HK1248260B - Mab-driven chimeric antigen receptor systems for sorting/depleting engineered immune cells - Google Patents

Description

mAb-driven chimeric antigen receptor system for sorting/depletion of engineered immune cells

Technical Field

The present invention relates to an improved chimeric antigen receptor (CAR) for immunotherapy, wherein the extracellular binding domain (scFv) has been modified by the insertion of mAb specific epitopes to allow sorting and/or removal (depletion) of immune cells with the CAR. The present invention also relates to immune cells expressing the CAR, to methods for removing and/or sorting the CAR-expressing immune cells in vivo, and to their therapeutic uses.

Background Art

Adoptive immunotherapy (adoptive immunotherapy), which involves the transfer of autologous antigen-specific T cells generated ex vivo, is a promising strategy for treating viral infections and cancer. T cells for adoptive immunotherapy can be generated by expansion of antigen-specific T cells or redirection of T cells (by genetic engineering) (Park, Rosenberg et al. 2011). The transfer of viral antigen-specific T cells is a well-established procedure for treating transplant-associated viral infections and rare virus-associated malignancies. Similarly, the isolation and transfer of tumor-specific T cells has been shown to be successful in treating melanoma.

By gene transfer of transgenic T cell receptors or chimeric antigen receptors (CARs), novel specificities have been successfully generated in T cells (Jena, Dotti et al. 2010). CAR is a synthetic receptor that is composed of a targeting moiety that is associated with one or more signaling domains in a single fusion molecule. In general, the binding moiety of CAR is composed of the antigen binding domains of a single-chain antibody (scFv), which comprises light and heavy variable fragments of a monoclonal antibody connected by a flexible linker. Binding moieties based on receptor or ligand domains have also been successfully used. The signaling domains for first-generation CARs are derived from the cytoplasmic region of CD3ζ or Fc receptor gamma chains. First-generation CARs have been shown to successfully redirect T cell cytotoxicity, however, they do not provide extended expansion and anti-tumor activity (in vivo). Signaling domains from costimulatory molecules (including CD28, OX-40 (CD134), ICOS, and 4-1BB (CD137)) have been added alone (second generation) or in combination (third generation) to enhance the survival of CAR-modified T cells and increase the proliferation of CAR-modified T cells. CARs have successfully allowed the redirection of T cells against antigens expressed on the surface of tumor cells from various malignancies including lymphomas and solid tumors (Jena, Dotti et al. 2010).

However, despite their unprecedented efficacy for in vivo tumor eradication, CAR T cells can promote acute adverse events after being transferred into patients. Among the well-documented adverse events are graft-versus-host disease (GvHD), on-target off-tumor activity, or aberrant lymphocyte proliferation capacity (due to vector-derived insertional mutagenesis). Therefore, it is necessary to develop cell-specific clearance systems to prevent such deleterious events in vivo.

There is ongoing research to develop safer CAR-based immunotherapies, such as those targeting inhibitory signals known as immune checkpoints (e.g., CTLA-4 or PD-1), which are crucial for maintaining self-tolerance and also for limiting immune-mediated collateral tissue damage (Dolan et al., 2014). Recently, inhibitory chimeric antigen receptors (iCARs) have been designed to apply a brake on T cell function after encountering off-target cells (Federov et al., 2013). Budde et al. (2013) describe another system in which a CD20 chimeric antigen receptor is coupled to an inducible caspase 9 (iC9) suicide switch. In application US 2014/0286987, a mutant FK506 binding protein (FKBP1) gene was rendered functional by binding to the prodrug AP1903 (tacrolimus) in the presence of the latter. A clinical trial sponsored by Bellicum is ongoing, in which the aforementioned caspase technology (CaspaCIDe ^™ ) is designed into GD2-targeted third-generation CAR T cells. A similar apoptosis-inducing system based on a multimerizing agent is described in application WO 2014/152177.

Philip et al. (2014) described the RQR8 system, which is used as a compact marker/suicide gene to allow selection of transduced cells. RQR8 is derived from a combination of target epitopes from the CD34 and CD20 antigens. This construct allows selection using the clinically approved CliniMACS CD34 system (Miltenyi). In addition, this RQR8 construct is combined with the widely used drug antibody rituximab, resulting in the selective depletion of transgene-expressing cells. In this system, RQR8 is co-expressed with the CAR in a retroviral vector and with the foot-and-mouth disease 2A peptide, resulting in the expression of two independent transgenes (RQR8 and CAR) on the T cell surface. From an industrial perspective, this system has several limitations: first, it requires cloning of large retroviral inserts, and second, it is necessary to ensure that transformed cells express both the RQR8 and CAR polypeptides to eliminate possible "false positives," i.e., T cells that do not express either polypeptide, and especially the RQR8 suicide gene, which allows for the elimination of engineered immune cells in the event of adverse effects.

In the clinic, in the case of autoimmune diseases and transplantation, the conception of removing T cells has been successfully practiced for decades. In order to remove cell-mediated immunity, including T cells, immunosuppressive drugs such as glucocorticoids or cell inhibitors such as alkylating agents (cyclophosphamide, nitrosoureas, platinum compounds ...) or antimetabolites (methotrexate, azathioprine, fluorouracil ...) have been widely used. However, although they have immunosuppressive efficacy, these drugs do not have discrimination because they affect the proliferation of all T and B cells. Antibodies are sometimes used as fast and effective immunosuppressive treatments to prevent acute rejection and lymphoproliferative or autoimmune diseases, especially anti-CD20 monoclonal antibodies (monoclonal). The elimination of T cell subsets in vivo was carried out by Benjamin and Waldmann (1986) to determine the role of CD4+T cells in producing antibody responses to soluble proteins, and by Cobbold et al. (1986) to determine the role of CD4+ and CD8+T cells in rejecting bone marrow and tissue allografts. In vivo clearance has been extensively performed to study different topics, including the control of antiviral cytotoxic T lymphocyte (CTL) responses (Buller et al., 1987). However, the antibodies that have been used so far for T cells involve antigens (CD3, CD4, CD52), which are widely present on resting or activated T cells and on other cell types. Therefore, the use of the above antibodies will not allow the selective elimination of engineered immune cells with CAR.

As presented subsequently, the inventors have sought an "all-in-one" system that allows for optimized in vitro sorting of CAR-expressing immune cells by reducing "false positives" while allowing for in vivo clearance of immune cells expressing the CAR in the event of an adverse clinical event.

Summary of the Invention

The present invention relates to a chimeric antigen receptor (CAR) that modifies its extracellular binding domain (scFv) in such a way as to allow cell sorting and cell removal (for illustrative embodiments, see Figure 2). This structure (referred to as a mAb-driven sorting/removal system) is composed of an epitope selected by insertion into the scFv; this epitope has a specificity recognized by a specific antibody (preferably mAb). In view of the following facts (mainly, the external ligand binding domain of the modified CAR is to include an epitope), different CAR structures can be envisioned: single chain or multi-chain. The chimeric scFv of the present invention (which is formed by VH and VL polypeptides and specific epitopes) may itself have different structures, depending on the insertion position of the epitope and the use of a joint. The present invention also relates to a method for sorting and/or removing engineered immune cells with modified CAR.

A variety of epitope-mAb pairs can be used to generate such systems; particularly those already approved for medical use, such as CD20/rituximab (as a non-limiting example).

To further enhance the cytotoxicity of engineered immune cells, epitope-specific antibodies can be combined with cytotoxic drugs. CDC cytotoxicity can also be promoted by utilizing engineered antibodies onto which components of the complement system are grafted.

Finally, the invention includes therapeutic methods in which activation of engineered immune cells with CARs is regulated by depleting cells using antibodies directed against the external ligand binding domain of the CAR.

The present invention can be summarized by the following items.

1. A polypeptide encoding a chimeric antigen receptor (CAR) comprising at least one extracellular binding domain comprising an scFv formed by at least a VH chain and a VL chain specific for an antigen, wherein the extracellular binding domain comprises at least one mAb-specific epitope.

2. The polypeptide according to claim 1, wherein the mAb-specific epitope is located between the VH and VL chains.

3. A polypeptide according to item 1 or 2, wherein the VH and VL chains, and the mAb-specific epitope are bound together by at least one linker and are bound to the transmembrane domain of the CAR via a hinge.

4. The polypeptide according to claim 3, wherein the mAb epitope is linked to the VH and VL chains by two linkers.

5. The polypeptide according to any one of items 1 to 3, wherein the mAb-specific epitope is an epitope bound by an epitope-specific mAb, for in vitro cell sorting and/or in vivo cell depletion of T cells expressing a CAR comprising such an epitope.

6. The polypeptide according to any one of items 1 to 5, wherein the polypeptide comprises an extracellular binding domain, wherein the extracellular binding domain further comprises a hinge, and the polypeptide further comprises

- a transmembrane domain, and,

-Intracellular domain.

7. The polypeptide according to any one of items 1 to 6, wherein the extracellular binding domain comprises 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mAb-specific epitopes.

8. The polypeptide according to any one of items 1 to 7, wherein the extracellular binding domain comprises 1, 2, 3, or 4 mAb-specific epitopes.

9. The polypeptide according to any one of items 1 to 8, wherein the extracellular binding domain comprises 2, 3, or 4 mAb-specific epitopes.

10. The polypeptide according to any one of items 1 to 9, wherein the extracellular binding domain comprises the sequence

V ₁ -L ₁ -V ₂ -(L) _x -epitope 1-(L) _x -;

V ₁ -L ₁ -V ₂ -(L) _x -epitope 1-(L) _x -epitope 2-(L) _x -;

V ₁ -L ₁ -V ₂ -(L) _x -epitope 1-(L) _x -epitope 2-(L) _x -epitope 3-(L) _x -;

(L) _x -epitope 1-(L) _x -V ₁ -L ₁ -V ₂ ;

(L) _x -epitope 1-(L) _x -epitope 2-(L) _x -V ₁ -L ₁ -V ₂ ;

Epitope 1 - (L) _x - Epitope 2 - (L) _x - Epitope 3 - (L) _x - V ₁ - _{L 1} - V ₂ ;

(L) _x -epitope 1-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x -epitope 2-(L) _x ;

(L) _x -epitope 1-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x -epitope 2-(L) _x -epitope 3-(L) _x -;

(L) _x -epitope 1-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x -epitope 2-(L) _x -epitope 3-(L) _x -epitope 4-(L) _x -;

(L) _x -epitope 1-(L) _x -epitope 2-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x -epitope 3-(L) _x -;

(L) _x -epitope 1-(L) _x -epitope 2-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x -epitope 3-(L) _x -epitope 4-(L) _x -;

V ₁ -(L) _x -epitope 1-(L) _x -V ₂ ;

V ₁ -(L) _x -epitope 1-(L) _x -V ₂ -(L) _x -epitope 2-(L) _x ;

V ₁ -(L) _x -epitope 1-(L) _x -V ₂ -(L) _x -epitope 2-(L) _x -epitope 3-(L) _x ;

V ₁ -(L) _x -epitope 1-(L) _x -V ₂ -(L) _x -epitope 2-(L) _x -epitope 3-(L) _x -epitope 4-(L) _x ;

(L) _x -epitope 1-(L) _x -V ₁ -(L) _x -epitope 2-(L) _x -V ₂ ; or,

(L) _x -epitope 1-(L) _x -V ₁ -(L) _x -epitope 2-(L) _x -V ₂ -(L) _x -epitope 3-(L) _x ;

in,

_V1 is _VL and _V2 is _VH or _V1 is _VH and _V2 is _VL ;

_L1 is a linker suitable for connecting the _VH chain to the _VL chain;

L is a linker comprising glycine and serine residues, and each occurrence of L in the extracellular binding domain may be the same as or different from every other occurrence of L in the same extracellular binding domain, and,

x is 0 or 1 and each occurrence of x is independently selected from the others; and,

Epitope 1, Epitope 2, and Epitope 3 are mAb-specific epitopes and may be the same or different.

11. The polypeptide according to item 10, wherein the extracellular binding domain comprises the following sequence

V ₁ -L ₁ -V ₂ -L-epitope 1; V ₁ -L ₁ -V ₂ -L-epitope 1-L; V ₁ -L ₁ -V ₂ -L-epitope 1-L-epitope 2; V ₁ -L ₁ -V ₂ -L-epitope 1-L-epitope 2-L; V ₁ -L ₁ -V ₂ -L-epitope 1-L-epitope 2-L-epitope 3; V ₁ -L ₁ -V ₂ -L-epitope 1-L-epitope ₂ -L-epitope 3-L; V ₁ -L _{1 -V 2} -epitope 1; V _{1 -L 1} -V ₂ -epitope 1-L; V ₁ -L ₁ -V 2 -epitope 1-L-epitope 2; V ₁ -L ₁ -V ₂ -epitope 1-L-epitope 2-L _; -epitope 1-L-epitope 2-L-epitope 3; V ₁ -L ₁ -V ₂ -epitope 1-L-epitope 2-L-epitope 3-L; epitope 1-V ₁ -L ₁ -V ₂ ; epitope 1-LV ₁ -L ₁ -V ₂ ; L-epitope 1-V ₁ -L ₁ -V ₂ ; L-epitope 1-LV ₁ -L ₁ -V ₂ ; epitope 1-L-epitope 2-LV ₁ -L ₁ -V ₂ ; L-epitope 1- _{L-epitope 2-V 1 -L 1 -V 2 ; L - epitope 1} -L-epitope 2-LV ₁ -L ₁ -V ₂ ; epitope 1-L-epitope 2-L-epitope 3-V ₁ -L ₁ -V ₂ ; epitope 1 -L-epitope 2 -L-epitope 3 -LV ₁ -L ₁ -V ₂ ; L-epitope 1 -L-epitope 2 -L-epitope 3 -V ₁ -L ₁ -V ₂ ; L-epitope 1 -L-epitope 2 -L-epitope 3 -LV ₁ -L ₁ -V ₂ ; V ₁ -L-epitope 1 -LV ₂ ; L-epitope 1 -LV ₁ -L-epitope 2 -LV ₂ ; V ₁ -L-epitope 1 -LV ₂ -L-epitope 2 -L; V ₁ -L-epitope 1 -LV ₂ -L-epitope 2 -L-epitope 3; V ₁ -L-epitope 1 -LV ₂ -L-epitope 2 -epitope 3; V ₁ -L-epitope 1 -LV ₂ -L-epitope 2 -L-epitope 3 -epitope 4; L-epitope 1 -LV ₁ -L-epitope 2-LV ₂ -L-epitope 3-L; epitope 1-LV ₁ -L-epitope 2-LV ₂ -L-epitope 3-L; L-epitope 1-LV ₁ -L-epitope 2-LV ₂ -L-epitope 3; L-epitope 1-LV ₁ -L ₁ -V ₂ -L-epitope 2-L; L-epitope 1-LV ₁ -L ₁ -V ₂ -L-epitope 2-L-epitope 3; L-epitope 1-LV ₁ -L ₁ -V ₂ -L-epitope 2-epitope 3, or epitope 1-LV ₁ -L ₁ -V ₂ -L-epitope 2-L-epitope 3-epitope 4, wherein

_V1 is _VL and _V2 is _VH or _V1 is _VH and _V2 is _VL ;

_L1 is any linker suitable for connecting the _VH chain to the _VL chain;

L is a linker comprising glycine and serine residues, and each occurrence of L in the extracellular binding domain may be the same as or different from every other occurrence of L in the same extracellular binding domain, and,

Epitope 1, Epitope 2, and Epitope 3 are mAb-specific epitopes and may be the same or different.

12. The polypeptide according to item 10, wherein _L1 is a linker comprising glycine and/or serine.

13. The polypeptide according to item 12, wherein _L1 is a linker comprising the amino acid sequence (Gly-Gly-Gly-Ser) _n or (Gly-Gly-Gly-Gly-Ser) _n , wherein n is 1, 2, 3, 4 or 5, or a linker comprising the amino acid sequence ( _Gly4Ser ) ₄ or ( _Gly4Ser ) ₃ .

14. The polypeptide according to any one of items 10 to 13, wherein L is a linker comprising glycine and/or serine.

15. The polypeptide according to item 14, wherein L is a linker having an amino acid sequence selected from the group consisting of SGG, GGS, SGGS, SSGGS, GGGG, SGGGG, GGGGS, SGGGGGS, SGGGGG, GSGGGGGS, GGGGGGGS, SGGGGGGGS, SGGGGGGGS, or SGGGGSGGGGS.

16. The polypeptide according to item 14, wherein L is SGGGG, GGGGS or SGGGGS.

17. The polypeptide according to any one of items 10 to 16, wherein epitope 1, epitope 2, epitope 3 and epitope 4 are independently selected from the group consisting of mAb-specific epitopes specifically recognized by ibritumomab, tiuxetan, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab vedotin, cetuximab, infliximab, rituximab, alemtuzumab, bevacizumab, certolizumab pegol), daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitumumab, QBEND-10, and ustekinumab.

18. The polypeptide according to any one of items 10 to 16, wherein epitope 1, epitope 2, epitope 3 and epitope 4 are independently selected from mAb-specific epitopes having the amino acid sequence of SEQ ID NO 35, SEQ ID NO 36, SEQ ID NO 37, SEQ ID NO 38, SEQ ID NO 39, SEQ ID NO 40, SEQ ID NO 41, SEQ ID NO 42, SEQ ID NO 144 or SEQ ID NO 174.

19. The polypeptide according to any one of items 10 to 18, wherein epitope 1 is a mAb-specific epitope having the amino acid sequence of SEQ ID NO 35.

20. The polypeptide according to any one of items 10 to 19, wherein epitope 2 is a mAb-specific epitope having the amino acid sequence of SEQ ID NO 35.

21. The polypeptide according to any one of items 10 to 20, wherein epitope 3 is a mAb-specific epitope having the amino acid sequence of SEQ ID NO 35 or SEQ ID NO 144.

22. The polypeptide according to any one of items 10 to 21, wherein epitope 4 is a mAb-specific epitope having the amino acid sequence of SEQ ID NO 35.

23. The polypeptide according to item 22, wherein epitope 1, epitope 2 and epitope 4 are mAb-specific epitopes having the amino acid sequence of SEQ ID NO 35, and epitope 3 is a mAb-specific epitope having the amino acid sequence of SEQ ID NO 144.

24. The polypeptide according to any one of items 1 to 9, wherein the mAb-specific epitope is from a polypeptide selected from those listed in Table 1.

25. The polypeptide according to any one of items 1 to 9, wherein the mAb-specific epitope is selected from the group consisting of mAb-specific epitopes specifically recognized by ibritumomab tiuxetan, imolomab, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab, cetuximab, infliximab, rituximab, alemtuzumab, bevacizumab, tocilizumab, daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitumumab, QBEND-10, and ustekinumab.

26. The polypeptide according to any one of items 1 to 9, wherein the mAb-specific epitope is selected from the group consisting of mAb-specific epitopes having the amino acid sequence of SEQ ID NO 35, SEQ ID NO 36, SEQ ID NO 37, SEQ ID NO 38, SEQ ID NO 39, SEQ ID NO 40, SEQ ID NO 41, SEQ ID NO 42, SEQ ID NO 144 or SEQ ID NO 174.

27. The polypeptide according to any one of items 1 to 9, wherein the mAb-specific epitope has the amino acid sequence of SEQ ID NO 35.

28. A polypeptide according to any one of items 1 to 27, wherein the VH and VL chains have antigen target sequences that are more than 80%, preferably more than 90%, and more preferably more than 95% identical to the following: SEQ ID NO 43 (CD19 antigen), SEQ ID NO 44 (CD38 antigen), SEQ ID NO 45 (CD123 antigen), SEQ ID NO 46 (CS1 antigen), SEQ ID NO 47 (BCMA antigen), SEQ ID NO 48 (FLT-3 antigen), SEQ ID NO 49 (CD33 antigen), SEQ ID NO50 (CD70 antigen), SEQ ID NO 51 (EGFR-3v antigen) and SEQ ID NO 52 (WT1 antigen).

29. The polypeptide according to any one of items 1 to 27, wherein the antigen is a cell surface marker antigen.

30. The polypeptide according to any one of items 1 to 27, wherein the antigen is a tumor-associated surface antigen.

31. The polypeptide according to any one of items 1 to 27, wherein the antigen is selected from ErbB2 (HER2/neu), carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), epidermal growth factor receptor (EGFR), EGFR variant III (EGFRvIII), CD19, CD20, CD30, CD40, disialoganglioside GD2, GD3, C-type lectin-like molecule-1 (CLL-1), ductal epithelial mucin, gp36, TAG-72, glycosphingolipids, glioma-associated antigen, β-human chorionic gonadotropin, alpha-fetoprotein (AFP), lectin-reactive AFP, thyroglobulin, RAGE-1, MN-CA IX, human telomerase reverse transcriptase, RU1, RU2 (AS), intestinal carboxylesterase, mut hsp70-2, M-CSF, prostase, prostate enzyme-specific antigen (PSA), PAP, NY-ESO-1, LAGA-1a, p53, prostate protein, PSMA, survivin and telomerase, prostate cancer tumor antigen-1 (PCTA-1), MAGE, ELF2M, neutrophil elastase, ephrin B2, CD22, insulin growth factor (IGF1)-I, IGF-II, IGF1 receptor, mesothelin, major histocompatibility complex (MHC) molecules presenting tumor-specific peptide epitopes, 5T4, ROR1, Nkp30, NKG2D, tumor stromal antigen, extra domain A (EDA) and extra domain B (EDB) of fibronectin, and the A1 domain of tenascin-C (TnC) A1) and fibroblast-associated protein (fap), LRP6, melanoma-associated chondroitin sulfate proteoglycan (MCSP), CD38/CS1, MART1, WT1, MUC1, LMP2, idiotype, NY-ESO-1, Ras mutant, gp100, proteinase 3, bcr-abl, tyrosinase, hTERT, EphA2, ML-TAP, ERG, NA17, PAX3, ALK, and androgen receptor; Lineage-specific or tissue-specific antigens such as CD3, CD4, CD8, CD24, CD25, CD33, CD34, CD70, CD79, CD116, CD117, CD135, CD123, CD133, CD138, CTLA-4, B7-1 (CD80), B7-2 (CD86), endoglin, major histocompatibility complex (MHC) molecules, BCMA (CD269, TNFRSF 17) or FLT-3.

32. The polypeptide according to any one of items 1 to 27, wherein VH and VL are selected from

SEQ ID NO 65 VH and SEQ ID NO 66 VL; SEQ ID NO 67 VH and SEQ ID NO 68 VL; SEQ ID NO 69 VH and SEQ ID NO 70 VL; SEQ ID NO 71 VH and SEQ ID NO 72 VL; SEQ ID NO 77 VH and SEQ ID NO 78 VL; SEQ ID NO 79 VH and SEQ ID NO 80 VL; SEQ ID NO 81 VH and SEQ ID NO 82 VL; SEQ ID NO 83 VH and SEQ ID NO 84 VL; SEQ ID NO 85 VH and SEQ ID NO 86 VL; SEQ ID NO 87 VH and SEQ ID NO 88 VL; SEQ ID NO 89 VH and SEQ ID NO 90 VL; SEQ ID NO 91 VH and SEQ ID NO 92 VL; SEQ ID NO 93 VH and SEQ ID NO 94 VL; SEQ ID NO 95 VH and SEQ ID NO 96 VL; SEQ ID NO 97 VH and SEQ ID NO 98 VL; SEQ ID NO 99 VH and SEQ ID NO 100 VL; SEQ ID NO 101 VH and SEQ ID NO 102 VL; SEQ ID NO 103 VH and SEQ ID NO 104 VL; SEQ ID NO 105 VH and SEQ ID NO 106 VL; SEQ ID NO 107 VH and SEQ ID NO 108 VL; SEQ ID NO 109 VH and SEQ ID NO 110 VL; SEQ ID NO 111 VH and SEQ ID NO 112 VL; SEQ ID NO 113 VH and SEQ ID NO 114 VL; SEQ ID NO 115 VH and SEQ ID NO 116 VL; SEQ ID NO 117 VH and SEQ ID NO 118 VL; SEQ ID NO 119 VH and SEQ ID NO 120 VL; SEQ ID NO 121 VH and SEQ ID NO 122 VL; SEQ ID NO 123 VH and SEQ ID NO 124 VL; SEQ ID NO 125 VH and SEQ ID NO 126 VL; SEQ ID NO 127 VH and SEQ ID NO 128 VL; SEQ ID NO 129 VH and SEQ ID NO 130 VL; SEQ ID NO 131 VH and SEQ ID NO 132 170 and the VL of SEQ ID NO 171; the VH of SEQ ID NO 172 and the VL of SEQ ID NO 173; or, the VH of SEQ ID NO 186 and the VL of SEQ ID NO 187.

33. The polypeptide according to any one of items 2 to 32, wherein the hinge comprises a PD-1 hinge, an IgG4 hinge, a CD8α hinge or an FcγRIIIα hinge.

34. A polypeptide according to any one of items 2 to 33, wherein the transmembrane domain comprises the transmembrane region of the α, β or ζ chain of the T cell receptor, PD-1, 4-1BB, OX40, ICOS, CTLA-4, LAG3, 2B4, BTLA4, TIM-3, TIGIT, SIRPA, CD28, CD3ε, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 or CD154.

35. The polypeptide according to any one of items 2 to 33, wherein the transmembrane domain comprises the transmembrane region of PD-1 or CD8α.

36. The polypeptide according to any one of items 2 to 33, wherein the transmembrane domain comprises the transmembrane region of CD8α.

37. The polypeptide according to any one of items 2 to 37, wherein the intracellular domain comprises the CD3 zeta signaling domain.

38. The polypeptide according to any one of items 2 to 37, wherein the intracellular domain comprises a 4-1BB domain.

39. The polypeptide according to any one of items 1 to 38, wherein the CAR is a single-chain CAR.

40. The polypeptide according to item 1, wherein the polypeptide has greater than 80%, greater than 90%, greater than 95% identity, or is identical to: SEQ ID NOs 1 to 10, SEQ ID NOs 125 to 141 or SEQ ID nos 145 to 150 or SEQ ID NOs 152 to 169.

41. The polypeptide according to any one of items 1-38, wherein the CAR is a multi-chain CAR.

42. A polynucleotide encoding the polypeptide of any one of items 1 to 41.

43. A polynucleotide encoding the chimeric antigen receptor of any one of items 1 to 41, wherein the CAR comprises a CD3ζ signaling domain and a co-stimulatory domain from 4-1BB.

44. An expression vector comprising the nucleic acid of item 42 or 43.

45. An engineered immune cell expressing the polypeptide of any one of items 1 to 41 on its cell surface.

46. The engineered immune cell according to item 45, wherein the cell is derived from an inflammatory T lymphocyte, a cytotoxic T lymphocyte, a regulatory T lymphocyte or a helper T lymphocyte.

47. Use of the engineered immune cells according to item 45 or 46 as a medicament.

48. A method for engineering the immune cell of any one of items 45-47, comprising:

(a) providing immune cells;

(b) introducing into said cell at least one polynucleotide encoding the chimeric antigen receptor of any one of items 1 to 41;

(c) expressing the polynucleotide into the cell.

49. The method for engineering immune cells of item 48, wherein the immune cells are T cells.

50. A method for in vitro sorting of engineered immune cells, said engineered immune cells expressing on their cell surface a polypeptide comprising at least one mAb-specific epitope according to any one of items 1 to 41, comprising:

- contacting a population of immune cells comprising the engineered immune cells with a monoclonal antibody specific for a mAb-specific epitope;

-Select cells that bind to the monoclonal antibody to obtain a cell population enriched with engineered immune cells.

51. The method according to item 50, wherein the monoclonal antibody specific for the mAb-specific epitope is conjugated to a fluorophore and the step of selecting cells bound to the monoclonal antibody is performed by fluorescence activated cell sorting (FACS).

52. The method according to item 50, wherein the monoclonal antibody specific for the mAb specific epitope is bound to magnetic particles and the step of selecting cells bound to the monoclonal antibody is performed by magnetic activated cell sorting (MACS).

53. The method according to any one of items 50 to 52, wherein the polypeptide comprises a mAb-specific epitope having the amino acid sequence of SEQ ID NO 35, and the monoclonal antibody is rituximab.

54. The method according to any one of items 50 to 52, wherein the polypeptide comprises a mAb-specific epitope having the amino acid sequence of SEQ ID NO 144, and the antibody used to contact the immune cell population is QBEND-10.

55. A method according to any one of items 50 to 54, wherein the cell population enriched with engineered immune cells contains at least 70%, 75%, 80%, 85%, 90%, 95% CAR-expressing immune cells.

56. A method for in vivo depletion in a patient of engineered immune cells expressing on their cell surface a polypeptide comprising at least one mAb-specific epitope of any one of items 1 to 41, comprising contacting the engineered immune cells with at least one epitope-specific mAb.

57. The method according to item 56, wherein the mAb-specific epitope is a CD20 epitope or a mimotope, and the epitope-specific mAb is rituximab.

58. The method according to item 57, wherein the mAb-specific epitope has the amino acid sequence of SEQ ID NO 35.

59. The method according to any one of items 56 to 58, wherein the epitope-specific mAb is bound by a molecule capable of activating the complement system.

60. The method according to any one of items 56 to 59, wherein the cytotoxic drug is conjugated to an epitope-specific mAb.

61. A method for in vivo depletion in a patient of engineered immune cells that express on their cell surface a polypeptide comprising at least one mAb-specific epitope of any one of items 1 to 41, comprising contacting the engineered immune cells with a bispecific mAb (BsAb) capable of binding both to the mAb-specific epitope carried on the cells and to surface antigens carried by effector cells (and cytotoxic cells).

62. The method of any one of items 48 to 61, wherein the immune cell is a T cell.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1: Schematic structure of the mAb-driven sorting/clearing system of the present invention, where a single-chain CAR scaffold is used; various configurations are shown for chimeric scFvs with VH and VL chains and different positions of mAb-specific epitopes.

Figure 2: Schematic diagram of cell sorting and cell clearance by utilizing the mAb-driven system of the present invention. The addition of specific mAb (+/- complement) allows purification of CAR+T cells by recognizing their epitopes within the chimeric scFv. During the cell clearance step, the same specific mAb (+/- complement) causes specific lysis of CAR+T cells by binding to their specific epitopes within the chimeric scFv.

Figure 3: Schematic diagram of cell elimination using bispecific antibodies. By binding to both CAR-expressing immune cells and effector cells, this system allows the recruitment of effector cells on the surface of CAR-expressing immune cells and triggers their specific in vivo elimination.

Fig. 4: the CAR structure of 10 kinds of CARs expressing the anti-CD123 scFv with CD20 mimetic epitopes used in Example 1-2. A series of 10 kinds of chimeric scFvs were designed, in which one or two copies of CD20 mimetic epitopes (black boxes, named "mimotopes") were inserted between the anti-CD123 scFv and the hinge. As shown in Figure 4, all 10 kinds of CARs have the same hinge (CD8 hinge), transmembrane domain (CD8 TM), costimulatory domain (4-1BB) and stimulatory domain (ITAMCD3ζ). SEQ ID NO 1-10 includes the leader sequence MALPVTALLLPLALLLHAARP, which is present when CAR is initially expressed, but is not a part of the CAR expressed on the surface of the cell.

In view of the scFv, depending on the location of the mimetic epitope, three series of CARs were designed (anti-CD123 No 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 correspond to SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, respectively):

- First series: SEQ ID NOs 1-2 and 3-4 correspond to configurations in which one and two CD20 mimotopes, respectively, are inserted between the anti-CD123 scFv and the hinge; in SEQ ID NO 2, a GS linker connects the CD20 mimotope to the hinge. In SEQ ID NOs 3-4, a GS linker separates the two mimotopes, and in SEQ ID NO 4, there is an additional GS linker between the mimotope and the hinge.

