed to ensure heterozygous and homozygous mice.

Example 12. Determination of the binding of anti-CD93 antibody to CD93-expressing cells by flow cytometry.

The ability of recombinant parental anti-CD93 antibody to bind to HUVEC cells in the presence or absence of human serum was evaluated. Sequences 16E4, 7F3, 16A1, and 17B10 obtained from hybridoma cells were recombinantly expressed with the human CH1 domain and the mouse IgG1 CH2 and CH3Fc domains. The antibody was purified using Protein G agarose. The binding ability of the resulting antibody to various CD93-expressing cell lines was tested. HUVEC cells were isolated by incubation with TrypLE reagent (Gibco catalog number 12604-013), which preserves the integrity of the CD93 on the cell surface. Cells were quenched with culture medium and then counted. Cells were resuspended in FACS buffer (ice-cold PBS containing 0.5% BSA), human serum was added to 20% (10% final volume), and the cells were placed on ice for approximately 20 minutes. Cells were seeded at 5 × ^10⁴ cells per well in 100 μL of culture medium and incubated on ice for 2 hours with serially diluted 100 μL of anti-CD93 antibody. Cells were then washed by rotating them at 1200 rpm for 5 minutes. The culture medium was discarded, and the cells were resuspended in 200 μL of ice-cold FACS buffer. The washing step was repeated, and the cells were resuspended in 100 μL of secondary antibody, Alexa Fluor 647-conjugated anti-human IgG or anti-mouse IgG antibody (Jackson ImmunoResearch), diluted 1:500 in FACS buffer. The plate was protected from light and incubated at 4°C for 1 hour. The cells were then washed again and resuspended in 200 μL of ice-cold FACS buffer. The cells were washed again and resuspended in 200 μL of fixative (PBS containing 1% formaldehyde). Samples were stored at 4°C with foil and then collected in a NovoCyte flow cytometer and analyzed using NovoExpress software. Results obtained from serum-containing samples are shown in Figure 19. Results from serum-free samples are shown in Figure 20.

Figures 19 and 20 show that 16E4, 7F3, and 17B10 successfully bound to HUVEC cells under the experimental conditions. The serum-containing sample (Figure 19) showed similar binding ability to the serum-free sample (Figure 20), indicating that the Fc binding of these antibodies had minimal impact on HUVEC cells.

CHO cells expressing CD93 were isolated by incubation with TrypLE reagent (Gibco catalog number 12604-013), which maintained the integrity of CD93 on the cell surface. Cells were quenched with culture medium and then counted. Cells were resuspended in FACS buffer (ice-cold PBS containing 0.5% BSA), human serum was added to 20% (10% final volume), and the cells were placed on ice for approximately 20 minutes. ⁵ x 10⁴ cells were seeded in 100 μL per well and incubated on ice for 2 hours with serially diluted 100 μL of anti-CD93 antibody. Samples were then washed by rotating them at 1200 rpm for 5 minutes. The culture medium was discarded, and cells were resuspended in 200 μL of ice-cold FACS buffer. Cells were washed again and resuspended in 100 μL of secondary antibody, Alexa Fluor 647-conjugated anti-human IgG or anti-mouse IgG antibody (Jackson ImmunoResearch), diluted 1:500 in FACS buffer. Cover the plate with foil to protect it from light and incubate on ice for 1 hour. Wash the cells again and resuspend them in 200 μL of ice-cold FACS buffer. Wash the cells again and resuspend them in 200 μL of fixative (PBS containing 1% formaldehyde). Store the samples covered with foil at 4°C, then collect them in a NovoCyte flow cytometer and analyze them using NovoExpress software. The results are shown in Figure 21.

Figure 21 shows that 16E4, 7F3, 16A1, and 17B10 successfully bound to human CD93CHO cells under experimental conditions. 16E4, 7F3, and 17B10 showed similar binding affinity to hCD93CHO cells, while 16A1 showed a relatively lower affinity for human CD93 compared to other antibodies.

U937 cells were isolated by incubation with TrypLE reagent (Gibco catalog number 12604-013), which maintained the integrity of the CD93 on the cell surface. Cells were quenched with culture medium and then counted. Cells were resuspended in FACS buffer (ice-cold PBS containing 0.5% BSA) and placed on ice for approximately 20 minutes. ⁵ x 10⁴ cells were seeded in 100 μL per well and incubated on ice for 2 hours with serially diluted 100 μL of anti-CD93 antibody. The samples were then washed by rotating them at 1200 rpm for 5 minutes. The culture medium was discarded, and the cells were resuspended in 200 μL of ice-cold FACS buffer. The cells were washed again and resuspended in 100 μL of secondary antibody, Alexa Fluor 647-conjugated anti-human IgG or anti-mouse IgG antibody (Jackson ImmunoResearch), diluted 1:500 in FACS buffer. The plate was covered with foil to protect from light and incubated on ice for 1 hour. The samples were then washed again and resuspended in 200 μL of ice-cold FACS buffer. Cells were washed again and resuspended in 200 μL of fixative (PBS containing 1% formaldehyde). Samples were stored at 4°C with foil covering, and then collected in a NovoCyte flow cytometer and analyzed using NovoExpress software.

Figure 22 shows that, under the experimental conditions, 16E4, 7F3 and 17B10 successfully bound to U937 cells.

Example 13.17 Cell-based assay analysis of the B10 antibody

1. Binding of humanized 17B10 to CHO cells overexpressing human CD93

In ExpiHEK, various humanized 17B10 antibodies were prepared by combining one of three humanized heavy chains with one of three humanized light chains, containing chimeric Fcs with mouse IgG1 CH2 and CH3 domains and human CH1 domain (see Example 10, Tables 6-7). The binding of the resulting antibodies to CHO cells overexpressing human CD93 was tested using FACS analysis. The results are shown in Figures 25A-25B. As shown, all tested antibodies (i.e., H1L1, H1L2, H1L3, H2L1, H2L2, H2L3, H3L1, H3L2, H3L3) effectively bound to CHO cells overexpressing human CD93.

2. Binding of humanized 17B10 to KG1a and U937 cells

As described in Example 12, the binding of humanized 17B10 (VH3VL3, i.e., H3L3) to KG1a and U937 cells was tested. The experiment was repeated using two batches of 17B10 antibody. Figures 26A-26B show that 17B10 binds to KG1a and U937 cells with high affinity.

3. Binding of humanized 17B10 (VH3VL3) to mouse CHO cells

Parental 17B10 antibody and humanized 17B10 were prepared in ExpiHEK. The humanized 17B10 possessed the VH sequence of SEQ ID NO:349 and the VL sequence of SEQ ID NO:352, as well as a chimeric Fc containing mouse IgG1 CH2 and CH3 domains and a human CH1 domain. CHO cells expressing mouse CD93 were isolated by incubation with TrypLE reagent (Thermo Fisher), which maintained the integrity of the CD93 on the cell surface. Cells were then incubated with either parental 17B10 antibody or humanized 17B10 anti-CD93 antibody (50 μg/mL) at 4°C for 30 min. After washing with FACS buffer, cells were incubated with Alexa Fluor 488-conjugated anti-human IgG or anti-mouse IgG antibody (Jackson ImmunoResearch) at 4°C for 30 min. After washing twice with FACS buffer, samples were collected in a NovoCyte flow cytometer and analyzed using NovoExpress software.

Figure 27 shows that humanized 17B10 binds to cells expressing mouse CD93 at a concentration of 50 μg/mL.

4. Combination of humanized 17B10 (VH3VL3) with mCD93 HEK

HEK cells expressing mouse CD93 were isolated by incubation with TrypLE reagent (Thermo Fisher), which maintained the integrity of the CD93 on the cell surface. Cells were then incubated with serially diluted parental 17B10 and humanized 17B10 (H3L3) anti-CD93 antibodies at 4°C for 30 min. After washing with FACS buffer, cells were incubated with Alexa Fluor 488-conjugated anti-human IgG or anti-mouse IgG antibodies (Jackson ImmunoResearch) at 4°C for 30 min. After washing twice with FACS buffer, samples were collected in a NovoCyte flow cytometer and analyzed using NovoExpress software.

Figure 28 shows that both parental 17B10 and humanized 17B10 (H3L3) bind to HEK cells expressing mouse CD93 at a concentration of 50 μg/mL.

4. HUVEC tube formation test

The inhibitory effect of humanized 17B10 anti-CD93 antibody (H3L3) on angiogenesis was tested in a HUVEC tube formation assay. Human umbilical vein endothelial cells (HUVEC, Thermo Fisher Scientific, Waltham, MA) were cultured in 200g of medium supplemented with low serum growth supplement (LSGS, Thermo Fisher Scientific, Waltham, MA) at 37°C and 5% _CO2 . 96-well plates were coated with 50 μl of Geltrex reduced growth factor basement membrane matrix (Thermo Fisher Scientific) and incubated at 37°C for 30 min. To investigate the effect of the humanized 17B10 antibody on tube formation, ¹ x 10⁴ HUVEC cells were seeded onto the matrix-coated _plates and incubated at 37°C and 5% CO2 for 18 h with and without different concentrations of purified antibody. Cells were stained with calcein AM, and images were collected. Figures 23-24 show that, compared with the control, humanized 17B10 inhibited tube formation at certain concentrations.

5.17B10 antibody blocking ability

17B10 antibodies (parental and humanized) were tested in cell-based assays.

Neither the parental nor the humanized 17B10 antibody significantly blocked the binding of IGFBP7 to CD93 or MMRN2 to CD93 (data not shown).

Example 14. ELISA binding assay of anti-CD93 antibody

The parental 16E4 and 7F3 generated by hybridomas were compared with the recombinant and chimeric forms of antibodies. His-tagged human CD93 was coated onto 96-well plates overnight at 4°C with 1 μg/mL in 1X PBS. The plates were washed with ELISA wash buffer (Boston BioProduct, Inc.) and the wells were blocked with ELISA blocking buffer at 37°C for 1 hour. The purified antibodies were serially diluted in ELISA blocking buffer (Boston BioProduct, Inc.) and incubated on the receptor at 37°C for 1 hour. The plates were washed with ELISA wash buffer. HRP-conjugated anti-mouse Fc was diluted in ELISA blocking buffer and added to wells containing hybridoma-generated 16E4 and 7F3 (16E4-Hyb and 7F3-Hyb in Figure 30). HRP-conjugated anti-human Fc was added to wells containing humanized 16E4 and 7F3 antibodies (16E4-hIgG1 and 7F3-hIgG1 in Figure 30) and incubated at 37°C for 1 hour. The plate was washed with ELISA wash buffer. HRP substrate was added for indirect detection of antibodies binding to CD93. Figure 30 shows that the recombinant chimeric antibody has a stronger affinity for CD93 than the parent antibody under this method.

Humanized 7F3 antibodies were stored in the dark at 40°C for 2 or 4 weeks. His-tagged human CD93 was coated onto 96-well plates overnight at 4°C at a concentration of 1 μg/mL in 1X PBS. The plates were washed with ELISA wash buffer (Boston BioProduct, Inc.) and the wells were blocked with ELISA blocking buffer at 37°C for 1 hour. The purified 7F3 antibody was serially diluted in ELISA blocking buffer (Boston BioProduct, Inc.) and incubated on the receptor at 37°C for 1 hour. The plates were washed with ELISA wash buffer. HRP-conjugated anti-human Fc antibodies were incubated at 37°C for 1 hour. The plates were washed with ELISA wash buffer. HRP substrate was added for indirect detection of antibodies binding to CD93. Figure 31 shows that no difference was observed between treated and untreated samples by ELISA.

Humanized 16E4 antibody was stored in the dark at 40°C for 2 or 4 weeks. His-tagged human CD93 was coated onto 96-well plates overnight at 4°C at a concentration of 1 μg/mL in 1X PBS. The plates were washed with ELISA wash buffer (Boston BioProduct, Inc.) and the wells were blocked with ELISA blocking buffer at 37°C for 1 hour. The purified 16E4 antibody was serially diluted in ELISA blocking buffer (Boston BioProduct, Inc.) and incubated on the receptor at 37°C for 1 hour. The plates were washed with ELISA wash buffer. HRP-conjugated anti-human Fc antibody was incubated at 37°C for 1 hour. The plates were washed with ELISA wash buffer. HRP substrate was added for indirect detection of the antibody binding to CD93. Figure 32 shows that no difference was observed between treated and untreated samples by ELISA.

Hybridoma-derived 17B10 antibody (17B10-Hyb in Figure 33) was compared with recombinant parental 17B10-hFc (17B10-hIgG1 in Figure 33) and humanized 17B10-mFc (h17B10-H3L3 in Figure 33) to determine binding to human CD93. His-tagged human CD93 was coated onto 96-well plates overnight at 4°C at a concentration of 1 μg/mL in 1X PBS. The plates were washed with ELISA wash buffer (Boston BioProduct, Inc.) and the wells were blocked with ELISA blocking buffer at 37°C for 1 hour. The purified 17B10 antibody was serially diluted in ELISA blocking buffer (Boston BioProduct, Inc.) and incubated on the receptor at 37°C for 1 hour. The plates were washed with ELISA wash buffer. HRP-conjugated anti-mouse Fc was diluted in ELISA blocking buffer and added to wells containing hybridoma-generated 17B10. HRP-conjugated anti-human Fc was added to wells containing recombinant 17B10 antibody, and the plates were incubated at 37°C for 1 hour. The plates were washed with ELISA washing buffer. HRP substrate was added for indirect detection of antibodies binding to CD93. Figure 33 shows that the molecule containing mouse Fc binds weakly to human CD93 compared to the recombinant parent 17B10 containing human Fc.

Chimeric 17B10 molecules were prepared using humanized CDR and human CH1 domains, but mouse IgG1 CH2 and CH3 domains. The binding ability of this molecule to mouse MMRN2-mFc and human CD93 was compared. His-tagged human CD93 was coated onto 96-well plates overnight at 4°C at a concentration of 1 μg/mL in 1X PBS. The plates were washed three times with ELISA wash buffer (PBS containing Tween; Boston Bioproducts catalog number BB-171), and then blocked with 200 μL ELISA blocking buffer (5% BSA in PBS (VWR catalog number #0332)) at room temperature for 1 hour. The plates were then washed three times with ELISA wash buffer, and the purified 17B10 antibody and mouse MMRN2-mFc were serially diluted in ELISA blocking buffer (5% BSA in PBS) and incubated on the receptor at 100 rpm for 2 hours at room temperature. Wash the plate three times with ELISA wash buffer, then add HRP-conjugated anti-mouse Fc antibody (Jackson ImmunoResearch catalog number 115-035-164) to 17B10 and mouse MMRN2-mFc, and incubate at 100 rpm for 1 hour at room temperature on a cyclotron. Add HRP-conjugated anti-mouse Fc antibody (Jackson ImmunoResearch catalog number 115-035-164) to each well and incubate at 100 rpm for 1 hour at room temperature on a cyclotron. Wash the plate three times with ELISA wash buffer, then add 100 μL TMB (SeraCare catalog number 5120-0077) to each well and allow mixing for 1–5 minutes, then stop by adding 100 μL 1.0N sulfuric acid (VWR catalog number BDH7232-1). Measure the absorbance at 450 nm. The absorbance signal was corrected by subtracting the average background signal from the control wells containing only secondary HRP Ab. Figure 34 shows that the binding of 17B10 to human CD93-his by ELISA is superior to that of mouse MMRN2-mFc.

Example 15. FACS-based binding assay of anti-CD93 antibody

The binding of anti-CD93 antibodies 7F3 and 16E4 to CHO cells expressing human CD93 on their cell surface was determined by fluorescence-activated cell sorting (FACS) assays. CHO cells expressing human CD93 were isolated by incubation with TrypLE reagent (Thermo Fisher), which maintained the integrity of the CD93 on the cell surface. Cells were then incubated with serially diluted anti-CD93 antibodies at 4°C for 30 min. After washing with FACS buffer, cells were incubated with Alexa Fluor 647-conjugated anti-human IgG (Jackson Immuno Research) at 4°C for 30 min. After washing twice with FACS buffer, samples were collected in a NovoCyte flow cytometer and analyzed using NovoExpress software. Recombinant 16E4 bound cells at 0.24 nM EC50, while recombinant 7F3 antibody bound cells at 0.4 nM EC50 (Figure 35).

The binding of humanized 7F3 anti-CD93 antibody to CHO cells expressing human CD93 on their cell surface was determined by fluorescence-activated cell sorting (FACS) assay. The humanized 7F3 antibody was stored in the dark at 40°C for 2 or 4 weeks. CHO cells expressing human CD93 were isolated by incubation with TrypLE reagent (Thermo Fisher), which maintained the integrity of the CD93 on the cell surface. Cells were then incubated with serially diluted anti-CD93 antibody at 4°C for 30 minutes. After washing with FACS buffer, cells were incubated with Alexa Fluor 647-conjugated anti-human IgG (Jackson ImmunoResearch) at 4°C for 30 minutes. After washing twice with FACS buffer, samples were collected in a NovoCyte flow cytometer and analyzed using NovoExpress software. The affinity of the 7F3 antibody for CD93 did not change due to high-temperature treatment (Figure 36).

Humanized 16E4 antibody was stored in the dark at 40°C for 2 or 4 weeks. CHO cells expressing human CD93 were isolated by incubation with TrypL reagent (Thermo Fisher), which maintained the integrity of CD93 on the cell surface. Cells were then incubated with serially diluted anti-CD93 antibody at 4°C for 30 minutes. After washing with FACS buffer, cells were incubated with Alexa Fluor 647-conjugated anti-human IgG (Jackson ImmunoResearch) at 4°C for 30 minutes. After washing twice with FACS buffer, samples were collected in a NovoCyte flow cytometer and analyzed using NovoExpress software. Incubation with humanized 16E4 at 40°C did not reduce the binding of the antibody to CD93-expressing cells (Figure 37).

Humanized 7F3 antibodies were stored in the dark at 40°C for 2 or 4 weeks. HUVEC cells were isolated by incubation with TrypLE reagent (Thermo Fisher), which maintained the integrity of CD93 on the cell surface. Cells were then incubated with serially diluted anti-CD93 antibody at 4°C for 30 minutes. After washing with FACS buffer, cells were incubated with Alexa Fluor 647-conjugated anti-human IgG (Jackson ImmunoResearch) at 4°C for 30 minutes. After washing twice with FACS buffer, samples were collected in a NovoCyte flow cytometer and analyzed using NovoExpress software. Incubation with humanized 7F3 at 40°C did not reduce antibody binding to HUVEC cells (Figure 38).