- Second series: SEQ ID NO 5-6 correspond to conformations in which one copy of the CD20 mimotope is inserted within the anti-CD123 scFv; the sequence differences are on either side from the presence of a short GS linker (SEQ ID NO 5) and a long GS linker (SEQ ID NO 6), respectively.

- Third series: SEQ ID NOs 7 to 10 correspond to configurations in which the anti-CD123 scFv is positioned between the CD20 mimotope and the hinge. In SEQ ID NOs. 7-8 and 9-10, one and two copies of the CD20 mimotope, respectively, are inserted. A GS linker is inserted between the two CD20 mimotopes, and in the case of SEQ ID NO. 10, a supplementary GS linker connects the mimotope to the anti-CD123 scFv.

Fig. 5 shows the cytolytic activity of the T cells expressing the anti-CD123 CAR of SEQ ID NO 1-4 or 142 or the control T cells not expressing any anti-CD123 CAR (simulation T cells, without the transfection step of any mRNA).Cytolytic activity is expressed as the frequency of specific cell lysis, as described in detail in Example 1.

Fig. 6 shows the result of CDC determination, wherein together with rituximab (RTX) and baby rabbit complement (Baby Rabbit Complement) (BRC), incubate the T cell of the anti-CD123 CAR expressing SEQ ID NO 1-4 or do not express the control T cell (simulation T cell (transfection step, without any mRNA)) of any anti-CD123 CAR.Results are expressed as the relative frequency (relative to control experiment) of living cells in anti-CD123CAR positive T cells, as described in detail in Example 3.

Figure 7A, 7B and 7C disclose the general structure of the CAR of SEQ ID NO 125 to 141 designed and tested in Examples 4 to 6. Anti-BCMA ScFV is used in all these CARs. In different positions (i.e. upstream of ScFv, downstream of ScFv or between the variable chains (referred to as V1 and V2) of ScFv) include one, two, three or four epitopes selected from CD20 mimotopes (black boxes, referred to as "mimotopes") and/or CD34 epitopes (grey boxes, referred to as "CD34"). As shown in Figure 7, all CARs have the same hinge (CD8 hinge), transmembrane domain (CD8 TM), costimulatory domain (4-1BB) and stimulatory domain (ITAM CD3 ζ).

Figures 8A and 8B show the results of a CDC assay in which T cells expressing anti-BCMA CAR of SEQ ID NOs 125 or 130 to 141 were incubated with RTX and BRC. The results are expressed as the relative frequency of viable cells in anti-BCMA CAR-positive T cells (relative to the control experiment), as described in detail in Example 4.

Figure 9 shows the cytolytic activity of T cells expressing anti-BCMA CAR of SEQ ID NO 125 or 130 to 139 or control T cells (T cells) that do not express any anti-BCMA CAR. Cytolytic activity is expressed as the frequency of viable cells H929, as described in detail in Example 4.

Figure 10A shows the frequency of T cells expressing the CAR of SEQ ID NO 128 comprising a CD34 epitope and two CD20 mimotopes before and after purification by means of the CD34 MicroBead kit or in the flow through fraction.

FIG10B shows the number of T cells expressing CAR comprising SEQ ID NO 128 of the CD34 epitope before and after purification with the aid of the CD34 MicroBead kit or in the flow-through fraction.

FIG11 shows the concentration of INFγ produced by T cells expressing anti-BCMA CAR of SEQ ID NOs 125 or 130 to 139 in the presence of RTX, phytohemagglutinin (PHA), or in the absence of RTX and PHA.

FIG12 shows the frequency of CAR-positive T cells detected from T cells expressing CAR of SEQ ID NOs 125 or 130 to 139 using BCMA-Fc fusion protein and labeled anti-Fc antibody or RTX and labeled anti-Fc antibody.

FIG13 shows the frequency of CAR-positive T cells generated from the detection of T cells expressing the CAR of SEQ ID NO 128 using RTX and labeled anti-Fc antibody or labeled QBEND-10.

Figures 14A and 14B show that, by flow cytometry, the detection of T cells expressing BCMA CAR (which contains CD20 mimetic epitopes) of SEQ ID NO 145 (BC30, wild type), 146 (LM), 147 (LML), 148 (LMLM) and 149 (LMLML). CART cells were detected by flow cytometry and using soluble biotinylated BCMA protein followed by PE-bound streptavidin (sBCMA biotin (PE)) or anti-CD20 antibody rituximab followed by FITC-bound anti-human IgG (rituximab (FITC)).

Figure 15 shows the detection of co-expression of anti-BCMA CAR of SEQ ID NO 145 and RQR8 (SEQ ID NO 150) (BC30-RQR8) or BCMA CAR of SEQ ID NO 149 (which contains a CD20 mimetic epitope) in non-transduced T cells transduced with lentivirus by flow cytometry. CAR-T cells were detected by flow cytometry using soluble biotinylated BCMA protein followed by PE-conjugated streptavidin (sBCMA biotin (PE)) or anti-CD20 antibody rituximab followed by FITC-conjugated anti-human IgG (rituximab (FITC)).

Figure 16 shows the results of CDC assays, wherein anti-BCMA CAR (BC30-R2) expressing SEQ ID NO 149, anti-BCMA CAR of SEQ ID NO 145, or T cells co-expressing anti-BCMA CAR and RQR8 (SEQ ID NO 150) (BC30-RQR8) of SEQ ID NO 145 were incubated together with RTX and BRC. The percentage of cytotoxicity was determined by flow cytometry analysis using biotinylated BCMA protein. The results are expressed as the frequency of cell lysis in anti-BCMA CAR-positive T cells relative to the control (cells incubated with BRC alone).

Figure 17 shows the cytolytic activity of T cells with/without RTX, wherein the above-mentioned T cells express the anti-BCMA CAR (BC30-R2) of SEQ ID NO 149 or co-express the anti-BCMA CAR (BC30) and RQR8 (SEQ ID NO 150) (BC30-RQR8) of SEQ ID NO 145. Cytolytic activity is expressed as the percentage of calculated cell lysis, as disclosed in Example 7.5, and is determined at different ratios of effector (CAR T cells): target (MM1S cells expressing BCMA).

Figure 18 shows the percentage of activated T cells expressing the anti-BCMA CAR of SEQ ID NO 149 in the presence of PBS (control), anti-CD3 OKT3 antibody (αCD3), or rituximab (RTX). T cell activation was assessed by measuring the expression of activation markers CD25 and CD69 using flow cytometry.

Table 1: List of drug-approved mAbs and their antigenic targets. The sequences of the latter are provided, as well as the epitopes of some of them.

Table 2: List of various mimotopes and epitopes corresponding to their mAbs provided in Example 2.

Table 3: List of VH and VL chains of scFvs targeting CD19, CD33, 5T4, ROR1, EGFRvIII, BCMA, CS1 and CD123 antigens.

Table 4: Exemplary sequences of CAR components

DETAILED DESCRIPTION

The present invention relates to a polypeptide encoding a chimeric antigen receptor (CAR) comprising at least one extracellular binding domain, comprising a scFv formed by at least a VH chain and a VL chain specific for an antigen, preferably a cell surface marker antigen, wherein the extracellular binding domain comprises at least one mAb specific epitope. In one embodiment, the mAb specific epitope is an epitope bound by an epitope-specific mAb for in vitro cell sorting and/or in vivo cell removal expressing a CAR comprising such an epitope.

The present invention relates to a polypeptide encoding a chimeric antigen receptor (CAR) comprising at least one extracellular binding domain comprising an scFv formed by at least a VH chain and a VL chain specific for a cell surface marker antigen, wherein the extracellular binding domain comprises at least one mAb-specific epitope to be bound by an epitope-specific mAb, for in vitro cell sorting and/or in vivo cell elimination of T cells expressing the CAR.

In some embodiments, the present invention relates to a CAR comprising

- an extracellular domain comprising

at least one, preferably one, extracellular binding domain comprising a scFv formed by at least a VH chain and a VL chain specific for an antigen, preferably a cell surface marker antigen, wherein said extracellular binding domain comprises at least one mAb-specific epitope, and,

- hinges,

- a transmembrane domain, and,

-Intracellular domain.

In some embodiments, the present invention relates to a CAR comprising

- Extracellular domain, containing

- at least one extracellular binding domain comprising a scFv formed by at least a VH chain and a VL chain specific for a cell surface marker antigen, wherein the extracellular binding domain comprises at least one mAb-specific epitope to be bound by an epitope-specific mAb, for in vitro cell sorting and/or in vivo cell depletion of T cells expressing the CAR, and,

- hinges,

- a transmembrane domain, and,

-Intracellular domain.

In an embodiment, the CAR of the present invention comprises an extracellular binding domain.

"Chimeric scFv" refers to a polypeptide corresponding to a single-chain variable fragment composed of heavy and light chains ( _VH and _VL , respectively) and an epitope that was not originally included in the _VH and _VL chains. When capable of being specifically bound by an antibody, particularly a monoclonal antibody, the latter epitope is referred to as a "mAb-specific epitope". In some embodiments, the mAb-specific epitope is not an epitope recognized by a ScFv. In some embodiments, the mAb-specific epitope is not derived from the extracellular domain of a CAR. The components of this chimeric scFv (i.e., the light and heavy variable fragments of the ligand binding domain and the mAb-specific epitope) can be connected together by at least one linker, typically a flexible linker. These components are typically connected to the transmembrane domain of the CAR via a hinge.

Chimeric scFv conformation

The structures of the chimeric scFv of the present invention can be various, as shown in FIG1 , depending on the positions of the major components ( _VH and _VL and the m-Ab specific epitope).

Several conformations are possible for the chimeric scFv of the present invention, at least nine when considering the number of possible permutations of a _VH , a _VL , and an epitope.

Preferably, each component (VH, VL and epitope) is interconnected with its immediate neighbors via at least one flexible linker as described above. Suitable combinations according to the present invention are those that provide good affinity/specificity in both binding: between the mAb-specific epitope and the injected mAb, and between the VH and VL chains of the chimeric scFv and the antigen of the cellular target ligand.

According to one embodiment, the extracellular binding domain of the CAR comprises at least two linkers, both of which connect the epitope to the VH and VL chains; and a hinge, which connects the scFv-epitope to the transmembrane domain of the CAR.

For example, if the predicted CAR conformation is such that the mAb-specific epitope is located adjacent to the VH and VL chains, then screening is performed when the CAR is expressed and tested for cytotoxicity and/or mAb clearance.

When seeking mAb-specific epitopes located between the VH and VL chains, screening can be performed by phage display prior to testing and/or transient expression of the CAR construct. This can be achieved by transfection of mRNA, which is sufficient for primary cytotoxicity and/or mAb clearance testing.

In some embodiments, the extracellular binding domain comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mAb-specific epitopes.

In some embodiments, the extracellular binding domain comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mAb-specific epitopes.

In some embodiments, the extracellular binding domain comprises 1, 2, or 3 mAb-specific epitopes.

In some embodiments, when the extracellular binding domain comprises multiple mAb-specific epitopes, all mAb-specific epitopes are the same.

In some embodiments, when the extracellular binding domain comprises multiple mAb-specific epitopes, the mAb-specific epitopes are not identical. For example, the extracellular binding domain can comprise three mAb-specific epitopes, two of which are identical and the third is different.

In some embodiments, the extracellular binding domain comprises VH, VL, and one or more mAb-specific epitopes, preferably 1, 2, or 3, more preferably 2 or 3 mAb-specific epitopes.

In some embodiments, the extracellular binding domain comprises the following sequence (N-terminus is on the left-hand side):

_V1 - _L1 - _V2- (L) _x -epitope 1-(L) _x ; _V1- L1 _-V2- (L) _x -epitope _1- (L) _x -epitope 2-(L) _x ; _V1 - _{L1-V2- (} L) _x -epitope 1-(L) _x -epitope 2-(L) _x -epitope 3-(L) _x ; (L) _x -epitope 1-(L) _x - _V1 - _L1 - _V2 ; (L) _x -epitope 1-(L) _x -epitope 2-(L) _x - _V1 - _L1 - _V2 ; epitope 1-(L) _x -epitope 2-(L) _x -epitope 3-(L) _x - _V1 - _L1 - _V2 ; (L) _x -epitope 1-(L) _x - _V1 - _L1 - _V2- (L) _x -epitope 2-(L) _x ；(L) _x -epitope 1-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x -epitope 2-(L) _x -epitope 3-(L) _x ；(L) _x -epitope 1-(L) _x -V ₁ -L ₁ -V ₂ -(L) x -epitope 2-(L) _x -epitope 3-(L) _x -epitope 4-(L) _x ；(L) _x -epitope 1-(L) _x -epitope 2-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x -epitope 3-(L _{) x} ；(L) _x -epitope 1-(L) x -epitope 2-(L) _x -V ₁ -L ₁ -V ₂ -(L) _x -epitope 3-(L) _x -epitope 4-(L _{) x} ；V ₁ -(L) _x -epitope 1-(L) _x -V ₂ ; V ₁ -(L) _x -epitope 1-(L) _x -V ₂ -(L) _x -epitope 2-(L) _x ; V ₁ -(L) _x -epitope 1-(L) x -V ₂ -(L) _x -epitope 2-(L) _x -epitope 3-(L) _x ; _{V 1} -(L) _x -epitope 1-(L) _x -V ₂ -(L) _x -epitope 2-(L) _x -epitope 3-(L) _x -epitope 4-(L) _x ; (L) _x -epitope 1-(L) _x -V ₁ -(L) _x -epitope 2-(L) _x -V ₂ ; (L) _x -epitope 1-(L) _x -V ₁ -(L) _x -epitope 2-(L) _x -V ₂ -(L) _x -epitope 3-(L) _x ; V ₁ -L ₁ -V ₂ -L-epitope 1; V ₁ -L ₁ -V ₂ -L-epitope 1-L; V ₁ -L ₁ -V ₂ -L-epitope 1-L-epitope 2; V ₁ -L ₁ -V ₂ -L-epitope 1-L-epitope 2-L; V ₁ -L ₁ -V ₂ -L-epitope 1-L-epitope 2-L-epitope 3; V ₁ -L ₁ -V ₂ -L-epitope 1-L-epitope ₂ -L-epitope 3-L; V ₁ -L _{1 -V 2} -epitope 1; V ₁ -L ₁ -V ₂ -epitope ₁ -L; V 1 -L 1 -V ₂ -epitope 1-L-epitope 2; V ₁ -L ₁ -V 2 -epitope ₁ -L-epitope ₂ -L _; -epitope 1-L-epitope 2-L-epitope 3; V ₁ -L ₁ -V ₂ -epitope 1-L-epitope 2-L-epitope 3-L; epitope 1-V ₁ -L ₁ -V ₂ ; epitope 1-LV ₁ -L ₁ -V ₂ ; L-epitope 1-V ₁ -L ₁ -V ₂ ; L-epitope 1-LV ₁ -L ₁ -V ₂ ; epitope 1-L-epitope 2-LV ₁ -L ₁ -V ₂ ; L-epitope 1- _{L-epitope 2-V 1 -L 1 -V 2 ; L - epitope 1} -L-epitope 2-LV ₁ -L ₁ -V ₂ ; epitope 1-L-epitope 2-L-epitope 3-V ₁ -L ₁ -V ₂ ; epitope 1 -L-epitope 2 -L-epitope 3 -LV ₁ -L ₁ -V ₂ ; L-epitope 1 -L-epitope 2 -L-epitope 3 -V ₁ -L ₁ -V ₂ ; L-epitope 1 -L-epitope 2 -L-epitope 3 -LV ₁ -L ₁ -V ₂ ; V ₁ -L-epitope 1 -LV ₂ ; L-epitope 1 -LV ₁ -L-epitope 2 -LV ₂ ; V ₁ -L-epitope 1 -LV ₂ -L-epitope 2 -L; V ₁ -L-epitope 1 -LV ₂ -L-epitope 2 -L-epitope 3; V ₁ -L-epitope 1 -LV ₂ -L-epitope 2 -epitope 3; V ₁ -L-epitope 1 -LV ₂ -L-epitope 2 -L-epitope 3 -epitope 4; L-epitope 1 -LV ₁ -L-epitope 2-LV ₂ -L-epitope 3-L; epitope 1-LV ₁ -L-epitope 2-LV ₂ -L-epitope 3-L; L-epitope 1-LV ₁ -L-epitope 2-LV ₂ -L-epitope 3; L-epitope 1-LV ₁ -L ₁ -V ₂ -L-epitope 2-L; L-epitope 1-LV ₁ -L ₁ -V ₂ -L-epitope 2-L-epitope 3; L-epitope 1-LV ₁ -L ₁ -V ₂ -L-epitope 2-epitope 3, or epitope 1-LV ₁ -L ₁ -V ₂ -L-epitope 2-L-epitope 3-epitope 4.

in,

_V1 and _V2 are _VH and _VL of a ScFv (i.e., _V1 is _VL and _V2 is _VH or _V1 is _VH and _V2 is _VL );

_L1 is any linker suitable for connecting the VH chain to the _VL chain in ScFv;

L is a linker which preferably comprises glycine and serine residues, and each occurrence of L in the extracellular binding domain may be the same or different from every other occurrence of L in the same extracellular binding domain, and,

x is 0 or 1 and each occurrence of x is independent from the others; and,

Epitope 1, Epitope 2, and Epitope 3 are mAb-specific epitopes and may be the same or different.

In some embodiments, the extracellular binding domain comprises the following sequence (N-terminus is on the left-hand side):

_VH - _L1 -VL- _L -epitope 1-L-epitope 2-L; L-epitope 1-LVH- _L -epitope 2-LVL- _L -epitope 3-L; _VL - ^L1 -VH- _L -epitope 1-L-epitope 2-L; or, L-epitope 1- _LVL -L-epitope 2-LVH- _L -epitope 3-L,

wherein L, L ₁ , epitope 1 , epitope 2 and epitope 3 are as defined above.

In some embodiments, L ₁ is a linker comprising glycine and/or serine. In some embodiments, L ₁ is a linker comprising the amino acid sequence (Gly-Gly-Gly-Ser) _n or (Gly-Gly-Gly-Gly-Ser) _n , wherein n is 1, 2, 3, 4, or 5. In some embodiments, L ₁ is (Gly ₄ Ser) ₄ or (Gly ₄ Ser) ₃ .

In some embodiments, L is a flexible linker, which preferably comprises glycine and/or serine. In some embodiments, L has an amino acid sequence selected from SGG, GGS, SGGS, SSGGS, GGGG, SGGGG, GGGGS, SGGGGGS, GGGGGGS, SGGGGG, GSGGGGGGS, GGGGGGGS, or SGGGGSGGGGS, preferably SGG, SGGS, SSGGS, GGGG, SGGGGGS, SGGGGGGS, GSGGGGGS, or SGGGGSGGGGS. In some embodiments, when the extracellular binding domain comprises several occurrences of L, all L are identical. In some embodiments, when the extracellular binding domain comprises several occurrences of L, L is not all identical. In some embodiments, L is SGGGGS. In some embodiments, the extracellular binding domain comprises several occurrences of L and all L are SGGGGS.

In some embodiments, epitope 1, epitope 2, and epitope 3 are the same or different and are selected from mAb-specific epitopes having the following amino acid sequences: SEQ ID NO 35, SEQ ID NO 36, SEQ ID NO 37, SEQ ID NO 38, SEQ ID NO 39, SEQ ID NO 40, SEQ ID NO 41, or SEQ ID NO 42, SEQ ID NO 144, or SEQ ID NO 174.

In some embodiments, epitope 1, epitope 2, and epitope 3 are the same or different and are selected from mAb-specific epitopes specifically recognized by ibritumomab tiuxetan, imolomab, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab, cetuximab, infliximab, rituximab, alemtuzumab, bevacizumab, tocilizumab, daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitumumab, QBEND-10, and ustekinumab.

In some embodiments, epitope 1 is a mAb-specific epitope having the amino acid sequence of SEQ ID NO 35.

In some embodiments, epitope 2 is a mAb-specific epitope having the amino acid sequence of SEQ ID NO 35.

In some embodiments, epitope 3 is a mAb-specific epitope having the amino acid sequence of SEQ ID NO 35.

In some embodiments, epitope 4 is a mAb-specific epitope having the amino acid sequence of SEQ ID NO 35.

In some embodiments, epitope 2 is a mAb-specific epitope having the amino acid sequence of SEQ ID NO 35, and epitope 3 is a mAb-specific epitope having the amino acid sequence of SEQ ID NO 144.

In some embodiments, one of epitope 1, epitope 2, epitope 3, and epitope 4 is a CD34 epitope, preferably the epitope of SEQ ID NO 144. In some embodiments, one of epitope 1, epitope 2, epitope 3, and epitope 4 is a CD34 epitope, preferably the epitope of SEQ ID NO 144, and the other mAb-specific epitope is a CD20 mimotope, preferably the mimotope of SEQ ID NO 35.

Inserted mAb-specific epitope

According to the present invention, the epitope to be inserted into the chimeric scFv is specific for a monoclonal antibody (mAb), which is used in cell sorting and/or cell depletion procedures.

In a preferred embodiment, the epitopes introduced into the chimeric scFv are selected for regulatory/safety purposes based on their approval by national health agencies as part of mAb-specific epitope/epitope-specific mAb pairs. Such pairs are given in Table 1 below.

Table 1: List of pharmaceutically approved monoclonal antibodies with antigenic targets

Table 2: Examples of mAb-specific epitopes (and their corresponding mAbs) that can be used in the extracellular binding domain of the CAR of the present invention, such as, for example, mimotopes and epitopes with their corresponding mAbs, as used in Examples 1-2.

In a preferred embodiment, the epitope introduced within the chimeric scFv is the CD20 antigen, preferably SEQ ID NO 35 and the injected mAb, which is used to target it for sorting and/or depletion purposes, is rituximab.

In some embodiments, the mAb-specific epitope has the following amino acid sequence: SEQ ID NO 35, SEQ ID NO 36, SEQ ID NO 37, SEQ ID NO 38, SEQ ID NO 39, SEQ ID NO 40, SEQ ID NO 41, SEQ ID NO 42, SEQ ID NO 144, or SEQ ID NO 174.

In some embodiments, the extracellular binding domain of the CAR of the present invention comprises one mAb-specific epitope of SEQ ID NO 35, two mAb-specific epitopes of SEQ ID NO 35, three mAb-specific epitopes of SEQ ID NO 35, one mAb-specific epitope of SEQ ID NO 35 and one mAb-specific epitope of SEQ ID NO 144, two mAb-specific epitopes of SEQ ID NO 35 and one mAb-specific epitope of SEQ ID NO 144, three mAb-specific epitopes of SEQ ID NO 35 and one mAb-specific epitope of SEQ ID NO 144.

According to another embodiment, the epitope is a mimetic epitope. As a macromolecule, often a peptide, the structure of the mimetic epitope has the advantage of being smaller than a conventional epitope, so it may be beneficial to non-conformational sequences and more easily replicate such CARs in the form of long polypeptides. Known mimetic epitopes are used for mAbs approved by several drugs, such as two 10 amino acid peptides for cetuximab (Riemer et al., 2005), or 24aa for palivizumab (Arbiza et al, 1992). Because these mimetic epitopes can be determined by phage display, several of them can be tried to obtain sequences that do not disrupt the scFv for the same mAb. In addition, their use can enhance complement-dependent cytotoxicity (CDC).

scFv

As used herein, the term "extracellular ligand binding domain" refers to an oligonucleotide or polypeptide capable of binding a ligand. Preferably, the domain is sought that is capable of interacting with a cell surface molecule. For example, the extracellular ligand binding domain can be selected to recognize a ligand that is a cell surface marker on a target cell associated with a specific disease state. Examples of cell surface markers that can thus serve as ligands include those associated with viral, bacterial and parasitic infections, autoimmune diseases and cancer cells. In particular, the extracellular ligand binding domain can comprise an antigen binding domain derived from an antibody directed against a target antigen. As a non-limiting example, the target antigen can be a tumor-associated surface antigen as described above. In some embodiments, the extracellular binding domain is an extracellular ligand binding domain as defined above. According to the present invention, the extracellular ligand binding domain is a single-chain antibody fragment (scFv) comprising a light ( _VL ) and heavy ( _VH ) variable fragment of a target antigen-specific monoclonal antibody, and a mAb epitope-specific antigen. In some embodiments, the extracellular binding domain comprises a single-chain antibody fragment (scFv) comprising the light ( _VL ) and heavy ( _VH ) variable fragments of a monoclonal antibody specific for a cell surface target antigen.

Binding domains other than scFvs can also be used for the intended targeting of lymphocytes, such as camelid single domain antibody fragments, receptor ligands like vascular endothelial growth factor polypeptides, integrin binding peptides, neuregulin (nerve growth factor) or IL-13 muteins, antibody binding domains, antibody hypervariable loops or CDRs (as non-limiting examples).

In another embodiment, the extracellular binding domain can be a DARPin (engineered ankyrin repeat protein). DARPins are genetically engineered antibody-mimicking proteins that typically exhibit highly specific and high-affinity target protein binding. They are derived from natural ankyrins and contain at least three, and typically four or five, repeat motifs of these proteins. DARPins are small, single-domain proteins that can be selected to bind any given target protein with high affinity and specificity (Epa, Dolezal et al. 2013; Friedrich, Hanauer et al. 2013; Jost, Schilling et al. 2013). According to the present invention, DARPins can be designed to contain multiple antigen recognition sites. Thus, the DARPin can be used to recognize a range of sequentially different antigens as well as unique antigens. Thus, the present invention relates to a method comprising providing an immune cell and expressing a chimeric antigen receptor on the surface of the immune cell, which comprises an engineered ankyrin repeat protein capable of recognizing at least one specific ligand, preferably two specific ligands.

As non-limiting examples, the ligand of the target or the antigen recognized by the extracellular binding domain, preferably by ScFv, can be a tumor-associated surface antigen, such as ErbB2 (HER2/neu), carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), epidermal growth factor receptor (EGFR), EGFR variant III (EGFRvIII), CD19, CD20, CD30, CD40, disialoganglioside GD2, GD3, C-type lectin-like molecule-1 (CLL-1), ductal epithelial mucin, gp36, TAG-72, glycosphingolipids, glioma-associated antigen, β-human chorionic gonadotropin, alpha-fetoprotein (AFP), lectin-reactive AFP, thyroglobulin, RAGE-1, MN-CA IX, human telomerase reverse transcriptase, RU1, RU2 (AS), intestinal carboxylesterase, mut hsp70-2, M-CSF, prostate enzyme, prostate enzyme-specific antigen (PSA), PAP, NY-ESO-1, LAGA-1a, p53, prostate protein, PSMA, survival and telomerase, prostate cancer tumor antigen-1 (PCTA-1), MAGE, ELF2M, neutrophil elastase, ephrin B2, CD22, insulin growth factor (IGF1)-I, IGF-II, IGF1 receptor, mesothelin, major histocompatibility complex (MHC) molecules presenting tumor-specific peptide epitopes, 5T4, ROR1, Nkp30, NKG2D, tumor stromal antigen, extra domain A (EDA) and extra domain B (EDB) of fibronectin, and the A1 domain of tenascin-C (TnC) A1) and fibroblast-associated protein (FAP), LRP6, melanoma-associated chondroitin sulfate proteoglycan (MCSP), CD38/CS1, MART1, WT1, MUC1, LMP2, idiotype, NY-ESO-1, Ras mutant, gp100, proteinase 3, bcr-abl, tyrosinase, hTERT, EphA2, ML-TAP, ERG, NA17, PAX3, ALK, and androgen receptor; lineage-specific or tissue-specific antigens such as CD3, CD4, CD8, CD24, CD25, CD33, CD34, CD70, CD79, CD116, CD117, CD135, CD123, CD133, CD138, CTLA-4, B7-1 (CD80), B7-2 (CD86), endoglin, major histocompatibility complex (MHC) molecules, BCMA (CD269, TNFRSF 17), FLT-3, or virus-specific surface antigens such as HIV-specific antigens (such as HIV gp120); EBV-specific antigens, CMV-specific antigens, HPV-specific antigens, Lassa virus-specific antigens, influenza virus-specific antigens, and any derivatives or variants of these surface markers. In specific cases, the ligand recognized by the chimeric antigen receptor is present on the surface of the target cell, particularly a cancer cell or a viral cell. In some embodiments, the ligand recognized by the chimeric antigen receptor is present in the tumor microenvironment. In some aspects of the invention, the ligand recognized by the chimeric antigen receptor is a growth factor.

In a preferred embodiment, the VH and VL chains, as antigen target sequences, have more than 80% identity, preferably more than 90%, and more preferably more than 95% identity relative to SEQ ID NO 43 (CD19 antigen), SEQ ID NO 44 (CD38 antigen), SEQ ID NO 45 (CD123 antigen), SEQ ID NO 46 (CS1 antigen), SEQ ID NO 47 (BCMA antigen), SEQ ID NO 48 (FLT-3 antigen), SEQ ID NO 49 (CD33 antigen), SEQ ID NO 50 (CD70 antigen), SEQ ID NO 51 (EGFR-3v antigen), and SEQ ID NO 52 (WT1 antigen).

In a more preferred embodiment, the VH and VL chains, as antigen target sequences, have an identity of more than 80%, preferably more than 90%, and more preferably more than 95%, relative to SEQ ID NOs 53-64 (CD19 antigen), SEQ ID NOs 65-76 (CD33 antigen), SEQ ID NOs 77-84 (5T4 antigen), SEQ ID NOs 85-90 (ROR1 antigen), SEQ ID NOs 91-94 (EGFRvIII antigen), SEQ ID NOs 95-102 (BCMA antigen), SEQ ID NOs 103-112 (CS1 antigen) and SEQ ID NOs 113-124 (CD123 antigen) as shown in Table 3, or are identical to SEQ ID NOs 53-64 (CD19 antigen), SEQ ID NOs 65-76 (CD33 antigen), SEQ ID NOs 77-84 (5T4 antigen), SEQ ID NOs 85-90 (ROR1 antigen), SEQ ID NOs 91-94 (EGFRvIII antigen), SEQ ID NOs 95-102 (BCMA antigen), SEQ ID NOs 103-112 (CS1 antigen) and SEQ ID NOs 113-124 (CD123 antigen) as shown in Table 3. 91-94 (EGFRvIII antigen), SEQ ID NOs 95-102 (BCMA antigen), SEQ ID NOs 103-112 (CS1 antigen) and SEQ ID NOs 113-124 (CD123 antigen).

In some embodiments, the antigen recognized by the extracellular binding domain, preferably by ScFv, is selected from SEQ ID NO43 (CD19 antigen), SEQ ID NO 44 (CD38 antigen), SEQ ID NO 45 (CD123 antigen), SEQ ID NO 46 (CS1 antigen), SEQ ID NO 47 (BCMA antigen), SEQ ID NO 48 (FLT-3 antigen), SEQ ID NO 49 (CD33 antigen), SEQ ID NO 50 (CD70 antigen), SEQ ID NO 51 (EGFR-vIII antigen) or SEQ ID NO 52 (WT1 antigen).