Binding of 7F3 anti-CD93 antibody to KG1a cells was determined by fluorescence-activated cell sorting (FACS) assay. Humanized 7F3 antibody was stored in the dark at 40°C for 2 or 4 weeks. KG1a cells were isolated by incubation with TrypLE reagent (ThermoFisher), which maintained the integrity of CD93 on the cell surface. Cells were then incubated with serially diluted anti-CD93 antibody at 4°C for 30 minutes. After washing with FACS buffer, cells were incubated with Alexa Fluor 647-conjugated anti-human IgG (Jackson ImmunoResearch) at 4°C for 30 minutes. After washing twice with FACS buffer, samples were collected in a NovoCyte flow cytometer and analyzed using NovoExpress software. Incubation of 7F3 at 40°C did not reduce antibody binding to KG1a cells (Figure 39).

Humanized 16E4 antibody was stored in the dark at 40°C for 2 or 4 weeks. KG1a cells were isolated by incubation with TrypLE reagent (Thermo Fisher), which maintained the integrity of CD93 on the cell surface. Cells were then incubated with serially diluted anti-CD93 antibody at 4°C for 30 min. After washing with FACS buffer, cells were incubated with Alexa Fluor 647-conjugated anti-human IgG (Jackson ImmunoResearch) at 4°C for 30 min. After washing twice with FACS buffer, samples were collected in a NovoCyte flow cytometer and analyzed using NovoExpress software. Incubation with 16E4 at 40°C did not reduce antibody binding to KG1a cells (Figure 40).

Example 16. Anti-CD93 antibody Octet binding assay

The binding affinity of the anti-CD93 antibody was determined using a biolayer interferometry assay with Octet QKe (Fortebio). Humanized 7F3 antibodies were stored in the dark at 40°C for 2 or 4 weeks. Recombinant human CD93 protein (Sino Biological Inc., catalog number 12589-H08H) was biotinylated using EZ-LINK NHS-PEG4 biotin (ThermoFisher Scientific). A streptavidin biosensor (Fortebio) was used to load the biotinylated CD93 protein (300 seconds, 5 μg/ml). The baseline was stabilized for 60 seconds in 1X kinetic buffer (Fortebio) before allowing serially diluted anti-CD93 antibody to associate with the captured protein for 300 seconds. The sensor was then dissociated in 1X kinetic buffer for 600 seconds. Data analysis was performed using ForteBio Data Analysis HT 11.1 software. The binding affinity of the humanized 7F3 antibody to CD93 was not affected by incubation at 40°C (Figure 41).

The binding affinity of the anti-CD93 antibody was determined using a biolayer interferometry assay with Octet QKe (Fortebio). Humanized 16E4 antibody was stored in the dark at 40°C for 2 or 4 weeks. Recombinant human CD93 protein (Sino Biological Inc., catalog number 12589-H08H) was biotinylated using EZ-LINK NHS-PEG4 biotin (ThermoFisher Scientific). A streptavidin biosensor (Fortebio) was used to load the biotinylated CD93 protein (300 seconds, 5 μg/ml). The baseline was stabilized for 60 seconds in 1X kinetic buffer (Fortebio) before allowing serially diluted anti-CD93 antibody to associate with the captured protein for 300 seconds. The sensor was then dissociated in 1X kinetic buffer for 600 seconds. Data analysis was performed using ForteBio Data Analysis HT 11.1 software. The binding affinity of the humanized 16E4 antibody to CD93 was not affected by incubation at 40°C (Figure 42).

Figure 43 summarizes the binding affinity of 16E4 and 7F3.

Example 17. Anti-CD93 antibody blocking function test

The blocking effect of 7F3 anti-CD93 antibody on the binding of MMRN2 to CHO cells expressing human CD93 on their cell surface was determined by fluorescence activated cell sorting (FACS) assay. Humanized 7F3 antibody was stored in the dark at 40°C for 2 or 4 weeks. CHO cells expressing human CD93 (1 x ^10⁵ cells per well) were treated with serially diluted anti-CD93 7F3 antibody or an isotype control at 4°C for 30 min. Cells were then incubated with 0.1 μg/ml hMMRN2 _495-674 . After incubation, cells were washed with FACS buffer and incubated with an APC-conjugated anti-His tag (BioLegend) at 4°C for 30 min to detect MMRN2 binding. After washing twice with FACS buffer, samples were analyzed and data acquired in NovoCyte Flow. Recombinant his-tagged hMMRN2 _495-674 was generated internally in *E. coli* following standard procedures. Incubation of 7F3 at 40°C did not affect its ability to block the binding of MMRN2 to CHO cells expressing human CD93 (Figure 44).

The blocking effect of humanized 7F3 and 16E4 anti-CD93 antibodies on the binding of MMRN2 to CHO cells expressing human CD93 on their cell surface was also determined by fluorescence activated cell sorting (FACS) assays. CHO cells expressing human CD93 ( ¹ x 10⁵ cells per well) were treated with serially diluted anti-CD93 7F3 or 16E4 antibodies or an allotype control at 4°C for 30 min. Cells were then incubated with 0.1 μg/ml hMMRN2 _495-674 . An APC-conjugated anti-His tag (BioLegend) was used to detect MMRN2 binding. Cells were then washed with FACS buffer and incubated with 1 μg/ml APC-conjugated anti-His-tagged antibody at 4°C for 30 min. After washing twice with FACS buffer, samples were analyzed and data acquired in NovoCyte Flow. Recombinant his-tagged hMMRN2 _495-674 was generated internally in Expi_HEK according to standard procedures. Humanized 7F3 can block the binding of MMRN2 to CHO cells expressing human CD93, but humanized 16E4 cannot (Figure 45).

The blocking effect of humanized 7F3 anti-CD93 antibody on the binding of IGFBP7 to the cell surface of HUVEC cells was determined by FACS. HUVEC cells ( ¹ x 10⁵ cells per well) were treated with serially diluted humanized anti-CD93 7F3 antibody or an allotype control at 4°C for 30 min. Cells were then incubated with His-tagged recombinant human IGFBP7 protein (0.1 μg/ml) at 4°C for another 30 min. After incubation, cells were washed with FACS buffer and incubated with an APC-conjugated anti-His tag (BioLegend) at 4°C for 30 min to detect IGFBP7 binding. After washing twice with FACS buffer, samples were analyzed and data acquired in NovoCyte Flow. As shown in Figure 46, the 7F3 antibody blocked the binding of IGFBP7 to HUVEC cells.

The blocking effect of 7F3 and 16E4 on the binding of IGFBP7 to CD93 was determined using biolayer interferometry (BLI). The blocking effect of anti-CD93 antibodies 7F3 and 16E4 on the binding of IGFBP7 to hCD93 was determined using OctetQKe (Fortebio) via biolayer interferometry. Recombinant human CD93 protein (Sino Biological Inc., catalog number 12589-H08H) was biotinylated using EZ-LINK NHS-PEG4 biotin (Thermo Fisher Scientific). A streptavidin biosensor (Fortebio) was used to load the biotinylated CD93 protein (300 seconds, 5 μg/mL). The baseline was stabilized in 1X kinetic buffer (Fortebio) for 60 seconds before allowing the anti-CD93 antibody and negative control antibody (9F9) (90 μg/mL) to associate with the captured protein for 300 seconds. IGFBP7 was added for 300 seconds of association. The sensor was then dissociated in 1X kinetic buffer for 600 seconds. Data analysis was performed using ForteBio Data Analysis HT 11.1 software. Hybridoma and humanized 7F3 and 16E4 antibodies were able to block the association between IGFBP7 and human CD93 (Figures 47 and 48).

Example 18. Anti-CD93 antibody tube formation assay

The inhibitory effects of humanized 7F3 and 16E4 anti-CD93 antibodies on angiogenesis were tested in a HUVEC tube formation assay. Human umbilical vein endothelial cells (HUVEC, Thermo Fisher Scientific, Waltham, MA) were cultured in 200 mL of medium supplemented with low serum growth supplement (LSGS, Thermo Fisher Scientific, Waltham, MA) at 37°C and 5% _CO2 . 96-well plates were coated with 50 μL of Geltrex reduced growth factor basement membrane matrix (Thermo Fisher Scientific) and incubated at 37°C for 30 min. To investigate the effect of humanized 7F3 and 16E4 antibodies on tube formation, ² x 10⁴ HUVEC cells were seeded onto the matrix-coated plates and incubated at 37°C and 5% _CO2 for 18 h with or without purified antibody (40 μg/mL). Cells were stained with calcein AM, and images were collected. Figures 49 and 50 show that, compared with the control, humanized 16E4 showed 92.5% tube formation, while humanized 7F3 showed 72.5% tube formation.

Example 19. Antitumor effect of CD93 antibody in KI mouse model

The antitumor activity of anti-CD93 antibodies was evaluated in a B16F10 melanoma syngeneic hCD93 KI mouse model using conventional techniques in the art. The mice used in the study had heterozygous human CD93 knock-in, so that half of the mouse CD93 was completely replaced by human CD93.

For the syngeneic mouse model, a mouse cell line containing B16F10 tumor cells (0.2 x ^10⁶ ) in serum-free medium was implanted into heterozygous human CD93 KI-C57BL/6J mice. When the tumor reached 40-50 ^mm³ , mice (n = 8/test sample) were randomly assigned to groups. Anti-CD93 antibodies, including h16E4 (humanized 16E4, VH4+VL6), h7F3 (humanized 7F3, VH3+VL3), 17B10 chimeric (m17B10-hIgG1), and an isotype control antibody, were administered intraperitoneally twice weekly for 4 weeks at 15 mg/kg. Tumor volume and body weight were measured for each mouse. After the study, the tumors were surgically removed, weighed, measured, and rapidly frozen for cell analysis. The antitumor efficacy of the anti-CD93 antibodies was assessed based on total tumor volume. Body weight was measured throughout the study to ensure the overall health of the animals.

Table 8: Anti-B16 tumor activity of CD93 antibody on day 5 post-injection in humanized CD93 knock-in mouse model

Standard error of group mean +/- mean, tumor volume ( ^mm³ )

Average growth

Average growth = Average (T/T0) × 100%

T - Current value

T0 - Initial value

As shown in Table 8, all tested CD93 antibodies significantly blocked tumor growth as early as 5 days after injection, reducing tumor growth by 2.6 to 2.8 times. No significant difference was found in the antitumor activity of the three tested CD93 antibodies.

This study confirms that the CD93 antibody of this invention can inhibit tumors in vivo.

See Figure 51 for a summary of the characteristics of 16E4, 7F3, 16A1, and 17B10.

Example 20: Animal study of human CD93 KI heterozygous mice using the B16F10 model.

1. Development of a human CD93 knock-in mouse model

Design a knock-in model to replace mouse CD93 protein with human CD93 protein. Two methods described below are used to develop the knock-in mouse model.

Two cuts were performed using CRISPR/Cas9, with guide RNA #1 targeting the ATG region of the 5'UTR of mouse CD93 and guide RNA #2 targeting the beginning of the 3'UTR. Homologous-directed repair was performed by fusing the mouse 5'UTR to the human CD93 cDNA frame using a donor, enabling expression from the endogenous CD93 promoter. Repair downstream of the stop codon ensured that the CD93 hybrid transcript contained the mouse 3'UTR. Pure C57BL/6N mice were used as the background for the knock-in model. Embryonic stem cell clones were generated and amplified using the knock-in human CD93 gene. After sequence confirmation, blastocyst injection was performed to establish a chimeric basis. From there, the embryos were cultured, and genotyping was used to identify heterozygous and homozygous pups.

Alternatively, CRISPR/Cas9 was used to remove mouse exon 1 of CD93, which corresponds to the extracellular domain of CD93 (S25-N572). In homology-directed repair, the donor DNA contained the human CD93 sequence from T26-K580. The resulting construct expressed proteins containing the humanized extracellular domain of CD93, as well as mouse transmembrane and intracellular domains. After sequence confirmation, C57BL/6 mouse embryonic stem cells were used for the knock-in model. Ozgene used its proprietary Go-Germiline blastocysts for injection to establish a chimeric basis. Genotyping and phenotyping were performed to ensure the generation of heterozygous and homozygous mice.

2. B16F10 murine melanoma

B16F10 (CCL-6475 ^™ ) is a murine melanoma cell line derived from C57BL/6J mice. It is a subclone of the B16 tumor line. B16F10 is generated through the following steps: B16 tumor cells are injected into mice, secondary tumor growth is collected and cultured, and these cells are injected into new mice, repeated 10 times. The cells adhere in an epithelial morphology. B16F10 cells are highly metastatic and will form tumors and metastasize after implantation into syngeneic C57BL/6 mice.

B16F10 cell lines were maintained as monolayer cultures in vitro at 37°C in a humidified incubator with a 5% _CO2 atmosphere in Dulbecco's Modified Eagle's medium (DMEM) supplemented with GlutaMAX ^™ and 10% fetal bovine serum (FBS). Tumor cells were routinely subcultured 2–3 times weekly with trypsin-EDTA treatment, depending on growth rate and division rate. For cell seeding, cells in the exponential growth phase were harvested, centrifuged at 335 g in a refrigerated centrifuge, and the medium was aspirated. The cell aggregates were resuspended in 10 × 10⁶ volumes of serum-free medium and counted. The cell suspension was centrifuged again as described above, resuspended in serum-free medium, and brought to a final cell concentration of 2.0 × ^10⁶ cells/mL (50% serum-free medium and 50% GelTrex), delivering the required number of cells per 0.1 mL seeding. The cell suspension was kept on ice until seeding.

3. A human CD93 KI heterozygous B16F10 mouse model for evaluating the efficacy of anti-CD93 antibodies.

The antitumor effects of humanized anti-CD93 7F3, 16E4, and 17B10 antibodies in human CD93 KI heterozygous mice were evaluated in a B16F10 melanoma model. The experimental design is shown in Table 9.

Table 9: Experimental design for antibody efficacy evaluation using the B16F10 mouse model

The 17B10 antibody is the same as that used in Example 11 (Animal Studies Using the 17B10 Antibody).

When the tumor reached 50-60 ^mm³ , mice (n = 8 mice/group) were randomly assigned to groups. Anti-CD93 antibody (and isotype control) was administered intraperitoneally at 0.3 mg/mice on days 0, 5, 8, and 11. Efficacy was assessed based on total tumor volume. Body weight was measured to ensure that the overall health of the animals was not affected by the test.

Figure 52A shows that mice in the 7F3 and 16E4 groups exhibited smaller tumor volumes compared to mice in the 17B10 chimeric group. The mean tumor volume in the 7F3 and 16E4 groups was approximately 50% of the mean tumor volume in the control group and approximately 60% of the mean tumor volume in the 17B10 chimeric group. The body weight of mice in all tested antibody groups, including the isotype control group, was not affected by the test product.

4. A human CD93 KI homozygous mouse B16F10 model for evaluating the molecular efficacy against CD93.

To evaluate the antitumor effects of humanized anti-CD93 7F3, 16E4 and 17B10 antibodies in human CD93 KI homozygous mice in the B16F10 melanoma model.

Table 11: Experimental design for evaluating the efficacy of antibody-fusion protein using the B16F10 mouse model

17B10 antibody is a humanized therapeutic antibody.

When the tumor reached 50-60 ^mm³ , mice (n = 8/test sample) were randomly assigned to groups. Anti-CD93 antibody (and isotype control) was administered intraperitoneally at 0.3 mg/mice on days 0, 3, 6, and 11. Efficacy was assessed based on total tumor volume. Body weight was measured to ensure the overall health of the animals was not affected by the test.

By displaying tumor volume +/- SEM from the isotype control baseline, Figure 52C shows that mice in the 7F3, 16E4, 17B10, and 7F3/VEGFRFc groups exhibited significant tumor growth inhibition (p<0.05) compared to mice in the IgG1 isotype control group, indicating excellent antitumor efficacy. The body weight of mice in all tested antibody groups, including the isotype control group, was not affected by the test.

Example 21. Generation and evaluation of bispecific anti-CD93 antibody and VEGFR fusion protein

1. Design of bispecific anti-CD93 antibody and VEGFR fusion protein

Design and generation of anti-CD93 constructs also targeting VEGF. See Figure 53A. For example, a VEGF-trap (aflibercept, e.g., SEQ ID NO:325) is fused to the C-terminus of both heavy chains of a full-length human IgG1 antibody, wherein the full-length human IgG1 antibody includes a heavy chain variable region and a light chain variable region of either 7F3 or its humanized sequence. An exemplary construct of h7F3/VEGFR having the heavy chain-aflibercept fusion of SEQ ID NO:366 and the light chain of SEQ ID NO:367 is denoted as h7F3/VEGFRFc and used for further characterization.

2. The binding of primitive mouse 7F3, humanized 7F3, and humanized 7F3/VEGFRFc to CHO cells expressing human CD93 on their cell surface was determined by fluorescence activated cell sorting (FACS) assay.

CHO cells expressing human CD93 were isolated by incubation with TrypLE reagent (Thermos Fisher), which maintained the integrity of CD93 on the cell surface. Cells were then incubated with pristine mouse 7F3, humanized 7F3, and humanized 7F3/VEGFRFc at 10 μg/ml at 4°C for 30 min. After washing with FACS buffer, cells were incubated with Alexa Fluor 488-conjugated anti-human IgG or anti-mouse IgG antibody (Jackson ImmunoResearch) at 4°C for 30 min. After washing twice with FACS buffer, samples were acquired in a NovoCyte flow cytometer and analyzed using NovoExpress software.

As shown in Figure 53B, the original murine 7F3, humanized 7F3, and the humanized 7F3/VEGFRFc bispecific fusion protein all showed strong binding to CHO cells expressing hCD93. No binding was observed in the IgG isotype control.

3. IGFBP7/CD93 blocking assay in CHO cells expressing human CD93 by treatment with original mouse 7F3, humanized 7F3, and humanized 7F3/VEGFRFc

CHO cells expressing human CD93 (1 × ^10⁵ /well) were treated with 50 μg/ml of original mouse 7F3, humanized 7F3, and humanized 7F3/VEGFRFc bispecific fusion protein or an isotype control at 4 °C for 30 min. Cells were then incubated with HIS-tagged human IGFBP7 recombinant protein (0.5 μg/ml) at 4 °C for 30 min. Cells were then washed with FACS buffer and incubated with 1 μg/ml rabbit anti-IGFBP7 antibody (Sino Biological Inc, catalog number 13100-R003) at 4 °C for 30 min. After incubation, cells were washed with FACS buffer and incubated with PE-conjugated anti-rabbit IgG antibody (Biolegend) at 4 °C for 30 min. After washing twice with FACS buffer, samples were analyzed and data acquired in NovoCyte Flow.

As shown in Figure 53C, the original murine 7F3, humanized 7F3, and humanized 7F3/VEGFRFc can block the interaction between CD93 and IGFBP7. The isotype control antibody cannot block the interaction between CD93 and IGFBP7.