In some embodiments, the extracellular binding domain comprises:

- VH of SEQ ID NO 65 and VL of SEQ ID NO 66; VH of SEQ ID NO 67 and VL of SEQ ID NO 68; VH of SEQ ID NO 69 and VL of SEQ ID NO 70; VH of SEQ ID NO 71 and VL of SEQ ID NO 72; VH of SEQ ID NO 77 and VL of SEQ ID NO 78; VH of SEQ ID NO 79 and VL of SEQ ID NO 80;

- VH of SEQ ID NO 81 and VL of SEQ ID NO 82; VH of SEQ ID NO 83 and VL of SEQ ID NO 84; VH of SEQ ID NO 85 and VL of SEQ ID NO 86; VH of SEQ ID NO 87 and VL of SEQ ID NO 88; VH of SEQ ID NO 89 and VL of SEQ ID NO 90; VH of SEQ ID NO 91 and VL of SEQ ID NO 92; VH of SEQ ID NO 93 and VL of SEQ ID NO 94; VH of SEQ ID NO 95 and VL of SEQ ID NO 96; VH of SEQ ID NO 97 and VL of SEQ ID NO 98; VH of SEQ ID NO 99 and VL of SEQ ID NO 100; VH of SEQ ID NO 101 and VL of SEQ ID NO 102; VH of SEQ ID NO 103 and VL of SEQ ID NO 104; 105 VH and SEQ ID NO 106 VL; SEQ ID NO 107 VH and SEQ ID NO 108 VL; SEQ ID NO 109 VH and SEQ ID NO 110 VL; SEQ ID NO 111 VH and SEQ ID NO 112 VL; SEQ ID NO 113 VH and SEQ ID NO 114 VL; SEQ ID NO 115 VH and SEQ ID NO 116 VL; SEQ ID NO 117 VH and SEQ ID NO 118 VL; SEQ ID NO 119 VH and SEQ ID NO 120 VL; SEQ ID NO 121 VH and SEQ ID NO 122 VL; SEQ ID NO 123 VH and SEQ ID NO 124 VL; SEQ ID NO 170 VH and SEQ ID NO 171 VL; SEQ ID NO 172 VH and SEQ ID NO 173 VL; SEQ ID NO 174 VH and SEQ ID NO 175 VL; SEQ ID NO 176 VH and SEQ ID NO 177 VL; SEQ ID NO 178 VH and SEQ ID NO 179 VL; SEQ ID NO 180 VH and SEQ ID NO 181 VL; SEQ ID NO 182 VH and SEQ ID NO 183 VL; SEQ ID NO 184 VH and SEQ ID NO 185 VL; SEQ ID NO 186 VH and SEQ ID NO 187 VL; SEQ ID NO 188 VH and SEQ ID NO 189 VL; SEQ ID NO 190 VH and SEQ ID NO 191 VL; SEQ ID NO 192 VH and SEQ ID NO 193 VL 172 and the VL of SEQ ID NO 173; or, the VH of SEQ ID NO 186 and the VL of SEQ ID NO 187.

Table 3: List of VH and VL chains of scFvs targeting CD19, CD33, 5T4, ROR1, EGFRvIII, BCMA, CS1 and CD123 antigens

In another preferred embodiment, the VH and VL chains, as epitope target sequences, have an identity of more than 80%, preferably more than 90%, and more preferably more than 95% with respect to SEQ ID NO 11 (CD20 antigen).

The extracellular ligand binding domain can also comprise a peptide binding antigen of the target, a peptide or protein binding antibody that binds to an antigen of the target, a peptide or protein ligand such as a growth factor, cytokine or hormone (as non-limiting examples) that binds to a receptor on the target, or a domain derived from a receptor such as a growth factor receptor, cytokine receptor or hormone receptor (as non-limiting examples) that binds to a peptide or protein ligand on the target. Preferably, the target is a cell or a virus.

The antigen binding domain of the CAR can be any domain that binds to a cellular target antigen, including but not limited to monoclonal antibodies, recombinant antibodies, human antibodies, humanized antibodies, and functional fragments thereof.

Humanized antibodies can be produced using various techniques known in the art, including but not limited to CDR grafting (see, e.g., European Patent No. EP 239,400; International Publication No. WO 91/09967; and U.S. Patent Nos. 5,225,539, 5,530,101, and 5,585,089, the entire contents of each of which are incorporated herein by reference), covering or recoating (see, e.g., European Patent Nos. EP 592,106 and EP 519,596; Padlan, 1991, Molecular Immunology, 28(4/5):489-498; Studnicka et al., 1994, Protein Engineering, 7(6):805-814; and Roguska et al., 1995, Protein Engineering, 7(6):815-820; and Roguska et al., 1996, Protein Engineering, 7(6):825-830). al., 1994, PNAS, 91:969-973, each of which is incorporated herein by reference in its entirety), chain shuffling (see, e.g., U.S. Patent No. 5,565,332, the entirety of which is incorporated herein by reference), and in, e.g., U.S. Patent Application Publication No. US2005/0042664, U.S. Patent Application Publication No. US2005/0048617, U.S. Patent No. 6,407,213, U.S. Patent No. 5,766,886, International Publication No. WO 9317105, Tan et al., J. Immunol., 169:1119-25 (2002), Caldase et al., Protein Eng., 13(5):353-60 (2000), Morea et al., Methods, 20(3):267-79 (2000), Baca et al. et al., J. Biol. Chem., 272(16):10678-84 (1997), Roguska et al., Protein Eng., 9(10):895-904 (1996), Couto et al., Cancer Res., 55(23 Supp):5973s-5977s (1995), Couto et al., Cancer Res., 55(8):1717-22 (1995), Sandhu JS, Gene, 150(2):409-10 (1994), and Pedersen et al., J. Mol. Biol., 235(3):959-73 (1994), the entire contents of each of which are incorporated herein by reference. Often, framework residues in the framework regions will be replaced by corresponding residues from the CDR donor antibody to alter, e.g., improve, antigen binding. These framework substitutions are determined by methods well known in the art, for example, by modeling the interactions of the CDR and framework residues to determine framework residues that are important for antigen binding and sequence comparison to identify unusual framework residues at specific positions (see, e.g., Queen et al., U.S. Pat. No. 5,585,089; and Riechmann et al., 1988, Nature, 332:323, the entire contents of which are incorporated herein by reference).

According to the present invention, the scFv may be a nanobody (natural single domain antibody), which may be obtained by immunization of dromedaries, camels, llamas, alpacas or sharks.

Linkers within chimeric scFv

The flexibility of scFv linker engineering can be combined with the inherent rapid adaptability characteristics of surface coupling chemistry (e.g., electrostatic, hydrogen bonding, or covalent attachment). Peptide linkers can be 10 to 25 amino acids in length and are usually, but not always, composed of hydrophilic amino acids such as glycine (G) and serine (S). Peptide linkers of shorter lengths (0–4 amino acids) have also been used. However, scFvs carrying shorter linkers may form multimers. Typically, (GGGGS) ₃ peptides are used as scFv peptide linkers. This 15 amino acid linker sequence [designated as (GGGGS) ₃ linker] is used in the recombinant phage antibody system (RPAS kit) commercially available from Amersham. Previous studies have shown that scFvs (MW ∼27 000) containing a metal-binding amino acid (i.e., cysteine or histidine) in the scFv peptide linker can be directly immobilized onto a gold surface in a favorable antigen-binding orientation at high density, which significantly increased the sensitivity of assays for whole IgG or Fab antibody fragments by more than 3–5 fold, respectively (Shen Z, Mernaugh RL, Yan H, Yu L, Zhang Y, Zeng X. Anal. Chem. 2005; 77: 6834–6842; Shen Z, Stryker GA, Mernaugh RL, Yu L, Yan H, Zeng X. Anal. Chem. 2005; 77: 797–805).

Among other linkers suitable for use in the present invention is a 15-mer peptide linker (RGRGRGRGRSRGGGS) (Zhihong Shen, Heping Yan, Ying Zhang, Raymond L. Mernaugh, and Xiangqun Zeng (2008), Anal Chem. 80(6): 1910-1917).

In some embodiments, as used in the context of scFv, a "linker" refers to a peptide linker composed of amino acids such as glycine and/or serine residues, used alone or in combination, to link the variable heavy chain region and the variable light chain region together. In one embodiment, the flexible polypeptide linker is a glycine/serine linker and comprises the amino acid sequence (Gly-Gly-Gly-Ser) _n or (Gly-Gly-Gly-Gly-Ser) _n , wherein n is a positive integer equal to or greater than 1. For example, n=1, n=2, n=3, n=4, n=5, n=6, n=7, n=8, n=9, and n=10. In one embodiment, flexible polypeptide linkers include, but are not limited to, (Gly ₄ Ser) ₄ or (Gly ₄ Ser) ₃ . In another embodiment, the linker comprises multiple repeats of (Gly _x Ser) _n , wherein x = 1, 2, 3, 4 or 5 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, such as multiple repeats of (GlySer), (Gly ₂ Ser) or (Gly ₅ Ser). Also included within the scope of the present invention are linkers described in WO 2012/138475, which is incorporated herein by reference.

Chimeric Antigen Receptor (CAR)

The CAR according to the present invention is sought to enable engineered immune cells to trigger the destruction of pathological cells, especially malignant cells. They can be designed according to single-chain or multi-chain structures. In some embodiments, the extracellular ligand binding domain, the transmembrane domain, and the intracellular signaling domain are in one polypeptide, that is, in a single chain. In WO2014039523, a multi-chain structure is more specifically disclosed.

Multi-chain CARs are usually formed from different polypeptides such as:

- a transmembrane polypeptide comprising at least one extracellular ligand binding domain and;

- a transmembrane polypeptide comprising at least one signal transduction domain.

Signaling polypeptides are responsible for activating at least one of the normal functions of engineered immune cells. For example, the function of a T cell may be cytolytic activity or helper cell activity, including the secretion of cytokines. Thus, the term "signaling protein" refers to a protein that transduces a transmitter domain functional signal and directs cells to perform specialized functions. In a specific embodiment, the transmitter domain may be a signaling protein. The transmission of signals may result from: protein/protein interactions, protein/DNA interactions, protein/RNA interactions, protein/small molecule interactions, post-translational protein modifications, conformational changes, and subcellular relocalization.

Signal proteins can activate genes in the nucleus. Examples of signal proteins can be members of the NFAT transcription factor family, which are inducible factors that can bind to the interleukin-2 promoter in activated T cells. The regulation of NFAT proteins involves metabolites and proteins such as calcium, calcineurin, and Homer scaffold proteins. The signal protein can be an activated engineering form of NFAT, thereby avoiding regulation by calcineurin and Homer proteins. The signal protein can be an NF-κB engineered form to avoid the sequestration of Iκb in the cytoplasm, thereby allowing activation of T cells. The signal protein can also be the expression of three IKK subunits (IKKα, IKKδ, IKKγ). Reconstructing the IKK complex activates the NF-κB pathway, wherein ubiquitination of IκB is triggered. In addition, activation of the JNK signal can be triggered by direct expression of the signal protein AP-1 (transcription factor). The signal protein can be an engineered transcriptional activator-like effector (TALE) binding domain, which will specifically target and activate the transcription of the same gene, such as for NFAT and NF-kb.

According to the present invention, the signaling protein can inhibit the signaling pathway through protein-protein interaction or can activate genes in the cell nucleus to inhibit the signaling pathway. The signaling protein can be vaccinia H1-related protein (VHR), a member of the mitogen-activated protein kinase phosphatase (MKP) family, which dephosphorylates and inactivates the extracellular signal-regulated kinase (ERK) signaling protein.

According to the present invention, the signal transduction domain for use in CAR can be a cytoplasmic sequence and a co-receptor of a T cell receptor that acts in concert to initiate signal transduction after antigen receptor engagement, as well as any derivatives or variants of these sequences, and any synthetic sequence with the same functional capability. The signal transduction domain can comprise two different classes of cytoplasmic signal sequences, those that initiate antigen-dependent primary activation, and those that act in an antigen-independent manner to provide secondary or costimulatory signals.

In certain embodiments, the signal transduction domain of the CAR of the present invention comprises a co-stimulatory signaling molecule. Co-stimulatory molecules are cell surface molecules other than antigen receptors or their ligands that are required for an effective immune response.

"Costimulatory ligand" refers to a molecule on an antigen presenting cell that specifically binds to a cognate costimulatory molecule on a T cell, thereby providing a signal that, in addition to the primary signal provided by, for example, the binding of the TCR/CD3 complex to the MHC molecule-loaded peptide, mediates T cell responses, including but not limited to proliferation activation, differentiation, etc. "Costimulatory molecule" refers to a related binding partner on a T cell that specifically binds to a costimulatory ligand, thereby mediating a co-stimulatory response by the cell, such as but not limited to proliferation. Costimulatory molecules include but are not limited to MHC class I molecules, BTLA, and Toll ligand receptors.

For example, a multi-chain CAR may be derived from the structure of an Fc receptor, preferably FcεRI, and comprise at least two of the following components:

a) a polypeptide comprising the transmembrane domain of the FcRI α chain fused to an extracellular ligand-binding domain,

b) a polypeptide comprising a portion of the N-terminal and C-terminal cytoplasmic tail fused to the transmembrane domain of the FcRI β chain, and/or

c) Two additional polypeptides, each comprising a portion of the intracytoplasmic tail and/or the transmembrane domain of the FcRI gamma chain.

In general, these different polypeptides spontaneously multimerize together to form dimeric, trimeric, or tetrameric structures that appear on the cell surface in a juxtamembrane location.

In some embodiments, the invention relates to an immune cell comprising a single chain CAR as well defined in the prior art and in any of the following documents: US7446190, WO2008/121420, US8252592, US20140024809, WO2012/079000, WO2014153270, WO2012/099973, WO2014/011988, WO2014/011987, WO2013/067492, WO2013/070468, WO2013/040557, WO2013/126712, WO2013/126729, WO2013/126730, WO2013/126749, WO2013/126750, WO2013/126761, WO2013/126770, WO2013/126781, WO2013/126790, WO2013/126791 O2013/126726, WO2013/126733, US8399645, US20130266551, US20140023674, WO2014039523, US7514537, US8324353, WO2010/025177, US744617 9. WO2010/025177, WO2012/031744, WO2012/136231A1, WO2012/050374A2, WO2013074916, WO/2009/091826A3, WO2013/176915 or WO/2013/059593.

In some embodiments, the present invention relates to a CAR comprising:

- an extracellular domain comprising

at least one extracellular binding domain comprising a scFv formed by at least a VH chain and a VL chain specific for an antigen, preferably a cell surface marker antigen, wherein said extracellular binding domain comprises at least one mAb-specific epitope, and

- hinges,

- a transmembrane domain, and,

-Intracellular domain.

In one embodiment, the transmembrane domain comprises the transmembrane region of the α, β, or ζ chain of the T cell receptor, PD-1, 4-1BB, OX40, ICOS, CTLA-4, LAG3, 2B4, BTLA4, TIM-3, TIGIT, SIRPA, CD28, CD3ε, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, or CD154.

In another embodiment, the hinge is an IgG4 hinge or a CD8α hinge, preferably a CD8α hinge.

The obvious features of suitable membrane spaning domains include the following abilities: expression on the surface of cells, preferably immune cells, particularly lymphocytes or natural killer (NK) cells in the present invention, and interacting together to instruct immune cells to react with predefined target cells. The membrane spaning domain can be derived from natural or synthetic sources. The membrane spaning domain can be derived from any membrane-bound or transmembrane protein. As non-limiting examples, membrane spaning polypeptides can be subunits of T cell receptors such as α, β, γ or δ, polypeptides constituting CD3 complexes, IL2 receptor p55 (α chain), p75 (β chain) or γ chain, subunit chains of Fc receptors, especially Fcγ receptor III or CD proteins. Alternatively, the membrane spaning domain can be synthetic and can include mainly hydrophobic residues such as leucine and valine. In a preferred embodiment, the membrane spaning domain is derived from human CD8 α chain (e.g., NP_001139345.1). The membrane spaning domain can also be CD8 membrane spaning domain (α and β chain). The transmembrane domain can be designed to produce obligate heterodimers or homodimers. In a specific embodiment, the CAR may include a transmembrane domain or an intracellular domain, which can only dimerize after ligand recognition. Another example of a transmembrane domain can be an NKG2-D receptor. NKG2D (natural killer cell group 2D) is a C-type lectin-like receptor expressed on NK cells, γδ-TcR ⁺ T cells and CD8 ⁺ αβ-TcR ⁺ T cells (Bauer, Groh et al., 1999, Science 285 (5428): 727-9). NKG2D is associated with transmembrane adapter protein DAP10 (Wu, Song et al. 1999, Science 285 (5428): 730-2), and its cytoplasmic domain is bound to the p85 subunit of PI-3 kinase.

The transmembrane domain can also be an integrin. Integrins are heterodimeric integral membrane proteins composed of α and β chains that combine to form LFA-1 (integrin lymphocyte function-associated antigen-1), which is expressed on all white blood cells. LFA-1 plays a central role in leukocyte intercellular adhesion, through its interaction with its ligand, ICAM1-3 (intercellular adhesion molecules 1 to 3), and it also plays an important role in lymphocyte co-stimulatory signals (Chen and Flies 2013, Nat Rev Immunol 13 (4): 227-42). The molecular details of the binding of LAF-1 to its immunoglobulin ICAM-1 are well known, allowing for the careful design of the LAF-1 binding site. By replacing its C-terminal helix, its conformation is related to the change of a specific loop in LAF-1 to regulate the affinity of the α _L domain for ICAM-1. The active and low conformations differ by 500 and 10,000 times. It is also interesting to note that two types of antagonists are known for LFA-1, and their mechanisms of action are known. Integrins, cell surface adhesion receptors, can transmit signals from the outside in, but not vice versa. There are cytoskeletal proteins, such as Talin, that bind to the integrin tail of LFA-1 to transfer information from the inside out.

According to one embodiment, the transmembrane domain comprises the transmembrane region of PD-1 or the transmembrane region of CD8α.

In one aspect of the invention, the transmembrane domain is connected to the extracellular domain of CAR by a hinge, for example, a hinge from a human protein. For example, in one embodiment, the hinge can be a human Ig (immunoglobulin) hinge, for example, a PD-1 hinge, an IgG4 hinge, or a CD8 alpha hinge.

In a preferred embodiment, the hinge of the CAR is a human immunoglobulin hinge.

In a more preferred embodiment, the hinge of the CAR is an IgG4 hinge or a CD8α hinge.

In some embodiments, the hinge is an FcγRIIIα hinge.

In some embodiments, the hinge is a CD8α hinge.

In some embodiments, the hinge is a CD8α hinge having an amino acid sequence and having at least about 70% sequence identity, preferably at least 80%, more preferably at least 90%, 95%, 97%, or 99% relative to the amino acid sequence shown in SEQ.IDNO:179, 180 or 181.

As used herein, the term "hinge region" (also referred to as stem region in the literature) generally refers to any oligonucleotide or polypeptide that is used to connect a membrane spaning domain to an extracellular ligand binding domain. In particular, the stem region is used to provide greater flexibility and accessibility for the extracellular ligand binding domain. The stem region can comprise up to 300 amino acids, preferably 10 to 100 amino acids and most preferably 25 to 50 amino acids. The stem region can be derived from all or part of a naturally occurring molecule, such as all or part of the extracellular region of CD8, CD4, CD28 or RTK, or from all or part of an antibody constant region. Alternatively, the stem region can be a synthetic sequence corresponding to a naturally occurring stem sequence, or can be a fully synthetic stem sequence.

Intracellular domain (also referred to herein as "cytoplasmic signaling domain" or "intracellular signaling domain") includes a functional signaling domain derived from a stimulatory molecule as defined below. In some embodiments, the stimulatory molecule is a zeta chain associated with a T cell receptor complex. In some embodiments, the cytoplasmic signaling domain further includes one or more functional signaling domains derived from at least one costimulatory molecule as defined below. In some embodiments, the costimulatory molecule is selected from 4-1BB (i.e., CD137), CD27 and/or CD28.

The term "stimulatory molecule" refers to a molecule expressed by a T cell, which provides a positive cytoplasmic signal sequence, and for at least some aspects of the T cell signaling pathway, in a stimulating manner, the positive cytoplasmic signal sequence regulates the positive activation of the TCR complex. In some embodiments, by, for example, the combination of the TCR/CD3 complex and the MHC molecule loaded peptide, a positive signal is initiated, and the mediation of the T cell response is caused, including but not limited to proliferation, activation, differentiation, etc. The positive cytoplasmic signal sequence (also referred to as "positive signal domain" or positive intracellular signal domain) that works in a stimulating manner can contain a signal motif, which is referred to as an activation motif or ITAM based on immunoreceptor tyrosine. The example of the ITAM containing a positive cytoplasmic signal sequence includes but is not limited to those ITAMs, which are derived from TCR ζ (or CD3 ζ), FcR γ, FcR β, CD3 γ, CD3 δ, CD3 ε, CD5, CD22, CD79a, CD79b, CD278 (also referred to as "ICOS") and CD66d. In some embodiments, the intracellular signaling domain of CAR may comprise a CD3ζ signaling domain having an amino acid sequence, wherein the amino acid sequence has a sequence identity of at least about 70%, preferably at least 80%, more preferably at least 90%, 95%, 97%, or 99% relative to the amino acid sequence shown in SEQ.IDNO:175.

In some aspects, the intracellular signaling domain of CAR generates a signal that promotes the immune effector functions of cells containing CAR. Examples of immune effector functions, for example, in CAR T cells, include cytolytic activity and helper cell activity, including the secretion of cytokines.

The term "costimulatory molecule" refers to a binding partner on a T cell that specifically binds to a costimulatory ligand, thereby mediating a co-stimulatory response of the T cell, such as, but not limited to, proliferation. Costimulatory molecules are cell surface molecules other than antigen receptors, or their ligands, that are required for an effective immune response. Costimulatory molecules include, but are not limited to, MHC class I molecules, BTLA and Toll ligand receptors, as well as OX40, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD11a/CD18), and 4-IBB (CD137).

Costimulatory intracellular signaling domain can be the intracellular part of costimulatory molecules.Costimulatory molecules can be represented by the following protein family：TNF receptor protein, immunoglobulin-like protein, cytokine receptor, integrin, signal lymphocyte activation molecule (SLAM protein) and activation NK cell receptor.The example of above-mentioned molecule includes CD27, CD28, 4-1BB (CD137), OX40, GITR, CD30, CD40, ICOS, BAFFR, HVEM, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 and specifically bind to the part etc. of CD83. In some embodiments, the intracellular signaling domain of the CAR of the present invention comprises an amino acid sequence that has at least 70%, preferably at least 80%, and more preferably at least 90%, 95%, 97%, or 99% sequence identity relative to the amino acid sequences shown in SEQ.ID NO: 176 and SEQ.ID NO: 177.

Table 4 provides exemplary sequences of CAR components

CARs and immune cells comprising them have been widely disclosed and can be prepared by a skilled person according to known methods. For example, methods for preparing CARs and cells comprising such CARs are disclosed in US7446190, WO2008/121420, US8252592, US20140024809, WO2012/079000, WO2014153270, WO2012/099973, WO2014/011988, WO2014/011987, WO2013/067492, WO2013/070468, WO2013/040557, WO2013/126712, WO2013/126729, WO2013/126726, WO2013 /126733, US8399645, US20130266551, US20140023674, WO2014039523, US7514537, US8324353, WO2010/025177, US7446179, WO2010/025177, WO2012/031744, WO2012/136231A1, WO2012/050374A2, WO2013074916, WO2009/091826A3, WO2013/176915 or WO/2013/059593, the entire contents of which are incorporated herein by reference.

The present invention includes a recombinant DNA construct comprising a sequence encoding a CAR as defined above, wherein the CAR comprises an extracellular domain such as an antibody fragment, which is characteristically bound to a cell target antigen, and wherein the sequence of the extracellular domain is adjacent to the nucleic acid sequence and in the same reading frame as the nucleic acid sequence, wherein the nucleic acid sequence encodes a transmembrane domain and an intracellular domain. An exemplary CAR construct may include an optional leader sequence, an extracellular cell target antigen binding domain, a hinge, a transmembrane domain, and an intracellular inhibitory signal domain.

In some embodiments, the present invention relates to a recombinant DNA construct comprising a sequence encoding a CAR as defined above. In some embodiments, the CAR comprises an extracellular domain comprising

- at least one extracellular binding domain comprising a scFv formed by at least a VH chain and a VL chain specific for a cell surface marker antigen, wherein the extracellular binding domain comprises at least one mAb-specific epitope to be bound by an epitope-specific mAb, for in vitro cell sorting and/or in vivo cell depletion of T cells expressing the CAR, and wherein the extracellular binding domain is contained, and,

- hinges,

- a transmembrane domain, and,

-Intracellular domain.

Method for sorting CAR-positive immune cells

According to one aspect, the present invention relates to a method for sorting CAR-expressing immune cells in vitro, which comprises contacting the engineered immune population with an antigen-specific antibody (preferably a monoclonal antibody) to collect only cells expressing CAR.

In some embodiments, the present invention relates to a method for in vitro sorting of CAR-expressing immune cells, wherein the CAR comprises at least one extracellular binding domain comprising at least one mAb-specific epitope as described above, the method comprising

- contacting the population of immune cells with a monoclonal antibody specific for the mAb-specific epitope to collect only the CAR-expressing immune cells.

In some embodiments, the present invention relates to a method for in vitro sorting of CAR-expressing immune cells, wherein the CAR comprises at least one extracellular binding domain comprising at least one mAb-specific epitope, the method comprising

- contacting said population of immune cells with a monoclonal antibody specific for said mAb-specific epitope (epitope-specific mAb),

-select cells that bind to the monoclonal antibody,

To obtain a cell population enriched with CAR-expressing immune cells.

In some embodiments, the monoclonal antibody specific for the mAb-specific epitope is conjugated to a fluorophore and the step of selecting cells that bind to the monoclonal antibody is performed by fluorescence activated cell sorting (FACS).

In some embodiments, the monoclonal antibody specific for the mAb-specific epitope is bound to magnetic particles and the step of selecting cells that bind to the monoclonal antibody is performed by magnetic activated cell sorting (MACS).

In some embodiments, the extracellular binding domain of the CAR comprises the mAb-specific epitope of SEQ ID NO 144.

In some embodiments, the extracellular binding domain of the CAR comprises a mAb-specific epitope of SEQ ID NO 144 and the antibody used to contact the population of immune cells is QBEND-10.

In some embodiments, the extracellular binding domain of the CAR comprises the mAb-specific epitope of SEQ ID NO 35.

In some embodiments, the extracellular binding domain of the CAR comprises a mAb-specific epitope of SEQ ID NO 35 and the antibody used to contact the population of immune cells is rituximab.

In some embodiments, the population CAR-expressing immune cells obtained when the method for in vitro sorting CAR-expressing immune cells described above is used include at least 70%, 75%, 80%, 85%, 90%, 95% CAR-expressing immune cells. In some embodiments, the population CAR-expressing immune cells obtained when the method for in vitro sorting CAR-expressing immune cells described above is used include at least 85% CAR-expressing immune cells.

In some embodiments, compared to the initial (unsorted) cell population, and using the protocol described in Example 7.5, the colony of CAR expressing immune cells obtained when using the method for in vitro sorting CAR expressing immune cells described above shows increased cytotoxic activity in vitro. In a preferred embodiment, the cytotoxic activity is increased by 10%, 20%, 30% or 50% in vitro.

Preferably, the mAb is previously bound to a support such as a column or beads, as routinely accomplished by a person skilled in the art.

According to an advantageous embodiment, the immune cells are T cells.

According to the present invention, cells to be administered to a recipient may be enriched in vitro from an autologous population.

Methods for expanding source populations are well known in the art and may include selecting cells expressing an antigen, such as CD34, using a combination of density centrifugation, immunomagnetic purification, affinity chromatography, and fluorescence activated cell sorting known to those skilled in the art.

Flow cytometry

Flow cytometry is widely used in the art and is a well-known method used by those of ordinary skill in the art to sort and quantify specific cell types within a cell population. Generally speaking, flow cytometry is a method that quantifies components or structural features of cells primarily by optical means. Because different cell types can be distinguished by quantifying structural features, flow cytometry and cell sorting can be used to count and sort cells of different phenotypes in a mixture.

Flow cytometric analysis involves two basic steps: 1) labeling cell types with one or more markers, and 2) determining the number of labeled cells relative to the total number of cells in the population.

The main method of labeling cell types is by binding a labeled antibody to a marker expressed by a specific cell type. Antibodies can be labeled directly with a fluorescent compound or indirectly using, for example, a fluorescently labeled secondary antibody that recognizes the primary antibody.

In a preferred embodiment, the method used to sort CAR-expressing T cells is magnetic activated cell sorting (MACS).

Magnetic activated cell sorting (MACS) is a method for separating various cell populations using superparamagnetic nanoparticles and columns, which depend on their surface antigens (CD molecules). In order to obtain pure cell populations, only a few simple steps are required. Cells in a single cell suspension are magnetically labeled with microbeads. The sample is applied to a column composed of ferromagnetic spheres, which is covered with a cell-friendly coating, thereby allowing cells to be separated quickly and gently. Unlabeled cells pass through while magnetically labeled cells are retained in the column. The flow-through can be collected as the unlabeled cell portion. After a short washing step, the column is removed from the separator and the magnetically labeled cells are then eluted from the column.

In other technologies, FACS is the technology that is used for purifying the cell colony of known phenotype that is selected, because can realize the very high purity of desired colony, or when target cell colony expresses very low level identification marker, or when needing to separate cell colony based on the marker density that has difference.In addition, FACS is based on internal dyeing or intracellular protein expression, as genetically modified fluorescent protein marker, separates the only available purification technology of cell.FACS allows to purify single cell based on size, granularity and fluorescence.In order to purify interested cell, first dye them with fluorescently labeled monoclonal antibody (mAb), and it identifies the specific surface marker on desired cell colony.

Detailed protocols for purifying specific cell populations such as T cells can be found in Basu S et al. (2010). (Basu S, Campbell HM, Dittel BN, Ray A. Purification of specific cell population by fluorescence activated cell sorting (FACS). J Vis Exp. (41): 1546).

In a preferred embodiment of the present invention, the mAb used in the method for sorting CAR-expressing T cells is selected from ibritumomab tiuxetan, imolomab, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab, cetuximab, infliximab, rituximab, alemtuzumab, bevacizumab, tocilizumab, daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitumumab, QBEND-10 and ustekinumab.

In a more preferred embodiment, the mAb is rituximab.

In a more preferred embodiment, the mAb is QBEND-10.

Methods for depleting CAR-expressing immune cells

In the present invention, "in vivo clearance" refers to administering a treatment to a mammalian organism that is intended to stop the proliferation of CAR-expressing immune cells by inhibiting or eliminating them.

One aspect of the present invention relates to a method for clearing engineered immune cells expressing CAR in vivo, wherein the CAR comprises a mAb specific epitope as described above, wherein the method includes contacting the engineered immune cell or the CAR expressing immune cell with at least one epitope-specific mAb. Another aspect of the present invention relates to a method for clearing immune CAR expressing immune cells in vivo, wherein the cell comprises the chimeric scFv (formed by inserting a mAb specific epitope), wherein the engineered immune cell is contacted with an epitope-specific antibody.

Preferably, the immune cells are T cells and/or the antibodies are monoclonal.

According to one embodiment, the in vivo depletion of immune engineered cells is performed on engineered immune cells that have previously been sorted using the in vitro method of the invention. In this case, this will be the same injected mAb used.

According to a preferred embodiment, the mAb specific antigen is the CD20 antigen and the epitope specific mAb is rituximab.

In some embodiments, the present invention relates to a method for in vivo depletion of engineered immune cells expressing CAR in a patient, wherein the CAR comprises a mAb-specific epitope as described above (CAR-expressing immune cell), the method comprising contacting the CAR-expressing immune cell with at least one epitope-specific mAb.

In a preferred embodiment of the present invention, the mAb used in the method of depleting CAR-expressing engineered immune cells is selected from the group consisting of ibritumomab tiuxetan, imolizumab, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab, cetuximab, infliximab, rituximab, alemtuzumab, bevacizumab, tocilizumab, daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitumumab, QBEND-10, and ustekinumab.

In some embodiments, the mAb-specific epitope is a CD20 epitope or mimotope, preferably SEQ ID NO 35, and the epitope-specific mAb is rituximab.

In some embodiments, the step of contacting the engineered immune cells or the CAR-expressing immune cells with at least one epitope-specific mAb comprises infusing the epitope-specific mAb, preferably rituximab, into the patient. In some embodiments, the amount of epitope-specific mAb administered to the patient is sufficient to eliminate at least 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the CAR-expressing immune cells in the patient.

In some embodiments, the step of contacting the engineered immune cells or the CAR-expressing immune cells with at least one epitope-specific mAb comprises infusing 375 mg/m ² of rituximab into the patient once or several times, preferably once a week.

In some embodiments, when epitope-specific mAb is used to eliminate immune cells expressing CAR (which comprises mAb-specific epitopes) (CAR-expressing immune cells) in a CDC assay, the amount of CAR-expressing immune cells that can be present is reduced, preferably by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%. Preferably, the CDC assay is an assay disclosed in Example 3, Example 4 or Example 7.4. In some embodiments, the mAb-specific epitope is a CD20 epitope or a mimotope, preferably SEQ ID NO 35, and the epitope-specific mAb is rituximab.

In a specific embodiment, in vivo clearance of CAR-engineered immune cells is performed by injecting bispecific antibodies. By definition, bispecific monoclonal antibodies (BsAbs) are artificial proteins that are composed of fragments of two different monoclonal antibodies and therefore bind to two different types of antigens. These BsAbs and their use in immunotherapy have been extensively reviewed in Müller D and Kontermann RE (2010) Bispecific Antibodies for Cancer Immunotherapy, BioDrugs 24 (2): 89-98.

The term "effector cells" includes immune cells such as lymphocytes, macrophages, dendritic cells, natural killer cells (NK cells), cytotoxic T lymphocytes (CTL).

According to another specific embodiment, the injection of bispecific mAb can bind to the mAb specific epitope carried by the engineered immune cells expressing the chimeric scFv and bind to the surface antigens on effector and cytotoxic cells. This aspect is shown in Figure 3. By doing so, clearance of the engineered immune cells triggered by the BsAb can occur by antibody-dependent cellular cytotoxicity (ADCC). Such a conformation can be seen, for example, in Deo Y M, Sundarapandiyan K, Keler T, Wallace PK, and Graziano RF, (2000), Journal of Immunology, 165 (10): 5954-5961].

According to a specific embodiment, cytotoxic drugs are coupled to epitope-specific mAbs, which are used to remove CAR-expressing immune cells. By combining the targeting ability of monoclonal antibodies with the cancer-killing ability of cytotoxic drugs, antibody-drug conjugates (ADCs) allow for sensitive differentiation between healthy and diseased tissues when compared to using only drugs. Several ADCs have received market approval; the technology used to make them, especially with regard to connectors, is presented in large quantities in the following prior art (Payne, G. (2003) Cancer Cell 3: 207-212; Trail et al (2003) Cancer Immunol. Immunother. 52: 328-337; Syrigos and Epenetos (1999) Anticancer Research 19: 605-614; Niculescu-Duvaz and Springer (1997) Adv. Drug Del. Rev. 26: 151-172; U.S. Patent No. 4,975,278).

According to another specific embodiment, the epitope-specific mAb to be injected is pre-bound to a molecule capable of promoting complement-dependent cytotoxicity (CDC). Thus, the complement system assists or supplements the ability of antibodies to clear pathogens from an organism. Upon exposure to one of a variety of stimuli, an activation cascade is triggered, resulting in a large-scale amplification of the response and activation of the cell-killing membrane attack complex.

Different molecules can be used to bind mAbs, such as glycans [Courtois, A, Gac-Breton, S., Berthou, C., Guézennec, J., Bordron, A. and Boisset, C. (2012), Complement dependent cytotoxitityactivity of therapeutic antidody fragments is acquired by immunogenic glycan coupling, Electronic Journal of Biotechnology ISSN: 0717-3458; http://www.ejbiotechnology.info DOI: 10.2225/vol15-issue5].

In some embodiments of the invention, the epitope-specific mAbs used in the methods for sorting and depleting CAR-expressing engineered immune cells are the same and are selected from ibritumomab tiuxetan, imolomab, muromonab-CD3, tositumomab, abciximab, basiliximab, brentuximab, cetuximab, infliximab, rituximab, alemtuzumab, bevacizumab, tocilizumab, daclizumab, eculizumab, efalizumab, gemtuzumab, natalizumab, omalizumab, palivizumab, ranibizumab, tocilizumab, trastuzumab, vedolizumab, adalimumab, belimumab, canakinumab, denosumab, golimumab, ipilimumab, ofatumumab, panitumumab, QBEND-10, and ustekinumab.

In some embodiments of the present invention, different antibodies are used to sort and deplete cells. In some embodiments, the extracellular binding domain comprises at least one epitope specifically bound by rituximab, such as a mAb-specific epitope having an amino acid sequence of SEQ ID NO 35, and at least one epitope specifically bound by QBEND10, such as SEQ ID NO 144, and the mAb used to sort cells is QBEND10 and the mAb used to deplete cells is rituximab.

Methods for engineering immune cells

The present inventors have developed a method for designing immune cells that express chimeric antigen receptors (CARs), preferably CARs as described above, and have all the components necessary for triggering cell surface target antigens and for expansion/amplification. Moreover, this CAR has the characteristics of carrying chimeric scFvs, wherein the scFvs are modified to include epitopes that can be specifically recognized by antibodies for cell sorting and/or cell clearance purposes.

In one embodiment, a method for designing an immune cell chimeric antigen receptor (CAR) comprising at least one extracellular binding domain comprising a scFv formed by at least a VH chain and a VL chain specific for a cell surface marker antigen and a mAb-specific epitope to be bound by an epitope-specific mAb comprises:

(a) providing immune cells;

(b) introducing at least one polynucleotide encoding the chimeric antigen receptor into the cell;

(c) expressing the polynucleotide into the cell.

In one embodiment, a method for designing an immune cell expressing a chimeric antigen receptor (CAR) as described above, preferably comprising at least one extracellular binding domain comprising a scFv formed by at least a VH chain and a VL chain specific for a cell surface marker antigen and a mAb-specific epitope to be bound by an epitope-specific mAb, comprises:

(a) providing immune cells;

(b) introducing at least one polynucleotide encoding the chimeric antigen receptor into the cell; and,

(c) expressing the polynucleotide into the cell.

CARs and immune cells containing them have been widely disclosed and can be prepared by a skilled person according to known methods. For example, methods for preparing CARs and cells containing the above-mentioned CARs have been disclosed earlier. Immune cells containing CARs can be prepared by a skilled person according to the methods disclosed in the above-mentioned references. In a preferred embodiment, immune cells containing CARs can be prepared by a skilled person according to the methods disclosed in WO2013/176915.

In some embodiments, the immune cells may be derived from inflammatory T lymphocytes, cytotoxic T lymphocytes, regulatory T lymphocytes, or helper T lymphocytes.

In some embodiments, the immune cells are obtained from a healthy donor. In some embodiments, the immune cells are obtained from a patient.

In some embodiments, the method for designing the cell of the present invention further includes one or more additional genome modification steps. Through the additional genome modification steps, it can be intended to introduce one or more proteins of interest into the cell. The protein of interest can be a CAR.

In some embodiments, methods for designing T cells of the present invention may comprise:

(a) modifying T cells, wherein the modification is performed by inactivating at least:

- a first gene, the expression of which is a target for an immunosuppressant, and

- A second gene that encodes a component of the T cell receptor (TCR)

(b) expanding said cells, optionally in the presence of said immunosuppressant.

Immunosuppressants are preparations that suppress immune function through one of several mechanisms of action. In other words, immunosuppressants are the role played by compounds that are presented by reducing the degree and/or voracity of immune response. As non-limiting examples, immunosuppressants can be calcineurin inhibitors, target of rapamycin, interleukin-2u chain blockers, inhibitors of inosine monophosphate dehydrogenase, inhibitors of dihydrofolate reductase, corticosteroids or immunosuppressive antimetabolites.

In a specific embodiment, the genetic modification step of the above method relies on the inactivation of one gene selected from the group consisting of CD52, GR, TCRα, and TCRβ. In another embodiment, the genetic modification step of the above method relies on the inactivation of two genes selected from the group consisting of CD52 and GR, CD52 and TCRα, CDR52 and TCRβ, GR and TCRα, GR and TCRβ, and TCRα and TCRβ. In another embodiment, the genetic modification step of the above method relies on the inactivation of more than two genes. Preferably, the genetic modification is performed ex vivo.

The rare-cutting endonuclease used to inactivate genes in T cells is preferably a transcription activator-like effector (TALE), but can also be Cas9 coupled to an RNA guide, as described in WO 2013/176915 and WO 2014/191128, respectively.

Delivery Method

The different methods described above involve expressing CAR on the surface of cells. As a non-limiting example, the CAR can be expressed by introducing it into cells. The CAR can be introduced as a transgene encoded by a plasmid vector. The plasmid vector can also contain a selection marker that provides identification and/or selection of cells that receive the vector.

Owing to the result of introducing the polynucleotide encoding the polypeptide in the cell, polypeptide can be synthesized in situ in the cell.Alternatively, the polypeptide can be produced extracellularly and then introduced therein.The method for introducing the polynucleotide construct into the cell is known in the art and includes, as non-limiting examples, a stable transformation method, in which the polynucleotide construct is integrated into the genome of the cell, a transient transformation method, in which the polynucleotide construct is not integrated into the genome of the cell, and a virus-mediated method. For example, the polynucleotide can be introduced into the cell by recombinant viral vectors (such as retrovirus, adenovirus), liposomes, etc. For example, the transient transformation method includes, for example, microinjection, electroporation or particle bombardment. In view of being expressed in the cell, the polynucleotide can be included in a carrier, more specifically a plasmid or a virus.

Polynucleotides and vectors

In one embodiment, the isolated cell according to the present invention comprises a polynucleotide encoding a chimeric antigen receptor carrying a chimeric scFv.

The present invention also relates to polynucleotides, vectors, encoding the above-mentioned CAR according to the present invention.

The polynucleotide can be present in an expression cassette or expression vector (e.g., an alpha plasmid for introduction into bacterial host cells, or a viral vector such as a baculovirus vector for transfection of insect host cells, or a plasmid or viral vector such as a lentivirus for transfection of mammalian host cells).

Those skilled in the art will appreciate that, in view of the degeneracy of the genetic code, sizable sequence variations in these polynucleotide molecules are possible. Preferably, codon-optimized nucleotide sequences of the present invention are used for expression in mammalian cells, preferably for expression in human cells. Codon-optimized refers to a sequence of interest in which a codon that is usually rare in the highly expressed genes of a given species is exchanged with a codon that is normally frequent in the highly expressed genes of the above-mentioned species, with such codon-encoded amino acids being the codon being exchanged.

Therapeutic applications

In another embodiment, the isolated cells or immune cells expressing CAR obtained by the different methods as described herein, or cell lines derived from the isolated cells (as described above) can be used as medicaments.

In another embodiment, the agent can be used to treat a disease such as cancer in a patient in need thereof.

In another embodiment, the isolated cells or immune cells expressing the CAR according to the present invention as described herein, or cell lines derived from the isolated cells can be used to manufacture a medicament for treating a disease such as cancer in a patient in need thereof.

In another aspect, the present invention relies on a method for treating a patient in need thereof, said method comprising at least one of the following steps:

(a) providing immune cells obtainable by any of the above methods;

(b) administering the transformed immune cells to the patient.

In one embodiment, the immune cells, preferably T cells, of the present invention can undergo robust T cell expansion in vivo and can persist for an extended period of time.

The treatment can be ameliorative, curative, or preventive. It can be part of an autoimmune therapy or part of an allogeneic immunotherapy. Autologous means that the cells, cell lines, or cell populations used to treat the patient are derived from the patient or from a human leukocyte antigen (HLA)-compatible donor. Allogeneic means that the cells or cell populations used to treat the patient are not derived from the patient but from a donor.

The treatment can be used to treat patients diagnosed with cancer, viral infection, autoimmune disease or graft-versus-host disease (GvHD). Cancers that can be treated include tumors that are not vascularized or not substantially vascularized and vascularized. Cancer can include non-solid tumors (such as blood tumors, for example, leukemia and lymphoma) or can include solid tumors. The types of cancers to be treated with the CAR of the present invention include but are not limited to cancer, blastoma and sarcoma, and certain leukemia or lymphoid malignancies, benign and malignant tumors, and malignant tumors such as sarcoma, cancer, and melanoma. Adult tumors/cancers and children's tumors/cancers are also included. It can be a treatment together with one or more treatments for cancer, wherein the above-mentioned treatment for cancer is selected from: antibody therapy, chemotherapy, cytokine therapy, dendritic cell therapy, gene therapy, hormone therapy, laser therapy and radiotherapy.

Cells or cell colonies according to the present invention can be administered in any convenient manner, including by aerosol inhalation, injection, ingestion, infusion, implantation or transplantation. Compositions described herein can be administered to patients subcutaneously, intradermally, intratumorally, intranodally, intramedullaryly, intramuscularly, by intravenous or intralymphatic injection, or intraperitoneally. In one embodiment, the cell composition of the present invention is preferably administered by intravenous injection.

Administration of cells or cell colonies can include administration of 10 ⁴ -10 ⁹ cells/kg body weight, preferably 10 ⁵ to 10 ⁶ cells/kg body weight, including all integer values of cell numbers within those ranges. Cells or cell colonies can be administered in one or more doses. In another embodiment, the effective amount of cells is administered as a single dose. In another embodiment, the effective amount of cells is administered as more than one dose over a period of time. The timing of administration is within the discretion of the managing physician and depends on the patient's clinical condition. Cells or cell colonies can be obtained from any source, such as a blood bank or donor. Although individual needs vary, determining the optimal range of effective amounts of a given cell type for a specific disease or condition is within the technical scope of the art. An effective amount refers to an amount that provides a therapeutic or preventive benefit. The dosage administered will depend on the age, health status, and weight of the recipient, the type of treatment (if any), the frequency of treatment, and the characteristics of the desired effect.

In another embodiment, the effective amount of cells or a composition comprising those cells is administered parenterally. The administration can be intravenous. The administration can be performed directly by injection into the tumor.

In certain embodiments of the invention, cells are administered to a patient in conjunction with (e.g., before, simultaneously, or after) any number of related treatment modalities, including but not limited to treatment with agents such as antiviral therapy for MS patients, cidofovir and interleukin-2, cytarabine (also known as ARA-C), or natalizumab treatment, or efalizumab treatment for psoriasis patients, or other treatments for PML patients. In further embodiments, the T cells of the invention can be used in conjunction with chemotherapy, radiation, immunosuppressants such as cyclosporine, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunosuppressants such as CAMPATH, anti-CD3 antibodies, or other antibody therapies, cytotoxins, fludarabine, cyclosporine, FK506, rapamycin, mycophenolic acid, steroids, FR901228, cytokines, and radiation. These drugs inhibit the calcium-dependent phosphatase calcineurin (cyclosporine and FK506) or inhibit p70S6 kinase, which is important for growth factor-induced signaling (rapamycin) (Henderson, Naya et al. 1991, Immunology 73 (3): 316-21; Liu, Albers et al. 1992, 31 (16): 3896-901; Bierer, Hollander et al. 1993, Curr Opin Immunol 5 (5): 763-73). In further embodiments, the cell compositions of the invention are administered to a patient in conjunction with (e.g., before, simultaneously with, or after) bone marrow transplantation, T cell ablative therapy using chemotherapeutic agents such as fludarabine, external beam radiation therapy (XRT), cyclophosphamide, or antibodies such as OKT3 or CAMPATH. In another embodiment, the cell compositions of the invention are administered after B cell ablative therapy, such as an agent that reacts with CD20, for example, rituximab. For example, in one embodiment, a subject may undergo standard treatment: high-dose chemotherapy followed by a peripheral blood stem cell transplant. In certain embodiments, after the transplant, the subject receives an infusion of expanded immune cells of the present invention. In other embodiments, the expanded cells are administered before or after surgery.

Other definitions

- Amino acid residues in polypeptide sequences are designated herein according to the single-letter code, in which, for example, Q refers to a Gln or glutamine residue, R refers to an Arg or arginine residue, and D refers to an Asp or aspartic acid residue.

Nucleotides are designated as follows: A single-letter code is used to designate the nucleoside bases: a is adenine, t is thymine, c is cytosine, and g is guanine. For degenerate nucleotides, r represents g or a (purine nucleotides), k represents g or t, s represents g or c, w represents a or t, m represents a or c, y represents t or c (pyrimidine nucleotides), d represents g, a or t, v represents g, a or c, b represents g, t or c, h represents a, t or c, and n represents g, a, t or c.

- "As used herein, "nucleic acid" or "polynucleotide" refers to nucleotides and/or polynucleotides, such as deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), oligonucleotides, fragments generated by polymerase chain reaction (PCR), and fragments generated by any of ligation, cleavage, endonuclease action, and exonuclease action. Nucleic acid molecules can be composed of monomers that are naturally occurring nucleotides (such as DNA and RNA), or analogs of naturally occurring nucleotides (e.g., enantiomeric forms of naturally occurring nucleotides), or a combination of both. Modified nucleotides can have alterations in the sugar moiety and/or in the pyrimidine or purine base moiety. Sugar modifications include, for example, replacement of one or more hydroxyl groups with halogens, alkyl groups, amines, and azide groups, and sugars can be functionalized as ethers or esters. In addition, sterically and electronically similar structures such as azasugars and carbocyclic rings can be used. Sugar analogs, to replace the entire sugar part. Examples of modifications in the base part include alkylated purines and pyrimidines, acylated purines or pyrimidines or other well-known heterocyclic substitutes. Nucleic acid monomers can be connected by phosphodiester bonds or analogs of the above bonds. Nucleic acids can be single-stranded or double-stranded. -Chimeric antigen receptor (CAR) refers to a molecule that combines with respect to the binding domain of the assembly present on the target cell, such as specificity for the desired antigen (e.g., tumor antigen) based on an antibody, and activates the intracellular domain with the T cell receptor to generate a chimeric protein that presents specific anti-target cell immune activity. Typically, CAR is composed of extracellular single-chain antibodies (scFv), which are fused to the intracellular signaling domain of the T cell antigen receptor complex ζ chain (scFv:ζ), and, based on the specificity of monoclonal antibodies, when expressed in T cells, have the ability to redirect antigen recognition.

- "Delivery vector" refers to any delivery vehicle that can be used in the present invention to enter cell contact (i.e., "contact") or deliver (i.e., "introduce") the formulations/chemicals and molecules (proteins or nucleic acids) required in the present invention into a cell or subcellular compartment. It includes, but is not limited to, liposome delivery vehicles, viral delivery vehicles, drug delivery vehicles, chemical vehicles, polymeric vehicles, cationic liposomes (lipoplexes), polymer complexes (polyplexes), dendrimers, microbubbles (ultrasound contrast agents), nanoparticles, emulsions or other suitable transfer vehicles. These delivery vehicles allow the delivery of molecules, chemicals, macromolecules (genes, proteins), or other vectors such as plasmids, peptides developed by Diatos. In these cases, the delivery vehicle is a molecular vector. "Delivery vector" is also intended to refer to a delivery method used for transfection. - The term "vector" refers to a nucleic acid molecule that is capable of transporting another nucleic acid to which it has been linked. In the present invention, "vector" includes, but is not limited to, viral vectors, plasmids, RNA vectors or linear or circular DNA or RNA molecules that can be composed of chromosomal, non-chromosomal, semisynthetic or synthetic nucleic acids. Preferred vectors are those capable of autonomous replication (episomal vectors) and/or expression of nucleic acids to which they have been linked (expression vectors).A large number of suitable vectors are known to those skilled in the art and are commercially available.

Viral vectors include retroviruses, adenoviruses, parvoviruses (e.g., adeno-associated virus), coronaviruses, negative-strand RNA viruses such as orthomyxoviruses (e.g., influenza virus), rhabdoviruses (e.g., rabies and vesicular stomatitis virus), paramyxoviruses (e.g., measles and Sendai), positive-strand RNA viruses such as picornaviruses and alphaviruses, and double-stranded DNA viruses, including adenoviruses, herpesviruses (e.g., herpes simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus), and vaccinia viruses (e.g., cowpox, fowlpox, and canarypox). Other viruses include, for example, Norwalk virus, togavirus, flavivirus, reovirus, papovavirus, hepadnavirus, and hepatitis virus. Examples of retroviruses include: avian leukosis sarcoma, mammalian type C, type B, type D viruses, HTLV-BLV groups, lentiviruses, and foamy viruses (Coffin, J.M., Retroviridae: The viruses and their replication, In Fundamental Virology, Third Edition, B.N. Fields, et al., Eds., Lippincott-Raven Publishers, Philadelphia, 1996).

"Lentiviral vector" refers to a lentiviral vector based on HIV, which is very promising for gene delivery due to its relatively large packaging capacity, reduced immunogenicity and its ability to stably transduce a wide range of different cell types with high efficiency. Lentiviral vectors are usually generated after three (packaging, envelope and transport) or more plasmids are transiently transfected into producer cells. Like HIV, lentiviral vectors enter target cells through the interaction of viral surface glycoproteins with receptors on the cell surface. After entry, viral RNA undergoes reverse transcription, which is mediated by the viral reverse transcriptase complex. The product of reverse transcription is double-stranded linear viral DNA, which is a substrate for viral integration in the DNA of infected cells. "Integrative lentiviral vector (or LV)" refers to such a vector, as a non-limiting example, which is able to integrate the genome of the target cell. In contrast, "non-integrative lentiviral vector (or NILV)" refers to an effective gene delivery vector that does not integrate the genome of the target cell through the action of viral integrase.

The delivery vehicle and the vector may be linked or combined with the aid of any cell permeabilization technique such as sonoporation or electroporation or derivatives of these techniques.

"Mutation" refers to the substitution, deletion, or insertion of up to one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, twenty, twenty-five, thirty, forty, fifty, or more nucleotides/amino acids in a polynucleotide (cDNA, gene) or polypeptide sequence. A mutation may affect the coding sequence of a gene or its regulatory sequences. It may also affect the structure of the genomic sequence or the structure/stability of the encoded mRNA.

"Functional variant" refers to a catalytically active mutant of a protein or protein domain; such a mutant may have the same activity, or a higher or lower activity, compared to its parent protein or protein domain or another property.

"Identity" refers to the sequence identity between two nucleic acid molecules or polypeptides. Identity can be determined by comparing positions in each sequence that can be aligned for comparison purposes. When a position in the compared sequences is occupied by the same base, then the molecules are identical at that position. The degree of similarity or identity between nucleic acid or amino acid sequences is a function of the number of identical or matching nucleotides at positions shared by the nucleic acid sequences. A variety of alignment algorithms and/or programs can be used to calculate the identity between two sequences, including FASTA or BLAST, which are available as part of the GCG sequence analysis package (University of Wisconsin, Madison, Wis.) and can be used together with, for example, default settings. For example, it is envisioned that polypeptides having at least 70%, 85%, 90%, 95%, 98% or 99% identity relative to the specific polypeptides described herein and preferably exhibiting substantially the same function, as well as polynucleotides encoding such polypeptides.

As used herein, the term "subject" or "patient" includes all members of the animal kingdom, including non-human primates and humans. In some embodiments, the patient is a human.

In addition to the above features, the present invention includes further features, which will be derived from the following examples, which illustrate methods for in vitro sorting or in vivo elimination of CAR-expressing immune cells for immunotherapy, and the accompanying drawings.

Example 1. Generation of a rituximab-driven clearance system embedded in an anti-CD123 CAR

In the case of chimeric scFv (anti-CD123 scFv with CD20 mimotope), all 10 CARs with different conformations are shown in FIG4 : their resulting polypeptide sequences are shown in SEQ ID NOs 1 to 10.

By in vitro transcription, the DNA constructs of the 10 CARs were transcribed into their corresponding mRNAs and used to transfect primary T cells freshly isolated from the buffy coat by standard Ficoll procedures using electroporation. One day after transfection, T cells were recovered and used for flow-based cytotoxicity assays as described below.

Generation of anti-CD123 CAR T cells

In order to produce primary T cells expressing anti-CD123 CAR, primary T cells were first purified from buffy coat samples and then activated using Dynabeads human T activator CD3/CD28. 3 days after activation, under the control of the Ef1α promoter, at a multiplicity of infection (MOI) of 1, 1 million activated T cells were transduced using a lentiviral vector containing an anti-CD123 CAR expression cassette. At 37°C, in the presence of 5% CO ₂ , 20ng/ml IL-2 (final concentration) and 5% X-vivo-15 culture medium (Lonza). In the presence of human AB serum in medium, T cells were kept in culture for further characterization. 5 days after transduction, cells were used to perform flow-based cytotoxicity assays.

Flow-based cytotoxicity assay

As routinely performed, the cytolytic activity and specificity of anti-CD123 CAR T cells were assessed by flow cytometry-based cytotoxicity assays (see, for example, Valton. et Al (2015) Mol Ther; 23(9): 1507–1518). This assay involved labeling 10 ⁴ CD123-positive tumor cells and 10 ⁴ CD123-negative control cells with 0.5 mM CellTrace ^™ CFSE and 0.5 mM CellTrace ^™ Purple (Life Technology), and then incubating them together with 10 ⁵ effector CAR T cells (E/T ratio of 10: 1) for 5 hours at 37°C in a final volume of 100 μl X-Vivo-15 culture medium. The cells were then recovered and labeled with eFluor780 viability markers (as described above) before being fixed with 4% PFA. The fixed cells were then analyzed by flow cytometry to determine their viability. The frequency of specific cell lysis was calculated and displayed as follows:

Frequency of specific cell lysis = (viable CD123+ cells with T/CD123- cells with T) / (viable CD123+ cells/viable CD123- cells)

wherein viable CD123+ with T and viable CD123- with T correspond to the % of live CD123+ cells and CD123- cells, respectively, obtained after 5 hours in the presence of CAR T cells, and wherein viable CD123+ cells and viable CD123- cells correspond to the % of CD123+ cells and CD123- cells, respectively, obtained after 5 hours in the absence of CAR T cells.

As a result, the cells transfected with engineering anti-CD123 CAR can kill CD123 positive tumor cell models. As shown in Figure 5, the result from the cytotoxicity assay based on flow described above shows that the T cells expressing SEQ ID 1-4 show and express the same activity (Fig. 5) of the T cells of unmodified anti-CD123 CAR SEQ ID 142. These data show that the insertion of CD20 mimetic epitopes in the sequence of anti-CD123 CAR (SEQ ID 142) does not significantly damage its ability to specifically identify CD123 antigens and kill CD123 expressing tumor cells. In some embodiments, the CAR comprising two mAb specific epitopes of the present invention, preferably SEQ ID NO 35, can specifically identify the antigen targeted by CAR and kill the cell expressing the antigen.

Consistent with these findings, transfected CAR T cells were tested for their ability to degranulate when exposed to CD123 recombinant protein plated on 96-well plates. Together, our experiments aimed to show that the insertion of the CD20 mimetic epitope into the sequence of the anti-CD123 CAR did not significantly impair its ability to specifically recognize the CD123 antigen.

To demonstrate the ability of rituximab to inhibit T cell cytotoxic function through specific recognition of the CD20 mimotope, transfected T cells were incubated in the presence of CD123-positive tumor cells in the presence or absence of rituximab and baby rabbit complement. The goal was to show that the cytotoxic activity and degranulation capacity of the transfected T cells were impaired in the presence of rituximab and baby rabbit complement, which further indicates that effective recognition of the engineered anti-CD123 CAR by rituximab leads to T cell elimination.

Example 2. Flexibility of mAb-driven clearance system in anti-CD123 chimeric antigen receptor

In order to further demonstrate the flexibility of mAb driven clearance system, using the same procedure and structure as described in Example 1 for CD20 mimetic epitopes, different epitopes or mimetic epitopes (SEQ ID NO 35-42) with specificity for cetuximab, palivizumab and nivolumab mAb are inserted into anti-CD123 CAR constructs. The results are intended to show that transfected T cells retain their cytolytic activity and degranulation ability for CD123 positive tumor cells. In addition, the experiment is also intended to show that, by some of the above-mentioned mAbs, transfected T cells are removed.

Example 3. Rituximab-dependent clearance of anti-CD123 CAR containing a mAb-driven clearance system

To explore the ability of the mAb-driven clearance system to allow clearance of anti-CD123 CAR T cells, transduced T cells expressing SEQ ID NO 1, 2, 3 or 4 CAR, or unmodified anti-CD123 CAR (SEQ ID NO 142), were subjected to complement dependent cytotoxicity assays (CDC).

CDC assay

The CDC assay includes incubating 0.2 10 6 transduced T cells for 3 hours at 37 ° C in a final volume of ⁴⁰⁰ μL of Xvivo 10% FBS, either alone or in the presence of rituximab (RTX, ROCHE, 400 ng) and baby rabbit complement (BRC, AbD Serotec, ref#C12CA, 100 μL of solution, diluted according to the manufacturer's protocol). At the end of the incubation, anti-CD123-CAR T cells were recovered and labeled with recombinant CD123 proteins fused to FC fragments (SEQ ID 143) and PE-labeled anti-FC secondary monoclonal antibodies (Jackson ImmunoResearch, ref#115-115-164, 1/200 dilution). Cells were then recovered in PFA 4% before being analyzed by flow cytometry. The flow cytometry gating strategy includes determining the viability of anti-CD123 CAR positive T cells (PE positive cells) in the simple state found in the total cell population. This analysis is performed on cells incubated alone and in the presence of RTX and BRC. The results are expressed as a ratio, which is named "Relative frequency of viable cells in anti-CD123 CAR positive T cells (relative to control experiment)", and is described as follows:

(Frequency of viable cells in anti-CD123 CAR-positive T cells obtained in the presence of RTX and BRC) x 100/(Frequency of viable cells in anti-CD123 CAR-positive T cells obtained in the absence of RTX and BRC).

The results showed that all CAR structures allowed RTX-dependent clearance of CAR T cells (Figure 6). CAR T cells expressing SEQ ID NOs 3 and 4 were more effectively cleared than CAR T cells expressing SEQ ID NOs 1 and 2, suggesting that the number of CD20 mimetic epitopes present in the CAR structure affects the extent and/or kinetics of T cell clearance.

In some embodiments, the CAR of the present invention, which has the structure shown in Figure 4, allows rituximab-dependent elimination of CAR T cells. In some embodiments, the CAR of the present invention, which comprises at least two mAb-specific epitopes, preferably having a CAR structure of SEQ ID NO 3 or 4, is particularly effectively eliminated.

Example 4. Efficiency of mAb-driven clearance system in cells expressing anti-BCMA CAR containing one or more mAb-specific epitopes in the extracellular domain.

To explore the ability of mAb-driven clearance systems to allow clearance of anti-BCMA CAR T cells, 15 different CAR structures were constructed (SEQ ID 125-139, Figure 7). These structures were designed to contain 1, 2 or 3 CD20 mimetic epitopes located in different parts of the extracellular domain of anti-BCMA CAR (SEQ ID NO 125), i.e., in the N-terminal domain, in the linker domain separating V1 and V2 of ScFv, or upstream of the CD8 hinge that connects ScFv to the transmembrane domain of CAR.

In order to generate primary T cells expressing anti-BCMA CAR, primary T cells were first purified from buffy coat samples and activated using Dynabeads human T activator CD3/CD28. Three days after activation, 5 million activated T cells were transfected with 15 or 30 μg of polyadenylated mRNA encoding different anti-BCMA CAR structures (SEQ ID 125-139, Fig. 7). Then, at 37 ° C, in the presence of 5% CO ₂ , 20 ng/ml IL-2 (final concentration) and 5% human AB serum in X-vivo-15 culture medium (Lonza), T cells were kept in culture for further characterization. One day after transfection, cells were used to perform CDC assays, flow-based cytotoxicity assays, detection assays, and interferon gamma (IFNγ) release assays.