4. MMRN2/CD93 blocking assay in CHO cells expressing human CD93 by treatment with original mouse 7F3, humanized 7F3, and humanized 7F3/VEGFRFc

CHO cells expressing human CD93 (1 × ^10⁵ /well) were treated at 4 °C for 30 min with 50 μg/ml of the original mouse 7F3, humanized 7F3, and humanized 7F3/VEGFRFc bispecific fusion protein, or an isotype control. Cells were then incubated at 4 °C for another 30 min with biotinylated MMRN2 protein (0.001 μg/ml). After incubation, cells were washed with FACS buffer and incubated at 4 °C for 30 min with streptavidin-conjugated APCs at a ratio of 1:1000. After washing twice with FACS buffer, samples were analyzed and data acquired in NovoCyte Flow.

As shown in Figure 53D, the original mouse 7F3, humanized 7F3, and humanized 7F3/VEGFRFc effectively blocked the interaction between MMRN2 and CD93, but the isotype control antibody did not show any blocking of the interaction between MMRN2 and CD93.

5. ELISA combination assay of primitive rodent 7F3, humanized 7F3, and humanized 7F3/VEGFRFc

At 4°C, coat 96-well plates with His-tagged human CD93, rh VEGFA (recombinant human VEGFA), or unrelated His protein at a concentration of 1 μg/mL in 1×PBS overnight. Wash the plates with ELISA wash buffer (Boston BioProduct, Inc.) and block the wells for 1 hour at 37°C with 3% BSA/PBS ELISA block buffer. Incubate Avastin, humanized 7F3, and humanized 7F3/VEGFRFc on ice for 1 hour. Wash the plates with ELISA wash buffer. Add HRP-conjugated anti-human Fc and incubate at 37°C for 1 hour. Wash the plates with ELISA wash buffer and read them at 405 nm using a microplate reader.

The results shown in Figure 53E demonstrate that 7F3/VEGFRFc and Avastin bind strongly to VEGFA, while chimeric 7F3 and humanized 7F3/VEGFRFc bind strongly to rhCD93. None of Avastin, chimeric 7F3, and humanized 7F3/VEGFRFc showed binding to unrelated His proteins.

His-tagged human CD93, cynomolgus monkey CD93, human VEGFA, and mouse VEGFA were coated onto 96-well plates overnight at 4°C with a concentration of 1 μg/mL in 1×PBS. The plates were washed with ELISA wash buffer (Boston BioProduct, Inc.) and the wells were blocked for 1 hour at 37°C with 3% BSA/PBS ELISA block buffer. Avastin, humanized 7F3, chimeric 7F3/VEGFRFc, and humanized 7F3/VEGFRFc, along with control human IgG Fc, were incubated on ice for 1 hour. The cultures were washed with ELISA wash buffer. HRP-conjugated anti-human Fc was added and incubated at 37°C for 1 hour. The plates were washed with ELISA wash buffer and read at 405 nm using a microplate reader.

As shown in Figure 53F, chimeric 7F3, chimeric 7F3/VEGFRFc, and humanized 7F3/VEGFRFc strongly bound to rh CD93 (recombinant human CD93), cynomolgus monkey CD93, rh VEGFA (recombinant human VEGFA), and rm VEGFA (recombinant mouse VEGFA). Chimeric 7F3 did not show binding to rh VEGFA. Avastin did not show binding to either rh CD93 or rm VEGFA. Avastin, chimeric 7F3, chimeric 7F3/VEGFRFc, and humanized 7F3/VEGFRFc did not exhibit binding activity with control hIgG Fc.

6. Octet binding affinity analysis of Avastin, VEGFRFc, and humanized 7F3/VEGFRFc

The binding affinity of Avastin, VEGFRFc, and humanized 7F3/VEGFRFc to rh VEGFA was determined using Octet QKe (Fortebio) via biolayer interference. A pre-made rh VEGFA was biotinylated using EZ-LINK NHS-PEG4 biotin (Thermo Fisher Scientific). A streptavidin biosensor (Fortebio) was used to load the biotinylated VEGFA protein (at 5 μg/ml for 300 seconds). The baseline was stabilized in 1× kinetic buffer (Fortebio) for 60 seconds before allowing serially diluted Avastin, VEGFRFc, and humanized 7F3/VEGFRFc to associate with the captured protein for 300 seconds. The sensor was then dissociated in 1× kinetic buffer for 600 seconds. Data analysis was performed using ForteBio data analysis software HT 11.1.

Figure 53G shows that the binding affinity of VEGFRFc and humanized 7F3/VEGFRFc to rh VEGFA protein is similar (VEGFRFc trap is 0.93 nM, and 7F3/VEGFRFc is 2 nM).

sequence list

Sequence List

<110> Dangkang Biotechnology Co., Ltd.

<120> Anti-CD93 constructs and their applications

<130> PG02945A

<140> Not yet allocated

<141> At the same time

<150> PCT/US2021/043784

<151> 2021-07-29

<150> PCT/US2021/035542

<151> 2021-06-02

<150> US 63/084,474

<151> 2020-09-28

<160> 422

<170> Windows FastSEQ version 4.0

<210> 1

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 1

Ser Phe Gly Val Asn

1 5

<210> 2

<211> 16

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 2

Val Ile Trp Ser Gly Gly Ser Thr Asp Tyr Asn Val Ala Phe Ile Ser

1 5 10 15

<210> 3

<211> 13

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 3

Asn Trp Arg Tyr Asp Gly Tyr Phe Tyr Ala Met Asp Tyr

1 5 10

<210> 4

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 4

Lys Ala Ser Gln Asn Val Gly Thr Asn Val Ala

1 5 10

<210> 5

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 5

Ser Ala Ser Tyr Arg Phe Ile

1 5

<210> 6

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 6

Gln Gln Tyr Asn Arg Asn Pro Ile Thr

1 5

<210> 7

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 7

Asp Phe Ser Leu Ser Ser Phe Gly

1 5

<210> 8

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 8

Ile Trp Ser Gly Gly Ser Thr

1 5

<210> 9

<211> 15

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 9

Ala Arg Asn Trp Arg Tyr Asp Gly Tyr Phe Tyr Ala Met Asp Tyr

1 5 10 15

<210> 10

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 10

Gln Asn Val Gly Thr Asn

1 5

<210> 11

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 11

Ser Ala Ser

1

<210> 12

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 12

Gln Gln Tyr Asn Arg Asn Pro Ile Thr

1 5

<210> 13

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 13

Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln

1 5 10 15

Ser Leu Ser Ile Thr Cys Thr Val Ser Asp Phe Ser Leu Ser Ser Phe

20 25 30

Gly Val Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Ser Gly Gly Ser Thr Asp Tyr Asn Val Ala Phe Ile

50 55 60

Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Phe

65 70 75 80

Lys Met Asn Asn Leu Gln Ala Asp Asp Thr Ala Ile Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Arg Tyr Asp Gly Tyr Phe Tyr Ala Met Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 14

<211> 107

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 14

Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Thr Gly

1 5 10 15

Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile

35 40 45

Tyr Ser Ala Ser Tyr Arg Phe Ile Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Val Gln Ser

65 70 75 80

Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Arg Asn Pro Ile

85 90 95

Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 15

<211> 364

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 15

caggtgcagc tgaagcagtc aggacctggc ctagtgcagc cctcacagag cctgtccatc 60

acctgcacag tctctgattt ctcattatct agctttggtg taaactgggt tcgccagcct 120

ccaggaaagg gtctggagtg gctgggggtg atatggagtg gtggaagtac agactataat 180

gtagctttca tatccagact gagcatcagc aaggacaact ccaagagcca agttttcttt 240

aaaatgaaca atctgcaagc tgatgacaca gccatatact actgtgccag aaattggagg 300

tatgatggtt acttctatgc tatggactac tggggtcaag gaacctcagt caccgtctcc 360

tcag 364

<210> 16

<211> 322

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 16

gacattgtga tgacccagtc tcaaaaattc atgtccacat caacaggaga cagggtcagc 60

gtcacctgca aggccagtca gaatgtgggt actaatgtag cctggtatca acagaaacca 120

ggacagtctc ctaaagcact gatttactcg gcatcatacc gattcattgg agtccctgat 180

cgcttcacag gcagtggatc tgggacagat ttcactctca ccatcaccaa tgtgcagtct 240

gaagacttgg cagagtattt ctgtcagcaa tataacagaa atcctatcac gttcggctcg 300

gggacaaagt tggaaataaa ac 322

<210> 17

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 17

Ser Tyr Trp Met His

1 5

<210> 18

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 18

Glu Ile Asp Pro Ser Ala Ser Tyr Thr Tyr Tyr Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 19

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 19

Ser Val Tyr Tyr Gly Asn Lys Tyr Phe Asp Val

1 5 10

<210> 20

<211> 15

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 20

Lys Ala Ser Gln Ser Val Asp Tyr Ala Gly Asp Ser Tyr Met Asn

1 5 10 15

<210> 21

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 21

Ala Ala Ser Asn Leu Glu Ser

1 5

<210> 22

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 22

Gln Gln Thr Asn Glu Asp Pro Arg Thr

1 5

<210> 23

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 23

Gly Tyr Thr Phe Thr Ser Tyr Trp

1 5

<210> 24

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 24

Ile Asp Pro Ser Ala Ser Tyr Thr

1 5

<210> 25

<211> 13

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 25

Ala Arg Ser Val Tyr Tyr Gly Asn Lys Tyr Phe Asp Val

1 5 10

<210> 26

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 26

Gln Ser Val Asp Tyr Ala Gly Asp Ser Tyr

1 5 10

<210> 27

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 27

Ala Ala Ser

1

<210> 28

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 28

Gln Gln Thr Asn Glu Asp Pro Arg Thr

1 5

<210> 29

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 29

Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asp Pro Ser Ala Ser Tyr Thr Tyr Tyr Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Val Tyr Tyr Gly Asn Lys Tyr Phe Asp Val Trp Gly Ala

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 30

<211> 111

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 30

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Ala

20 25 30

Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His

65 70 75 80

Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Tyr Cys Gln Gln Thr Asn

85 90 95

Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 31

<211> 360

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 31

caggtccagc ttcagcagcc tggggctgaa ctggtgaagc ctggggcttc agtgaagctg 60

tcctgcaagg cttctggata caccttcact agctactgga tgcactgggt gaagcagagg 120

cctggacaag gccttgagtg gatcggagag attgatcctt ctgctagtta tacttactac 180

aatcaaaagt tcaagggcaa ggccacattg actgtagaca aatcctccag cacagcctac 240

atgcaactca gcagcctgac atctgaggac tctgcggtct attactgtgc aagatcggtc 300

tactatggta acaagtattt cgatgtctgg ggcgcaggga ccacggtcac cgtctcctca 360

<210> 32

<211> 334

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 32

gacattgtgc tgacccaatc tccagcttct ttggctgtgt ctctagggca gaggccacc 60

atctcctgca aggccagcca aagtgttgat tatgccggtg atagttatat gaactggtac 120

caacagaaac caggacagcc acccaaactc ctcatctatg ctgcatccaa tctagaatct 180

gggatcccag ccaggtttag tggcagtggg tctgggacag acttcaccct caacatccat 240

cctgtggagg aggaggatgc tgcaacctat tactgtcagc aaactaatga ggatcctcgg 300

acgttcggtg gaggcaccaa gctggaaatc aaac 334

<210> 33

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 33

Thr Tyr Trp Met Asn

1 5

<210> 34

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 34

Arg Ile Phe Pro Gly Asp Gly Asp Ala Asn Tyr Asn Gly Lys Phe Lys

1 5 10 15

Gly

<210> 35

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 35

Thr Gly Ala Ala Tyr Asp Phe Asp Pro Phe Pro Tyr

1 5 10

<210> 36

<211> 16

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 36

Ser Ser Ser Lys Ser Leu Leu His Ser Asn Gly Val Thr Tyr Leu Tyr

1 5 10 15

<210> 37

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 37

Arg Met Ser Asn Leu Ala Ser

1 5

<210> 38

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 38

Ala Gln Met Leu Glu Arg Pro Phe Thr

1 5

<210> 39

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 39

Gly Tyr Ala Phe Ser Thr Tyr Trp

1 5

<210> 40

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 40

Ile Phe Pro Gly Asp Gly Asp Ala

1 5

<210> 41

<211> 14

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 41

Thr Arg Thr Gly Ala Ala Tyr Asp Phe Asp Pro Phe Pro Tyr

1 5 10

<210> 42

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 42

Lys Ser Leu Leu His Ser Asn Gly Val Thr Tyr

1 5 10

<210> 43

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 43

Arg Met Ser

1

<210> 44

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 44

Ala Gln Met Leu Glu Arg Pro Phe Thr

1 5

<210> 45

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 45

Gln Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Thr Tyr

20 25 30

Trp Met Asn Trp Val Lys Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Arg Ile Phe Pro Gly Asp Gly Asp Ala Asn Tyr Asn Gly Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Thr Arg Thr Gly Ala Ala Tyr Asp Phe Asp Pro Phe Pro Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ala

115 120

<210> 46

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 46

Asp Ile Val Met Thr Gln Ala Ala Phe Ser Asn Pro Val Thr Leu Gly

1 5 10 15

Thr Ser Ala Ser Ile Ser Cys Ser Ser Ser Lys Ser Leu Leu His Ser

20 25 30

Asn Gly Val Thr Tyr Leu Tyr Trp Tyr Leu Gln Arg Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Ala Gln Met

85 90 95

Leu Glu Arg Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 47

<211> 364

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 47

caggttcagc tgcagcagtc tggacctgac ctggtgaagc ctggggcctc agtgaagatt 60

tcctgcaaag cttctggcta cgcattcagt acctactgga tgaactgggt gaagcagagg 120

cctggaaagg gtcttgagtg gattggacgg attttcctg gagatggaga tgctaactac 180

aatgggaagt tcaagggcaa ggccacactg actgcagaca aatcctccag cacagcctac 240

atgcaactca gcagcctgac atctgaggac tctgcggtct acttctgtac aagaactggg 300

gccgcctatg atttcgaccc ttttccttac tggggccaag ggactctggt cactgtctct 360

gcag 364

<210> 48

<211> 337

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 48

gatattgtga tgacgcaggc tgcattctcc aatccagtca ctcttggaac atcagcttcc 60

atctcttgca gttctagtaa gagtctccta catagtaatg gcgtcactta tttgtattgg 120

tatctgcaga ggccaggcca gtctcctcag ctcctgatat atcggatgtc caaccttgcc 180

tcaggagtcc cagacaggtt cagtggcagt gggtcaggaa ctgatttcac actgagaatc 240

agcagagtgg aggctgagga tgtgggtatt tattactgtg ctcaaatgct agaacgccca 300

ttcacgttcg gctcggggac aaagttggaa ataaac 337

<210> 49

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 49

Asp Tyr Tyr Met Asn

1 5

<210> 50

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 50

Arg Val Asn Pro Asn Asn Gly Gly Lys Thr Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 51

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 51

Trp Arg Leu Arg Pro Val Asp Tyr Gly Met Asp Tyr

1 5 10

<210> 52

<211> 15

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 52

Arg Ala Ser Gln Ser Val Ser Thr Ser Ser Tyr Ser Tyr Met His

1 5 10 15

<210> 53

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 53

Tyr Ala Ser Asn Leu Glu Ser

1 5

<210> 54

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 54

Gln His Ser Trp Glu Ile Pro Phe Thr

1 5

<210> 55

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 55

Gly Tyr Thr Phe Thr Asp Tyr Tyr

1 5

<210> 56

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 56

Val Asn Pro Asn Asn Gly Gly Lys

1 5

<210> 57

<211> 14

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 57

Ala Arg Trp Arg Leu Arg Pro Val Asp Tyr Gly Met Asp Tyr

1 5 10

<210> 58

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 58

Gln Ser Val Ser Thr Ser Ser Tyr Ser Tyr

1 5 10

<210> 59

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 59

Tyr Ala Ser

1

<210> 60

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 60

Gln His Ser Trp Glu Ile Pro Phe Thr

1 5

<210> 61

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 61

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Arg Val Asn Pro Asn Asn Gly Gly Lys Thr Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Leu Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Trp Arg Leu Arg Pro Val Asp Tyr Gly Met Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 62

<211> 111

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 62

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr

20 25 30

Ser Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His

65 70 75 80

Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Ser Trp

85 90 95

Glu Ile Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 63

<211> 364

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 63

gaggtccagc tgcaacagtc tggacctgag ctggtgaagc ctggggcttc agtgaagatg 60

tcctgtaagg cttctggata cacattcact gactactaca tgaactgggt gaagcagagt 120

catggaaaga gtcttgagtg gattggacgt gttaatccta acaatggtgg taaaacctac 180

aaccagaagt tcaagggcaa ggccacattg acagtagaca aatccctcag cacagcctac 240

atgcagctca acagcctgac atctgaggac tctgcggtct attactgtgc aagatggagg 300

ctacggcccg ttgactatgg tatggactac tggggtcaag gaacctcagt caccgtctcc 360

tcag 364

<210> 64

<211> 334

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 64

gacattgtgc tgacacagtc tcctgcttcc ttggctgtat ctctggggca gagggccacc 60

atctcatgca gggccagcca aagtgtcagt acatctagct atagttatat gcactggtac 120

caacagaaac caggacagcc acccaaactc ctcatcaagt atgcatccaa cctagaatct 180

ggggtccctg ccaggttcag tggcagtggg tctggggacag acttcaccct caacatccat 240

cctgtggagg aggaggatac tgcaacatat tactgtcagc acagttggga gattccattc 300

acgttcggct cggggacaaa gttggaaata aaac 334

<210> 65

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 65

Asp Tyr Glu Met His

1 5

<210> 66

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 66

Gly Ile Asp Pro Glu Thr Gly Gly Thr Ala Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 67

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 67

Gly Ala Trp Phe Ala Tyr

1 5

<210> 68

<211> 14

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 68

Arg Ser Ser Thr Gly Ala Val Thr Thr Ser Asn Ser Ala Asn

1 5 10

<210> 69

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 69

Gly Thr Asn Asn Arg Ala Pro

1 5

<210> 70

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 70

Ala Leu Trp Tyr Asn Asn His Phe Val

1 5

<210> 71

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 71

Gly Tyr Thr Phe Thr Asp Tyr Glu

1 5

<210> 72

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 72

Ile Asp Pro Glu Thr Gly Gly Thr

1 5

<210> 73

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 73

Thr Arg Gly Ala Trp Phe Ala Tyr

1 5

<210> 74

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 74

Thr Gly Ala Val Thr Thr Thr Ser Asn Ser

1 5

<210> 75

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 75

Gly Thr Asn

1

<210> 76

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 76

Ala Leu Trp Tyr Asn Asn His Phe Val

1 5

<210> 77

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 77

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Glu Met His Trp Val Arg Gln Thr Pro Val His Gly Leu Glu Trp Ile