CDC assay

The CDC assay involves incubating 0.2 10 6 transfected cells for 2 hours at 37 ° C in a final volume of 400 μL of Xvivo 10 ^% FBS, alone or in the presence of rituximab (RTX, ROCHE, 400 ng) and baby rabbit complement (BRC, AbD Serotec, ref#C12CA, 100 μL of solution, diluted according to the manufacturer's protocol). At the end of the incubation, anti-BCMA-CAR T cells were recovered and labeled with recombinant BCMA protein fused to the FC fragment (SEQ ID NO 151) and PE-labeled anti-FC secondary monoclonal antibody (Jackson ImmunoResearch, ref#115-115-164, 1/200 dilution). The cells were then recovered in PFA 4% before being analyzed by flow cytometry. The flow cytometry gating strategy was to determine the viability of anti-BCMA CAR-positive T cells (PE-positive cells) in the simple state found in the total cell population. This analysis was performed on cells incubated alone and in the presence of RTX and BRC. The results are expressed as a ratio, entitled "Relative frequency of viable cells in BCMA CAR-positive T cells (relative to control experiment)", and are described as follows:

(Frequency of viable cells in anti-BCMA CAR-positive T cells obtained in the presence of RTX and BRC) x 100 / (Frequency of viable cells in anti-BCMA CAR-positive T cells obtained in the absence of RTX and BRC)

Flow-based cytotoxicity assay

The cytolytic activity and specificity of anti-BCMA CAR T cells were evaluated according to the flow cytometry-based cytotoxicity assay reported in Valton. et Al (2015) Mol Ther; 23 (9): 1507–1518. This assay involves labeling BCMA-positive tumor target cells (T, H929) with 0.5 mM CellTrace ^™ CFSE (Life Technology, incubated for 10 minutes at 37°C according to the manufacturer's protocol) and then co-incubating them with 10 ⁵ anti-BCMA CAR T effector (E) cells (E/T ratio of 10:1) in a final volume of 100 μl X-Vivo-15 medium at 37°C for 5 hours. The cells were then recovered and labeled with eFluor780 viability marker before being fixed with 4% PFA. The fixed cells were then analyzed by flow cytometry to determine their viability.

IFNγ release assay

In order to study the self-activation of T cells expressing various anti-BCMA CARs, wherein the above-mentioned anti-BCMA CARs include RTX-specific epitopes, one day after transfection, in X-vivo-15 culture medium supplemented with 5% AB serum, 20ng/mL IL2, in the absence of 500μg/mL RTX or in the presence of 500μg/mL RTX, at a concentration of ^0.1106 cells/well, in a final volume of 100μl, primary T cells transfected with mRNA encoding SEQ ID 125, 130-139 were incubated for 72 hours. The CAR T cells were then centrifuged, the supernatant was recovered and analyzed by ELISA (using human IFN-γQuantikine ELISA kit, RandD systems, ref#DIF50) to determine the amount of IFNγ released in the culture medium. As a positive control for CAR T cell activation and IFNγ release, cells were incubated with 10μg/mL phytohemagglutinin (PHA).

Purification of anti-BCMA CAR T cells using the Miltenyi CD34 purification kit

To test the ability of certain anti-BCMA CAR constructs (containing the CD34 epitope, SEQ ID NO 144, recognized by the QBEND10 antibody) to be purified, 100 10 ⁶ primary T cells stably expressing SEQ ID 128 were purified using the CD34 MicroBead kit (Miltenyi, ref# 130-046-702) following the manufacturer's protocol.

result

Depletability of anti-BCMA CAR-positive T cells

The results showed that compared to the unmodified anti-BCMA CAR (SEQ ID NO 125), which was not significantly cleared (depletion), T cells expressing SEQ ID 126-139 were cleared by BRC and RTX to varying degrees (Figure 8A). The results showed that the efficiency of clearance increased with the increase in the number of CD20 mimetic epitopes present in the CAR structure. In addition, the results showed that separating multiple CD20 mimetic epitopes by a domain larger than the GS linker increased the efficiency of clearance, as seen when comparing the clearance obtained by means of T cells, wherein the above-mentioned T cells expressed SEQ ID NO 127 and SEQ ID NO 137 containing 3 CD20 mimetic epitopes and SEQ ID NO 139 and SEQ ID NO 136 containing 2 CD20 mimetic epitopes (Figures 7-8A).

In some embodiments, the CAR of the present invention has a CAR structure of SEQ ID NO126-139, allowing rituximab-dependent clearance of CART cells. In some embodiments, the CAR of the present invention has a CAR structure as in SEQ ID, 136, 137, 138, i.e., wherein the CAR comprises at least two identical mAb-specific epitopes, which are separated by one or more other domains (such as VH, VL, VH-L1-VL ...), and are particularly effectively cleared.

Cytotoxic activity of anti-BCMA CAR+T cells

The results of the flow-based cytotoxicity assay showed that all structures (SEQ ID 126-139) were able to recognize and kill BCMA-expressing H929 tumor cells to a similar extent compared to T cells expressing the unmodified version of the anti-BCMA CAR structure (SEQ ID NO 125, Figure 9). Consistent with the results obtained in Example 1, the presence of 1, 2 or 3 mAb-specific epitopes, and especially 1, 2 or 3 CD20 mimetic epitopes, within the CAR structure did not significantly affect the cytolytic activity of anti-BCMA CAR T cells.

In some embodiments, the CARs of the present invention, which have the CAR structures of SEQ ID NOs 126-139, have similar cytotoxic activity compared to CARs without mAb-specific epitopes, such as the CAR of SEQ ID 125.

Anti-BCMA-positive CAR T cells sorted from heterogeneous cell populations

In order to test the ability of T cells expressing SEQ ID 128 anti-BCMA CAR (Fig. 7A) to be purified from heterogeneous cell populations, ^100x106 primary T cells containing 31.5% of CAR positive cells of different species (heterogeneous) populations were purified using the CD34 MicroBead kit and in accordance with the manufacturer's protocol. The results showed that the purified fraction contained approximately 90% of anti-BCMA CAR positive T cells, which indicated that the purification process was effective (Fig. 10). After purification, approximately ^20x106 anti-BCMA CAR positive T cells were recovered from ^31.5x106 anti-BCMA CAR positive T cells, which indicated that less than 40% of anti-BCMA CAR positive T cells were lost throughout the purification process.

IFNγ release assay

ELISA assay results showed that the presence of one or more CD20 mimetic epitopes within the CAR structure did not affect the propensity of CART cells to be activated by RTX (Figure 11). Indeed, the results showed that in the presence of RTX, the level of IFNγ released by all structures was similar to the basal level of IFNγ released in the absence of RTX.

Example 5. Hybrid anti-BCMA chimeric antigen receptor constructs for optimal depletion and purification of CAR T cells.

In order to improve the clearance of anti-BCMA CAR T cells and at the same time allow them to be sorted, two new hybrid CAR structures SEQ ID NO 140 and 141 (Figure 7C) were designed. These two structures contain three CD20 mimetic epitopes separated from each other by protein domains, and a CD34 epitope. By CDC determination, and according to the protocol described in Example 4, their ability to be cleared by RTX and BRC was evaluated. The results showed that, to a similar extent as T cells expressing SEQ ID 137, these two structures were effectively cleared (Figure 8B). Their cytolytic properties were also evaluated using the flow-based assay described above. The results showed that they shared similar cytotoxic activity with T cells expressing unmodified anti-BCMA CAR T cells (SEQ ID NO 125), which showed that the presence of CD20 mimetic epitopes and CD34 epitopes (SEQ ID NO 35 and 144, respectively) did not negatively affect the cytolytic activity of CAR T cells.

In some embodiments, the CAR of the present invention, which has a CAR structure as in SEQ ID 140, 141, i.e., wherein the CAR comprises three identical mAb-specific epitopes that are recognized by approved antibodies such as rituximab, which can be used for cell clearance, with one mAb-specific epitope that can be used for purification, is particularly effectively cleared and can also be effectively purified.

According to the protocol described in Example 4, additional CARs based on the structures of SEQ ID NOs 140 and 141 and comprising VH and VL of ScFvs specific for CD19 (CARs of SEQ ID NOs 162-163 and 168-169), CD123 (CARs of SEQ ID NOs 164-165), and CD20 (CARs of SEQ ID NOs 166-167) were assembled. Their ability to be cleared by RTX and BRC can be assessed by CDC assays according to the protocol described in Example 4.

Example 6. Universal detection of CAR T cells carrying mAb-driven clearance system

Due to the lack of a universal detection system, in vivo monitoring and comparison of the proliferation of different CAR T cells has been tedious and slow. The ability of different CAR structures to be tested was tested by flow cytometry, using RTX as a primary antibody and FITC-coupled anti-Fab'2 monoclonal antibody (Life technologies, ref#H10101C, 1/200 dilution), or using APC-labeled anti-CD34 monoclonal antibody, named QBEND10 (Miltenyi Biotec, ref#130-090-954, 1/25 dilution). The results were compared side by side with the detection performed with recombinant BCMA protein fused to FC fragment (SEQ ID NO 151) and PE-labeled anti-FC secondary monoclonal antibody (Jackson ImmunoResearch, ref#115-115-164, 1/200 dilution).

The results showed that the frequency of positive CAR T cells expressing SEQ ID NO 128 and 130-139 detected by RTX was similar to the frequency obtained when they were detected by recombinant BCMA protein (Figure 12). Similar results were found when CAR T cells expressing SEQ ID NO 128 were detected by QBEND10 and rituximab (Figure 13). In summary, the results show that the presence of CD20 mimetic epitopes or CD34 epitopes allows for efficient and universal detection of different CAR structures.

Example 7 - Anti-BCMA CAR T cells expressing anti-BCMA CAR, wherein the anti-BCMA CAR comprises one, two or three mAb-specific epitopes

7.1-Plasmid

The following CAR containing the CD20 mimetic epitope was codon-optimized using EcoRI (5') and MluI (3') restriction sites (thus removing the IRES-Puro cassette), synthesized, and subcloned into the lentiviral vector pLVX-EF1a-IRES-Puro (Clontech). Lentivirus was produced using psPAX2, an HIV-1 gag-pol packaging plasmid, and pMD2.G, a VSV-G expression plasmid.

BC30 (SEQ ID NO 145) contains the following domains:

Leader sequence-BCMA30 VH-Linker-BCMA30 VL-CD8 Hinge-CD8 TM-4-1BB-CD3z, wherein BCMA30 VH and BCMA30 VL are SEQ ID NO 97 and SEQ ID NO 98, respectively.

BC30-LM (SEQ ID NO 146) contains the following domains:

Leader sequence-BCMA30 VH-Linker-BCMA30 VL-Linker (L)-Mimetope (M)-CD8 Hinge-CD8 TM-4-1BB-CD3z, wherein BCMA30 VH and BCMA30 VL are SEQ ID NO 97 and SEQ ID NO 98, respectively, and the mimotope is SEQ ID NO 35.

BC30-LML (SEQ ID NO 147) contains the following domains:

Leader sequence-BCMA30 VH-Linker-BCMA30 VL-Linker (L)-Mimetope (M)-Linker (L)-CD8 Hinge-CD8 TM-4-1BB-CD3z, wherein BCMA30 VH and BCMA30 VL are SEQ ID NO 97 and SEQ ID NO 98, respectively, and the mimotope is SEQ ID NO 35.

BC30-LMLM (SEQ ID NO 148) contains the following domains:

Leader sequence-BCMA30 VH-Linker-BCMA30 VL-Linker (L)-Mimetope (M)-Linker (L)-Mimetope (M)-CD8 Hinge-CD8 TM-4-1BB-CD3z, wherein BCMA30 VH and BCMA30 VL are SEQ ID NO 97 and SEQ ID NO 98, respectively, and the mimotopes are both SEQ ID NO 35.

BC30-LMLML (SEQ ID NO 149) contains the following domains:

Leader sequence-BCMA30 VH-Linker-BCMA30 VL-Linker (L)-Mimetope (M)-Linker (L)-Mimetope (M)-Linker (L)-CD8 Hinge-CD8 TM-4-1BB-CD3z, wherein BCMA30 VH and BCMA30 VL are SEQ ID NO 97 and SEQ ID NO 98, respectively, and the mimotopes are both SEQ ID NO 35.

7.2-T cell activation and lentiviral transduction

Untouched T cells were isolated from human peripheral blood mononuclear cells (PBMCs) using the Pan T cell isolation kit (Miltenyi Biotec) and activated for three days using antibodies against human CD2, CD3, and CD28 (T cell activation/expansion kit - Miltenyi Biotec). Lentiviral vectors (LVs) were generated by transient transfection of subconfluent HEK-293T/17 (American Type Culture Collection (ATCC)) cells in 6-well plates. Briefly, pLVX, psPAX2, and pMD2.G plasmids were transfected at a 4:3:1 ratio using Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions. The next day, the culture medium was replaced with T cell culture medium (5% human AB serum in X-vivo-15 culture medium (Lonza)), and 48 hours after transfection, the LV supernatant was harvested and filtered through a 0.45 μm syringe filter (Millipore). Activated T cells were seeded at 0.25 x 10 ⁶ cells/mL in T cell culture medium containing 40 ng/ml IL-2 and then transduced by adding an equal volume of fresh LV supernatant. Cells were cultured for three days at 37°C and 5% CO 2 and used for flow cytometry analysis or expanded in fresh T cell culture medium containing 20 ng/ml IL-2.

7.3-Detection of BCMA CARs containing CD20 mimotopes by flow cytometry

In order to test the practicality of internal CAR CD20 mimetic epitopes for detecting and tracking CAR-T cells, flow cytometry analysis was performed on transduced T cells using biotinylated BCMA protein, which binds to the scFV region of CAR, followed by PE-bound streptavidin, or anti-CD20 antibody rituximab, followed by FITC-bound anti-human IgG (rituximab (FITC)). Figures 14A and 14B show that by flow cytometry, biotinylated BCMA, followed by PE-bound streptavidin, T cells transduced with CARs containing different CD20 mimetic epitopes were detected with comparable efficiency. Detection of internal CAR CD20 mimetic epitopes by rituximab in cells transduced with LM constructs was weak (15.5%), but very high in all other formats tested. For example, LMLML CAR was detected in 85.6% of cells, which shows that this format allows identification of almost all cells expressing CAR (Figures 14A and 14B). Therefore, the presence of two CD20 epitopes separated by a flexible linker allows for enhanced binding to rituximab and provides an optimal system to detect CAR+ cells.

By comparing with the RQR8 marker / suicide gene system (SEQ ID NO 150), which is composed of a self-tight protein containing two CD20 epitopes and a CD34 epitope, which is usually co-expressed together with CAR (Philip, Blood 2014), the function of the CD20 epitope in CAR for CAR-T cell detection was evaluated. For this experiment, the transduction of T cells was by means of a lentivirus, which allowed the co-expression of BCMA30 CAR (SEQ ID NO 145) and RQR8 protein (SEQ ID NO 150) (BC30-RQR8 construct). For comparison, T cells were transduced with the BCMA30 LMLML CAR construct (BC30-R2 construct-SEQ ID NO149) and analyzed by flow cytometry three days after transduction. In addition, non-transduced (NT) T cells served as negative controls. Figure 15 is intended to show that incorporating the CD20 epitope into the CAR molecule significantly improves the detection of CAR-T cells by means of the anti-CD20 antibody rituximab. In addition, compared to those cells transduced with vectors and CAR encoding RQR8, increased transduction efficiency and CAR expression were observed in cells transduced with the BC30-R2 construct, as indicated by flow cytometry analysis with biotinylated BCMA (Figure 15). Thus, the insertion of the CD20 epitope into the CAR molecule enables the provision of increased transduction, improved detection, and an absolute correlation between CAR expression and mAb specific epitope expression.

7.4-CAR CD20 epitope sensitizes CAR-T cells to complement-dependent cytotoxicity

Using CDC determination, the ability of the CD20 epitope in CAR to selectively eliminate CAR-T cells was assessed in vitro. The purpose is to show that the presence of the CD20 epitope in the CAR molecule makes CAR-T cells highly susceptible to rituximab-mediated clearance. For this experiment, T cells transduced with the BC30-R2 construct or BC30-RQR8 construct were mixed with 25% baby rabbit complement (AbD serotec) in the presence or absence of rituximab (100 μg/mL) and then incubated for 4 hours at 37 ° C and 5% CO2. The selective deletion of CAR-T cells was determined by flow cytometry analysis and biotinylated BCMA protein. Figure 16 shows that when both the CD20 epitope suicide gene system in RQR8 and CAR enables CAR-T cells to be cleared, cells transduced with the BC30-R2 construct are more effectively cleared than those expressing RQR8. As expected, T cells expressing the BCMA30 CAR but without the CD20 epitope (BC30 construct) were redundant. These differences may be due to the high expression of the BC30-R2 CAR and the absolute correlation between CAR expression and suicide gene expression.

7.5-CD20 epitope incorporation into CAR does not impair the cytolytic activity of CAR-T cells

In the cytotoxicity assay, the possibility that the insertion of the CD20 epitope between the hinge and the scFv region of CAR may impair the activity of CAR was assessed. Briefly, at different ratios, T cells expressing BC30-R2 constructs or BC30-RQR8 constructs were incubated together with luciferase-positive MM1S target cells. For these killing assays, cells were seeded in 96-well white opaque tissue culture plates with a final volume of 100 μl of 5% human AB serum (in X-vivo-15 culture medium (Lonza)). After 4 hours, the cells were equilibrated to room temperature and one volume of Bright-Glo ^™ Reagent (Promega) was added to each well. Fluorescence was measured using a GLOMAX 96 microplate photometer (Promega) and the percentage of cell lysis was calculated according to the following formula:

100x(1-(sample lysis-maximal lysis)/(spontaneous lysis-maximal lysis)). Maximum lysis was determined by adding 8% Triton X-100 (Sigma) to Luc+MM1S cells. For spontaneous lysis, MM1S cells were incubated without effector CAR-T cells.

The results showed that BC30-R2 CAR-T cells effectively eliminated BCMA-expressing MM1S cells in vitro (Figure 17). In addition, rituximab (100 μg/mL), which was added to the effector cell population 2 hours before these cells were mixed with target cells, did not affect the cytolytic activity of BC30-R2 CAR-T cells (Figure 17). This experiment was designed to demonstrate that even in the presence of rituximab, the insertion of the CD20 epitope into the BC30 CAR molecule did not affect its ability to mediate killing of BCMA+ target cells.

7.6 Rituximab binding to the CD20 epitope within CAR does not lead to CAR-T cell activation

In order to study whether the cross-linking of CAR by rituximab may cause T cell activation, it is due to the aggregation of CAR on the cell surface, in the presence of rituximab, BC30-R2 CAR-T cells are grown. Anti-CD3 OKT3 antibodies (eBioscience) cause cross-linking of T cell receptors (TCR), thereby causing cell activation and proliferation, and are used as positive controls. Briefly, BC30-R2 CAR-T cells are cultured in T cell culture medium for three days with/without rituximab. T cell activation is then assessed using flow cytometry by measuring the expression of activation markers CD25 and CD69. This experiment shows that the percentage of activated T cells in the presence of RTX is not significantly different from that of control (PBS). Therefore, soluble rituximab has no significant effect on the activation state of BC30-R2CAR-T cells (Figure 18).

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-Philip B, Kokalaki E, Mekkaoui L, Thomas S, et al. A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood2014;124(8):1277-87.

Modes for Carrying Out the Invention

1. A polypeptide encoding a chimeric antigen receptor (CAR) comprising at least one extracellular binding domain comprising an scFv formed by at least a VH chain and a VL chain specific for a cell surface marker antigen, wherein the extracellular binding domain comprises at least one mAb-specific epitope to be bound by an epitope-specific mAb, for in vitro cell sorting and/or in vivo cell elimination of immune cells expressing the CAR.

2. The polypeptide according to embodiment 1, wherein the mAb-specific epitope is located between the VH and VL chains.

3. A polypeptide according to embodiment 1 or 2, wherein the VH and VL chains, and the mAb-specific epitope are bound together by at least one linker and bound to the transmembrane domain of the CAR via a hinge.

4. The polypeptide according to embodiment 3, wherein the mAb epitope is connected to the VH and VL chains via two linkers.

5. The polypeptide according to any one of embodiments 1 to 4, wherein the mAb epitope is from a polypeptide selected from those listed in Table 1.

6. A polypeptide according to any one of embodiments 1 to 4, wherein the VH and VL chains, as antigen target sequences, have an identity of more than 80%, preferably more than 90%, and more preferably more than 95%, relative to SEQ ID NO 43 (CD19 antigen), SEQ ID NO 44 (CD38 antigen), SEQ ID NO 45 (CD123 antigen), SEQ ID NO 46 (CS1 antigen), SEQ ID NO 47 (BCMA antigen), SEQ ID NO 48 (FLT-3 antigen), SEQ ID NO 49 (CD33 antigen), SEQ ID NO 50 (CD70 antigen), SEQ ID NO 51 (EGFR-3v antigen) and SEQ ID NO 52 (WT1 antigen).

7. A polypeptide according to any one of embodiments 1 to 5, wherein the VH and VL chains, as antigen target sequences, have an identity of more than 80%, preferably more than 90%, and more preferably more than 95%, relative to SEQ ID NOs 53-64 (CD19 antigen), SEQ ID NOs 65-76 (CD33 antigen), SEQ ID NOs 77-84 (5T4 antigen), SEQ ID NOs 85-90 (ROR1 antigen), SEQ ID NOs 91-94 (EGFRvIII antigen), SEQ ID NOs 95-102 (BCMA antigen), SEQ ID NOs 103-112 (CS1 antigen) and SEQ ID NOs 113-124 (CD123 antigen).

8. A polypeptide according to any one of embodiments 1-7, wherein the VH and VL chains, as epitope target sequences, have more than 80% identity, preferably more than 90%, and more preferably more than 95% identity relative to the CD20 antigen of SEQ ID NO.11.

9. The polypeptide according to any one of embodiments 1-8, wherein the CAR is a single-chain CAR.

10. The polypeptide according to embodiment 9, wherein the CAR polypeptide shares more than 80% identity, preferably more than 90%, and more preferably more than 95% identity with respect to SEQ ID NOs 1 to 10.

11. The polypeptide according to any one of embodiments 1-10, wherein the CAR is a multi-chain CAR.

12. A polynucleotide encoding a chimeric antigen receptor according to any one of embodiments 1 to 9, wherein the CAR comprises a CD3ζ signaling domain and a co-stimulatory domain derived from 4-1BB.

13. An expression vector comprising the nucleic acid of embodiment 12.

14. An engineered immune cell expressing the chimeric antigen receptor according to any one of embodiments 1 to 12 on its cell surface.

15. The engineered immune cell according to embodiment 14, which is derived from inflammatory T lymphocytes, cytotoxic T lymphocytes, regulatory T lymphocytes or helper T lymphocytes.

16. The engineered immune cell according to embodiment 14 or 15, for use as a medicament.

17. A method for designing the immune cell of any one of embodiments 14-16, comprising:

(a) providing immune cells;

(b) introducing into said cell at least one polynucleotide encoding a chimeric antigen receptor according to any one of embodiments 1 to 12;

(c) expressing the polynucleotide into the cell.

18. A method for engineering the immune cell of embodiment 17, wherein the immune cell is a T cell.

19. A method for sorting CAR-expressing immune cells, comprising contacting a population of immune cells designed according to any one of embodiments 14-16 with an antigen-specific mAb to collect only CAR-expressing immune cells.

20. A method for sorting CAR-expressing immune cells according to embodiment 19, wherein the mAb is rituximab.

21. A method for sorting CAR-expressing immune cells according to any one of embodiments 19-20, wherein the immune cells are T cells.

22. A method for clearing immune cells designed according to any one of embodiments 14-16 or CAR-expressing immune cells sorted according to any one of embodiments 19-21, comprising contacting the immune cells or the CAR-expressing immune cells with an epitope-specific mAb.

23. A method for depleting immune cells or CAR-expressing immune cells according to embodiment 22, wherein the epitope-specific mAb is bound by a molecule capable of activating the complement system.

24. A method for depleting immune cells CAR-expressing immune cells according to any one of embodiments 22-23, wherein the cytotoxic drug is coupled to an epitope-specific mAb.

25. A method for depleting immune cells CAR-expressing immune cells according to any one of embodiments 22-24, wherein the mAb-specific antigen is CD20 antigen and the epitope-specific mAb is rituximab.

26. A method for clearing immune cells CAR-expressing immune cells according to any one of embodiments 22-25, comprising contacting the immune cells or CAR-expressing immune cells with a bispecific mAb (BsAb) that is capable of binding to mAb-specific epitopes carried by the cells and to surface antigens carried by effector (and cytotoxic) cells.

27. A method for clearing immune cells expressing immune cells CAR according to any one of embodiments 22-26, wherein the immune cells are T cells.

28. A method for regulating activation of engineered immune cells, comprising at least the following steps:

(i) endowing the immune cell with a CAR whose extracellular binding domain comprises a scFv that recognizes a cell surface marker linked to a mAb-specific epitope

(ii) expanding the immune cells, which express the CAR and the mAb epitope on their surface

(iii) contacting the generated immune cells with mAb specific for the epitope to immobilize the immune cells.

Sequence Listing

<110> Rayner; Celectis

<120> mAb-driven chimeric antigen receptor system for sorting/depletion of engineered immune cells

<130> P81500233PCT00

<150> PA201570044

<151> 2015-01-26

<160> 187

<170> PatentIn version 3.5

<210> 1

<211> 511

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-CD123 NO1

<400> 1

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu

20 25 30

Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr

35 40 45

Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys

50 55 60

Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr

65 70 75 80

Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser

85 90 95

Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr

100 105 110

Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln

145 150 155 160

Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser

165 170 175

Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His

180 185 190

Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg

195 200 205

Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly

210 215 220

Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp

225 230 235 240

Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe

245 250 255

Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly

260 265 270

Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr

275 280 285

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

290 295 300

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

305 310 315 320

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

325 330 335

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

340 345 350

Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

355 360 365

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

370 375 380

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

385 390 395 400

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

405 410 415

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

420 425 430

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

435 440 445

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

450 455 460

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

465 470 475 480

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

485 490 495

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu

500 505 510

<210> 2

<211> 517

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-CD123 No. 2

<400> 2

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu

20 25 30

Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr

35 40 45

Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys

50 55 60

Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr

65 70 75 80

Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser

85 90 95

Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr

100 105 110

Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln

145 150 155 160

Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser

165 170 175

Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His

180 185 190

Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg

195 200 205

Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly

210 215 220

Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp

225 230 235 240

Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe

245 250 255

Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly

260 265 270

Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly

275 280 285

Gly Gly Ser Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

290 295 300

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

305 310 315 320

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

325 330 335

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

340 345 350

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys

355 360 365

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

370 375 380

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

385 390 395 400

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

405 410 415

Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

420 425 430

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

435 440 445

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

450 455 460

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

465 470 475 480

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

485 490 495

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

500 505 510

Leu Pro Pro Arg Glu

515

<210> 3

<211> 526

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-CD123 No3

<400> 3

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu

20 25 30

Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr

35 40 45

Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys

50 55 60

Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr

65 70 75 80

Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser

85 90 95

Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr

100 105 110

Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln

145 150 155 160

Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser

165 170 175

Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His

180 185 190

Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg

195 200 205

Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly

210 215 220

Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp

225 230 235 240

Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe

245 250 255

Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly

260 265 270

Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly

275 280 285

Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr

290 295 300

Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln

305 310 315 320

Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala

325 330 335

Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala

340 345 350

Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr

355 360 365

Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln

370 375 380

Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser

385 390 395 400

Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys

405 410 415

Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln

420 425 430

Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu

435 440 445

Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg

450 455 460

Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met

465 470 475 480

Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly

485 490 495

Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp

500 505 510

Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu

515 520 525

<210> 4

<211> 532

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-CD123 No.4

<400> 4

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu

20 25 30

Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr

35 40 45

Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys

50 55 60

Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr

65 70 75 80

Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser

85 90 95

Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr

100 105 110

Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln

145 150 155 160

Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser

165 170 175

Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His

180 185 190

Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg

195 200 205

Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly

210 215 220

Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp

225 230 235 240

Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe

245 250 255

Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly

260 265 270

Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly

275 280 285

Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly

290 295 300

Gly Ser Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

305 310 315 320

Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg

325 330 335

Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys

340 345 350

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

355 360 365

Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu

370 375 380

Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln

385 390 395 400

Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly

405 410 415

Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

420 425 430

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

435 440 445

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

450 455 460

Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu

465 470 475 480

Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys

485 490 495

Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu

500 505 510

Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu

515 520 525

Pro Pro Arg Glu

530

<210> 5

<211> 495

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-CD123 No5

<400> 5

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu

20 25 30

Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr

35 40 45

Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys

50 55 60

Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr

65 70 75 80

Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser

85 90 95

Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr

100 105 110

Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Cys Pro

130 135 140

Tyr Ser Asn Pro Ser Leu Cys Gly Gly Gly Gly Ser Asp Ile Val Leu

145 150 155 160

Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr

165 170 175

Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe

180 185 190

Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile

195 200 205

Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly

210 215 220

Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala

225 230 235 240

Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro

245 250 255

Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr

260 265 270

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

275 280 285

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

290 295 300

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

305 310 315 320

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

325 330 335

Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

340 345 350

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

355 360 365

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

370 375 380

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

385 390 395 400

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

405 410 415

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

420 425 430

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

435 440 445

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

450 455 460

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

465 470 475 480

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu

485 490 495

<210> 6

<211> 501

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-CD123 No6

<400> 6

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu

20 25 30

Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr

35 40 45

Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys

50 55 60

Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr

65 70 75 80

Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser

85 90 95

Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr

100 105 110

Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Gly

130 135 140

Gly Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gly Gly Gly Gly Gly

145 150 155 160

Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser

165 170 175

Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp

180 185 190

Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln

195 200 205

Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile

210 215 220

Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr

225 230 235 240

Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln

245 250 255

Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu

260 265 270

Lys Arg Ser Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

275 280 285

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

290 295 300

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

305 310 315 320

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

325 330 335

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys

340 345 350

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

355 360 365

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

370 375 380

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

385 390 395 400

Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

405 410 415

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

420 425 430

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

435 440 445

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

450 455 460

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

465 470 475 480

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

485 490 495

Leu Pro Pro Arg Glu

500

<210> 7

<211> 508

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-CD123 No7

<400> 7

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys

35 40 45

Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile

50 55 60

Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser

65 70 75 80

Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr

85 90 95

Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala

100 105 110

Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala

115 120 125

Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp

130 135 140

Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

145 150 155 160

Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser

165 170 175

Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys

180 185 190

Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp

195 200 205

Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala

210 215 220

Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser

225 230 235 240

Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val

245 250 255

Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly

260 265 270

Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro

275 280 285

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

290 295 300

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

305 310 315 320

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

325 330 335

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

340 345 350

Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

355 360 365

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

370 375 380

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

385 390 395 400

Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr

405 410 415

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

420 425 430

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

435 440 445

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

450 455 460

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

465 470 475 480

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

485 490 495

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu

500 505

<210> 8

<211> 514

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-CD123 No. 8

<400> 8

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Ser Gly Gly Gly Gly Ser Gly Gln Ile Gln Leu Val Gln