35 40 45

Gly Gly Ile Asp Pro Glu Thr Gly Gly Thr Ala Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Gly Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ala

115

<210> 78

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 78

Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu

1 5 10 15

Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Thr

20 25 30

Asn Ser Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly

35 40 45

Leu Ile Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala

65 70 75 80

Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Asn Asn

85 90 95

His Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 79

<211> 346

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 79

caggttcaat tgcagcagtc tggggctgag ctggtgaggc ctggggcttc agtgaagctg 60

tcctgcaagg cttcgggcta tacatttact gactatgaaa tgcactgggt gaggcagaca 120

cctgtgcatg gcctggaatg gattggaggt attgatcctg aaactggtgg tactgcctac 180

aatcagaagt tcaagggcaa ggccacactg actgcagaca aatcctccag cacagcctac 240

atggagctcc gcagcctgac atctgaggac tctgccgtct attactgtac acgaggggcc 300

tggtttgctt actggggcca agggactctg gtcactgtct ctgcag 346

<210> 80

<211> 328

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 80

caggctgttg tgactcagga atctgcactc accacatcac ctggtgaaac agtcacactc 60

acttgtcgct caagtactgg ggctgttaca actagtaact ctgccaactg ggtccaagaa 120

aaaccagatc atttattcac tggtctaatc ggtggtacca acaaccgagc tccaggtgtt 180

cctgccagat tctcaggctc cctgattgga gacaaggctg ccctcaccat cacaggggca 240

cagactgagg atgaggcaat atatttctgt gctctatggt acaacaacca tttcgtgttc 300

ggtggaggca ccaaactgac tgtcctag 328

<210> 81

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 81

Ser Tyr Trp Met His

1 5

<210> 82

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 82

Ala Ile Tyr Pro Gly Asn Ser Asp Thr Ser Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 83

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 83

Gly Gly Phe Asp Tyr Ser Asn Tyr Trp Phe Ala Tyr

1 5 10

<210> 84

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 84

Lys Ala Ser Gln Ser Val Ser Asn Asp Val Ala

1 5 10

<210> 85

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 85

Tyr Ala Ser Asn Arg Tyr Thr

1 5

<210> 86

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 86

Gln Gln Asp Tyr Ser Ser Tyr Thr

1 5

<210> 87

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 87

Gly Tyr Thr Phe Thr Ser Tyr Trp

1 5

<210> 88

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 88

Ile Tyr Pro Gly Asn Ser Asp Thr

1 5

<210> 89

<211> 14

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 89

Thr Arg Gly Gly Phe Asp Tyr Ser Asn Tyr Trp Phe Ala Tyr

1 5 10

<210> 90

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 90

Gln Ser Val Ser Asn Asp

1 5

<210> 91

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 91

Tyr Ala Ser

1

<210> 92

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 92

Gln Gln Asp Tyr Ser Ser Tyr Thr

1 5

<210> 93

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 93

Glu Val Gln Leu Gln Gln Ser Gly Thr Val Leu Ala Arg Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Ala Ile Tyr Pro Gly Asn Ser Asp Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Lys Leu Thr Ala Val Thr Ser Ala Ser Thr Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Thr Asn Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Gly Gly Phe Asp Tyr Ser Asn Tyr Trp Phe Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ala

115 120

<210> 94

<211> 106

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 94

Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala

65 70 75 80

Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Ser Ser Tyr Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 95

<211> 363

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 95

gaggttcagc tccagcagtc tgggactgtg ctggcaaggc ctggggcttc agtgaagatg 60

tcctgcaagg cttctggcta cacctttacc agctactgga tgcactgggt aaaacagagg 120

cctggacagg gtctggaatg gattggcgct atttatcctg gaaatagtga tactagctac 180

aaccagaagt tcaagggcaa ggccaaactg actgcagtca catctgccag cactgcctac 240

atggagctca gcagcctgac aaatgaggac tctgcggtct attactgtac aagaggagga 300

tttgactata gtaactactg gtttgcttac tggggccaag ggactctggt cactgtctct 360

gca 363

<210> 96

<211> 319

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 96

agtattgtga tgacccagac tcccaaattc ctgcttgtat cagcaggaga cagggttacc 60

ataacctgca aggccagtca gagtgtgagt aatgatgtag cttggtacca acagaagcca 120

gggcagtctc ctaaactgct gatatactat gcatccaatc gctacactgg agtccctgat 180

cgcttcactg gcagtggata tgggacggat ttcactttca ccatcagcac tgtgcaggct 240

gaagacctgg cagtttattt ctgtcagcag gattatagct cgtacacgtt cggagggggg 300

accaagctgg aaataaaac 319

<210> 97

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 97

Arg Ser Trp Met Asn

1 5

<210> 98

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 98

Trp Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe Lys

1 5 10 15

Gly

<210> 99

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 99

Ser Ala Thr Leu Pro Tyr Trp Tyr Phe Asp Val

1 5 10

<210> 100

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 100

Lys Ala Ser Gln Asp Ile Lys Ser Tyr Leu Ser

1 5 10

<210> 101

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 101

Tyr Ala Thr Asn Leu Ala Asp

1 5

<210> 102

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 102

Leu Gln His Val Glu Ser Pro Trp Thr

1 5

<210> 103

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 103

Gly Tyr Ala Phe Ser Arg Ser Trp

1 5

<210> 104

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 104

Ile Tyr Pro Gly Asp Gly Asp Thr

1 5

<210> 105

<211> 13

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 105

Ala Arg Ser Ala Thr Leu Pro Tyr Trp Tyr Phe Asp Val

1 5 10

<210> 106

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 106

Gln Asp Ile Lys Ser Tyr

1 5

<210> 107

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 107

Tyr Ala Thr

1

<210> 108

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 108

Leu Gln His Val Glu Ser Pro Trp Thr

1 5

<210> 109

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 109

Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Arg Ser

20 25 30

Trp Met Asn Trp Val Lys Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ala Tyr Phe Cys

85 90 95

Ala Arg Ser Ala Thr Leu Pro Tyr Trp Tyr Phe Asp Val Trp Gly Ala

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 110

<211> 107

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 110

Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly

1 5 10 15

Glu Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Lys Ser Tyr

20 25 30

Leu Ser Trp Tyr Gln Gln Lys Pro Trp Lys Ser Pro Lys Thr Leu Ile

35 40 45

Tyr Tyr Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Gly Ser

65 70 75 80

Asp Asp Thr Ala Thr Tyr Tyr Cys Leu Gln His Val Glu Ser Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 111

<211> 361

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 111

caggtccagc tgcagcagtc tggacctgag ctggtgaagc ctggggcctc agtgaagatt 60

tcctgcaaag cttctggcta tgcattcagt cgctcctgga tgaactgggt aaagcagagg 120

cctggaaagg gtcttgagtg gattggatgg atttatcctg gagatggtga tactaactac 180

aatggaaagt tcaagggcaa ggccacactg actgcagaca aatcctcaag cacagcctac 240

atgcagctca gcagcctgac atctgaggac tctgcggcct atttctgtgc aaggtcggct 300

accctacctt actggtactt cgatgtctgg ggcgcaggga ccacggtcac cgtctcctca 360

g 361

<210> 112

<211> 322

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 112

gacatcaaga tgacccagtc tccatcctcc atgtatgcat cgctgggaga gagagtcact 60

atcacttgca aggcgagtca ggacattaaa agctatttaa gttggtacca gcagaaacca 120

tggaaatctc ctaagaccct gatctattat gcaacaaact tggcagatgg ggtcccatca 180

agattcagtg gcagtggatc tgggcaggat tattctctaa ccatcagcag cctggggtct 240

gacgatacag caacttatta ctgtctacag catgttgaga gcccgtggac gttcggtgga 300

ggcaccaagc tggaaatcaa ac 322

<210> 113

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 113

Ala Tyr Val Met His

1 5

<210> 114

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 114

Tyr Ile Phe Pro Tyr Asn Asp Gly Thr Glu Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 115

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 115

Arg Thr Asp Gly Asn Pro Tyr Thr Met Asp Tyr

1 5 10

<210> 116

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 116

Lys Ala Ser Gln Asp Val Ser Thr Ala Val Ala

1 5 10

<210> 117

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 117

Ser Ala Ser Tyr Arg Tyr Thr

1 5

<210> 118

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 118

Gln Gln His Tyr Ser Thr Pro Phe Thr

1 5

<210> 119

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 119

Gly Tyr Thr Phe Thr Ala Tyr Val

1 5

<210> 120

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 120

Ile Phe Pro Tyr Asn Asp Gly Thr

1 5

<210> 121

<211> 13

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 121

Ala Arg Arg Thr Asp Gly Asn Pro Tyr Thr Met Asp Tyr

1 5 10

<210> 122

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 122

Gln Asp Val Ser Thr Ala

1 5

<210> 123

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 123

Ser Ala Ser

1

<210> 124

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 124

Gln Gln His Tyr Ser Ser Pro Phe Thr

1 5

<210> 125

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 125

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Asn Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ala Tyr

20 25 30

Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Phe Pro Tyr Asn Asp Gly Thr Glu Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Thr Asp Gly Asn Pro Tyr Thr Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 126

<211> 107

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 126

Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly

1 5 10 15

Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile

35 40 45

His Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Arg Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala

65 70 75 80

Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Phe

85 90 95

Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 127

<211> 361

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 127

gaggtccagc tgcagcagtc tggacctgag ttggtaaatc ctggggcttc agtgaagatg 60

tcctgcaagg cttctggata cacattcact gcctatgtta tgcactgggt gaaacagaag 120

cctgggcagg gccttgagtg gattggatat attttcctt acaatgatgg tactgagtac 180

aatgagaagt tcaaaggcaa ggccacactg acttcagaca aatcctccag cacagcctac 240

atggagctca gcagcctgac ctctgaggac tctgcggtct attactgtgc aaggaggaca 300

gatggtaacc cctatactat ggactattgg ggtcaaggaa cctcagtcac cgtctcctca 360

g 361

<210> 128

<211> 322

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 128

gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60

atcacctgca aggccagtca ggatgtgagt actgctgtag cctggtatca acagaaacca 120

ggacaatctc ctaaactact gattcattcg gcatcctacc ggtacactgg agtccctgat 180

cgcttcactg gcagaggatc tgggacggat ttcactttca ccatcagcag tgtgcaggct 240

gaagacctgg cagtttatta ctgtcagcaa cattatagta ctccattcac gttcggctcg 300

gggacaaagt tggaaataaa ac 322

<210> 129

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 129

Asp Tyr Tyr Ile His

1 5

<210> 130

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 130

Glu Ile Tyr Pro Gly Ser Asp Asp Ala Tyr Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 131

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 131

Glu Thr Thr Ala Thr Ala Tyr

1 5

<210> 132

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 132

Ser Ala Ser Ser Ser Val Ser Leu Ile Tyr

1 5 10

<210> 133

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 133

Ser Thr Ser Asn Leu Ala Ser

1 5

<210> 134

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 134

Gln Gln Arg Ser Gly Tyr Pro Pro Thr

1 5

<210> 135

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 135

Gly Tyr Thr Phe Thr Asp Tyr Tyr

1 5

<210> 136

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 136

Ile Tyr Pro Gly Ser Asp Asp Ala

1 5

<210> 137

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 137

Thr Arg Glu Thr Thr Ala Thr Ala Tyr

1 5

<210> 138

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 138

Ser Ser Val Ser Leu

1 5

<210> 139

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 139

Ser Thr Ser

1

<210> 140

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 140

Gln Gln Arg Ser Gly Tyr Pro Pro Thr

1 5

<210> 141

<211> 116

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 141

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Tyr Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Tyr Pro Gly Ser Asp Asp Ala Tyr Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Thr Arg Glu Thr Thr Ala Thr Ala Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ala

115

<210> 142

<211> 106

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 142

Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly

1 5 10 15

Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Leu Ile

20 25 30

Tyr Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Ile Tyr

35 40 45

Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Gly Tyr Pro Pro Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 143

<211> 351

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 143

ctgaggtcca gctgcagcag tctggacctg agctggttaa gcctggggct tcagtgaagg 60

tatcctgcaa ggcctctgga tacacattca ctgactacta tatacactgg gtgaagcaga 120

ggcctgggca gggccttgag tggattggag agatttatcc tggaagtgat gatgcttact 180

acaatgagaa attcaagggc aaggccacac tgactgcaga caaatcctcc agcacagcct 240

acatgcagct cagcagcctg acatctgagg actctgcagt ctatttctgt acaagagaga 300

ctacggctac ggcttactgg ggccaaggga ctctggtcac tgtctctgca g 351

<210> 144

<211> 319

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 144

caaattgttc tcacccagtc tccagcaatc atgtctgcat ctccagggga gaaggtcacc 60

ataacctgca gtgccagctc aagtgtaagt ctcatttact ggttccagca gaagccaggc 120

acttctccca aactctggat ttatagcaca tccaacctgg cttctggagt ccctgctcgc 180

ttcagtggca gtggatctgg gacctcttac tctctcacaa tcagccgaat ggaggctgaa 240

gatgctgcca cttattactg ccagcaaagg agtggttacc cacccacgtt cggagggggg 300

accaagctgg aaataaaac 319

<210> 145

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 145

Asp His Gly Ile His

1 5

<210> 146

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 146

Asn Ile Ser Pro Gly Asn Gly Asp Ile Lys Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 147

<211> 4

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 147

Tyr Phe Val Asp

1

<210> 148

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 148

Lys Ser Ser Gln Ser Leu Leu Asn Ser Asn Asn Gln Lys Asn Cys Leu

1 5 10 15

Ala

<210> 149

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 149

Phe Ala Cys Thr Arg Glu Ser

1 5

<210> 150

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 150

Gln Gln His Cys Asn Thr Pro Leu Thr

1 5

<210> 151

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 151

Gly Tyr Thr Phe Thr Asp His Gly

1 5

<210> 152

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 152

Ile Ser Pro Gly Asn Gly Asp Ile

1 5

<210> 153

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 153

Thr Thr Tyr Phe Val Asp

1 5

<210> 154

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 154

Gln Ser Leu Leu Asn Ser Asn Asn Gln Lys Asn Cys

1 5 10

<210> 155

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 155

Phe Ala Cys

1

<210> 156

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 156

Gln Gln His Cys Asn Thr Pro Leu Thr

1 5

<210> 157

<211> 113

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 157

Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Thr

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp His

20 25 30

Gly Ile His Trp Val Lys Gln Arg Pro Glu Arg Gly Leu Glu Trp Ile

35 40 45

Gly Asn Ile Ser Pro Gly Asn Gly Asp Ile Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Val Tyr

65 70 75 80

Met Gln Val Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Thr Thr Tyr Phe Val Asp Trp Gly Arg Gly Thr Leu Val Thr Val Ser

100 105 110

Ala

<210> 158

<211> 113

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 158

Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Met Ser Ile Gly

1 5 10 15

Gln Arg Val Thr Met Ser Cys Lys Ser Gln Ser Leu Leu Asn Ser

20 25 30

Asn Asn Gln Lys Asn Cys Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Arg Leu Leu Ile Tyr Phe Ala Cys Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ile Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Tyr Tyr Phe Cys Gln Gln

85 90 95

His Cys Asn Thr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu

100 105 110

Lys

<210> 159

<211> 340

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 159

caggttcagc tgcaacagtc tgacgctgag ttggtgaaac ctgggacttc agtgaagata 60

tcctgcaagg cttctggcta caccttcact gaccatggta ttcactgggt gaaacagagg 120

cctgaacggg gcctggaatg gattggaaat attctcccg gaaatggtga tattaagtat 180

aatgagaagt tcaagggcaa ggccacgctg actgcagaca aatcctccag cactgtctac 240

atgcaggtca acagcctgac atctgaggat tctgcagtgt atttctgtac aacctatttt 300

gttgactggg gccgggggac tctggtcact gtctctgcag 340

<210> 160

<211> 340

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 160

gacattgtga tgacacagtc tccatcctcc ctggctatgt caattggaca gaggtcact 60

atgagctgca agtccagtca gagcctttta aatagtaaca atcaaaagaa ctgtttggcc 120

tggtaccagc agaaaccagg acagtctcct agacttctga tttactttgc atgtactagg 180

gaatcggggg tccctgatcg cttcattggc agtggatctg ggacagattt cacccttacc 240

atcagcagtg tgcaggctga agacctggca tattacttct gtcagcaaca ttgtaacact 300

ccgctcacgt tcggtgctgg gaccaagctg gagctgaaac 340

<210> 161

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 161

Thr Tyr Trp Met Asn

1 5

<210> 162

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 162

Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asp Gly Lys Phe Lys

1 5 10 15

Gly

<210> 163

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 163

Thr Gly Ala Ala Tyr Glu Phe Asp Pro Phe Pro Tyr

1 5 10

<210> 164

<211> 16

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 164

Ser Ser Thr Lys Ser Leu Leu His Ser Ser Gly Ile Thr Tyr Leu Tyr

1 5 10 15

<210> 165

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 165

Arg Met Ser Asn Leu Ala Ser

1 5

<210> 166

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 166

Ala Gln Met Leu Glu Arg Pro Phe Thr

1 5

<210> 167

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 167

Gly Tyr Ala Phe Ser Thr Tyr Trp

1 5

<210> 168

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 168

Ile Phe Pro Gly Asp Gly Asp Thr

1 5

<210> 169

<211> 14

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 169

Ala Arg Thr Gly Ala Ala Tyr Glu Phe Asp Pro Phe Pro Tyr

1 5 10

<210> 170

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 170

Lys Ser Leu Leu His Ser Ser Gly Ile Thr Tyr

1 5 10

<210> 171

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 171

Arg Met Ser

1

<210> 172

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 172

Ala Gln Met Leu Glu Arg Pro Phe Thr

1 5

<210> 173

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 173

Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ala Phe Ser Thr Tyr

20 25 30

Trp Met Asn Trp Val Lys Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asp Gly Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Thr Gly Ala Ala Tyr Glu Phe Asp Pro Phe Pro Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ala

115 120

<210> 174

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 174

Asp Ile Val Met Thr Gln Ala Ala Phe Ser Asn Pro Val Thr Leu Gly

1 5 10 15

Thr Ser Ala Ser Ile Ser Cys Ser Ser Thr Lys Ser Leu Leu His Ser

20 25 30

Ser Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Arg Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Met

85 90 95

Leu Glu Arg Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 175

<211> 364

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 175

caggttcagc tgcagcagtc tggacctgag ctggtgaagc ctggggcctc agtgaagatt 60

tcctgcaaag gttctggcta cgcattcagt acctactgga tgaactgggt gaagcagagg 120

cctggaaagg gtcttgagtg gattggacgg attttcctg gagatggaga tacagattac 180

gatgggaagt tcaagggcaa ggccacactg actgcagaca aatcctccaa cacagcctac 240

atgcaactca gcagcctgac atctgaagac tctgcggtct acttctgtgc aagaactggg 300

gccgcctatg aattcgaccc ttttccttac tggggccaag ggactctggt cactgtctct 360

gcag 364

<210> 176

<211> 337

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 176

gatattgtga tgacgcaggc tgcattctcc aatccagtca ctcttggaac atcagcttcc 60

atctcttgca gttctactaa gagtctccta catagtagcg gcatcactta tctgtattgg 120

tatctgcaga ggccaggcca gtctcctcag ctcctgatat atcggatgtc caaccttgcc 180

tcaggagtcc cagacaggtt cagtggcagt gggtcaggaa ctgatttcac actgagaatc 240

agcagagtgg aggctgagga tgtgggtgtt tattactgtg ctcaaatgct agaacgccca 300

ttcacgttcg gctcggggac aaagttggaa ataaac 337

<210> 177

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 177

Ser Tyr Trp Leu Asn

1 5

<210> 178

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 178

Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys

1 5 10 15

Gly

<210> 179

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 179

Gly Asp Gly Tyr Trp Ala Met Asp Tyr

1 5

<210> 180

<211> 16

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 180

Arg Phe Ser Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr

1 5 10 15

<210> 181

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 181

Gln Met Ser Asn Leu Ala Ser

1 5

<210> 182

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 182

Ala Gln Asn Leu Glu Leu Pro Trp Thr

1 5

<210> 183

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 183

Gly Tyr Ala Phe Ser Ser Tyr Trp

1 5

<210> 184

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 184

Ile Tyr Pro Gly Asp Gly Asp Thr

1 5

<210> 185

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 185

Val Arg Gly Asp Gly Tyr Trp Ala Met Asp Tyr

1 5 10

<210> 186

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 186

Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr

1 5 10

<210> 187

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 187

Gln Met Ser

1

<210> 188

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 188

Ala Gln Asn Leu Glu Leu Pro Trp Thr

1 5

<210> 189

<211> 118

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 189

Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr

20 25 30

Trp Leu Asn Trp Val Lys Gln Arg Pro Gly Lys Gly Leu Glu Trp Phe

35 40 45

Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Val Arg Gly Asp Gly Tyr Trp Ala Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Ser Val Thr Val Ser Ser

115

<210> 190

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 190

Asp Ile Val Met Thr Gln Ala Ala Phe Ser Asn Pro Val Thr Leu Gly

1 5 10 15

Thr Ser Ala Ser Ile Ser Cys Arg Phe Ser Lys Ser Leu Leu His Ser

20 25 30

Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Ser Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn

85 90 95

Leu Glu Leu Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 191

<211> 355

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 191

caggttcagc tgcagcagtc tggacctgag ctggtgaagc ctggggcctc ggtgaagatt 60

tcctgcaaag cttctggcta cgcattcagt agctactggc tgaactgggt gaagcagagg 120

cctggaaagg gtcttgagtg gtttggacgg atttatcctg gagatggaga tactgactac 180

aatgggaagt tcaagggcaa ggccacactg actgcagaca aatcctccag cacagcctac 240

atgcaactca gaagcctgac atctgaggac tctgcggtct acttctgtgt aagaggtgat 300

ggttactggg ctatggacta ctggggtcaa ggaacctcag tcaccgtctc ctcag 355

<210> 192

<211> 337

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 192

gatattgtga tgacgcaggc tgcattctcc aatccagtca ctcttggaac atcagcttcc 60

atctcctgca ggtttagtaa gagtctccta catagtaatg gcatcactta tttgtattgg 120

tatctgcaga agccaggcca gtctcctcag ctcctgattt atcagatgtc caaccttgcc 180

tcaggagtcc cagacaggtt cagtagcagt gggtcaggaa ctgatttcac actgagaatc 240

agcagagtgg aggctgagga tgtgggtgtt tattactgtg ctcaaaatct agaacttccg 300

tggacgttcg gtggaggcac caagctggaa atcaaac 337

<210> 193

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 193

Asn Tyr Tyr Met Ser

1 5

<210> 194

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 194

Thr Ile Ser Asn Asn Gly Asp Ser Thr Tyr Tyr Leu Asp Thr Val Lys

1 5 10 15

Gly

<210> 195

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 195

Val Gly Thr Gly Phe Thr Tyr

1 5

<210> 196

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 196

Arg Ala Ser Gln Ser Ile Asn Asn Tyr Leu His

1 5 10

<210> 197

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 197

Phe Ala Ser Gln Ser Ile Ser

1 5

<210> 198

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 198

Gln Gln Ser Asn Ser Trp Pro Leu Thr

1 5

<210> 199

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 199

Gly Phe Thr Phe Ser Asn Tyr Tyr

1 5

<210> 200

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 200

Ile Ser Asn Asn Gly Asp Ser Thr

1 5

<210> 201

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 201

Thr Arg Val Gly Thr Gly Phe Thr Tyr

1 5

<210> 202

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 202

Gln Ser Ile Asn Asn Tyr

1 5

<210> 203

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 203

Phe Ala Ser

1

<210> 204

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 204

Gln Gln Ser Asn Ser Trp Pro Leu Thr

1 5

<210> 205

<211> 116

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 205

Asp Val Asn Leu Val Glu Ser Gly Gly Gly Leu Val Lys Leu Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

Tyr Met Ser Trp Val Arg Gln Ser Pro Glu Lys Arg Leu Glu Trp Val

35 40 45

Ala Thr Ile Ser Asn Asn Gly Asp Ser Thr Tyr Tyr Leu Asp Thr Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala Glu Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Ile Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Val Gly Thr Gly Phe Thr Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ala

115

<210> 206

<211> 107

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 206

Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly

1 5 10 15

Asp Ser Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Asn Asn Tyr

20 25 30

Leu His Trp Tyr Gln Gln Arg Ser His Glu Ser Pro Arg Leu Leu Ile

35 40 45

Lys Phe Ala Ser Gln Ser Ile Ser Asp Ile Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Ile Glu Thr

65 70 75 80

Glu Asp Phe Gly Met Tyr Phe Cys Gln Gln Ser Asn Ser Trp Pro Leu

85 90 95

Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 207

<211> 349

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 207

gacgtgaacc tcgtggagtc tgggggaggc ttagtgaagc ttggagggtc cctgaaactc 60

tcctgtgcag cctctggatt cactttcagt aactactaca tgtcttgggt tcgccagagt 120

ccggagaaga ggctggagtg ggtcgcaacc attagtaata atggtgatag cacctactat 180

ctagacactg tgaagggccg attcaccatc tccagagaca gtgccgagaa caccctgtac 240

ctgcaaatga gcagtctgat ttctgaggac acagccgtgt attactgtac aagagttggg 300

acggggttta cttactgggg ccaagggact ctggtcactg tctctgcag 349

<210> 208

<211> 322

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 208

gatattgtgc taactcagtc tccagccacc ctgtctgtga ctccaggaga tagcgtcagt 60

ctttcctgca gggccagcca aagtattaac aactacctac actggtatca acaaagatca 120

catgagtctc caaggcttct catcaagttt gcttcccagt ccatctctga catcccctcc 180

aggttcagtg gcagtggatc agggacagat ttcactctca gtatcaacag tatagagact 240

gaagattttg gaatgtattt ctgtcaacag agtaacagct ggccgctcac gttcggtgct 300

gggaccaagc tggagctgaa ac 322

<210> 209

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 209

Ser Tyr Val Ile His

1 5

<210> 210

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 210

Tyr Ile Asn Pro Tyr Ser Asp Tyr Thr Gln Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 211

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 211

Arg Ala Asp Gly Asn Pro Tyr Ala Met Asp Tyr

1 5 10

<210> 212

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 212

Lys Ala Ser Gln Asp Val Ser Thr Ala Val Val

1 5 10

<210> 213

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 213

Ser Ala Ser Tyr Arg Tyr Thr

1 5

<210> 214

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 214

Gln Gln His Tyr Ser Thr Pro Phe Thr

1 5

<210> 215

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 215

Gly Tyr Thr Phe Thr Ser Tyr Val

1 5

<210> 216

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 216

Ile Asn Pro Tyr Ser Asp Tyr Thr

1 5

<210> 217

<211> 13

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 217

Ala Arg Arg Ala Asp Gly Asn Pro Tyr Ala Met Asp Tyr

1 5 10

<210> 218

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 218

Gln Asp Val Ser Thr Ala

1 5

<210> 219

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 219

Ser Ala Ser

1

<210> 220

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 220

Gln Gln His Tyr Ser Thr Pro Phe Thr

1 5

<210> 221

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 221

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Val Ile His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Asn Pro Tyr Ser Asp Tyr Thr Gln Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys

85 90 95

Ala Arg Arg Ala Asp Gly Asn Pro Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 222

<211> 107

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 222

Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly

1 5 10 15

Asp Arg Val Ser Thr Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Thr Ser Val Gln Ala

65 70 75 80

Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Phe

85 90 95

Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 223

<211> 361

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 223

gaggtccagc tacagcagtc tggacctgag ctggtaaagc ctggggcttc agtgaagatg 60

tcctgcaagg cttctggata cacattcact agctatgtta ttcactgggt aaagcagaag 120

cctgggcagg gccttgagtg gattggatat attaatcctt acagtgatta tactcagtac 180

aatgagaagt tcaaaggcaa ggccacactg acttcagaca aatcctccag cacagcctac 240

atggagctca gcagcctgac ctctgaggac tctgcggtct attcctgtgc aaggagggca 300

gatggtaacc cctatgctat ggactactgg ggtcaaggaa cctcagtcac cgtctcctca 360

g 361

<210> 224

<211> 322

<212> DNA

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 224

gacattgtga tgacccagtc tcacaaattc atgtccacat cagtaggaga cagggtcagc 60

accacctgca aggccagtca ggatgtgagt actgctgtag tctggtatca acagaaacca 120

ggacaatctc ctaaactact gatttactcg gcatcctacc ggtacactgg agtccctgat 180

cgcttcactg gcagtggatc tgggacggat ttcactttca ccatcaccag tgtgcaggct 240

gaagacctgg cagtttatta ctgtcagcaa cattatagta ctccattcac gttcggctcg 300

gggacaaagt tggaaataaa ac 322

<210> 225

<211> 1

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 1

<223> can exist repeatedly as any integer.

<400> 225

Gly

1

<210> 226

<211> 16

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> (3)..(16)

<223> Can exist or not exist

<400> 226

Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser

1 5 10 15

<210> 227

<211> 40

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> (6)..(40)

<223> Can exist or not exist

<400> 227

Gly Ser Gly Gly Ser Gly Ser Gly Gly Ser Gly Ser Gly Gly Ser Gly

1 5 10 15

Ser Gly Gly Ser Gly Ser Gly Gly Ser Gly Ser Gly Gly Ser Gly Ser

20 25 30

Gly Gly Ser Gly Ser Gly Gly Ser

35 40

<210> 228

<211> 40

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> (6)..(40)

<223> Can exist or not exist

<400> 228

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

20 25 30

Gly Gly Ser Gly Gly Gly Gly Ser

35 40

<210> 229

<211> 32

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> (5)..(32)

<223> Can exist or not exist

<400> 229

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser

20 25 30

<210> 230

<211> 15

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 230

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10 15

<210> 231

<211> 30

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 231

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

20 25 30

<210> 232

<211> 60

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> (16)..(60)

<223> Can exist or not exist

<400> 232

Gly Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Gly

1 5 10 15

Ser Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Gly Ser

20 25 30

Thr Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser Gly Ser Thr

35 40 45

Ser Gly Ser Gly Lys Pro Gly Ser Gly Glu Gly Ser

50 55 60

<210> 233

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 9, 10

<223> Xaa = AN or TD

<220>

<221> variant

<222> 12

<223> Xaa = N or D

<400> 233

Arg Ile Phe Pro Gly Asp Gly Asp Xaa Xaa Tyr Xaa Gly Lys Phe Lys

1 5 10 15

Gly

<210> 234

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 6

<223> Xaa = D or E

<400> 234

Thr Gly Ala Ala Tyr Xaa Phe Asp Pro Phe Pro Tyr

1 5 10

<210> 235

<211> 16

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 3

<223> Xaa = S or T

<220>

<221> variant

<222> 10

<223> Xaa = N or S

<220>

<221> variant

<222> 12

<223> Xaa = V or I

<400> 235

Ser Ser Xaa Lys Ser Leu Leu His Ser Xaa Gly Xaa Thr Tyr Leu Tyr

1 5 10 15

<210> 236

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 1

<223> Xaa = S or T

<220>

<221> variant

<222> 4

<223> Xaa = L or M

<400> 236

Xaa Tyr Trp Xaa Asn

1 5

<210> 237

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 3

<223> Xaa = Y or F

<220>

<221> variant

<222> 9, 10

<223> Xaa = AN or TD

<220>

<221> variant

<222> 12

<223> Xaa = N or D

<400> 237

Arg Ile Xaa Pro Gly Asp Gly Asp Xaa Xaa Tyr Xaa Gly Lys Phe Lys

1 5 10 15

Gly

<210> 238

<211> 16

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 1, 2, 3

<223> Xaa = SSS, SST, or RFS

<220>

<221> variant

<222> 10

<223> Xaa = N or S

<220>

<221> variant

<222> 12

<223> Xaa = V or I

<400> 238

Xaa Xaa Xaa Lys Ser Leu Leu His Ser Xaa Gly Xaa Thr Tyr Leu Tyr

1 5 10 15

<210> 239

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 1

<223> Xaa = R or Q

<400> 239

Xaa Met Ser Asn Leu Ala Ser

1 5

<210> 240

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 3

<223> Xaa = M or N

<220>

<221> variant

<222> 6

<223> Xaa = R or L

<220>

<221> variant

<222> 8

<223> Xaa = F or W

<400> 240

Ala Gln Xaa Leu Glu Xaa Pro Xaa Thr

1 5

<210> 241

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 1

<223> Xaa = A or S

<220>

<221> variant

<222> 4

<223> Xaa = M or I

<400> 241

Xaa Tyr Val Xaa His

1 5

<210> 242

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 3

<223> Xaa = F or N

<220>

<221> variant

<222> 6

<223> Xaa = N or S

<220>

<221> variant

<222> 8

<223> Xaa = G or Y

<220>

<221> variant

<222> 10

<223> Xaa = E or Q

<400> 242

Tyr Ile Xaa Pro Tyr Xaa Asp Xaa Thr Xaa Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 243

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 2, 8

<223> Xaa = T or A

<400> 243

Arg Xaa Asp Gly Asn Pro Tyr Xaa Met Asp Tyr

1 5 10

<210> 244

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 11

<223> Xaa = A or V

<400> 244

Lys Ala Ser Gln Asp Val Ser Thr Ala Val Xaa

1 5 10

<210> 245

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 5

<223> Xaa = N or D

<220>

<221> variant

<222> 7

<223> Xaa = G or S

<220>

<221> variant

<222> 9

<223> Xaa = N or A

<220>

<221> variant

<222> 11

<223> Xaa = A or V

<400> 245

Lys Ala Ser Gln Xaa Val Xaa Thr Xaa Val Xaa

1 5 10

<210> 246

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 6, 7

<223> Xaa = FI or YT

<400> 246

Ser Ala Ser Tyr Arg Xaa Xaa

1 5

<210> 247

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 3, 4, 5, 6

<223> Xaa = YNRN or HYST

<220>

<221> variant

<222> 8

<223> Xaa = I or F

<400> 247

Gln Gln Xaa Xaa Xaa Xaa Pro Xaa Thr

1 5

<210> 248

<211> 15

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 1

<223> Xaa = K or R

<220>

<221> variant

<222> 7, 8, 9, 10, 11

<223> Xaa = DYAGD or STSSY

<220>

<221> variant

<222> 15

<223> Xaa = N or H

<400> 248

Xaa Ala Ser Gln Ser Val Xaa Xaa Xaa Xaa Xaa Ser Tyr Met Xaa

1 5 10 15

<210> 249

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 1

<223> Xaa = A or Y

<400> 249

Xaa Ala Ser Asn Leu Glu Ser

1 5

<210> 250

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<220>

<221> variant

<222> 2, 3, 4, 5, 6

<223> Xaa = QTNED or HSWEI

<220>

<221> variant

<222> 8

<223> Xaa = R or F

<400> 250

Gln Xaa Xaa Xaa Xaa Xaa Pro Xaa Thr

1 5

<210> 251

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 251

Asp Thr Tyr Met Tyr

1 5

<210> 252

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 252

Arg Ile Asp Pro Ala Asn Asp Asn Thr Lys Tyr Ala Gln Lys Phe Gln

1 5 10 15

Gly

<210> 253

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 253

Ala Lys Asn Leu Leu Asn Tyr Phe Asp Tyr

1 5 10

<210> 254

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 254

Arg Ala Ser Gln Glu Ile Ser Gly Tyr Leu Ser

1 5 10

<210> 255

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 255

Ala Thr Ser Thr Leu Gln Ser

1 5

<210> 256

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 256

Leu Gln Tyr Ala Ile Tyr Pro Leu Thr

1 5

<210> 257

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 257

Gly Phe Thr Phe Ser Ser Tyr Thr

1 5

<210> 258

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 258

Ile Ser His Gly Gly Gly Asp Thr

1 5

<210> 259

<211> 16

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 259

Ala Arg His Ser Gly Tyr Glu Arg Gly Tyr Tyr Tyr Val Met Asp Tyr

1 5 10 15

<210> 260

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 260

Glu Ser Val Asp Tyr Tyr Gly Phe Ser Phe

1 5 10

<210> 261

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 261

Ala Ala Ser

1

<210> 262

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 262

Gln Gln Ser Lys Glu Val Pro Trp

1 5

<210> 263

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 263

Gly Tyr Thr Phe Thr Ser Tyr Thr

1 5

<210> 264

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 264

Ile Asn Pro Thr Thr Gly Tyr Thr

1 5

<210> 265

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 265

Ala Arg Asp Asp Ala Tyr Tyr Ser Gly Tyr

1 5 10

<210> 266

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 266

Glu Asn Ile Tyr Ser Asn Leu

1 5

<210> 267

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 267

Ala Ala Lys

1

<210> 268

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 268

Gln His Phe Trp Gly Thr Pro Trp Thr

1 5

<210> 269

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 269

Gly Phe Ala Phe Ser Ser Tyr Asp

1 5

<210> 270

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 270

Ile Thr Ile Gly Gly Gly Thr Thr

1 5

<210> 271

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 271

Ala Arg His Arg Tyr Asp Tyr Phe Ala Met Asp Asn

1 5 10

<210> 272

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 272

Glu Asn Val Asp Asn Tyr Gly Ile Asn Phe

1 5 10

<210> 273

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 273

Val Ser Ser

1

<210> 274

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 274

Gln Gln Ser Lys Asp Val Pro Trp

1 5

<210> 275

<211> 135

<212> PRT

<213> Mice

<400> 275

Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly

1 5 10 15

Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser

20 25 30

Tyr Thr Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp

35 40 45

Ile Gly Tyr Ile Asn Pro Thr Thr Gly Tyr Thr Asn Tyr Asn Gln Lys

50 55 60

Phe Lys Asp Lys Ala Asn Pro Thr Thr Thr Gly Tyr Thr Asn Tyr Asn Gln

65 70 75 80

Lys Phe Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr

85 90 95

Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr

100 105 110

Tyr Cys Ala Arg Asp Asp Ala Tyr Tyr Ser Gly Tyr Trp Gly Gln Gly

115 120 125

Thr Thr Leu Thr Val Ser Ser

130 135

<210> 276

<211> 108

<212> PRT

<213> Mice

<400> 276

Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Val Ser Val Gly

1 5 10 15

Glu Thr Val Thr Ile Thr Cys Arg Ala Ser Glu Asn Ile Tyr Ser Asn

20 25 30

Leu Ala Trp Tyr Arg Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val

35 40 45

Tyr Ala Ala Lys Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Asn Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His Phe Trp Gly Thr Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg

100 105

<210> 277

<211> 140

<212> PRT

<213> Mice

<400> 277

Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser

1 5 10 15

Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Ser Tyr Asp

20 25 30

Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Val Trp Val Ala

35 40 45

Tyr Ile Thr Ile Gly Gly Gly Thr Thr Tyr Tyr Tyr Ser Asp Thr Val Lys

50 55 60

Arg Leu Val Trp Val Ala Tyr Ile Thr Ile Gly Gly Gly Thr Thr Thr Tyr

65 70 75 80

Tyr Ser Asp Thr Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Arg His Arg Tyr Asp Tyr Phe Ala Met Asp

115 120 125

Asn Trp Gly His Gly Thr Ser Val Thr Val Ser Ser

130 135 140

<210> 278

<211> 112

<212> PRT

<213> Mice

<400> 278

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Glu

1 5 10 15

His Arg Ala Thr Ile Ser Cys Gln Ala Ser Glu Asn Val Asp Asn Tyr

20 25 30

Gly Ile Asn Phe Met Asn Trp Phe Gln His Lys Pro Ala Gln Pro Pro

35 40 45

Gln Leu Leu Ile Tyr Val Ser Ser Asn Leu Gly Ser Gly Val Pro Ala

50 55 60

Lys Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His

65 70 75 80

Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys

85 90 95

Asp Val Pro Trp Thr Phe Ser Gly Gly Thr Lys Leu Glu Ile Lys Arg

100 105 110

<210> 279

<211> 123

<212> PRT

<213> Mice

<400> 279

Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Thr Met Ser Trp Ile Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val

35 40 45

Ala Tyr Ile Ser His Gly Gly Gly Asp Thr Tyr Tyr Tyr Pro Asp Thr Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Arg His Ser Gly Tyr Glu Arg Gly Tyr Tyr Tyr Val Met Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 280

<211> 111

<212> PRT

<213> Mice

<400> 280

Asp Ile Val Leu Thr Gln Phe Pro Thr Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Tyr Tyr

20 25 30

Gly Phe Ser Phe Ile Asn Trp Phe Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asn Gln Gly Ser Gly Val Pro Ala

50 55 60

Arg Phe Gly Gly Ser Gly Ser Gly Thr Asp Phe Ser Leu Asn Ile His

65 70 75 80

Pro Met Glu Glu Asp Asp Thr Ala Met Tyr Phe Cys Gln Gln Ser Lys

85 90 95

Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 281

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 281

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Thr

20 25 30

Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Asp Pro Ala Asn Asp Asn Thr Lys Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Lys Asn Leu Leu Asn Tyr Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 282

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 282

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Thr

20 25 30

Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Arg Ile Asp Pro Ala Asn Asp Asn Thr Lys Tyr Ala Pro Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Lys Asn Leu Leu Asn Tyr Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 283

<211> 119

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 283

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Asn Ile Lys Asp Thr

20 25 30

Tyr Met Tyr Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Asp Pro Ala Asn Asp Asn Thr Lys Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Ile Thr Ala Asp Thr Ser Thr Asn Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ala Lys Asn Leu Leu Asn Tyr Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 284

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 284

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr

20 25 30

Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile

35 40 45

Tyr Ala Thr Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Ile Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg

100 105

<210> 285

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 285

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr

20 25 30

Leu Ser Trp Leu Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile

35 40 45

Tyr Ala Thr Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Arg Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Ile Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg

100 105

<210> 286

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 286

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Ile Ser Gly Tyr

20 25 30

Leu Ser Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile

35 40 45

Tyr Ala Thr Ser Thr Leu Asp Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Arg Ser Gly Ser Asp Tyr Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln Tyr Ala Ile Tyr Pro Leu

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg

100 105

<210> 287

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 287

Gln Val Gln Leu Gln Gln Ser Gly Ala Asp Leu Val Arg Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Glu Met His Trp Val Lys Gln Thr Pro Val Tyr Gly Leu Glu Trp Ile

35 40 45

Gly Gly Ile Asp Pro Glu Thr Gly Asp Thr Ala Tyr Asn Gln Asn Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Ala Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Asn Tyr Gly Asn Leu Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 288

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 288

Glu Asn Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly

1 5 10 15

Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

Tyr Leu His Trp Tyr Gln Gln Lys Ser Gly Ala Ser Pro Lys Leu Trp

35 40 45

Ile Tyr Ser Thr Ser Asn Leu Ala Phe Gly Val Pro Ala Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu

65 70 75 80

Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Gly Tyr Pro

85 90 95

Leu Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 289

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 289

Asp Tyr Glu Met His

1 5

<210> 290

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 290

Gly Ile Asp Pro Glu Thr Gly Asp Thr Ala Tyr Asn Gln Asn Phe Lys

1 5 10 15

Gly

<210> 291

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 291

Tyr Gly Asn Leu Tyr Tyr Tyr Ala Met Asp Tyr

1 5 10

<210> 292

<211> 12

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 292

Arg Ala Ser Ser Ser Val Ser Ser Tyr Leu His

1 5 10

<210> 293

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 293

Ser Thr Ser Asn Leu Ala Phe

1 5

<210> 294

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 294

Gln Gln Tyr Ser Gly Tyr Pro Leu Thr

1 5

<210> 295

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 295

Gly Tyr Thr Phe Thr Asp Tyr Glu

1 5

<210> 296

<211> 8

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 296

Ile Asp Pro Glu Thr Gly Asp Thr

1 5

<210> 297

<211> 13

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 297

Thr Asn Tyr Gly Asn Leu Tyr Tyr Tyr Ala Met Asp Tyr

1 5 10

<210> 298

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 298

Ser Ser Val Ser Ser Ser Tyr

1 5

<210> 299

<211> 3

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 299

Ser Thr Ser

1

<210> 300

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 300

Gln Gln Tyr Ser Gly Tyr Pro Leu Thr

1 5

<210> 301

<211> 15

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 301

Lys Ala Ser Gln Ser Val Asp Tyr Ala Gly Asp Ser Tyr Leu Asn

1 5 10 15

<210> 302

<211> 15

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 302

Arg Ala Ser Gln Ser Val Asp Tyr Ala Gly Asp Ser Tyr Met Asn

1 5 10 15

<210> 303

<211> 15

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 303

Arg Ala Ser Gln Ser Val Asp Tyr Ala Gly Asp Ser Tyr Leu Ala

1 5 10 15

<210> 304

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 304

Ser Tyr Trp Ile His

1 5

<210> 305

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 305

Glu Ile Glu Pro Ser Ala Ser Tyr Thr Tyr Tyr Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 306

<211> 15

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 306

Arg Ala Ser Gln Ser Val Asp Tyr Ala Gly Asp Ser Tyr Leu Asn

1 5 10 15

<210> 307

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 307

Gln Val Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Met

35 40 45

Gly Glu Ile Asp Pro Ser Ala Ser Tyr Thr Tyr Tyr Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Val Thr Ile Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Val Tyr Tyr Gly Asn Lys Tyr Phe Asp Val Trp Gly Pro

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 308

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 308

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Glu Ile Asp Pro Ser Ala Ser Tyr Thr Tyr Tyr Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Val Thr Met Thr Arg Asp Lys Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Asn Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Val Tyr Tyr Gly Asn Lys Tyr Phe Asp Val Trp Gly Ala

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 309

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 309

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Arg Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Val

35 40 45

Gly Glu Ile Asp Pro Ser Ala Ser Tyr Thr Tyr Tyr Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Asp Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Val Tyr Tyr Gly Asn Lys Tyr Phe Asp Val Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 310

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 310

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Glu Ile Asp Pro Ser Ala Ser Tyr Thr Tyr Tyr Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Val Thr Met Thr Arg Asp Lys Ser Ser Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Val Tyr Tyr Gly Asn Lys Tyr Phe Asp Val Trp Gly Ala

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 311

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 311

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Arg Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Glu Pro Ser Ala Ser Tyr Thr Tyr Tyr Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Val Thr Met Thr Arg Asp Lys Ser Ser Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Val Tyr Tyr Gly Asn Lys Tyr Phe Asp Val Trp Gly Ala

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 312

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 312

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asp Pro Ser Ala Ser Tyr Thr Tyr Tyr Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Val Thr Met Thr Arg Asp Lys Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Val Tyr Tyr Gly Asn Lys Tyr Phe Asp Val Trp Gly Ala

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 313

<211> 111

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 313

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Ser Val Asp Tyr Ala

20 25 30

Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Asp

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Thr Asn

85 90 95

Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 314

<211> 111

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 314

Asp Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Gln Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Asp Tyr Ala

20 25 30

Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Ser

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Val Ser

65 70 75 80

Ser Leu Glu Asp Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Asn

85 90 95

Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105 110

<210> 315

<211> 111

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 315

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Gln Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Asp Tyr Ala

20 25 30

Gly Asp Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

35 40 45

Arg Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Arg

65 70 75 80

Pro Leu Glu Glu Glu Asp Ala Ala Val Tyr Tyr Cys Gln Gln Thr Asn

85 90 95

Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 316

<211> 111

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 316

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Asp Tyr Ala

20 25 30

Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Ser

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Glu Asp Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Asn

85 90 95

Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 317

<211> 111

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 317

Asp Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Gln Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Asp Tyr Ala

20 25 30

Gly Asp Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ser

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Glu Asp Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Asn

85 90 95

Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 318

<211> 111

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 318

Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Asp Tyr Ala

20 25 30

Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Ser

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser

65 70 75 80

Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Asn

85 90 95

Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 319

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 319

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Met Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Glu Met His Trp Val Arg Gln Thr Pro Val Tyr Gly Leu Glu Trp Ile

35 40 45

Gly Gly Ile Asp Pro Glu Thr Gly Asp Thr Ala Tyr Asn Gln Asn Phe

50 55 60

Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Arg Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Asn Tyr Gly Asn Leu Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 320

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 320

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Glu Met His Trp Val Arg Gln Thr Pro Val Tyr Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Asp Pro Glu Thr Gly Asp Thr Ala Tyr Asn Gln Asn Phe

50 55 60

Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Asn Tyr Gly Asn Leu Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 321

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 321

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Glu Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Asp Pro Glu Thr Gly Asp Thr Ala Tyr Asn Gln Asn Phe

50 55 60

Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Asn Tyr Gly Asn Leu Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 322

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 322

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

Tyr Leu His Trp Tyr Gln Gln Lys Ser Gly Ala Ser Pro Arg Leu Leu

35 40 45

Ile Tyr Ser Thr Ser Asn Leu Ala Phe Gly Ile Pro Ala Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser Ser Leu Glu

65 70 75 80

Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln Tyr Ser Gly Tyr Pro

85 90 95

Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 323

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 323

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

Tyr Leu His Trp Tyr Gln Gln Lys Ser Gly Ala Ser Pro Arg Leu Trp

35 40 45

Ile Tyr Ser Thr Ser Asn Leu Ala Phe Gly Ile Pro Ala Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser Ser Leu Gln

65 70 75 80

Ser Glu Asp Phe Ala Ala Tyr Tyr Cys Gln Gln Tyr Ser Gly Tyr Pro

85 90 95

Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 324

<211> 108

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 324

Glu Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Ser Thr Ser Asn Leu Ala Phe Gly Val Pro Ser Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Ser Tyr Thr Phe Thr Ile Ser Ser Leu Gln

65 70 75 80

Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Gly Tyr Pro

85 90 95

Leu Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 325

<211> 203

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 325

Ser Asp Thr Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu

1 5 10 15

Ile Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val

20 25 30

Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp Thr

35 40 45

Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg Lys Gly Phe

50 55 60

Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly Leu Leu Thr Cys Glu

65 70 75 80

Ala Thr Val Asn Gly His Leu Tyr Lys Thr Asn Tyr Leu Thr His Arg

85 90 95

Gln Thr Asn Thr Ile Ile Asp Val Val Leu Ser Pro Ser His Gly Ile

100 105 110

Glu Leu Ser Val Gly Glu Lys Leu Val Leu Asn Cys Thr Ala Arg Thr

115 120 125

Glu Leu Asn Val Gly Ile Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys

130 135 140

His Gln His Lys Lys Leu Val Asn Arg Asp Leu Lys Thr Gln Ser Gly

145 150 155 160

Ser Glu Met Lys Lys Phe Leu Ser Thr Leu Thr Ile Asp Gly Val Thr

165 170 175

Arg Ser Asp Gln Gly Leu Tyr Thr Cys Ala Ala Ser Gly Leu Met

180 185 190

Thr Lys Lys Asn Ser Thr Phe Val Arg Val His

195 200

<210> 326

<211> 10

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 326

Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn

1 5 10

<210> 327

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 327

Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Ala Asp Phe Lys

1 5 10 15

Arg

<210> 328

<211> 14

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 328

Tyr Pro His Tyr Tyr Gly Ser Ser His Trp Tyr Phe Asp Val

1 5 10

<210> 329

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 329

Ser Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn

1 5 10

<210> 330

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 330

Phe Thr Ser Ser Leu His Ser

1 5

<210> 331

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 331

Gln Gln Tyr Ser Thr Val Pro Trp Thr

1 5

<210> 332

<211> 5

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 332

Ser Tyr Ser Met Asn

1 5

<210> 333

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 333

Ser Ile Ser Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 334

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 334

Val Thr Asp Ala Phe Asp Ile

1 5

<210> 335

<211> 11

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 335

Arg Ala Ser Gln Gly Ile Asp Asn Trp Leu Gly

1 5 10

<210> 336

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 336

Asp Ala Ser Asn Leu Asp Thr

1 5

<210> 337

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 337

Gln Gln Ala Lys Ala Phe Pro Pro Thr

1 5

<210> 338

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 338

Gly Ser Asp Lys Thr His Thr

1 5

<210> 339

<211> 98

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 339

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Lys Val

<210> 340

<211> 232

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 340

Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

1 5 10 15

Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro

20 25 30

Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val

35 40 45

Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val

50 55 60

Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln

65 70 75 80

Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln

85 90 95

Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala

100 105 110

Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro

115 120 125

Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr

130 135 140

Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser

145 150 155 160

Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr

165 170 175

Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr

180 185 190

Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe

195 200 205

Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys

210 215 220

Ser Leu Ser Leu Ser Pro Gly Lys

225 230

<210> 341

<211> 107

<212> PRT

<213> Homo sapiens

<400> 341

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

20 25 30

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

35 40 45

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

50 55 60

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

65 70 75 80

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

85 90 95

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

100 105

<210> 342

<211> 660

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 342

Gln Val Gln Leu Gln Gln Ser Gly Ala Asp Leu Val Arg Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Glu Met His Trp Val Lys Gln Thr Pro Val Tyr Gly Leu Glu Trp Ile

35 40 45

Gly Gly Ile Asp Pro Glu Thr Gly Asp Thr Ala Tyr Asn Gln Asn Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Ala Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Asn Tyr Gly Asn Leu Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys Gly Ser Asp Lys Thr His Thr Ser Asp Thr Gly Arg Pro Phe

450 455 460

Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His Met Thr Glu Gly

465 470 475 480

Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro Asn Ile Thr Val

485 490 495

Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg

500 505 510

Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr

515 520 525

Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val Asn Gly His Leu

530 535 540

Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn Thr Ile Ile Asp

545 550 555 560

Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly Glu Lys

565 570 575

Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Ile Asp

580 585 590

Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys Leu Val

595 600 605

Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys Phe Leu

610 615 620

Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr

625 630 635 640

Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser Thr Phe

645 650 655

Val Arg Val His

660

<210> 343

<211> 215

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 343

Glu Asn Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly

1 5 10 15

Glu Lys Val Thr Met Thr Cys Arg Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

Tyr Leu His Trp Tyr Gln Gln Lys Ser Gly Ala Ser Pro Lys Leu Trp

35 40 45

Ile Tyr Ser Thr Ser Asn Leu Ala Phe Gly Val Pro Ala Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu

65 70 75 80

Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Gly Tyr Pro

85 90 95

Leu Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala

100 105 110

Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

115 120 125

Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu

130 135 140

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

145 150 155 160

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

165 170 175

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

180 185 190

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

195 200 205

Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 344

<211> 19

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 344

Met Gly Trp Thr Leu Val Phe Leu Phe Leu Leu Ser Val Thr Ala Gly

1 5 10 15

Val His Ser

<210> 345

<211> 20

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 345

Met Val Ser Ser Ala Gln Phe Leu Gly Leu Leu Leu Leu Cys Phe Gln

1 5 10 15

Gly Thr Arg Cys

20

<210> 346

<211> 19

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 346

Met Gly Trp Ser Cys Ile Ile Leu Phe Leu Val Ala Thr Ala Thr Gly

1 5 10 15

Val His Ser

<210> 347

<211> 118

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 347

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr

20 25 30

Trp Leu Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Phe

35 40 45

Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe

50 55 60

Lys Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Val Arg Gly Asp Gly Tyr Trp Ala Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Thr Val Thr Val Ser Ser

115

<210> 348

<211> 118

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 348

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Val Lys Ser Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr

20 25 30

Trp Leu Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Phe

35 40 45

Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe

50 55 60

Lys Gly Arg Val Thr Leu Ile Arg Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Thr Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Val Arg Gly Asp Gly Tyr Trp Ala Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 349

<211> 118

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 349

Gln Val Gln Leu Val Gln Ser Gly Pro Glu Val Lys Lys Pro Gly Glu

1 5 10 15

Ser Leu Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr

20 25 30

Trp Leu Asn Trp Val Arg Gln Met Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe

50 55 60

Lys Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ser Gly Thr Ala Tyr

65 70 75 80

Leu Gln Leu Ser Ser Leu Lys Ala Ser Asp Thr Ala Val Tyr Phe Cys

85 90 95

Val Arg Gly Asp Gly Tyr Trp Ala Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 350

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 350

Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Phe Ser Gln Ser Leu Leu His Ser