35 40 45

Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys

50 55 60

Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys

65 70 75 80

Gln Ala Pro Gly Lys Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr

85 90 95

Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe

100 105 110

Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu

115 120 125

Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr

130 135 140

Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser

145 150 155 160

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp

165 170 175

Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln

180 185 190

Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly

195 200 205

Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys

210 215 220

Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg

225 230 235 240

Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro

245 250 255

Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu

260 265 270

Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser

275 280 285

Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

290 295 300

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

305 310 315 320

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

325 330 335

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

340 345 350

Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr

355 360 365

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu

370 375 380

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu

385 390 395 400

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln

405 410 415

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

420 425 430

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

435 440 445

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

450 455 460

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

465 470 475 480

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

485 490 495

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

500 505 510

Arg Glu

<210> 9

<211> 523

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-CD123 No9

<400> 9

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser

35 40 45

Leu Cys Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys

50 55 60

Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe

65 70 75 80

Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe

85 90 95

Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser

100 105 110

Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser

115 120 125

Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr

130 135 140

Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly

145 150 155 160

Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

165 170 175

Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro

180 185 190

Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg

195 200 205

Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr

210 215 220

Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser

225 230 235 240

Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg

245 250 255

Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala

260 265 270

Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala

275 280 285

Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro Ala

290 295 300

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

305 310 315 320

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

325 330 335

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

340 345 350

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

355 360 365

Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

370 375 380

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

385 390 395 400

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

405 410 415

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

420 425 430

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

435 440 445

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

450 455 460

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

465 470 475 480

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

485 490 495

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

500 505 510

Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu

515 520

<210> 10

<211> 529

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-CD123 No. 10

<400> 10

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro

20 25 30

Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser

35 40 45

Leu Cys Ser Gly Gly Gly Gly Ser Gly Gln Ile Gln Leu Val Gln Ser

50 55 60

Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys

65 70 75 80

Ala Ser Gly Tyr Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln

85 90 95

Ala Pro Gly Lys Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr

100 105 110

Gly Glu Ser Thr Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser

115 120 125

Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys

130 135 140

Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp

145 150 155 160

Pro Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly

165 170 175

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile

180 185 190

Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg

195 200 205

Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn

210 215 220

Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu

225 230 235 240

Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe

245 250 255

Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val

260 265 270

Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp

275 280 285

Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp

290 295 300

Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile

305 310 315 320

Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala

325 330 335

Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr

340 345 350

Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu

355 360 365

Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile

370 375 380

Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp

385 390 395 400

Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

405 410 415

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

420 425 430

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

435 440 445

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

450 455 460

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

465 470 475 480

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

485 490 495

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

500 505 510

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

Glu

<210> 11

<211> 297

<212> PRT

<213> Homo sapiens

<400> 11

Met Thr Thr Pro Arg Asn Ser Val Asn Gly Thr Phe Pro Ala Glu Pro

1 5 10 15

Met Lys Gly Pro Ile Ala Met Gln Ser Gly Pro Lys Pro Leu Phe Arg

20 25 30

Arg Met Ser Ser Leu Val Gly Pro Thr Gln Ser Phe Phe Met Arg Glu

35 40 45

Ser Lys Thr Leu Gly Ala Val Gln Ile Met Asn Gly Leu Phe His Ile

50 55 60

Ala Leu Gly Gly Leu Leu Met Ile Pro Ala Gly Ile Tyr Ala Pro Ile

65 70 75 80

Cys Val Thr Val Trp Tyr Pro Leu Trp Gly Gly Ile Met Tyr Ile Ile

85 90 95

Ser Gly Ser Leu Leu Ala Ala Thr Glu Lys Asn Ser Arg Lys Cys Leu

100 105 110

Val Lys Gly Lys Met Ile Met Asn Ser Leu Ser Leu Phe Ala Ala Ile

115 120 125

Ser Gly Met Ile Leu Ser Ile Met Asp Ile Leu Asn Ile Lys Ile Ser

130 135 140

His Phe Leu Lys Met Glu Ser Leu Asn Phe Ile Arg Ala His Thr Pro

145 150 155 160

Tyr Ile Asn Ile Tyr Asn Cys Glu Pro Ala Asn Pro Ser Glu Lys Asn

165 170 175

Ser Pro Ser Thr Gln Tyr Cys Tyr Ser Ile Gln Ser Leu Phe Leu Gly

180 185 190

Ile Leu Ser Val Met Leu Ile Phe Ala Phe Phe Gln Glu Leu Val Ile

195 200 205

Ala Gly Ile Val Glu Asn Glu Trp Lys Arg Thr Cys Ser Arg Pro Lys

210 215 220

Ser Asn Ile Val Leu Leu Ser Ala Glu Glu Lys Lys Glu Gln Thr Ile

225 230 235 240

Glu Ile Lys Glu Glu Val Val Gly Leu Thr Glu Thr Ser Ser Gln Pro

245 250 255

Lys Asn Glu Glu Asp Ile Glu Ile Ile Pro Ile Gln Glu Glu Glu Glu

260 265 270

Glu Glu Thr Glu Thr Asn Phe Pro Glu Pro Pro Gln Asp Gln Glu Ser

275 280 285

Ser Pro Ile Glu Asn Asp Ser Ser Pro

290 295

<210> 12

<211> 207

<212> PRT

<213> Homo sapiens

<400> 12

Met Gln Ser Gly Thr His Trp Arg Val Leu Gly Leu Cys Leu Leu Ser

1 5 10 15

Val Gly Val Trp Gly Gln Asp Gly Asn Glu Glu Met Gly Gly Ile Thr

20 25 30

Gln Thr Pro Tyr Lys Val Ser Ile Ser Gly Thr Thr Val Ile Leu Thr

35 40 45

Cys Pro Gln Tyr Pro Gly Ser Glu Ile Leu Trp Gln His Asn Asp Lys

50 55 60

Asn Ile Gly Gly Asp Glu Asp Asp Lys Asn Ile Gly Ser Asp Glu Asp

65 70 75 80

His Leu Ser Leu Lys Glu Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr

85 90 95

Val Cys Tyr Pro Arg Gly Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu

100 105 110

Tyr Leu Arg Ala Arg Val Cys Glu Asn Cys Met Glu Met Asp Val Met

115 120 125

Ser Val Ala Thr Ile Val Ile Val Asp Ile Cys Ile Thr Gly Gly Leu

130 135 140

Leu Leu Leu Val Tyr Tyr Trp Ser Lys Asn Arg Lys Ala Lys Ala Lys

145 150 155 160

Pro Val Thr Arg Gly Ala Gly Ala Gly Gly Arg Gln Arg Gly Gln Asn

165 170 175

Lys Glu Arg Pro Pro Pro Val Pro Asn Pro Asp Tyr Glu Pro Ile Arg

180 185 190

Lys Gly Gln Arg Asp Leu Tyr Ser Gly Leu Asn Gln Arg Arg Ile

195 200 205

<210> 13

<211> 1039

<212> PRT

<213> Homo sapiens

<400> 13

Met Ala Arg Ala Leu Cys Pro Leu Gln Ala Leu Trp Leu Leu Glu Trp

1 5 10 15

Val Leu Leu Leu Leu Gly Pro Cys Ala Ala Pro Pro Ala Trp Ala Leu

20 25 30

Asn Leu Asp Pro Val Gln Leu Thr Phe Tyr Ala Gly Pro Asn Gly Ser

35 40 45

Gln Phe Gly Phe Ser Leu Asp Phe His Lys Asp Ser His Gly Arg Val

50 55 60

Ala Ile Val Val Gly Ala Pro Arg Thr Leu Gly Pro Ser Gln Glu Glu

65 70 75 80

Thr Gly Gly Val Phe Leu Cys Pro Trp Arg Ala Glu Gly Gly Gln Cys

85 90 95

Pro Ser Leu Leu Phe Asp Leu Arg Asp Glu Thr Arg Asn Val Gly Ser

100 105 110

Gln Thr Leu Gln Thr Phe Lys Ala Arg Gln Gly Leu Gly Ala Ser Val

115 120 125

Val Ser Trp Ser Asp Val Ile Val Ala Cys Ala Pro Trp Gln His Trp

130 135 140

Asn Val Leu Glu Lys Thr Glu Glu Ala Glu Lys Thr Pro Val Gly Ser

145 150 155 160

Cys Phe Leu Ala Gln Pro Glu Ser Gly Arg Arg Ala Glu Tyr Ser Pro

165 170 175

Cys Arg Gly Asn Thr Leu Ser Arg Ile Tyr Val Glu Asn Asp Phe Ser

180 185 190

Trp Asp Lys Arg Tyr Cys Glu Ala Gly Phe Ser Ser Val Val Thr Gln

195 200 205

Ala Gly Glu Leu Val Leu Gly Ala Pro Gly Gly Tyr Tyr Phe Leu Gly

210 215 220

Leu Leu Ala Gln Ala Pro Val Ala Asp Ile Phe Ser Ser Tyr Arg Pro

225 230 235 240

Gly Ile Leu Leu Trp His Val Ser Ser Gln Ser Leu Ser Phe Asp Ser

245 250 255

Ser Asn Pro Glu Tyr Phe Asp Gly Tyr Trp Gly Tyr Ser Val Ala Val

260 265 270

Gly Glu Phe Asp Gly Asp Leu Asn Thr Thr Glu Tyr Val Val Gly Ala

275 280 285

Pro Thr Trp Ser Trp Thr Leu Gly Ala Val Glu Ile Leu Asp Ser Tyr

290 295 300

Tyr Gln Arg Leu His Arg Leu Arg Gly Glu Gln Met Ala Ser Tyr Phe

305 310 315 320

Gly His Ser Val Ala Val Thr Asp Val Asn Gly Asp Gly Arg His Asp

325 330 335

Leu Leu Val Gly Ala Pro Leu Tyr Met Glu Ser Arg Ala Asp Arg Lys

340 345 350

Leu Ala Glu Val Gly Arg Val Tyr Leu Phe Leu Gln Pro Arg Gly Pro

355 360 365

His Ala Leu Gly Ala Pro Ser Leu Leu Leu Thr Gly Thr Gln Leu Tyr

370 375 380

Gly Arg Phe Gly Ser Ala Ile Ala Pro Leu Gly Asp Leu Asp Arg Asp

385 390 395 400

Gly Tyr Asn Asp Ile Ala Val Ala Ala Pro Tyr Gly Gly Pro Ser Gly

405 410 415

Arg Gly Gln Val Leu Val Phe Leu Gly Gln Ser Glu Gly Leu Arg Ser

420 425 430

Arg Pro Ser Gln Val Leu Asp Ser Pro Phe Pro Thr Gly Ser Ala Phe

435 440 445

Gly Phe Ser Leu Arg Gly Ala Val Asp Ile Asp Asp Asn Gly Tyr Pro

450 455 460

Asp Leu Ile Val Gly Ala Tyr Gly Ala Asn Gln Val Ala Val Tyr Arg

465 470 475 480

Ala Gln Pro Val Val Lys Ala Ser Val Gln Leu Leu Val Gln Asp Ser

485 490 495

Leu Asn Pro Ala Val Lys Ser Cys Val Leu Pro Gln Thr Lys Thr Pro

500 505 510

Val Ser Cys Phe Asn Ile Gln Met Cys Val Gly Ala Thr Gly His Asn

515 520 525

Ile Pro Gln Lys Leu Ser Leu Asn Ala Glu Leu Gln Leu Asp Arg Gln

530 535 540

Lys Pro Arg Gln Gly Arg Arg Val Leu Leu Leu Gly Ser Gln Gln Ala

545 550 555 560

Gly Thr Thr Leu Asn Leu Asp Leu Gly Gly Lys His Ser Pro Ile Cys

565 570 575

His Thr Thr Met Ala Phe Leu Arg Asp Glu Ala Asp Phe Arg Asp Lys

580 585 590

Leu Ser Pro Ile Val Leu Ser Leu Asn Val Ser Leu Pro Pro Thr Glu

595 600 605

Ala Gly Met Ala Pro Ala Val Val Leu His Gly Asp Thr His Val Gln

610 615 620

Glu Gln Thr Arg Ile Val Leu Asp Cys Gly Glu Asp Asp Val Cys Val

625 630 635 640

Pro Gln Leu Gln Leu Thr Ala Ser Val Thr Gly Ser Pro Leu Leu Val

645 650 655

Gly Ala Asp Asn Val Leu Glu Leu Gln Met Asp Ala Ala Asn Glu Gly

660 665 670

Glu Gly Ala Tyr Glu Ala Glu Leu Ala Val His Leu Pro Gln Gly Ala

675 680 685

His Tyr Met Arg Ala Leu Ser Asn Val Glu Gly Phe Glu Arg Leu Ile

690 695 700

Cys Asn Gln Lys Lys Glu Asn Glu Thr Arg Val Val Leu Cys Glu Leu

705 710 715 720

Gly Asn Pro Met Lys Lys Asn Ala Gln Ile Gly Ile Ala Met Leu Val

725 730 735

Ser Val Gly Asn Leu Glu Glu Ala Gly Glu Ser Val Ser Phe Gln Leu

740 745 750

Gln Ile Arg Ser Lys Asn Ser Gln Asn Pro Asn Ser Lys Ile Val Leu

755 760 765

Leu Asp Val Pro Val Arg Ala Glu Ala Gln Val Glu Leu Arg Gly Asn

770 775 780

Ser Phe Pro Ala Ser Leu Val Val Ala Ala Glu Glu Gly Glu Arg Glu

785 790 795 800

Gln Asn Ser Leu Asp Ser Trp Gly Pro Lys Val Glu His Thr Tyr Glu

805 810 815

Leu His Asn Asn Gly Pro Gly Thr Val Asn Gly Leu His Leu Ser Ile

820 825 830

His Leu Pro Gly Gln Ser Gln Pro Ser Asp Leu Leu Tyr Ile Leu Asp

835 840 845

Ile Gln Pro Gln Gly Gly Leu Gln Cys Phe Pro Gln Pro Pro Val Asn

850 855 860

Pro Leu Lys Val Asp Trp Gly Leu Pro Ile Pro Ser Pro Ser Pro Ile

865 870 875 880

His Pro Ala His His Lys Arg Asp Arg Arg Gln Ile Phe Leu Pro Glu

885 890 895

Pro Glu Gln Pro Ser Arg Leu Gln Asp Pro Val Leu Val Ser Cys Asp

900 905 910

Ser Ala Pro Cys Thr Val Val Gln Cys Asp Leu Gln Glu Met Ala Arg

915 920 925

Gly Gln Arg Ala Met Val Thr Val Leu Ala Phe Leu Trp Leu Pro Ser

930 935 940

Leu Tyr Gln Arg Pro Leu Asp Gln Phe Val Leu Gln Ser His Ala Trp

945 950 955 960

Phe Asn Val Ser Ser Leu Pro Tyr Ala Val Pro Pro Leu Ser Leu Pro

965 970 975

Arg Gly Glu Ala Gln Val Trp Thr Gln Leu Leu Arg Ala Leu Glu Glu

980 985 990

Arg Ala Ile Pro Ile Trp Trp Val Leu Val Gly Val Leu Gly Gly Leu

995 1000 1005

Leu Leu Leu Thr Ile Leu Val Leu Ala Met Trp Lys Val Gly Phe

1010 1015 1020

Phe Lys Arg Asn Arg Pro Pro Leu Glu Glu Asp Asp Glu Glu Gly

1025 1030 1035

Glu

<210> 14

<211> 272

<212> PRT

<213> Homo sapiens

<400> 14

Met Asp Ser Tyr Leu Leu Met Trp Gly Leu Leu Thr Phe Ile Met Val

1 5 10 15

Pro Gly Cys Gln Ala Glu Leu Cys Asp Asp Asp Pro Pro Glu Ile Pro

20 25 30

His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr Met Leu Asn

35 40 45

Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly Ser Leu Tyr

50 55 60

Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp Asn Gln Cys

65 70 75 80

Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln Val Thr Pro

85 90 95

Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met Gln Ser Pro

100 105 110

Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys Arg Glu Pro

115 120 125

Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His Phe Val Val

130 135 140

Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg Ala Leu His

145 150 155 160

Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly Lys Thr Arg

165 170 175

Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu Thr Ser Gln

180 185 190

Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly Arg Pro Glu

195 200 205

Ser Glu Thr Ser Cys Leu Val Thr Thr Thr Asp Phe Gln Ile Gln Thr

210 215 220

Glu Met Ala Ala Thr Met Glu Thr Ser Ile Phe Thr Thr Glu Tyr Gln

225 230 235 240

Val Ala Val Ala Gly Cys Val Phe Leu Leu Ile Ser Val Leu Leu Leu

245 250 255

Ser Gly Leu Thr Trp Gln Arg Arg Gln Arg Lys Ser Arg Arg Thr Ile

260 265 270

<210> 15

<211> 595

<212> PRT

<213> Homo sapiens

<400> 15

Met Arg Val Leu Leu Ala Ala Leu Gly Leu Leu Phe Leu Gly Ala Leu

1 5 10 15

Arg Ala Phe Pro Gln Asp Arg Pro Phe Glu Asp Thr Cys His Gly Asn

20 25 30

Pro Ser His Tyr Tyr Asp Lys Ala Val Arg Arg Cys Cys Tyr Arg Cys

35 40 45

Pro Met Gly Leu Phe Pro Thr Gln Gln Cys Pro Gln Arg Pro Thr Asp

50 55 60

Cys Arg Lys Gln Cys Glu Pro Asp Tyr Tyr Leu Asp Glu Ala Asp Arg

65 70 75 80

Cys Thr Ala Cys Val Thr Cys Ser Arg Asp Asp Leu Val Glu Lys Thr

85 90 95

Pro Cys Ala Trp Asn Ser Ser Arg Val Cys Glu Cys Arg Pro Gly Met

100 105 110

Phe Cys Ser Thr Ser Ala Val Asn Ser Cys Ala Arg Cys Phe Phe His

115 120 125

Ser Val Cys Pro Ala Gly Met Ile Val Lys Phe Pro Gly Thr Ala Gln

130 135 140

Lys Asn Thr Val Cys Glu Pro Ala Ser Pro Gly Val Ser Pro Ala Cys

145 150 155 160

Ala Ser Pro Glu Asn Cys Lys Glu Pro Ser Ser Gly Thr Ile Pro Gln

165 170 175

Ala Lys Pro Thr Pro Val Ser Pro Ala Thr Ser Ser Ala Ser Thr Met

180 185 190

Pro Val Arg Gly Gly Thr Arg Leu Ala Gln Glu Ala Ala Ser Lys Leu

195 200 205

Thr Arg Ala Pro Asp Ser Pro Ser Ser Val Gly Arg Pro Ser Ser Asp

210 215 220

Pro Gly Leu Ser Pro Thr Gln Pro Cys Pro Glu Gly Ser Gly Asp Cys

225 230 235 240

Arg Lys Gln Cys Glu Pro Asp Tyr Tyr Leu Asp Glu Ala Gly Arg Cys

245 250 255

Thr Ala Cys Val Ser Cys Ser Arg Asp Asp Leu Val Glu Lys Thr Pro

260 265 270

Cys Ala Trp Asn Ser Ser Arg Thr Cys Glu Cys Arg Pro Gly Met Ile

275 280 285

Cys Ala Thr Ser Ala Thr Asn Ser Cys Ala Arg Cys Val Pro Tyr Pro

290 295 300

Ile Cys Ala Ala Glu Thr Val Thr Lys Pro Gln Asp Met Ala Glu Lys

305 310 315 320

Asp Thr Thr Phe Glu Ala Pro Pro Leu Gly Thr Gln Pro Asp Cys Asn

325 330 335

Pro Thr Pro Glu Asn Gly Glu Ala Pro Ala Ser Thr Ser Pro Thr Gln

340 345 350

Ser Leu Leu Val Asp Ser Gln Ala Ser Lys Thr Leu Pro Ile Pro Thr

355 360 365

Ser Ala Pro Val Ala Leu Ser Ser Thr Gly Lys Pro Val Leu Asp Ala

370 375 380

Gly Pro Val Leu Phe Trp Val Ile Leu Val Leu Val Val Val Val Gly

385 390 395 400

Ser Ser Ala Phe Leu Leu Cys His Arg Arg Ala Cys Arg Lys Arg Ile

405 410 415

Arg Gln Lys Leu His Leu Cys Tyr Pro Val Gln Thr Ser Gln Pro Lys

420 425 430

Leu Glu Leu Val Asp Ser Arg Pro Arg Arg Ser Ser Thr Gln Leu Arg

435 440 445

Ser Gly Ala Ser Val Thr Glu Pro Val Ala Glu Glu Arg Gly Leu Met

450 455 460

Ser Gln Pro Leu Met Glu Thr Cys His Ser Val Gly Ala Ala Tyr Leu

465 470 475 480

Glu Ser Leu Pro Leu Gln Asp Ala Ser Pro Ala Gly Gly Pro Ser Ser

485 490 495

Pro Arg Asp Leu Pro Glu Pro Arg Val Ser Thr Glu His Thr Asn Asn

500 505 510

Lys Ile Glu Lys Ile Tyr Ile Met Lys Ala Asp Thr Val Ile Val Gly

515 520 525

Thr Val Lys Ala Glu Leu Pro Glu Gly Arg Gly Leu Ala Gly Pro Ala

530 535 540

Glu Pro Glu Leu Glu Glu Glu Leu Glu Ala Asp His Thr Pro His Tyr

545 550 555 560

Pro Glu Gln Glu Thr Glu Pro Pro Leu Gly Ser Cys Ser Asp Val Met

565 570 575

Leu Ser Val Glu Glu Glu Gly Lys Glu Asp Pro Leu Pro Thr Ala Ala

580 585 590

Ser Gly Lys

595

<210> 16

<211> 1091

<212> PRT

<213> Homo sapiens

<400> 16

Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala

1 5 10 15

Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Val Cys Gln

20 25 30

Gly Thr Ser Asn Lys Leu Thr Gln Leu Gly Thr Phe Glu Asp His Phe

35 40 45

Leu Ser Leu Gln Arg Met Phe Asn Asn Cys Glu Val Val Leu Gly Asn

50 55 60

Leu Glu Ile Thr Tyr Val Gln Arg Asn Tyr Asp Leu Ser Phe Leu Lys

65 70 75 80

Thr Ile Gln Glu Val Ala Gly Tyr Val Leu Ile Ala Leu Asn Thr Val

85 90 95

Glu Arg Ile Pro Leu Glu Asn Leu Gln Ile Ile Arg Gly Asn Met Tyr

100 105 110

Tyr Glu Asn Ser Tyr Ala Leu Ala Val Leu Ser Asn Tyr Asp Ala Asn

115 120 125

Lys Thr Gly Leu Lys Glu Leu Pro Met Arg Asn Leu Gln Gly Gln Lys

130 135 140

Cys Asp Pro Ser Cys Pro Asn Gly Ser Cys Trp Gly Ala Gly Glu Glu

145 150 155 160

Asn Cys Gln Lys Leu Thr Lys Ile Ile Cys Ala Gln Gln Cys Ser Gly

165 170 175

Arg Cys Arg Gly Lys Ser Pro Ser Asp Cys Cys His Asn Gln Cys Ala

180 185 190

Ala Gly Cys Thr Gly Pro Arg Glu Ser Asp Cys Leu Val Cys Arg Lys

195 200 205

Phe Arg Asp Glu Ala Thr Cys Lys Asp Thr Cys Pro Pro Leu Met Leu

210 215 220

Tyr Asn Pro Thr Thr Tyr Gln Met Asp Val Asn Pro Glu Gly Lys Tyr

225 230 235 240

Ser Phe Gly Ala Thr Cys Val Lys Lys Cys Pro Arg Asn Tyr Val Val

245 250 255

Thr Asp His Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser Tyr Glu

260 265 270

Met Glu Glu Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly Pro Cys

275 280 285

Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp Ser Leu

290 295 300

Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr Ser Ile

305 310 315 320

Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp Ser Phe

325 330 335

Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu Lys Thr

340 345 350

Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro Glu Asn

355 360 365

Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg Gly Arg

370 375 380

Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val Val Ser Leu Asn Ile

385 390 395 400

Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly Asp Val

405 410 415

Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile Asn Trp

420 425 430

Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile Ser Asn

435 440 445

Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His Ala Leu

450 455 460

Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys Val Ser

465 470 475 480

Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys Asn Leu

485 490 495

Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys Ile Gln

500 505 510

Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys Thr Gly

515 520 525

Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp Gly Pro

530 535 540

His Cys Val Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn Asn Thr

545 550 555 560

Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val Cys His Leu Cys His

565 570 575

Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly Cys Pro

580 585 590

Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val Gly Ala

595 600 605

Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe Met Arg

610 615 620

Arg Arg His Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu Gln Glu

625 630 635 640

Arg Glu Leu Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro Asn Gln

645 650 655

Ala Leu Leu Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile Lys Val

660 665 670

Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp Ile Pro

675 680 685

Glu Gly Glu Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu Arg Glu

690 695 700

Ala Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala Tyr Val

705 710 715 720

Met Ala Ser Val Asp Asn Pro His Val Cys Arg Leu Leu Gly Ile Cys

725 730 735

Leu Thr Ser Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe Gly Cys

740 745 750

Leu Leu Asp Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser Gln Tyr

755 760 765

Leu Leu Asn Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr Leu Glu

770 775 780

Asp Arg Arg Leu Val His Arg Asp Leu Ala Ala Arg Asn Val Leu Val

785 790 795 800

Lys Thr Pro Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala Lys Leu

805 810 815

Leu Gly Ala Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys Val Pro

820 825 830

Ile Lys Trp Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr Thr His

835 840 845

Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu Met Thr

850 855 860

Phe Gly Ser Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile Ser Ser

865 870 875 880

Ile Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys Thr Ile

885 890 895

Asp Val Tyr Met Ile Met Val Lys Cys Trp Met Ile Asp Ala Asp Ser