20 25 30

Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn

85 90 95

Leu Glu Leu Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 351

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 351

Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly

1 5 10 15

Glu Pro Ala Ser Ile Ser Cys Arg Phe Ser Gln Ser Leu Leu His Ser

20 25 30

Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Thr Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn

85 90 95

Leu Glu Leu Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 352

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 352

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Arg Phe Ser Lys Ser Leu Leu His Ser

20 25 30

Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Pro

35 40 45

Pro Lys Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

65 70 75 80

Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Ala Gln Asn

85 90 95

Leu Glu Leu Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 353

<211> 16

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 353

Arg Phe Ser Gln Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr

1 5 10 15

<210> 354

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 354

Thr Met Ser Asn Leu Ala Ser

1 5

<210> 355

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 355

Lys Ser Ser Gln Ser Leu Leu Asn Ser Asn Asn Gln Lys Asn Tyr Leu

1 5 10 15

Ala

<210> 356

<211> 7

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 356

Phe Ala Ser Thr Arg Glu Ser

1 5

<210> 357

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 357

Gln Gln His Tyr Asn Thr Pro Leu Thr

1 5

<210> 358

<211> 17

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 358

Lys Ser Ser Gln Ser Leu Leu Asn Ser Asn Asn Gln Lys Asn Ser Leu

1 5 10 15

Ala

<210> 359

<211> 9

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 359

Gln Gln His Ser Asn Thr Pro Leu Thr

1 5

<210> 360

<211> 113

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 360

Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Thr

1 5 10 15

Thr Val Lys Ile Ala Cys Lys Val Ser Gly Tyr Thr Phe Thr Asp His

20 25 30

Gly Ile His Trp Val Gln Gln Ala Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Asn Ile Ser Pro Gly Asn Gly Asp Ile Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Arg Val Thr Leu Thr Ala Asp Lys Ser Ser Asp Thr Ala Tyr

65 70 75 80

Met Glu Leu Asn Thr Leu Arg Ser Glu Asp Thr Ala Ile Tyr Phe Cys

85 90 95

Thr Thr Tyr Phe Val Asp Trp Gly Arg Gly Thr Leu Val Thr Val Ser

100 105 110

Ser

<210> 361

<211> 113

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 361

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp His

20 25 30

Gly Ile His Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Leu

35 40 45

Gly Asn Ile Ser Pro Gly Asn Gly Asp Ile Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Thr Thr Tyr Phe Val Asp Trp Gly Arg Gly Thr Leu Val Thr Val Ser

100 105 110

Ser

<210> 362

<211> 113

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 362

Gln Val Gln Leu Leu Glu Ser Gly Ala Glu Ala Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp His

20 25 30

Gly Ile His Trp Val His Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Asn Ile Ser Pro Gly Asn Gly Asp Ile Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Arg Val Thr Ile Thr Val Asp Lys Ser Ala Ser Thr Ala Tyr

65 70 75 80

Met Glu Val Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Thr Thr Tyr Phe Val Asp Trp Gly Arg Gly Thr Leu Val Thr Val Ser

100 105 110

Ser

<210> 363

<211> 113

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 363

Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Leu Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

Asn Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Phe Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Val Ala Tyr Tyr Phe Cys Gln Gln

85 90 95

His Tyr Asn Thr Pro Leu Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile

100 105 110

Lys

<210> 364

<211> 113

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 364

Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

Asn Asn Gln Lys Asn Ser Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Tyr Phe Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Tyr Tyr Phe Cys Gln Gln

85 90 95

His Ser Asn Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile

100 105 110

Lys

<210> 365

<211> 113

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 365

Glu Ile Val Met Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser

20 25 30

Asn Asn Gln Lys Asn Cys Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ala Pro Arg Leu Leu Ile Tyr Phe Ala Ser Thr Arg Glu Ser Gly Ile

50 55 60

Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Tyr Tyr Phe Cys Gln Gln

85 90 95

His Cys Asn Thr Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile

100 105 110

Lys

<210> 366

<211> 660

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 366

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Glu Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Gly Ile Asp Pro Glu Thr Gly Asp Thr Ala Tyr Asn Gln Asn Phe

50 55 60

Lys Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Asn Tyr Gly Asn Leu Tyr Tyr Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val

115 120 125

Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala

130 135 140

Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser

145 150 155 160

Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val

165 170 175

Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro

180 185 190

Ser Ser Ser Leu Gly Thr Gln Thr Tyr Tyr Ile Cys Asn Val Asn His Lys

195 200 205

Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp

210 215 220

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

225 230 235 240

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

245 250 255

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

260 265 270

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

275 280 285

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

290 295 300

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

305 310 315 320

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

325 330 335

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

340 345 350

Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu

355 360 365

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

370 375 380

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

385 390 395 400

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

405 410 415

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

420 425 430

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

435 440 445

Gly Lys Gly Ser Asp Lys Thr His Thr Ser Asp Thr Gly Arg Pro Phe

450 455 460

Val Glu Met Tyr Ser Glu Ile Pro Glu Ile Ile His Met Thr Glu Gly

465 470 475 480

Arg Glu Leu Val Ile Pro Cys Arg Val Thr Ser Pro Asn Ile Thr Val

485 490 495

Thr Leu Lys Lys Phe Pro Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg

500 505 510

Ile Ile Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr

515 520 525

Lys Glu Ile Gly Leu Leu Thr Cys Glu Ala Thr Val Asn Gly His Leu

530 535 540

Tyr Lys Thr Asn Tyr Leu Thr His Arg Gln Thr Asn Thr Ile Ile Asp

545 550 555 560

Val Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly Glu Lys

565 570 575

Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Ile Asp

580 585 590

Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His Lys Lys Leu Val

595 600 605

Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu Met Lys Lys Phe Leu

610 615 620

Ser Thr Leu Thr Ile Asp Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr

625 630 635 640

Thr Cys Ala Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser Thr Phe

645 650 655

Val Arg Val His

660

<210> 367

<211> 215

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 367

Glu Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Ser Ser Val Ser Ser Ser

20 25 30

Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu

35 40 45

Ile Tyr Ser Thr Ser Asn Leu Ala Phe Gly Val Pro Ser Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Ser Tyr Thr Phe Thr Ile Ser Ser Leu Gln

65 70 75 80

Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Gly Tyr Pro

85 90 95

Leu Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala

100 105 110

Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser

115 120 125

Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu

130 135 140

Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser

145 150 155 160

Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu

165 170 175

Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val

180 185 190

Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys

195 200 205

Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 368

<400> 368

000

<210> 369

<400> 369

000

<210> 370

<400> 370

000

<210> 371

<400> 371

000

<210> 372

<400> 372

000

<210> 373

<400> 373

000

<210> 374

<400> 374

000

<210> 375

<400> 375

000

<210> 376

<400> 376

000

<210> 377

<400> 377

000

<210> 378

<400> 378

000

<210> 379

<400> 379

000

<210> 380

<400> 380

000

<210> 381

<400> 381

000

<210> 382

<400> 382

000

<210> 383

<400> 383

000

<210> 384

<400> 384

000

<210> 385

<400> 385

000

<210> 386

<400> 386

000

<210> 387

<400> 387

000

<210> 388

<400> 388

000

<210> 389

<400> 389

000

<210> 390

<400> 390

000

<210> 391

<400> 391

000

<210> 392

<400> 392

000

<210> 393

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 393

Gln Val Gln Leu Lys Gln Ser Gly Pro Gly Leu Val Gln Pro Ser Gln

1 5 10 15

Ser Leu Ser Ile Thr Cys Thr Val Ser Asp Phe Ser Leu Ser Ser Phe

20 25 30

Gly Val Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Ser Gly Gly Ser Thr Asp Tyr Asn Val Ala Phe Ile

50 55 60

Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Phe

65 70 75 80

Lys Met Asn Asn Leu Gln Ala Asp Asp Thr Ala Ile Tyr Tyr Cys Ala

85 90 95

Arg Asn Trp Arg Tyr Asp Gly Tyr Phe Tyr Ala Met Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 394

<211> 116

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 394

Asp Val Asn Leu Val Glu Ser Gly Gly Gly Leu Val Lys Leu Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

Tyr Met Ser Trp Val Arg Gln Ser Pro Glu Lys Arg Leu Glu Trp Val

35 40 45

Ala Thr Ile Ser Asn Asn Gly Asp Ser Thr Tyr Tyr Leu Asp Thr Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala Glu Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Ile Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Val Gly Thr Gly Phe Thr Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ala

115

<210> 395

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 395

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Tyr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Arg Val Asn Pro Asn Asn Gly Gly Lys Thr Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Leu Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Trp Arg Leu Arg Pro Val Asp Tyr Gly Met Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 396

<211> 113

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 396

Gln Val Gln Leu Gln Gln Ser Asp Ala Glu Leu Val Lys Pro Gly Thr

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp His

20 25 30

Gly Ile His Trp Val Lys Gln Arg Pro Glu Arg Gly Leu Glu Trp Ile

35 40 45

Gly Asn Ile Ser Pro Gly Asn Gly Asp Ile Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Val Tyr

65 70 75 80

Met Gln Val Asn Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Thr Thr Tyr Phe Val Asp Trp Gly Arg Gly Thr Leu Val Thr Val Ser

100 105 110

Ala

<210> 397

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 397

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Asn Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ala Tyr

20 25 30

Val Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Phe Pro Tyr Asn Asp Gly Thr Glu Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Arg Thr Asp Gly Asn Pro Tyr Thr Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 398

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 398

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Val Ile His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Asn Pro Tyr Ser Asp Tyr Thr Gln Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ser Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Ser Cys

85 90 95

Ala Arg Arg Ala Asp Gly Asn Pro Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 399

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 399

Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asp Pro Ser Ala Ser Tyr Thr Tyr Tyr Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Val Tyr Tyr Gly Asn Lys Tyr Phe Asp Val Trp Gly Ala

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 400

<211> 116

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 400

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Tyr Ile His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Tyr Pro Gly Ser Asp Asp Ala Tyr Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Thr Arg Glu Thr Thr Ala Thr Ala Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ala

115

<210> 401

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 401

Gln Val Gln Leu Gln Gln Ser Gly Pro Asp Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Thr Tyr

20 25 30

Trp Met Asn Trp Val Lys Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Arg Ile Phe Pro Gly Asp Gly Asp Ala Asn Tyr Asn Gly Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Thr Arg Thr Gly Ala Ala Tyr Asp Phe Asp Pro Phe Pro Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ala

115 120

<210> 402

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 402

Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ala Phe Ser Thr Tyr

20 25 30

Trp Met Asn Trp Val Lys Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asp Gly Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Thr Gly Ala Ala Tyr Glu Phe Asp Pro Phe Pro Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ala

115 120

<210> 403

<211> 120

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 403

Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Arg Ser

20 25 30

Trp Met Asn Trp Val Lys Gln Arg Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Asn Gly Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Ala Tyr Phe Cys

85 90 95

Ala Arg Ser Ala Thr Leu Pro Tyr Trp Tyr Phe Asp Val Trp Gly Ala

100 105 110

Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 404

<211> 118

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 404

Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Tyr

20 25 30

Trp Leu Asn Trp Val Lys Gln Arg Pro Gly Lys Gly Leu Glu Trp Phe

35 40 45

Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Val Arg Gly Asp Gly Tyr Trp Ala Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Ser Val Thr Val Ser Ser

115

<210> 405

<211> 115

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 405

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Glu Met His Trp Val Arg Gln Thr Pro Val His Gly Leu Glu Trp Ile

35 40 45

Gly Gly Ile Asp Pro Glu Thr Gly Gly Thr Ala Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Gly Ala Trp Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ala

115

<210> 406

<211> 121

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 406

Glu Val Gln Leu Gln Gln Ser Gly Thr Val Leu Ala Arg Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Ala Ile Tyr Pro Gly Asn Ser Asp Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Lys Leu Thr Ala Val Thr Ser Ala Ser Thr Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Thr Asn Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Gly Gly Phe Asp Tyr Ser Asn Tyr Trp Phe Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ala

115 120

<210> 407

<211> 109

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 407

Gln Ala Val Val Thr Gln Glu Ser Ala Leu Thr Thr Ser Pro Gly Glu

1 5 10 15

Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala Val Thr Thr Thr

20 25 30

Asn Ser Ala Asn Trp Val Gln Glu Lys Pro Asp His Leu Phe Thr Gly

35 40 45

Leu Ile Gly Gly Thr Asn Asn Arg Ala Pro Gly Val Pro Ala Arg Phe

50 55 60

Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr Ile Thr Gly Ala

65 70 75 80

Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu Trp Tyr Asn Asn

85 90 95

His Phe Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

100 105

<210> 408

<211> 107

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 408

Asp Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Thr Pro Gly

1 5 10 15

Asp Ser Val Ser Leu Ser Cys Arg Ala Ser Gln Ser Ile Asn Asn Tyr

20 25 30

Leu His Trp Tyr Gln Gln Arg Ser His Glu Ser Pro Arg Leu Leu Ile

35 40 45

Lys Phe Ala Ser Gln Ser Ile Ser Asp Ile Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Ser Ile Asn Ser Ile Glu Thr

65 70 75 80

Glu Asp Phe Gly Met Tyr Phe Cys Gln Gln Ser Asn Ser Trp Pro Leu

85 90 95

Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 409

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 409

Asp Ile Val Met Thr Gln Ala Ala Phe Ser Asn Pro Val Thr Leu Gly

1 5 10 15

Thr Ser Ala Ser Ile Ser Cys Ser Ser Ser Lys Ser Leu Leu His Ser

20 25 30

Asn Gly Val Thr Tyr Leu Tyr Trp Tyr Leu Gln Arg Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Ile Tyr Tyr Cys Ala Gln Met

85 90 95

Leu Glu Arg Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 410

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 410

Asp Ile Val Met Thr Gln Ala Ala Phe Ser Asn Pro Val Thr Leu Gly

1 5 10 15

Thr Ser Ala Ser Ile Ser Cys Ser Ser Thr Lys Ser Leu Leu His Ser

20 25 30

Ser Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Arg Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Met

85 90 95

Leu Glu Arg Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 411

<211> 112

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 411

Asp Ile Val Met Thr Gln Ala Ala Phe Ser Asn Pro Val Thr Leu Gly

1 5 10 15

Thr Ser Ala Ser Ile Ser Cys Arg Phe Ser Lys Ser Leu Leu His Ser

20 25 30

Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Ala Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Ser Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn

85 90 95

Leu Glu Leu Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 412

<211> 113

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 412

Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Met Ser Ile Gly

1 5 10 15

Gln Arg Val Thr Met Ser Cys Lys Ser Gln Ser Leu Leu Asn Ser

20 25 30

Asn Asn Gln Lys Asn Cys Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Arg Leu Leu Ile Tyr Phe Ala Cys Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ile Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Tyr Tyr Phe Cys Gln Gln

85 90 95

His Cys Asn Thr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu

100 105 110

Lys

<210> 413

<211> 106

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 413

Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala

65 70 75 80

Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Ser Ser Tyr Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 414

<211> 107

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 414

Asp Ile Val Met Thr Gln Ser Gln Lys Phe Met Ser Thr Ser Thr Gly

1 5 10 15

Asp Arg Val Ser Val Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Ala Leu Ile

35 40 45

Tyr Ser Ala Ser Tyr Arg Phe Ile Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Asn Val Gln Ser

65 70 75 80

Glu Asp Leu Ala Glu Tyr Phe Cys Gln Gln Tyr Asn Arg Asn Pro Ile

85 90 95

Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 415

<211> 107

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 415

Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly

1 5 10 15

Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile

35 40 45

His Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Arg Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Val Gln Ala

65 70 75 80

Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Phe

85 90 95

Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 416

<211> 107

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 416

Asp Ile Val Met Thr Gln Ser His Lys Phe Met Ser Thr Ser Val Gly

1 5 10 15

Asp Arg Val Ser Thr Thr Cys Lys Ala Ser Gln Asp Val Ser Thr Ala

20 25 30

Val Val Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Tyr Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Thr Ser Val Gln Ala

65 70 75 80

Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Phe

85 90 95

Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 417

<211> 107

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 417

Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly

1 5 10 15

Glu Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asp Ile Lys Ser Tyr

20 25 30

Leu Ser Trp Tyr Gln Gln Lys Pro Trp Lys Ser Pro Lys Thr Leu Ile

35 40 45

Tyr Tyr Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Ser Ser Leu Gly Ser

65 70 75 80

Asp Asp Thr Ala Thr Tyr Tyr Cys Leu Gln His Val Glu Ser Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 418

<211> 106

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 418

Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly

1 5 10 15

Glu Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Ser Val Ser Leu Ile

20 25 30

Tyr Trp Phe Gln Gln Lys Pro Gly Thr Ser Pro Lys Leu Trp Ile Tyr

35 40 45

Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Arg Ser Gly Tyr Pro Pro Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 419

<211> 111

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 419

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Ala

20 25 30

Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His

65 70 75 80

Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Tyr Cys Gln Gln Thr Asn

85 90 95

Glu Asp Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 420

<211> 111

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 420

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Gln Ser Val Ser Thr

20 25 30

Ser Tyr Ser Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His

65 70 75 80

Pro Val Glu Glu Glu Asp Thr Ala Thr Tyr Tyr Cys Gln His Ser Trp

85 90 95

Glu Ile Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 421

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 421

Ser Gly Thr Ser Thr Asp

1 5

<210> 422

<211> 6

<212> PRT

<213> Artificial Sequence

<220>

<223> Synthetic constructs

<400> 422

Thr Gly Thr Ser Asp Ala

1 5

Claims (57)

1. An anti-CD93 construct comprising an antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the antibody moiety competes with an antibody or antibody fragment containing a second heavy chain variable region (VH _-2 ) and a second light chain variable region (VL _-2 ) for a CD93 binding epitope, wherein: a) The V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:289, HC-CDR2 containing the amino acid sequence of SEQ ID NO:290, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:291, and the V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:292, LC-CDR2 containing the amino acid sequence of SEQ ID NO:293, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:294; b) The V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:17, HC-CDR2 containing the amino acid sequence of SEQ ID NO:18, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:19, and the V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:20, LC-CDR2 containing the amino acid sequence of SEQ ID NO:21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:22; c) The V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:33, HC-CDR2 containing the amino acid sequence of SEQ ID NO:34, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:35, and the V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:36, LC-CDR2 containing the amino acid sequence of SEQ ID NO:37, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:38; d) The V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:49, HC-CDR2 containing the amino acid sequence of SEQ ID NO:50, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:51, and the V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:52, LC-CDR2 containing the amino acid sequence of SEQ ID NO:53, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:54; e) The V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:65, HC-CDR2 containing the amino acid sequence of SEQ ID NO:66, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:67, and the V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:68, LC-CDR2 containing the amino acid sequence of SEQ ID NO:69, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:70; f) The V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:81, HC-CDR2 containing the amino acid sequence of SEQ ID NO:82, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:83, and the V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:84, LC-CDR2 containing the amino acid sequence of SEQ ID NO:85, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:86; g) The V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:97, HC-CDR2 containing the amino acid sequence of SEQ ID NO:98, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:99, and the V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:100, LC-CDR2 containing the amino acid sequence of SEQ ID NO:101, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:102; h) The V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:113, HC-CDR2 containing the amino acid sequence of SEQ ID NO:114, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:115, and the V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:116, LC-CDR2 containing the amino acid sequence of SEQ ID NO:117, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:118; i) The V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:129, HC-CDR2 containing the amino acid sequence of SEQ ID NO:130, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:131, and the V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:132, LC-CDR2 containing the amino acid sequence of SEQ ID NO:133, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:134; j) The V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:145, HC-CDR2 containing the amino acid sequence of SEQ ID NO:146, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:147, and the V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:148, 355, or 358, LC-CDR2 containing the amino acid sequence of SEQ ID NO:149 or 356, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:150, 357, or 359; k) The V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:161, HC-CDR2 containing the amino acid sequence of SEQ ID NO:162, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:163, and the V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:164, LC-CDR2 containing the amino acid sequence of SEQ ID NO:165, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:166; l) The V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:177, HC-CDR2 containing the amino acid sequence of SEQ ID NO:178, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:179, and the V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:180 or 353, LC-CDR2 containing the amino acid sequence of SEQ ID NO:181 or 354, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:182; m) The V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:193, HC-CDR2 containing the amino acid sequence of SEQ ID NO:194, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:195, and the V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:196, LC-CDR2 containing the amino acid sequence of SEQ ID NO:197, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:198; n) The V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:209, HC-CDR2 containing the amino acid sequence of SEQ ID NO:210, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:211, and the V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:212, LC-CDR2 containing the amino acid sequence of SEQ ID NO:213, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:214; o) The V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:1, HC-CDR2 containing the amino acid sequence of SEQ ID NO:2, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:3, and the V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:4, LC-CDR2 containing the amino acid sequence of SEQ ID NO:5, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:6; or p) The V _H-2 comprises HC-CDR1 containing the amino acid sequence of SEQ ID NO:17 or 304, HC-CDR2 containing the amino acid sequence of SEQ ID NO:18 or 305, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:19, and the V _L-2 comprises LC-CDR1 containing the amino acid sequence of SEQ ID NO:20, 301, 302, 303, or 306, LC-CDR2 containing the amino acid sequence of SEQ ID NO:21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:22. 2. The anti-CD93 construct as described in claim 1, wherein: a) The V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:289, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:290, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:291, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:292, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:293, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:294, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. b) The V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:17, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:18, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:19, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:20, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:22, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. c) The V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:33, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:34, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:35, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:36, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:37, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:38, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. d) The V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:49, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:51, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:52, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:53, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:54, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. e) The V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:65, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:66, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:67, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:68, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:69, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:70, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. f) The V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:81, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:82, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:83, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:84, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:85, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:86, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. g) The V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:97, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:98, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:99, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:100, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:101, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:102, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. h) The V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:113, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:114, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:115, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:116, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:117, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:118, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. i) The V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:129, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:130, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:131, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:132, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:133, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:134, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. j) The V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:145, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:146, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:147, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:148, 355, or 358, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:149 or 356, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:150, 357, or 359, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. k) The V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:161, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:162, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:163, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:164, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:165, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:166, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. l) The V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:177, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:178, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:179, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:180 or 353, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:181 or 354, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:182, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. m) The V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:193, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:194, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:195, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:196, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:197, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:198, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR, or n) The V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:209, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:210, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:211, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:212, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:213, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:214, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. o) The V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:1, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:2, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:3, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:4, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:5, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:6, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR, or p) The V _H comprises: HC-CDR1 containing the amino acid sequence of SEQ ID NO:17 or 304, HC-CDR2 containing the amino acid sequence of SEQ ID NO:18 or 305, and HC-CDR3 containing the amino acid sequence of SEQ ID NO:19, and the V _L comprises: LC-CDR1 containing the amino acid sequence of SEQ ID NO:20, 301, 302, 303, or 306, LC-CDR2 containing the amino acid sequence of SEQ ID NO:21, and LC-CDR3 containing the amino acid sequence of SEQ ID NO:22. 3. The anti-CD93 construct of claim 2, wherein the V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:289, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:290, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:291, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:292, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:293, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:294, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. 4. The anti-CD93 construct of claim 2, wherein the V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 17 or 304, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 18 or 305, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 19, or variants thereof comprising up to 5, 4, 3, 2 or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 20, 301, 302, 303 or 306, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 21, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 22, or variants thereof comprising up to 5, 4, 3, 2 or 1 amino acid substitutions in the LC-CDR. 5. The anti-CD93 construct of claim 2, wherein the V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:33, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:34, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:35, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR; and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:36, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:37, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:38, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. 6. The anti-CD93 construct of claim 2, wherein the V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:49, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:50, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:51, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:52, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:53, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:54, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. 7. The anti-CD93 construct of claim 2, wherein the V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:65, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:66, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:67, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:68, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:69, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:70, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. 8. The anti-CD93 construct of claim 2, wherein the V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:81, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:82, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:83, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:84, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:85, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:86, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. 9. The anti-CD93 construct of claim 2, wherein the V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 97, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 98, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 99, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 100, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 101, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 102, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. 10. The anti-CD93 construct of claim 2, wherein the V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 113, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 114, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 115, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 116, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 117, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 118, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. 11. The anti-CD93 construct of claim 2, wherein the V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 129, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 130, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 131, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 132, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 133, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 134, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. 12. The anti-CD93 construct of claim 2, wherein the V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 145, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 146, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 147, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 148, 355, or 358, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 149 or 356, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 150, 357, or 359, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. 13. The anti-CD93 construct of claim 2, wherein the V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:161, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:162, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:163, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:164, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:165, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:166, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. 14. The anti-CD93 construct of claim 2, wherein the V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 177, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 178, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 179, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and the V _L comprises: i) CDR1 comprising the amino acid sequence of SEQ ID NO: 180 or 353, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 181 or 354, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 182, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. 15. The anti-CD93 construct of claim 2, wherein the V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:193, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:194, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:195, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:196, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:197, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:198, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. 16. The anti-CD93 construct of claim 2, wherein the V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:209, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:210, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:211, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:212, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:213, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:214, or variants thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. 17. The anti-CD93 construct of claim 2, wherein the V _H comprises: i) HC-CDR1 comprising the amino acid sequence of SEQ ID NO:1, ii) HC-CDR2 comprising the amino acid sequence of SEQ ID NO:2, and iii) HC-CDR3 comprising the amino acid sequence of SEQ ID NO:3, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDR, and the V _L comprises: i) LC-CDR1 comprising the amino acid sequence of SEQ ID NO:4, ii) LC-CDR2 comprising the amino acid sequence of SEQ ID NO:5, and iii) LC-CDR3 comprising the amino acid sequence of SEQ ID NO:6, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDR. 18. An anti-CD93 construct comprising an antibody moiety that specifically binds to CD93, comprising: a) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:287 and 319-321; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:288 and 322-324; b) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:29 and 307-312; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:30 and 313-318; c) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:45; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:46; d) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:61; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:62; e) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:77; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:78; f) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:93; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:94; g) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:109; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:110; h) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:125; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:126; i) HC-CDR1, HC-CDR2 and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2 and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:141, and LC-CDR1, LC-CDR2 and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2 and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:142; j) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:157 and 360-362; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:158 and 363-365; k) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:173; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:174; l) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO: 189 and 347-349; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO: 190 and 350-352; m)HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:205; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:206; n) HC-CDR1, HC-CDR2 and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2 and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:221, and LC-CDR1, LC-CDR2 and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2 and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:222; o) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having the sequence shown in SEQ ID NO:13; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having the sequence shown in SEQ ID NO:14; p) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:307-312; and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:313-318; or q) HC-CDR1, HC-CDR2, and HC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _H chain region having any of the sequences shown in SEQ ID NO:319-321, and LC-CDR1, LC-CDR2, and LC-CDR3, which respectively contain the amino acid sequences of CDR1, CDR2, and CDR3 within the V _L chain region having any of the sequences shown in SEQ ID NO:322-324. 19. The anti-CD93 construct according to any one of claims 1-18, wherein the V _H comprises: an amino acid sequence of any one of SEQ ID NO: 13, 29, 45, 61, 77, 93, 109, 125, 141, 157, 173, 189, 205, 221, 287, 307-312 and 319-321 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and/or wherein the V _L comprises: an amino acid sequence of any one of SEQ ID NO: 14, 30, 46, 62, 78, 94, 110, 126, 142, 158, 174, 190, 206, 222, 288, 313-318 and 322-324 or a variant comprising an amino acid sequence having at least about 80% sequence identity. 20. The anti-CD93 construct of claim 19, wherein: a) The V _H comprises: an amino acid sequence of any one of SEQ ID NO:287 and 319-321 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V _L comprises: an amino acid sequence of any one of SEQ ID NO:288 and 322-324 or a variant comprising an amino acid sequence having at least about 80% sequence identity. b) The V _H comprises: an amino acid sequence of any one of SEQ ID NO:29 and 307-312 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V _L comprises: an amino acid sequence of any one of SEQ ID NO:30 and 313-318 or a variant comprising an amino acid sequence having at least about 80% sequence identity. c) The V _H comprises: the amino acid sequence of SEQ ID NO:45 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V _L comprises: the amino acid sequence of SEQ ID NO:46 or a variant comprising an amino acid sequence having at least about 80% sequence identity. d) The V _H comprises: the amino acid sequence of SEQ ID NO:61 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V _L comprises: the amino acid sequence of SEQ ID NO:62 or a variant comprising an amino acid sequence having at least about 80% sequence identity. e) The V _H comprises: the amino acid sequence of SEQ ID NO:77 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V _L comprises: the amino acid sequence of SEQ ID NO:78 or a variant comprising an amino acid sequence having at least about 80% sequence identity. f) The V _H comprises: the amino acid sequence of SEQ ID NO:93 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V _L comprises: the amino acid sequence of SEQ ID NO:94 or a variant comprising an amino acid sequence having at least about 80% sequence identity. g) The V _H comprises: the amino acid sequence of SEQ ID NO:109 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V _L comprises: the amino acid sequence of SEQ ID NO:110 or a variant comprising an amino acid sequence having at least about 80% sequence identity. h) The V _H comprises: the amino acid sequence of SEQ ID NO:125 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V _L comprises: the amino acid sequence of SEQ ID NO:126 or a variant comprising an amino acid sequence having at least about 80% sequence identity. i) The V _H comprises: the amino acid sequence of SEQ ID NO:141 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V _L comprises: the amino acid sequence of SEQ ID NO:142 or a variant comprising an amino acid sequence having at least about 80% sequence identity. j) The V _H comprises: the amino acid sequence of SEQ ID NO:157 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V _L comprises: the amino acid sequence of SEQ ID NO:158 or a variant comprising an amino acid sequence having at least about 80% sequence identity. k) The V _H comprises: the amino acid sequence of SEQ ID NO:173 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V _L comprises: the amino acid sequence of SEQ ID NO:174 or a variant comprising an amino acid sequence having at least about 80% sequence identity. l) The V _H comprises: an amino acid sequence of any one of SEQ ID NO:189 and 347-349 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V _L comprises: an amino acid sequence of any one of SEQ ID NO:190 and 350-352 or a variant comprising an amino acid sequence having at least about 80% sequence identity. m) The V _H comprises: the amino acid sequence of SEQ ID NO:205 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V _L comprises: the amino acid sequence of SEQ ID NO:206 or a variant comprising an amino acid sequence having at least about 80% sequence identity. n) The V _H comprises: the amino acid sequence of SEQ ID NO:221 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V _L comprises: the amino acid sequence of SEQ ID NO:222 or a variant comprising an amino acid sequence having at least about 80% sequence identity. o) The V _H comprises: the amino acid sequence of SEQ ID NO:13 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V _L comprises: the amino acid sequence of SEQ ID NO:14 or a variant comprising an amino acid sequence having at least about 80% sequence identity. p) The V _H comprises: an amino acid sequence of any one of SEQ ID NO:307-312 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V _L comprises: an amino acid sequence of any one of SEQ ID NO:313-318 or a variant comprising an amino acid sequence having at least about 80% sequence identity, or q) The V _H comprises: an amino acid sequence of any one of SEQ ID NO:319-321 or a variant comprising an amino acid sequence having at least about 80% sequence identity; and the V _L comprises: an amino acid sequence of any one of SEQ ID NO:322-324 or a variant comprising an amino acid sequence having at least about 80% sequence identity. 21. The anti-CD93 construct according to any one of claims 1-20, wherein the antibody portion is an antibody or an antigen-binding fragment selected from the group consisting of: full-length antibody, bispecific antibody, single-chain Fv(scFv) fragment, Fab fragment, Fab' fragment, F(ab')2, Fv fragment, disulfide-stabilized Fv fragment (dsFv), (dsFv) ₂ , Fv-Fc fusion, scFv-Fc fusion, scFv-Fv fusion, bisomatic antibody, trisomatic antibody, and tetrasomatic antibody. 22. The anti-CD93 construct of claim 21, wherein the antibody portion is a full-length antibody. 23. The anti-CD93 construct according to any one of claims 1-22, wherein the antibody portion has an Fc fragment selected from the group consisting of Fc fragments from IgG, IgA, IgD, IgE, IgM, and combinations and hybrids thereof. 24. The anti-CD93 construct of claim 23, wherein the Fc fragment is selected from the group consisting of Fc fragments from IgG1, IgG2, IgG3, IgG4, and combinations and hybrids thereof. 25. The anti-CD93 construct of claim 23 or 24, wherein the Fc fragment has reduced effector functionality compared to the corresponding wild-type Fc fragment. 26. The anti-CD93 construct of claim 23 or claim 24, wherein the Fc fragment has enhanced effector functionality compared to the corresponding wild-type Fc fragment. 27. The anti-CD93 construct according to any one of claims 1-26, wherein the antibody partially blocks the binding of CD93 to IGFBP7. 28. The anti-CD93 construct according to any one of claims 1-27, wherein the antibody partially blocks the binding of CD93 to MMRN2. 29. The anti-CD93 construct according to any one of claims 1-22, wherein the CD93 is human CD93. 30. An anti-CD93 construct comprising a first portion binding to CD93 and a second portion binding to VEGF, wherein the first portion comprises an anti-CD93 antibody moiety containing a heavy chain variable region ( _VH ) and a light chain variable region ( _VL ), wherein the _VH comprises: i) HC-CDR1 containing the amino acid sequence of SEQ ID NO:289, ii) HC-CDR2 containing the amino acid sequence of SEQ ID NO:290, and iii) HC-CDR3 containing the amino acid sequence of SEQ ID NO:291, and the _VL comprises: i) LC-CDR1 containing the amino acid sequence of SEQ ID NO:292, ii) LC-CDR2 containing the amino acid sequence of SEQ ID NO:293, and iii) LC-CDR3 containing the amino acid sequence of SEQ ID NO:294. 31. The anti-CD93 construct of claim 30, wherein the V _H comprises: the amino acid sequence shown in any one of SEQ ID NO:287 and 319-321, or a variant comprising an amino acid sequence having at least about 80% sequence identity, and wherein the V _L comprises: the amino acid sequence shown in any one of SEQ ID NO:288 and 322-324, or a variant comprising an amino acid sequence having at least about 80% sequence identity. 32. The anti-CD93 construct of claim 30 or 31, wherein the anti-CD93 antibody portion is a full-length anti-CD3 antibody comprising two heavy chains and two light chains, and wherein the second portion is fused to the C-terminus of the two heavy chains of the full-length anti-CD3 antibody. 33. The anti-CD93 construct of claim 32, wherein each of the two heavy chains fused with the second portion comprises: the amino acid sequence shown in SEQ ID NO: 342 or 366, or a variant comprising an amino acid sequence having at least about 80% sequence identity, and wherein each of the two light chains comprises: the amino acid sequence shown in SEQ ID NO: 343 or 367, or a variant comprising an amino acid sequence having at least about 80% sequence identity. 34. A pharmaceutical composition comprising the antiCD93 construct of any one of claims 1-33 and a pharmaceutically acceptable carrier. 35. An isolated nucleic acid encoding the anti-CD93 construct or a portion thereof as described in any one of claims 1-33. 36. A vector comprising the isolated nucleic acid of claim 35. 37. An isolated host cell comprising the isolated nucleic acid of claim 35 or the vector of claim 36. 38. An immunoconjugate comprising an antiCD93 construct of any one of claims 1-33 linked to a therapeutic agent or a marker. 39. A method for generating an anti-CD93 construct, comprising: a) Culturing the isolated host cells of claim 37 under conditions that effectively express the anti-CD93 construct; and b) Obtain the expressed anti-CD93 construct from the host cells. 40. A method of treating an individual disease or ailment, comprising administering to the individual an effective amount of the antiCD93 construct of any one of claims 1-33 or the pharmaceutical composition of claim 34. 41. The method of claim 40, wherein the disease or condition is related to abnormal vascular structure. 42. The method of claim 40 or claim 41, wherein the disease or condition is cancer. 43. The method of claim 42, wherein the cancer is a solid tumor. 44. The method of claim 42 or claim 43, wherein the cancer comprises CD93+ endothelial cells. 45. The method of any one of claims 42-44, wherein the cancer comprises IGFBP7+ vessels. 46. The method of any one of claims 42-45, wherein the cancer comprises MMRN2+ blood vessels. 47. The method of any one of claims 42-46, wherein the cancer is characterized by tumor hypoxia. 48. The method of any one of claims 42-47, wherein the cancer is locally advanced or metastatic cancer. 49. The method of any one of claims 4248, wherein the cancer is selected from the group consisting of: lymphoma, colon cancer, brain cancer, breast cancer, ovarian cancer, endometrial cancer, esophageal cancer, prostate cancer, cervical cancer, kidney cancer, bladder cancer, gastric cancer, non-small cell lung cancer, melanoma, and pancreatic cancer. 50. The method of any one of claims 40-49, wherein the anti-CD93 construct is administered to an individual parenterally. 51. The method of any one of claims 40-50, wherein the method further comprises administering a second therapy. 52. The method of claim 51, wherein the second therapy is selected from the group consisting of: surgery, radiotherapy, gene therapy, immunotherapy, bone marrow transplantation, stem cell transplantation, hormone therapy, targeted therapy, cryotherapy, ultrasound therapy, photodynamic therapy, and chemotherapy. 53. The method of claim 52, wherein the second therapy is immunotherapy. 54. The method of claim 53, wherein the immunotherapy comprises administering an immunomodulator. 55. The method of claim 54, wherein the immunomodulator is an immune checkpoint inhibitor. 56. The method of claim 55, wherein the immune checkpoint inhibitor comprises an anti-PD-L1 antibody or an anti-PD-1 antibody. 57. The method of any one of claims 40-56, wherein the individual is a person.