900 905 910

Arg Pro Lys Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met Ala Arg

915 920 925

Asp Pro Gln Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met His Leu

930 935 940

Pro Ser Pro Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp Glu Glu

945 950 955 960

Asp Met Asp Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro Gln Gln

965 970 975

Gly Phe Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu Ser Ser

980 985 990

Leu Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp Arg Asn

995 1000 1005

Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln Arg

1010 1015 1020

Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp

1025 1030 1035

Asp Thr Phe Leu Pro Val Pro Gly Glu Trp Leu Val Trp Lys Gln

1040 1045 1050

Ser Cys Ser Ser Thr Ser Ser Thr His Ser Ala Ala Ala Ser Leu

1055 1060 1065

Gln Cys Pro Ser Gln Val Leu Pro Pro Ala Ser Pro Glu Gly Glu

1070 1075 1080

Thr Val Ala Asp Leu Gln Thr Gln

1085 1090

<210> 17

<211> 233

<212> PRT

<213> Homo sapiens

<400> 17

Met Ser Thr Glu Ser Met Ile Arg Asp Val Glu Leu Ala Glu Glu Ala

1 5 10 15

Leu Pro Lys Lys Thr Gly Gly Pro Gln Gly Ser Arg Arg Cys Leu Phe

20 25 30

Leu Ser Leu Phe Ser Phe Leu Ile Val Ala Gly Ala Thr Thr Leu Phe

35 40 45

Cys Leu Leu His Phe Gly Val Ile Gly Pro Gln Arg Glu Glu Phe Pro

50 55 60

Arg Asp Leu Ser Leu Ile Ser Pro Leu Ala Gln Ala Val Arg Ser Ser

65 70 75 80

Ser Arg Thr Pro Ser Asp Lys Pro Val Ala His Val Val Ala Asn Pro

85 90 95

Gln Ala Glu Gly Gln Leu Gln Trp Leu Asn Arg Arg Ala Asn Ala Leu

100 105 110

Leu Ala Asn Gly Val Glu Leu Arg Asp Asn Gln Leu Val Val Pro Ser

115 120 125

Glu Gly Leu Tyr Leu Ile Tyr Ser Gln Val Leu Phe Lys Gly Gln Gly

130 135 140

Cys Pro Ser Thr His Val Leu Leu Thr His Thr Ile Ser Arg Ile Ala

145 150 155 160

Val Ser Tyr Gln Thr Lys Val Asn Leu Leu Ser Ala Ile Lys Ser Pro

165 170 175

Cys Gln Arg Glu Thr Pro Glu Gly Ala Glu Ala Lys Pro Trp Tyr Glu

180 185 190

Pro Ile Tyr Leu Gly Gly Val Phe Gln Leu Glu Lys Gly Asp Arg Leu

195 200 205

Ser Ala Glu Ile Asn Arg Pro Asp Tyr Leu Asp Phe Ala Glu Ser Gly

210 215 220

Gln Val Tyr Phe Gly Ile Ile Ala Leu

225 230

<210> 18

<211> 61

<212> PRT

<213> Homo sapiens

<400> 18

Met Lys Arg Phe Leu Phe Leu Leu Leu Thr Ile Ser Leu Leu Val Met

1 5 10 15

Val Gln Ile Gln Thr Gly Leu Ser Gly Gln Asn Asp Thr Ser Gln Thr

20 25 30

Ser Ser Pro Ser Ala Ser Ser Asn Ile Ser Gly Gly Ile Phe Leu Phe

35 40 45

Phe Val Ala Asn Ala Ile Ile His Leu Phe Cys Phe Ser

50 55 60

<210> 19

<211> 232

<212> PRT

<213> Homo sapiens

<400> 19

Met Asn Phe Leu Leu Ser Trp Val His Trp Ser Leu Ala Leu Leu Leu

1 5 10 15

Tyr Leu His His Ala Lys Trp Ser Gln Ala Ala Pro Met Ala Glu Gly

20 25 30

Gly Gly Gln Asn His His Glu Val Val Lys Phe Met Asp Val Tyr Gln

35 40 45

Arg Ser Tyr Cys His Pro Ile Glu Thr Leu Val Asp Ile Phe Gln Glu

50 55 60

Tyr Pro Asp Glu Ile Glu Tyr Ile Phe Lys Pro Ser Cys Val Pro Leu

65 70 75 80

Met Arg Cys Gly Gly Cys Cys Asn Asp Glu Gly Leu Glu Cys Val Pro

85 90 95

Thr Glu Glu Ser Asn Ile Thr Met Gln Ile Met Arg Ile Lys Pro His

100 105 110

Gln Gly Gln His Ile Gly Glu Met Ser Phe Leu Gln His Asn Lys Cys

115 120 125

Glu Cys Arg Pro Lys Lys Asp Arg Ala Arg Gln Glu Lys Lys Ser Val

130 135 140

Arg Gly Lys Gly Lys Gly Gln Lys Arg Lys Arg Lys Lys Ser Arg Tyr

145 150 155 160

Lys Ser Trp Ser Val Tyr Val Gly Ala Arg Cys Cys Leu Met Pro Trp

165 170 175

Ser Leu Pro Gly Pro His Pro Cys Gly Pro Cys Ser Glu Arg Arg Lys

180 185 190

His Leu Phe Val Gln Asp Pro Gln Thr Cys Lys Cys Ser Cys Lys Asn

195 200 205

Thr Asp Ser Arg Cys Lys Ala Arg Gln Leu Glu Leu Asn Glu Arg Thr

210 215 220

Cys Arg Cys Asp Lys Pro Arg Arg

225 230

<210> 20

<211> 1676

<212> PRT

<213> Homo sapiens

<400> 20

Met Gly Leu Leu Gly Ile Leu Cys Phe Leu Ile Phe Leu Gly Lys Thr

1 5 10 15

Trp Gly Gln Glu Gln Thr Tyr Val Ile Ser Ala Pro Lys Ile Phe Arg

20 25 30

Val Gly Ala Ser Glu Asn Ile Val Ile Gln Val Tyr Gly Tyr Thr Glu

35 40 45

Ala Phe Asp Ala Thr Ile Ser Ile Lys Ser Tyr Pro Asp Lys Lys Phe

50 55 60

Ser Tyr Ser Ser Gly His Val His Leu Ser Ser Glu Asn Lys Phe Gln

65 70 75 80

Asn Ser Ala Ile Leu Thr Ile Gln Pro Lys Gln Leu Pro Gly Gly Gln

85 90 95

Asn Pro Val Ser Tyr Val Tyr Leu Glu Val Val Ser Lys His Phe Ser

100 105 110

Lys Ser Lys Arg Met Pro Ile Thr Tyr Asp Asn Gly Phe Leu Phe Ile

115 120 125

His Thr Asp Lys Pro Val Tyr Thr Pro Asp Gln Ser Val Lys Val Arg

130 135 140

Val Tyr Ser Leu Asn Asp Asp Leu Lys Pro Ala Lys Arg Glu Thr Val

145 150 155 160

Leu Thr Phe Ile Asp Pro Glu Gly Ser Glu Val Asp Met Val Glu Glu

165 170 175

Ile Asp His Ile Gly Ile Ile Ser Phe Pro Asp Phe Lys Ile Pro Ser

180 185 190

Asn Pro Arg Tyr Gly Met Trp Thr Ile Lys Ala Lys Tyr Lys Glu Asp

195 200 205

Phe Ser Thr Thr Gly Thr Ala Tyr Phe Glu Val Lys Glu Tyr Val Leu

210 215 220

Pro His Phe Ser Val Ser Ile Glu Pro Glu Tyr Asn Phe Ile Gly Tyr

225 230 235 240

Lys Asn Phe Lys Asn Phe Glu Ile Thr Ile Lys Ala Arg Tyr Phe Tyr

245 250 255

Asn Lys Val Val Thr Glu Ala Asp Val Tyr Ile Thr Phe Gly Ile Arg

260 265 270

Glu Asp Leu Lys Asp Asp Gln Lys Glu Met Met Gln Thr Ala Met Gln

275 280 285

Asn Thr Met Leu Ile Asn Gly Ile Ala Gln Val Thr Phe Asp Ser Glu

290 295 300

Thr Ala Val Lys Glu Leu Ser Tyr Tyr Ser Leu Glu Asp Leu Asn Asn

305 310 315 320

Lys Tyr Leu Tyr Ile Ala Val Thr Val Ile Glu Ser Thr Gly Gly Phe

325 330 335

Ser Glu Glu Ala Glu Ile Pro Gly Ile Lys Tyr Val Leu Ser Pro Tyr

340 345 350

Lys Leu Asn Leu Val Ala Thr Pro Leu Phe Leu Lys Pro Gly Ile Pro

355 360 365

Tyr Pro Ile Lys Val Gln Val Lys Asp Ser Leu Asp Gln Leu Val Gly

370 375 380

Gly Val Pro Val Thr Leu Asn Ala Gln Thr Ile Asp Val Asn Gln Glu

385 390 395 400

Thr Ser Asp Leu Asp Pro Ser Lys Ser Val Thr Arg Val Asp Asp Gly

405 410 415

Val Ala Ser Phe Val Leu Asn Leu Pro Ser Gly Val Thr Val Leu Glu

420 425 430

Phe Asn Val Lys Thr Asp Ala Pro Asp Leu Pro Glu Glu Asn Gln Ala

435 440 445

Arg Glu Gly Tyr Arg Ala Ile Ala Tyr Ser Ser Leu Ser Gln Ser Tyr

450 455 460

Leu Tyr Ile Asp Trp Thr Asp Asn His Lys Ala Leu Leu Val Gly Glu

465 470 475 480

His Leu Asn Ile Ile Val Thr Pro Lys Ser Pro Tyr Ile Asp Lys Ile

485 490 495

Thr His Tyr Asn Tyr Leu Ile Leu Ser Lys Gly Lys Ile Ile His Phe

500 505 510

Gly Thr Arg Glu Lys Phe Ser Asp Ala Ser Tyr Gln Ser Ile Asn Ile

515 520 525

Pro Val Thr Gln Asn Met Val Pro Ser Ser Arg Leu Leu Val Tyr Tyr

530 535 540

Ile Val Thr Gly Glu Gln Thr Ala Glu Leu Val Ser Asp Ser Val Trp

545 550 555 560

Leu Asn Ile Glu Glu Lys Cys Gly Asn Gln Leu Gln Val His Leu Ser

565 570 575

Pro Asp Ala Asp Ala Tyr Ser Pro Gly Gln Thr Val Ser Leu Asn Met

580 585 590

Ala Thr Gly Met Asp Ser Trp Val Ala Leu Ala Ala Val Asp Ser Ala

595 600 605

Val Tyr Gly Val Gln Arg Gly Ala Lys Lys Pro Leu Glu Arg Val Phe

610 615 620

Gln Phe Leu Glu Lys Ser Asp Leu Gly Cys Gly Ala Gly Gly Gly Leu

625 630 635 640

Asn Asn Ala Asn Val Phe His Leu Ala Gly Leu Thr Phe Leu Thr Asn

645 650 655

Ala Asn Ala Asp Asp Ser Gln Glu Asn Asp Glu Pro Cys Lys Glu Ile

660 665 670

Leu Arg Pro Arg Arg Thr Leu Gln Lys Lys Ile Glu Glu Ile Ala Ala

675 680 685

Lys Tyr Lys His Ser Val Val Lys Lys Cys Cys Tyr Asp Gly Ala Cys

690 695 700

Val Asn Asn Asp Glu Thr Cys Glu Gln Arg Ala Ala Arg Ile Ser Leu

705 710 715 720

Gly Pro Arg Cys Ile Lys Ala Phe Thr Glu Cys Cys Val Val Ala Ser

725 730 735

Gln Leu Arg Ala Asn Ile Ser His Lys Asp Met Gln Leu Gly Arg Leu

740 745 750

His Met Lys Thr Leu Leu Pro Val Ser Lys Pro Glu Ile Arg Ser Tyr

755 760 765

Phe Pro Glu Ser Trp Leu Trp Glu Val His Leu Val Pro Arg Arg Lys

770 775 780

Gln Leu Gln Phe Ala Leu Pro Asp Ser Leu Thr Thr Trp Glu Ile Gln

785 790 795 800

Gly Val Gly Ile Ser Asn Thr Gly Ile Cys Val Ala Asp Thr Val Lys

805 810 815

Ala Lys Val Phe Lys Asp Val Phe Leu Glu Met Asn Ile Pro Tyr Ser

820 825 830

Val Val Arg Gly Glu Gln Ile Gln Leu Lys Gly Thr Val Tyr Asn Tyr

835 840 845

Arg Thr Ser Gly Met Gln Phe Cys Val Lys Met Ser Ala Val Glu Gly

850 855 860

Ile Cys Thr Ser Glu Ser Pro Val Ile Asp His Gln Gly Thr Lys Ser

865 870 875 880

Ser Lys Cys Val Arg Gln Lys Val Glu Gly Ser Ser Ser His Leu Val

885 890 895

Thr Phe Thr Val Leu Pro Leu Glu Ile Gly Leu His Asn Ile Asn Phe

900 905 910

Ser Leu Glu Thr Trp Phe Gly Lys Glu Ile Leu Val Lys Thr Leu Arg

915 920 925

Val Val Pro Glu Gly Val Lys Arg Glu Ser Tyr Ser Gly Val Thr Leu

930 935 940

Asp Pro Arg Gly Ile Tyr Gly Thr Ile Ser Arg Arg Lys Glu Phe Pro

945 950 955 960

Tyr Arg Ile Pro Leu Asp Leu Val Pro Lys Thr Glu Ile Lys Arg Ile

965 970 975

Leu Ser Val Lys Gly Leu Leu Val Gly Glu Ile Leu Ser Ala Val Leu

980 985 990

Ser Gln Glu Gly Ile Asn Ile Leu Thr His Leu Pro Lys Gly Ser Ala

995 1000 1005

Glu Ala Glu Leu Met Ser Val Val Pro Val Phe Tyr Val Phe His

1010 1015 1020

Tyr Leu Glu Thr Gly Asn His Trp Asn Ile Phe His Ser Asp Pro

1025 1030 1035

Leu Ile Glu Lys Gln Lys Leu Lys Lys Lys Leu Lys Glu Gly Met

1040 1045 1050

Leu Ser Ile Met Ser Tyr Arg Asn Ala Asp Tyr Ser Tyr Ser Val

1055 1060 1065

Trp Lys Gly Gly Ser Ala Ser Thr Trp Leu Thr Ala Phe Ala Leu

1070 1075 1080

Arg Val Leu Gly Gln Val Asn Lys Tyr Val Glu Gln Asn Gln Asn

1085 1090 1095

Ser Ile Cys Asn Ser Leu Leu Trp Leu Val Glu Asn Tyr Gln Leu

1100 1105 1110

Asp Asn Gly Ser Phe Lys Glu Asn Ser Gln Tyr Gln Pro Ile Lys

1115 1120 1125

Leu Gln Gly Thr Leu Pro Val Glu Ala Arg Glu Asn Ser Leu Tyr

1130 1135 1140

Leu Thr Ala Phe Thr Val Ile Gly Ile Arg Lys Ala Phe Asp Ile

1145 1150 1155

Cys Pro Leu Val Lys Ile Asp Thr Ala Leu Ile Lys Ala Asp Asn

1160 1165 1170

Phe Leu Leu Glu Asn Thr Leu Pro Ala Gln Ser Thr Phe Thr Leu

1175 1180 1185

Ala Ile Ser Ala Tyr Ala Leu Ser Leu Gly Asp Lys Thr His Pro

1190 1195 1200

Gln Phe Arg Ser Ile Val Ser Ala Leu Lys Arg Glu Ala Leu Val

1205 1210 1215

Lys Gly Asn Pro Pro Ile Tyr Arg Phe Trp Lys Asp Asn Leu Gln

1220 1225 1230

His Lys Asp Ser Ser Val Pro Asn Thr Gly Thr Ala Arg Met Val

1235 1240 1245

Glu Thr Thr Ala Tyr Ala Leu Leu Thr Ser Leu Asn Leu Lys Asp

1250 1255 1260

Ile Asn Tyr Val Asn Pro Val Ile Lys Trp Leu Ser Glu Glu Gln

1265 1270 1275

Arg Tyr Gly Gly Gly Phe Tyr Ser Thr Gln Asp Thr Ile Asn Ala

1280 1285 1290

Ile Glu Gly Leu Thr Glu Tyr Ser Leu Leu Val Lys Gln Leu Arg

1295 1300 1305

Leu Ser Met Asp Ile Asp Val Ser Tyr Lys His Lys Gly Ala Leu

1310 1315 1320

His Asn Tyr Lys Met Thr Asp Lys Asn Phe Leu Gly Arg Pro Val

1325 1330 1335

Glu Val Leu Leu Asn Asp Asp Leu Ile Val Ser Thr Gly Phe Gly

1340 1345 1350

Ser Gly Leu Ala Thr Val His Val Thr Thr Val Val His Lys Thr

1355 1360 1365

Ser Thr Ser Glu Glu Val Cys Ser Phe Tyr Leu Lys Ile Asp Thr

1370 1375 1380

Gln Asp Ile Glu Ala Ser His Tyr Arg Gly Tyr Gly Asn Ser Asp

1385 1390 1395

Tyr Lys Arg Ile Val Ala Cys Ala Ser Tyr Lys Pro Ser Arg Glu

1400 1405 1410

Glu Ser Ser Ser Gly Ser Ser His Ala Val Met Asp Ile Ser Leu

1415 1420 1425

Pro Thr Gly Ile Ser Ala Asn Glu Glu Asp Leu Lys Ala Leu Val

1430 1435 1440

Glu Gly Val Asp Gln Leu Phe Thr Asp Tyr Gln Ile Lys Asp Gly

1445 1450 1455

His Val Ile Leu Gln Leu Asn Ser Ile Pro Ser Ser Asp Phe Leu

1460 1465 1470

Cys Val Arg Phe Arg Ile Phe Glu Leu Phe Glu Val Gly Phe Leu

1475 1480 1485

Ser Pro Ala Thr Phe Thr Val Tyr Glu Tyr His Arg Pro Asp Lys

1490 1495 1500

Gln Cys Thr Met Phe Tyr Ser Thr Ser Asn Ile Lys Ile Gln Lys

1505 1510 1515

Val Cys Glu Gly Ala Ala Cys Lys Cys Val Glu Ala Asp Cys Gly

1520 1525 1530

Gln Met Gln Glu Glu Leu Asp Leu Thr Ile Ser Ala Glu Thr Arg

1535 1540 1545

Lys Gln Thr Ala Cys Lys Pro Glu Ile Ala Tyr Ala Tyr Lys Val

1550 1555 1560

Ser Ile Thr Ser Ile Thr Val Glu Asn Val Phe Val Lys Tyr Lys

1565 1570 1575

Ala Thr Leu Leu Asp Ile Tyr Lys Thr Gly Glu Ala Val Ala Glu

1580 1585 1590

Lys Asp Ser Glu Ile Thr Phe Ile Lys Lys Val Thr Cys Thr Asn

1595 1600 1605

Ala Glu Leu Val Lys Gly Arg Gln Tyr Leu Ile Met Gly Lys Glu

1610 1615 1620

Ala Leu Gln Ile Lys Tyr Asn Phe Ser Phe Arg Tyr Ile Tyr Pro

1625 1630 1635

Leu Asp Ser Leu Thr Trp Ile Glu Tyr Trp Pro Arg Asp Thr Thr

1640 1645 1650

Cys Ser Ser Cys Gln Ala Phe Leu Ala Asn Leu Asp Glu Phe Ala

1655 1660 1665

Glu Asp Ile Phe Leu Asn Gly Cys

1670 1675

<210> 21

<211> 1170

<212> PRT

<213> Homo sapiens

<400> 21

Met Lys Asp Ser Cys Ile Thr Val Met Ala Met Ala Leu Leu Ser Gly

1 5 10 15

Phe Phe Phe Phe Ala Pro Ala Ser Ser Tyr Asn Leu Asp Val Arg Gly

20 25 30

Ala Arg Ser Phe Ser Pro Pro Arg Ala Gly Arg His Phe Gly Tyr Arg

35 40 45

Val Leu Gln Val Gly Asn Gly Val Ile Val Gly Ala Pro Gly Glu Gly

50 55 60

Asn Ser Thr Gly Ser Leu Tyr Gln Cys Gln Ser Gly Thr Gly His Cys

65 70 75 80

Leu Pro Val Thr Leu Arg Gly Ser Asn Tyr Thr Ser Lys Tyr Leu Gly

85 90 95

Met Thr Leu Ala Thr Asp Pro Thr Asp Gly Ser Ile Leu Ala Cys Asp

100 105 110

Pro Gly Leu Ser Arg Thr Cys Asp Gln Asn Thr Tyr Leu Ser Gly Leu

115 120 125

Cys Tyr Leu Phe Arg Gln Asn Leu Gln Gly Pro Met Leu Gln Gly Arg

130 135 140

Pro Gly Phe Gln Glu Cys Ile Lys Gly Asn Val Asp Leu Val Phe Leu

145 150 155 160

Phe Asp Gly Ser Met Ser Leu Gln Pro Asp Glu Phe Gln Lys Ile Leu

165 170 175

Asp Phe Met Lys Asp Val Met Lys Lys Leu Ser Asn Thr Ser Tyr Gln

180 185 190

Phe Ala Ala Val Gln Phe Ser Thr Ser Tyr Lys Thr Glu Phe Asp Phe

195 200 205

Ser Asp Tyr Val Lys Arg Lys Asp Pro Asp Ala Leu Leu Lys His Val

210 215 220

Lys His Met Leu Leu Leu Thr Asn Thr Phe Gly Ala Ile Asn Tyr Val

225 230 235 240

Ala Thr Glu Val Phe Arg Glu Glu Leu Gly Ala Arg Pro Asp Ala Thr

245 250 255

Lys Val Leu Ile Ile Ile Thr Asp Gly Glu Ala Thr Asp Ser Gly Asn

260 265 270

Ile Asp Ala Ala Lys Asp Ile Ile Arg Tyr Ile Ile Gly Ile Gly Lys

275 280 285

His Phe Gln Thr Lys Glu Ser Gln Glu Thr Leu His Lys Phe Ala Ser

290 295 300

Lys Pro Ala Ser Glu Phe Val Lys Ile Leu Asp Thr Phe Glu Lys Leu

305 310 315 320

Lys Asp Leu Phe Thr Glu Leu Gln Lys Lys Ile Tyr Val Ile Glu Gly

325 330 335

Thr Ser Lys Gln Asp Leu Thr Ser Phe Asn Met Glu Leu Ser Ser Ser

340 345 350

Gly Ile Ser Ala Asp Leu Ser Arg Gly His Ala Val Val Gly Ala Val

355 360 365

Gly Ala Lys Asp Trp Ala Gly Gly Phe Leu Asp Leu Lys Ala Asp Leu

370 375 380

Gln Asp Asp Thr Phe Ile Gly Asn Glu Pro Leu Thr Pro Glu Val Arg

385 390 395 400

Ala Gly Tyr Leu Gly Tyr Thr Val Thr Trp Leu Pro Ser Arg Gln Lys

405 410 415

Thr Ser Leu Leu Ala Ser Gly Ala Pro Arg Tyr Gln His Met Gly Arg

420 425 430

Val Leu Leu Phe Gln Glu Pro Gln Gly Gly Gly His Trp Ser Gln Val

435 440 445

Gln Thr Ile His Gly Thr Gln Ile Gly Ser Tyr Phe Gly Gly Glu Leu

450 455 460

Cys Gly Val Asp Val Asp Gln Asp Gly Glu Thr Glu Leu Leu Leu Ile

465 470 475 480

Gly Ala Pro Leu Phe Tyr Gly Glu Gln Arg Gly Gly Arg Val Phe Ile

485 490 495

Tyr Gln Arg Arg Gln Leu Gly Phe Glu Glu Val Ser Glu Leu Gln Gly

500 505 510

Asp Pro Gly Tyr Pro Leu Gly Arg Phe Gly Glu Ala Ile Thr Ala Leu

515 520 525

Thr Asp Ile Asn Gly Asp Gly Leu Val Asp Val Ala Val Gly Ala Pro

530 535 540

Leu Glu Glu Gln Gly Ala Val Tyr Ile Phe Asn Gly Arg His Gly Gly

545 550 555 560

Leu Ser Pro Gln Pro Ser Gln Arg Ile Glu Gly Thr Gln Val Leu Ser

565 570 575

Gly Ile Gln Trp Phe Gly Arg Ser Ile His Gly Val Lys Asp Leu Glu

580 585 590

Gly Asp Gly Leu Ala Asp Val Ala Val Gly Ala Glu Ser Gln Met Ile

595 600 605

Val Leu Ser Ser Arg Pro Val Val Asp Met Val Thr Leu Met Ser Phe

610 615 620

Ser Pro Ala Glu Ile Pro Val His Glu Val Glu Cys Ser Tyr Ser Thr

625 630 635 640

Ser Asn Lys Met Lys Glu Gly Val Asn Ile Thr Ile Cys Phe Gln Ile

645 650 655

Lys Ser Leu Ile Pro Gln Phe Gln Gly Arg Leu Val Ala Asn Leu Thr

660 665 670

Tyr Thr Leu Gln Leu Asp Gly His Arg Thr Arg Arg Arg Gly Leu Phe

675 680 685

Pro Gly Gly Arg His Glu Leu Arg Arg Asn Ile Ala Val Thr Thr Ser

690 695 700

Met Ser Cys Thr Asp Phe Ser Phe His Phe Pro Val Cys Val Gln Asp

705 710 715 720

Leu Ile Ser Pro Ile Asn Val Ser Leu Asn Phe Ser Leu Trp Glu Glu

725 730 735

Glu Gly Thr Pro Arg Asp Gln Arg Ala Gln Gly Lys Asp Ile Pro Pro

740 745 750

Ile Leu Arg Pro Ser Leu His Ser Glu Thr Trp Glu Ile Pro Phe Glu

755 760 765

Lys Asn Cys Gly Glu Asp Lys Lys Cys Glu Ala Asn Leu Arg Val Ser

770 775 780

Phe Ser Pro Ala Arg Ser Arg Ala Leu Arg Leu Thr Ala Phe Ala Ser

785 790 795 800

Leu Ser Val Glu Leu Ser Leu Ser Asn Leu Glu Glu Asp Ala Tyr Trp

805 810 815

Val Gln Leu Asp Leu His Phe Pro Pro Gly Leu Ser Phe Arg Lys Val

820 825 830

Glu Met Leu Lys Pro His Ser Gln Ile Pro Val Ser Cys Glu Glu Leu

835 840 845

Pro Glu Glu Ser Arg Leu Leu Ser Arg Ala Leu Ser Cys Asn Val Ser

850 855 860

Ser Pro Ile Phe Lys Ala Gly His Ser Val Ala Leu Gln Met Met Phe

865 870 875 880

Asn Thr Leu Val Asn Ser Ser Trp Gly Asp Ser Val Glu Leu His Ala

885 890 895

Asn Val Thr Cys Asn Asn Glu Asp Ser Asp Leu Leu Glu Asp Asn Ser

900 905 910

Ala Thr Thr Ile Ile Pro Ile Leu Tyr Pro Ile Asn Ile Leu Ile Gln

915 920 925

Asp Gln Glu Asp Ser Thr Leu Tyr Val Ser Phe Thr Pro Lys Gly Pro

930 935 940

Lys Ile His Gln Val Lys His Met Tyr Gln Val Arg Ile Gln Pro Ser

945 950 955 960

Ile His Asp His Asn Ile Pro Thr Leu Glu Ala Val Val Gly Val Pro

965 970 975

Gln Pro Pro Ser Glu Gly Pro Ile Thr His Gln Trp Ser Val Gln Met

980 985 990

Glu Pro Pro Val Pro Cys His Tyr Glu Asp Leu Glu Arg Leu Pro Asp

995 1000 1005

Ala Ala Glu Pro Cys Leu Pro Gly Ala Leu Phe Arg Cys Pro Val

1010 1015 1020

Val Phe Arg Gln Glu Ile Leu Val Gln Val Ile Gly Thr Leu Glu

1025 1030 1035

Leu Val Gly Glu Ile Glu Ala Ser Ser Met Phe Ser Leu Cys Ser

1040 1045 1050

Ser Leu Ser Ile Ser Phe Asn Ser Ser Lys His Phe His Leu Tyr

1055 1060 1065

Gly Ser Asn Ala Ser Leu Ala Gln Val Val Met Lys Val Asp Val

1070 1075 1080

Val Tyr Glu Lys Gln Met Leu Tyr Leu Tyr Val Leu Ser Gly Ile

1085 1090 1095

Gly Gly Leu Leu Leu Leu Leu Leu Ile Phe Ile Val Leu Tyr Lys

1100 1105 1110

Val Gly Phe Phe Lys Arg Asn Leu Lys Glu Lys Met Glu Ala Gly

1115 1120 1125

Arg Gly Val Pro Asn Gly Ile Pro Ala Glu Asp Ser Glu Gln Leu

1130 1135 1140

Ala Ser Gly Gln Glu Ala Gly Asp Pro Gly Cys Leu Lys Pro Leu

1145 1150 1155

His Glu Lys Asp Ser Glu Ser Gly Gly Gly Lys Asp

1160 1165 1170

<210> 22

<211> 364

<212> PRT

<213> Homo sapiens

<400> 22

Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala

1 5 10 15

Met Asp Pro Asn Phe Trp Leu Gln Val Gln Glu Ser Val Thr Val Gln

20 25 30

Glu Gly Leu Cys Val Leu Val Pro Cys Thr Phe Phe His Pro Ile Pro

35 40 45

Tyr Tyr Asp Lys Asn Ser Pro Val His Gly Tyr Trp Phe Arg Glu Gly

50 55 60

Ala Ile Ile Ser Arg Asp Ser Pro Val Ala Thr Asn Lys Leu Asp Gln

65 70 75 80

Glu Val Gln Glu Glu Thr Gln Gly Arg Phe Arg Leu Leu Gly Asp Pro

85 90 95

Ser Arg Asn Asn Cys Ser Leu Ser Ile Val Asp Ala Arg Arg Arg Asp

100 105 110

Asn Gly Ser Tyr Phe Phe Arg Met Glu Arg Gly Ser Thr Lys Tyr Ser

115 120 125

Tyr Lys Ser Pro Gln Leu Ser Val His Val Thr Asp Leu Thr His Arg

130 135 140

Pro Lys Ile Leu Ile Pro Gly Thr Leu Glu Pro Gly His Ser Lys Asn

145 150 155 160

Leu Thr Cys Ser Val Ser Trp Ala Cys Glu Gln Gly Thr Pro Pro Ile

165 170 175

Phe Ser Trp Leu Ser Ala Ala Pro Thr Ser Leu Gly Pro Arg Thr Thr

180 185 190

His Ser Ser Val Leu Ile Ile Thr Pro Arg Pro Gln Asp His Gly Thr

195 200 205

Asn Leu Thr Cys Gln Val Lys Phe Ala Gly Ala Gly Val Thr Thr Glu

210 215 220

Arg Thr Ile Gln Leu Asn Val Thr Tyr Val Pro Gln Asn Pro Thr Thr

225 230 235 240

Gly Ile Phe Pro Gly Asp Gly Ser Gly Lys Gln Glu Thr Arg Ala Gly

245 250 255

Val Val His Gly Ala Ile Gly Gly Ala Gly Val Thr Ala Leu Leu Ala

260 265 270

Leu Cys Leu Cys Leu Ile Phe Phe Ile Val Lys Thr His Arg Arg Lys

275 280 285

Ala Ala Arg Thr Ala Val Gly Arg Asn Asp Thr His Pro Thr Thr Gly

290 295 300

Ser Ala Ser Pro Lys His Gln Lys Lys Ser Lys Leu His Gly Pro Thr

305 310 315 320

Glu Thr Ser Ser Cys Ser Gly Ala Ala Pro Thr Val Glu Met Asp Glu

325 330 335

Glu Leu His Tyr Ala Ser Leu Asn Phe His Gly Met Asn Pro Ser Lys

340 345 350

Asp Thr Ser Thr Glu Tyr Ser Glu Val Arg Thr Gln

355 360

<210> 23

<211> 1032

<212> PRT

<213> Homo sapiens

<400> 23

Met Ala Trp Glu Ala Arg Arg Glu Pro Gly Pro Arg Arg Ala Ala Val

1 5 10 15

Arg Glu Thr Val Met Leu Leu Leu Cys Leu Gly Val Pro Thr Gly Arg

20 25 30

Pro Tyr Asn Val Asp Thr Glu Ser Ala Leu Leu Tyr Gln Gly Pro His

35 40 45

Asn Thr Leu Phe Gly Tyr Ser Val Val Leu His Ser His Gly Ala Asn

50 55 60

Arg Trp Leu Leu Val Gly Ala Pro Thr Ala Asn Trp Leu Ala Asn Ala

65 70 75 80

Ser Val Ile Asn Pro Gly Ala Ile Tyr Arg Cys Arg Ile Gly Lys Asn

85 90 95

Pro Gly Gln Thr Cys Glu Gln Leu Gln Leu Gly Ser Pro Asn Gly Glu

100 105 110

Pro Cys Gly Lys Thr Cys Leu Glu Glu Arg Asp Asn Gln Trp Leu Gly

115 120 125

Val Thr Leu Ser Arg Gln Pro Gly Glu Asn Gly Ser Ile Val Thr Cys

130 135 140

Gly His Arg Trp Lys Asn Ile Phe Tyr Ile Lys Asn Glu Asn Lys Leu

145 150 155 160

Pro Thr Gly Gly Cys Tyr Gly Val Pro Pro Asp Leu Arg Thr Glu Leu

165 170 175

Ser Lys Arg Ile Ala Pro Cys Tyr Gln Asp Tyr Val Lys Lys Phe Gly

180 185 190

Glu Asn Phe Ala Ser Cys Gln Ala Gly Ile Ser Ser Phe Tyr Thr Lys

195 200 205

Asp Leu Ile Val Met Gly Ala Pro Gly Ser Ser Tyr Trp Thr Gly Ser

210 215 220

Leu Phe Val Tyr Asn Ile Thr Thr Asn Lys Tyr Lys Ala Phe Leu Asp

225 230 235 240

Lys Gln Asn Gln Val Lys Phe Gly Ser Tyr Leu Gly Tyr Ser Val Gly

245 250 255

Ala Gly His Phe Arg Ser Gln His Thr Thr Glu Val Val Gly Gly Ala

260 265 270

Pro Gln His Glu Gln Ile Gly Lys Ala Tyr Ile Phe Ser Ile Asp Glu

275 280 285

Lys Glu Leu Asn Ile Leu His Glu Met Lys Gly Lys Lys Leu Gly Ser

290 295 300

Tyr Phe Gly Ala Ser Val Cys Ala Val Asp Leu Asn Ala Asp Gly Phe

305 310 315 320

Ser Asp Leu Leu Val Gly Ala Pro Met Gln Ser Thr Ile Arg Glu Glu

325 330 335

Gly Arg Val Phe Val Tyr Ile Asn Ser Gly Ser Gly Ala Val Met Asn

340 345 350

Ala Met Glu Thr Asn Leu Val Gly Ser Asp Lys Tyr Ala Ala Arg Phe

355 360 365

Gly Glu Ser Ile Val Asn Leu Gly Asp Ile Asp Asn Asp Gly Phe Glu

370 375 380

Asp Val Ala Ile Gly Ala Pro Gln Glu Asp Asp Leu Gln Gly Ala Ile

385 390 395 400

Tyr Ile Tyr Asn Gly Arg Ala Asp Gly Ile Ser Ser Thr Phe Ser Gln

405 410 415

Arg Ile Glu Gly Leu Gln Ile Ser Lys Ser Leu Ser Met Phe Gly Gln

420 425 430

Ser Ile Ser Gly Gln Ile Asp Ala Asp Asn Asn Gly Tyr Val Asp Val

435 440 445

Ala Val Gly Ala Phe Arg Ser Asp Ser Ala Val Leu Leu Arg Thr Arg

450 455 460

Pro Val Val Ile Val Asp Ala Ser Leu Ser His Pro Glu Ser Val Asn

465 470 475 480

Arg Thr Lys Phe Asp Cys Val Glu Asn Gly Trp Pro Ser Val Cys Ile

485 490 495

Asp Leu Thr Leu Cys Phe Ser Tyr Lys Gly Lys Glu Val Pro Gly Tyr

500 505 510

Ile Val Leu Phe Tyr Asn Met Ser Leu Asp Val Asn Arg Lys Ala Glu

515 520 525

Ser Pro Pro Arg Phe Tyr Phe Ser Ser Asn Gly Thr Ser Asp Val Ile

530 535 540

Thr Gly Ser Ile Gln Val Ser Ser Arg Glu Ala Asn Cys Arg Thr His

545 550 555 560

Gln Ala Phe Met Arg Lys Asp Val Arg Asp Ile Leu Thr Pro Ile Gln

565 570 575

Ile Glu Ala Ala Tyr His Leu Gly Pro His Val Ile Ser Lys Arg Ser

580 585 590

Thr Glu Glu Phe Pro Pro Leu Gln Pro Ile Leu Gln Gln Lys Lys Glu

595 600 605

Lys Asp Ile Met Lys Lys Thr Ile Asn Phe Ala Arg Phe Cys Ala His

610 615 620

Glu Asn Cys Ser Ala Asp Leu Gln Val Ser Ala Lys Ile Gly Phe Leu

625 630 635 640

Lys Pro His Glu Asn Lys Thr Tyr Leu Ala Val Gly Ser Met Lys Thr

645 650 655

Leu Met Leu Asn Val Ser Leu Phe Asn Ala Gly Asp Asp Ala Tyr Glu

660 665 670

Thr Thr Leu His Val Lys Leu Pro Val Gly Leu Tyr Phe Ile Lys Ile

675 680 685

Leu Glu Leu Glu Glu Lys Gln Ile Asn Cys Glu Val Thr Asp Asn Ser

690 695 700

Gly Val Val Gln Leu Asp Cys Ser Ile Gly Tyr Ile Tyr Val Asp His

705 710 715 720

Leu Ser Arg Ile Asp Ile Ser Phe Leu Leu Asp Val Ser Ser Leu Ser

725 730 735

Arg Ala Glu Glu Asp Leu Ser Ile Thr Val His Ala Thr Cys Glu Asn

740 745 750

Glu Glu Glu Met Asp Asn Leu Lys His Ser Arg Val Thr Val Ala Ile

755 760 765

Pro Leu Lys Tyr Glu Val Lys Leu Thr Val His Gly Phe Val Asn Pro

770 775 780

Thr Ser Phe Val Tyr Gly Ser Asn Asp Glu Asn Glu Pro Glu Thr Cys

785 790 795 800

Met Val Glu Lys Met Asn Leu Thr Phe His Val Ile Asn Thr Gly Asn

805 810 815

Ser Met Ala Pro Asn Val Ser Val Glu Ile Met Val Pro Asn Ser Phe

820 825 830

Ser Pro Gln Thr Asp Lys Leu Phe Asn Ile Leu Asp Val Gln Thr Thr

835 840 845

Thr Gly Glu Cys His Phe Glu Asn Tyr Gln Arg Val Cys Ala Leu Glu

850 855 860

Gln Gln Lys Ser Ala Met Gln Thr Leu Lys Gly Ile Val Arg Phe Leu

865 870 875 880

Ser Lys Thr Asp Lys Arg Leu Leu Tyr Cys Ile Lys Ala Asp Pro His

885 890 895

Cys Leu Asn Phe Leu Cys Asn Phe Gly Lys Met Glu Ser Gly Lys Glu

900 905 910

Ala Ser Val His Ile Gln Leu Glu Gly Arg Pro Ser Ile Leu Glu Met

915 920 925

Asp Glu Thr Ser Ala Leu Lys Phe Glu Ile Arg Ala Thr Gly Phe Pro

930 935 940

Glu Pro Asn Pro Arg Val Ile Glu Leu Asn Lys Asp Glu Asn Val Ala

945 950 955 960

His Val Leu Leu Glu Gly Leu His His Gln Arg Pro Lys Arg Tyr Phe

965 970 975

Thr Ile Val Ile Ile Ser Ser Ser Leu Leu Leu Gly Leu Ile Val Leu

980 985 990

Leu Leu Ile Ser Tyr Val Met Trp Lys Ala Gly Phe Phe Lys Arg Gln

995 1000 1005

Tyr Lys Ser Ile Leu Gln Glu Glu Asn Arg Arg Asp Ser Trp Ser

1010 1015 1020

Tyr Ile Asn Ser Lys Ser Asn Asp Asp

1025 1030

<210> 24

<211> 257

<212> PRT

<213> Homo sapiens

<400> 24

Met Ala Pro Ala Met Glu Ser Pro Thr Leu Leu Cys Val Ala Leu Leu

1 5 10 15

Phe Phe Ala Pro Asp Gly Val Leu Ala Val Pro Gln Lys Pro Lys Val

20 25 30

Ser Leu Asn Pro Pro Trp Asn Arg Ile Phe Lys Gly Glu Asn Val Thr

35 40 45

Leu Thr Cys Asn Gly Asn Asn Phe Phe Glu Val Ser Ser Thr Lys Trp

50 55 60

Phe His Asn Gly Ser Leu Ser Glu Glu Thr Asn Ser Ser Leu Asn Ile

65 70 75 80

Val Asn Ala Lys Phe Glu Asp Ser Gly Glu Tyr Lys Cys Gln His Gln

85 90 95

Gln Val Asn Glu Ser Glu Pro Val Tyr Leu Glu Val Phe Ser Asp Trp

100 105 110

Leu Leu Leu Gln Ala Ser Ala Glu Val Val Met Glu Gly Gln Pro Leu

115 120 125

Phe Leu Arg Cys His Gly Trp Arg Asn Trp Asp Val Tyr Lys Val Ile

130 135 140

Tyr Tyr Lys Asp Gly Glu Ala Leu Lys Tyr Trp Tyr Glu Asn His Asn

145 150 155 160

Ile Ser Ile Thr Asn Ala Thr Val Glu Asp Ser Gly Thr Tyr Tyr Cys

165 170 175

Thr Gly Lys Val Trp Gln Leu Asp Tyr Glu Ser Glu Pro Leu Asn Ile

180 185 190

Thr Val Ile Lys Ala Pro Arg Glu Lys Tyr Trp Leu Gln Phe Phe Ile

195 200 205

Pro Leu Leu Val Val Ile Leu Phe Ala Val Asp Thr Gly Leu Phe Ile

210 215 220

Ser Thr Gln Gln Gln Val Thr Phe Leu Leu Lys Ile Lys Arg Thr Arg

225 230 235 240

Lys Gly Phe Arg Leu Leu Asn Pro His Pro Lys Pro Asn Pro Lys Asn

245 250 255

Asn

<210> 25

<211> 574

<212> PRT

<213> Homo sapiens

<400> 25

Met Glu Leu Leu Ile Leu Lys Ala Asn Ala Ile Thr Thr Ile Leu Thr

1 5 10 15

Ala Val Thr Phe Cys Phe Ala Ser Gly Gln Asn Ile Thr Glu Glu Phe

20 25 30

Tyr Gln Ser Thr Cys Ser Ala Val Ser Lys Gly Tyr Leu Ser Ala Leu

35 40 45

Arg Thr Gly Trp Tyr Thr Ser Val Ile Thr Ile Glu Leu Ser Asn Ile

50 55 60

Lys Glu Asn Lys Cys Asn Gly Thr Asp Ala Lys Val Lys Leu Ile Lys

65 70 75 80

Gln Glu Leu Asp Lys Tyr Lys Asn Ala Val Thr Glu Leu Gln Leu Leu

85 90 95

Met Gln Ser Thr Pro Pro Thr Asn Asn Arg Ala Arg Arg Glu Leu Pro

100 105 110

Arg Phe Met Asn Tyr Thr Leu Asn Asn Ala Lys Lys Thr Asn Val Thr

115 120 125

Leu Ser Lys Lys Arg Lys Arg Arg Phe Leu Gly Phe Leu Leu Gly Val

130 135 140

Gly Ser Ala Ile Ala Ser Gly Val Ala Val Ser Lys Val Leu His Leu

145 150 155 160

Glu Gly Glu Val Asn Lys Ile Lys Ser Ala Leu Leu Ser Thr Asn Lys

165 170 175

Ala Val Val Ser Leu Ser Asn Gly Val Ser Val Leu Thr Ser Lys Val

180 185 190

Leu Asp Leu Lys Asn Tyr Ile Asp Lys Gln Leu Leu Pro Ile Val Asn

195 200 205

Lys Gln Ser Cys Ser Ile Ser Asn Ile Glu Thr Val Ile Glu Phe Gln

210 215 220

Gln Lys Asn Asn Arg Leu Leu Glu Ile Thr Arg Glu Phe Ser Val Asn

225 230 235 240

Ala Gly Val Thr Thr Pro Val Ser Thr Tyr Met Leu Thr Asn Ser Glu

245 250 255

Leu Leu Ser Leu Ile Asn Asp Met Pro Ile Thr Asn Asp Gln Lys Lys

260 265 270

Leu Met Ser Asn Asn Val Gln Ile Val Arg Gln Gln Ser Tyr Ser Ile

275 280 285

Met Ser Ile Ile Lys Glu Glu Val Leu Ala Tyr Val Val Gln Leu Pro

290 295 300

Leu Tyr Gly Val Ile Asp Thr Pro Cys Trp Lys Leu His Thr Ser Pro

305 310 315 320

Leu Cys Thr Thr Asn Thr Lys Glu Gly Ser Asn Ile Cys Leu Thr Arg

325 330 335

Thr Asp Arg Gly Trp Tyr Cys Asp Asn Ala Gly Ser Val Ser Phe Phe

340 345 350

Pro Gln Ala Glu Thr Cys Lys Val Gln Ser Asn Arg Val Phe Cys Asp

355 360 365

Thr Met Asn Ser Leu Thr Leu Pro Ser Glu Ile Asn Leu Cys Asn Val

370 375 380

Asp Ile Phe Asn Pro Lys Tyr Asp Cys Lys Ile Met Thr Ser Lys Thr

385 390 395 400

Asp Val Ser Ser Ser Val Ile Thr Ser Leu Gly Ala Ile Val Ser Cys

405 410 415

Tyr Gly Lys Thr Lys Cys Thr Ala Ser Asn Lys Asn Arg Gly Ile Ile

420 425 430

Lys Thr Phe Ser Asn Gly Cys Asp Tyr Val Ser Asn Lys Gly Met Asp

435 440 445

Thr Val Ser Val Gly Asn Thr Leu Tyr Tyr Val Asn Lys Gln Glu Gly

450 455 460

Lys Ser Leu Tyr Val Lys Gly Glu Pro Ile Ile Asn Phe Tyr Asp Pro

465 470 475 480

Leu Val Phe Pro Ser Asp Glu Phe Asp Ala Ser Ile Ser Gln Val Asn

485 490 495

Glu Lys Ile Asn Gln Ser Leu Ala Phe Ile Arg Lys Ser Asp Glu Leu

500 505 510

Leu His Asn Val Asn Ala Gly Lys Ser Thr Thr Asn Ile Met Ile Thr

515 520 525

Thr Ile Ile Ile Val Ile Ile Val Ile Leu Leu Ser Leu Ile Ala Val

530 535 540

Gly Leu Leu Leu Tyr Cys Lys Ala Arg Ser Thr Pro Val Thr Leu Ser

545 550 555 560

Lys Asp Gln Leu Ser Gly Ile Asn Asn Ile Ala Phe Ser Asn

565 570

<210> 26

<211> 468

<212> PRT

<213> Homo sapiens

<400> 26

Met Leu Ala Val Gly Cys Ala Leu Leu Ala Ala Leu Leu Ala Ala Pro

1 5 10 15

Gly Ala Ala Leu Ala Pro Arg Arg Cys Pro Ala Gln Glu Val Ala Arg

20 25 30

Gly Val Leu Thr Ser Leu Pro Gly Asp Ser Val Thr Leu Thr Cys Pro

35 40 45

Gly Val Glu Pro Glu Asp Asn Ala Thr Val His Trp Val Leu Arg Lys

50 55 60

Pro Ala Ala Gly Ser His Pro Ser Arg Trp Ala Gly Met Gly Arg Arg

65 70 75 80

Leu Leu Leu Arg Ser Val Gln Leu His Asp Ser Gly Asn Tyr Ser Cys

85 90 95

Tyr Arg Ala Gly Arg Pro Ala Gly Thr Val His Leu Leu Val Asp Val

100 105 110

Pro Pro Glu Glu Pro Gln Leu Ser Cys Phe Arg Lys Ser Pro Leu Ser

115 120 125

Asn Val Val Cys Glu Trp Gly Pro Arg Ser Thr Pro Ser Leu Thr Thr

130 135 140

Lys Ala Val Leu Leu Val Arg Lys Phe Gln Asn Ser Pro Ala Glu Asp

145 150 155 160

Phe Gln Glu Pro Cys Gln Tyr Ser Gln Glu Ser Gln Lys Phe Ser Cys

165 170 175

Gln Leu Ala Val Pro Glu Gly Asp Ser Ser Phe Tyr Ile Val Ser Met

180 185 190

Cys Val Ala Ser Ser Val Gly Ser Lys Phe Ser Lys Thr Gln Thr Phe

195 200 205

Gln Gly Cys Gly Ile Leu Gln Pro Asp Pro Pro Ala Asn Ile Thr Val

210 215 220

Thr Ala Val Ala Arg Asn Pro Arg Trp Leu Ser Val Thr Trp Gln Asp

225 230 235 240

Pro His Ser Trp Asn Ser Ser Phe Tyr Arg Leu Arg Phe Glu Leu Arg

245 250 255

Tyr Arg Ala Glu Arg Ser Lys Thr Phe Thr Thr Trp Met Val Lys Asp

260 265 270

Leu Gln His His Cys Val Ile His Asp Ala Trp Ser Gly Leu Arg His

275 280 285

Val Val Gln Leu Arg Ala Gln Glu Glu Phe Gly Gln Gly Glu Trp Ser

290 295 300

Glu Trp Ser Pro Glu Ala Met Gly Thr Pro Trp Thr Glu Ser Arg Ser

305 310 315 320

Pro Pro Ala Glu Asn Glu Val Ser Thr Pro Met Gln Ala Leu Thr Thr

325 330 335

Asn Lys Asp Asp Asp Asn Ile Leu Phe Arg Asp Ser Ala Asn Ala Thr

340 345 350

Ser Leu Pro Val Gln Asp Ser Ser Ser Val Pro Leu Pro Thr Phe Leu

355 360 365

Val Ala Gly Gly Ser Leu Ala Phe Gly Thr Leu Leu Cys Ile Ala Ile

370 375 380

Val Leu Arg Phe Lys Lys Thr Trp Lys Leu Arg Ala Leu Lys Glu Gly

385 390 395 400

Lys Thr Ser Met His Pro Pro Tyr Ser Leu Gly Gln Leu Val Pro Glu

405 410 415

Arg Pro Arg Pro Thr Pro Val Leu Val Pro Leu Ile Ser Pro Pro Val

420 425 430

Ser Pro Ser Ser Leu Gly Ser Asp Asn Thr Ser Ser His Asn Arg Pro

435 440 445

Asp Ala Arg Asp Pro Arg Ser Pro Tyr Asp Ile Ser Asn Thr Asp Tyr

450 455 460

Phe Phe Pro Arg

465

<210> 27

<211> 1255

<212> PRT

<213> Homo sapiens

<400> 27

Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu

1 5 10 15

Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys

20 25 30

Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His

35 40 45

Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr

50 55 60

Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val

65 70 75 80

Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu

85 90 95

Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr

100 105 110

Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro

115 120 125

Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser

130 135 140

Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln

145 150 155 160

Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn

165 170 175

Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys

180 185 190

His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser

195 200 205

Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys

210 215 220

Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys

225 230 235 240

Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu

245 250 255

His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val

260 265 270

Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg

275 280 285

Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu

290 295 300

Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln

305 310 315 320

Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys

325 330 335

Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu

340 345 350

Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys

355 360 365

Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp

370 375 380

Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe

385 390 395 400

Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro

405 410 415

Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg

420 425 430

Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu

435 440 445

Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly

450 455 460

Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val

465 470 475 480

Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr

485 490 495

Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His

500 505 510

Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys

515 520 525

Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys

530 535 540

Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys

545 550 555 560

Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys

565 570 575

Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp

580 585 590

Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu

595 600 605

Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln

610 615 620

Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys

625 630 635 640

Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser

645 650 655

Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly

660 665 670

Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg

675 680 685

Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly

690 695 700

Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu

705 710 715 720

Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys

725 730 735

Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile

740 745 750

Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu

755 760 765

Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg

770 775 780

Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu

785 790 795 800

Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg

805 810 815

Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly

820 825 830

Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala

835 840 845

Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe

850 855 860

Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp

865 870 875 880

Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg

885 890 895

Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val

900 905 910

Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala

915 920 925

Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro

930 935 940

Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met

945 950 955 960

Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe

965 970 975

Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu

980 985 990

Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu

995 1000 1005

Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr

1010 1015 1020

Leu Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly

1025 1030 1035

Ala Gly Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg

1040 1045 1050

Ser Gly Gly Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu

1055 1060 1065

Glu Ala Pro Arg Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser

1070 1075 1080

Asp Val Phe Asp Gly Asp Leu Gly Met Gly Ala Ala Lys Gly Leu

1085 1090 1095

Gln Ser Leu Pro Thr His Asp Pro Ser Pro Leu Gln Arg Tyr Ser

1100 1105 1110

Glu Asp Pro Thr Val Pro Leu Pro Ser Glu Thr Asp Gly Tyr Val

1115 1120 1125

Ala Pro Leu Thr Cys Ser Pro Gln Pro Glu Tyr Val Asn Gln Pro

1130 1135 1140

Asp Val Arg Pro Gln Pro Pro Ser Pro Arg Glu Gly Pro Leu Pro

1145 1150 1155

Ala Ala Arg Pro Ala Gly Ala Thr Leu Glu Arg Pro Lys Thr Leu

1160 1165 1170

Ser Pro Gly Lys Asn Gly Val Val Lys Asp Val Phe Ala Phe Gly

1175 1180 1185

Gly Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln Gly Gly Ala

1190 1195 1200

Ala Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala Phe Asp

1205 1210 1215

Asn Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala Pro

1220 1225 1230

Pro Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr

1235 1240 1245

Leu Gly Leu Asp Val Pro Val

1250 1255

<210> 28

<211> 798

<212> PRT

<213> Homo sapiens

<400> 28

Met Val Ala Leu Pro Met Val Leu Val Leu Leu Leu Val Leu Ser Arg

1 5 10 15

Gly Glu Ser Glu Leu Asp Ala Lys Ile Pro Ser Thr Gly Asp Ala Thr

20 25 30

Glu Trp Arg Asn Pro His Leu Ser Met Leu Gly Ser Cys Gln Pro Ala

35 40 45

Pro Ser Cys Gln Lys Cys Ile Leu Ser His Pro Ser Cys Ala Trp Cys

50 55 60

Lys Gln Leu Asn Phe Thr Ala Ser Gly Glu Ala Glu Ala Arg Arg Cys

65 70 75 80

Ala Arg Arg Glu Glu Leu Leu Ala Arg Gly Cys Pro Leu Glu Glu Leu

85 90 95

Glu Glu Pro Arg Gly Gln Gln Glu Val Leu Gln Asp Gln Pro Leu Ser

100 105 110

Gln Gly Ala Arg Gly Glu Gly Ala Thr Gln Leu Ala Pro Gln Arg Val

115 120 125

Arg Val Thr Leu Arg Pro Gly Glu Pro Gln Gln Leu Gln Val Arg Phe

130 135 140

Leu Arg Ala Glu Gly Tyr Pro Val Asp Leu Tyr Tyr Leu Met Asp Leu

145 150 155 160

Ser Tyr Ser Met Lys Asp Asp Leu Glu Arg Val Arg Gln Leu Gly His

165 170 175

Ala Leu Leu Val Arg Leu Gln Glu Val Thr His Ser Val Arg Ile Gly

180 185 190

Phe Gly Ser Phe Val Asp Lys Thr Val Leu Pro Phe Val Ser Thr Val

195 200 205

Pro Ser Lys Leu Arg His Pro Cys Pro Thr Arg Leu Glu Arg Cys Gln

210 215 220

Ser Pro Phe Ser Phe His His Val Leu Ser Leu Thr Gly Asp Ala Gln

225 230 235 240

Ala Phe Glu Arg Glu Val Gly Arg Gln Ser Val Ser Gly Asn Leu Asp

245 250 255

Ser Pro Glu Gly Gly Phe Asp Ala Ile Leu Gln Ala Ala Leu Cys Gln

260 265 270

Glu Gln Ile Gly Trp Arg Asn Val Ser Arg Leu Leu Val Phe Thr Ser

275 280 285

Asp Asp Thr Phe His Thr Ala Gly Asp Gly Lys Leu Gly Gly Ile Phe

290 295 300

Met Pro Ser Asp Gly His Cys His Leu Asp Ser Asn Gly Leu Tyr Ser

305 310 315 320

Arg Ser Thr Glu Phe Asp Tyr Pro Ser Val Gly Gln Val Ala Gln Ala

325 330 335

Leu Ser Ala Ala Asn Ile Gln Pro Ile Phe Ala Val Thr Ser Ala Ala

340 345 350

Leu Pro Val Tyr Gln Glu Leu Ser Lys Leu Ile Pro Lys Ser Ala Val

355 360 365

Gly Glu Leu Ser Glu Asp Ser Ser Asn Val Val Gln Leu Ile Met Asp

370 375 380

Ala Tyr Asn Ser Leu Ser Ser Thr Val Thr Leu Glu His Ser Ser Leu

385 390 395 400

Pro Pro Gly Val His Ile Ser Tyr Glu Ser Gln Cys Glu Gly Pro Glu

405 410 415

Lys Arg Glu Gly Lys Ala Glu Asp Arg Gly Gln Cys Asn His Val Arg

420 425 430

Ile Asn Gln Thr Val Thr Phe Trp Val Ser Leu Gln Ala Thr His Cys

435 440 445

Leu Pro Glu Pro His Leu Leu Arg Leu Arg Ala Leu Gly Phe Ser Glu

450 455 460

Glu Leu Ile Val Glu Leu His Thr Leu Cys Asp Cys Asn Cys Ser Asp

465 470 475 480

Thr Gln Pro Gln Ala Pro His Cys Ser Asp Gly Gln Gly His Leu Gln

485 490 495

Cys Gly Val Cys Ser Cys Ala Pro Gly Arg Leu Gly Arg Leu Cys Glu

500 505 510

Cys Ser Val Ala Glu Leu Ser Ser Pro Asp Leu Glu Ser Gly Cys Arg

515 520 525

Ala Pro Asn Gly Thr Gly Pro Leu Cys Ser Gly Lys Gly His Cys Gln

530 535 540

Cys Gly Arg Cys Ser Cys Ser Gly Gln Ser Ser Gly His Leu Cys Glu

545 550 555 560

Cys Asp Asp Ala Ser Cys Glu Arg His Glu Gly Ile Leu Cys Gly Gly

565 570 575

Phe Gly Arg Cys Gln Cys Gly Val Cys His Cys His Ala Asn Arg Thr

580 585 590

Gly Arg Ala Cys Glu Cys Ser Gly Asp Met Asp Ser Cys Ile Ser Pro

595 600 605

Glu Gly Gly Leu Cys Ser Gly His Gly Arg Cys Lys Cys Asn Arg Cys

610 615 620

Gln Cys Leu Asp Gly Tyr Tyr Gly Ala Leu Cys Asp Gln Cys Pro Gly

625 630 635 640

Cys Lys Thr Pro Cys Glu Arg His Arg Asp Cys Ala Glu Cys Gly Ala

645 650 655

Phe Arg Thr Gly Pro Leu Ala Thr Asn Cys Ser Thr Ala Cys Ala His

660 665 670

Thr Asn Val Thr Leu Ala Leu Ala Pro Ile Leu Asp Asp Gly Trp Cys

675 680 685

Lys Glu Arg Thr Leu Asp Asn Gln Leu Phe Phe Phe Leu Val Glu Asp

690 695 700

Asp Ala Arg Gly Thr Val Val Leu Arg Val Arg Pro Gln Glu Lys Gly

705 710 715 720

Ala Asp His Thr Gln Ala Ile Val Leu Gly Cys Val Gly Gly Ile Val

725 730 735

Ala Val Gly Leu Gly Leu Val Leu Ala Tyr Arg Leu Ser Val Glu Ile

740 745 750

Tyr Asp Arg Arg Glu Tyr Ser Arg Phe Glu Lys Glu Gln Gln Gln Leu

755 760 765

Asn Trp Lys Gln Asp Ser Asn Pro Leu Tyr Lys Ser Ala Ile Thr Thr

770 775 780

Thr Ile Asn Pro Arg Phe Gln Glu Ala Asp Ser Pro Thr Leu

785 790 795

<210> 29

<211> 285

<212> PRT

<213> Homo sapiens

<400> 29

Met Asp Asp Ser Thr Glu Arg Glu Gln Ser Arg Leu Thr Ser Cys Leu

1 5 10 15

Lys Lys Arg Glu Glu Met Lys Leu Lys Glu Cys Val Ser Ile Leu Pro

20 25 30

Arg Lys Glu Ser Pro Ser Val Arg Ser Ser Lys Asp Gly Lys Leu Leu

35 40 45

Ala Ala Thr Leu Leu Leu Ala Leu Leu Ser Cys Cys Leu Thr Val Val

50 55 60

Ser Phe Tyr Gln Val Ala Ala Leu Gln Gly Asp Leu Ala Ser Leu Arg

65 70 75 80

Ala Glu Leu Gln Gly His His Ala Glu Lys Leu Pro Ala Gly Ala Gly

85 90 95

Ala Pro Lys Ala Gly Leu Glu Glu Ala Pro Ala Val Thr Ala Gly Leu

100 105 110

Lys Ile Phe Glu Pro Pro Ala Pro Gly Glu Gly Asn Ser Ser Gln Asn

115 120 125

Ser Arg Asn Lys Arg Ala Val Gln Gly Pro Glu Glu Thr Val Thr Gln

130 135 140

Asp Cys Leu Gln Leu Ile Ala Asp Ser Glu Thr Pro Thr Ile Gln Lys

145 150 155 160

Gly Ser Tyr Thr Phe Val Pro Trp Leu Leu Ser Phe Lys Arg Gly Ser

165 170 175

Ala Leu Glu Glu Lys Glu Asn Lys Ile Leu Val Lys Glu Thr Gly Tyr

180 185 190

Phe Phe Ile Tyr Gly Gln Val Leu Tyr Thr Asp Lys Thr Tyr Ala Met

195 200 205

Gly His Leu Ile Gln Arg Lys Lys Val His Val Phe Gly Asp Glu Leu

210 215 220

Ser Leu Val Thr Leu Phe Arg Cys Ile Gln Asn Met Pro Glu Thr Leu

225 230 235 240

Pro Asn Asn Ser Cys Tyr Ser Ala Gly Ile Ala Lys Leu Glu Glu Gly

245 250 255

Asp Glu Leu Gln Leu Ala Ile Pro Arg Glu Asn Ala Gln Ile Ser Leu

260 265 270

Asp Gly Asp Val Thr Phe Phe Gly Ala Leu Lys Leu Leu

275 280 285

<210> 30

<211> 269

<212> PRT

<213> Homo sapiens

<400> 30

Met Ala Glu Val Pro Glu Leu Ala Ser Glu Met Met Ala Tyr Tyr Ser

1 5 10 15

Gly Asn Glu Asp Asp Leu Phe Phe Glu Ala Asp Gly Pro Lys Gln Met

20 25 30

Lys Cys Ser Phe Gln Asp Leu Asp Leu Cys Pro Leu Asp Gly Gly Ile

35 40 45

Gln Leu Arg Ile Ser Asp His His Tyr Ser Lys Gly Phe Arg Gln Ala

50 55 60

Ala Ser Val Val Val Ala Met Asp Lys Leu Arg Lys Met Leu Val Pro

65 70 75 80

Cys Pro Gln Thr Phe Gln Glu Asn Asp Leu Ser Thr Phe Phe Pro Phe

85 90 95

Ile Phe Glu Glu Glu Pro Ile Phe Phe Asp Thr Trp Asp Asn Glu Ala

100 105 110

Tyr Val His Asp Ala Pro Val Arg Ser Leu Asn Cys Thr Leu Arg Asp

115 120 125

Ser Gln Gln Lys Ser Leu Val Met Ser Gly Pro Tyr Glu Leu Lys Ala

130 135 140

Leu His Leu Gln Gly Gln Asp Met Glu Gln Gln Val Val Phe Ser Met

145 150 155 160

Ser Phe Val Gln Gly Glu Glu Ser Asn Asp Lys Ile Pro Val Ala Leu

165 170 175

Gly Leu Lys Glu Lys Asn Leu Tyr Leu Ser Cys Val Leu Lys Asp Asp

180 185 190

Lys Pro Thr Leu Gln Leu Glu Ser Val Asp Pro Lys Asn Tyr Pro Lys

195 200 205

Lys Lys Met Glu Lys Arg Phe Val Phe Asn Lys Ile Glu Ile Asn Asn

210 215 220

Lys Leu Glu Phe Glu Ser Ala Gln Phe Pro Asn Trp Tyr Ile Ser Thr

225 230 235 240

Ser Gln Ala Glu Asn Met Pro Val Phe Leu Gly Gly Thr Lys Gly Gly

245 250 255

Gln Asp Ile Thr Asp Phe Thr Met Gln Phe Val Ser Ser

260 265

<210> 31

<211> 317

<212> PRT

<213> Homo sapiens

<400> 31

Met Arg Arg Ala Ser Arg Asp Tyr Thr Lys Tyr Leu Arg Gly Ser Glu

1 5 10 15

Glu Met Gly Gly Gly Pro Gly Ala Pro His Glu Gly Pro Leu His Ala

20 25 30

Pro Pro Pro Pro Ala Pro His Gln Pro Pro Ala Ala Ser Arg Ser Met

35 40 45

Phe Val Ala Leu Leu Gly Leu Gly Leu Gly Gln Val Val Cys Ser Val

50 55 60

Ala Leu Phe Phe Tyr Phe Arg Ala Gln Met Asp Pro Asn Arg Ile Ser

65 70 75 80

Glu Asp Gly Thr His Cys Ile Tyr Arg Ile Leu Arg Leu His Glu Asn

85 90 95

Ala Asp Phe Gln Asp Thr Thr Leu Glu Ser Gln Asp Thr Lys Leu Ile

100 105 110

Pro Asp Ser Cys Arg Arg Ile Lys Gln Ala Phe Gln Gly Ala Val Gln

115 120 125

Lys Glu Leu Gln His Ile Val Gly Ser Gln His Ile Arg Ala Glu Lys

130 135 140

Ala Met Val Asp Gly Ser Trp Leu Asp Leu Ala Lys Arg Ser Lys Leu

145 150 155 160

Glu Ala Gln Pro Phe Ala His Leu Thr Ile Asn Ala Thr Asp Ile Pro

165 170 175

Ser Gly Ser His Lys Val Ser Leu Ser Ser Trp Tyr His Asp Arg Gly

180 185 190

Trp Ala Lys Ile Ser Asn Met Thr Phe Ser Asn Gly Lys Leu Ile Val

195 200 205

Asn Gln Asp Gly Phe Tyr Tyr Leu Tyr Ala Asn Ile Cys Phe Arg His

210 215 220

His Glu Thr Ser Gly Asp Leu Ala Thr Glu Tyr Leu Gln Leu Met Val

225 230 235 240

Tyr Val Thr Lys Thr Ser Ile Lys Ile Pro Ser Ser His Thr Leu Met

245 250 255

Lys Gly Gly Ser Thr Lys Tyr Trp Ser Gly Asn Ser Glu Phe His Phe

260 265 270

Tyr Ser Ile Asn Val Gly Gly Phe Phe Lys Leu Arg Ser Gly Glu Glu

275 280 285

Ile Ser Ile Glu Val Ser Asn Pro Ser Leu Leu Asp Pro Asp Gln Asp

290 295 300

Ala Thr Tyr Phe Gly Ala Phe Lys Val Arg Asp Ile Asp

305 310 315

<210> 32

<211> 223

<212> PRT

<213> Homo sapiens

<400> 32

Met Ala Cys Leu Gly Phe Gln Arg His Lys Ala Gln Leu Asn Leu Ala

1 5 10 15

Thr Arg Thr Trp Pro Cys Thr Leu Leu Phe Phe Leu Leu Phe Ile Pro

20 25 30

Val Phe Cys Lys Ala Met His Val Ala Gln Pro Ala Val Val Leu Ala

35 40 45

Ser Ser Arg Gly Ile Ala Ser Phe Val Cys Glu Tyr Ala Ser Pro Gly

50 55 60

Lys Ala Thr Glu Val Arg Val Thr Val Leu Arg Gln Ala Asp Ser Gln

65 70 75 80

Val Thr Glu Val Cys Ala Ala Thr Tyr Met Met Gly Asn Glu Leu Thr

85 90 95

Phe Leu Asp Asp Ser Ile Cys Thr Gly Thr Ser Ser Gly Asn Gln Val

100 105 110

Asn Leu Thr Ile Gln Gly Leu Arg Ala Met Asp Thr Gly Leu Tyr Ile

115 120 125

Cys Lys Val Glu Leu Met Tyr Pro Pro Pro Tyr Tyr Leu Gly Ile Gly

130 135 140

Asn Gly Thr Gln Ile Tyr Val Ile Asp Pro Glu Pro Cys Pro Asp Ser

145 150 155 160

Asp Phe Leu Leu Trp Ile Leu Ala Ala Val Ser Ser Gly Leu Phe Phe

165 170 175

Tyr Ser Phe Leu Leu Thr Ala Val Ser Leu Ser Lys Met Leu Lys Lys

180 185 190

Arg Ser Pro Leu Thr Thr Gly Val Tyr Val Lys Met Pro Pro Thr Glu

195 200 205

Pro Glu Cys Glu Lys Gln Phe Gln Pro Tyr Phe Ile Pro Ile Asn

210 215 220

<210> 33

<211> 189

<212> PRT

<213> Homo sapiens

<400> 33

Met Leu Gly Ser Arg Ala Val Met Leu Leu Leu Leu Leu Pro Trp Thr

1 5 10 15

Ala Gln Gly Arg Ala Val Pro Gly Gly Ser Ser Pro Ala Trp Thr Gln

20 25 30

Cys Gln Gln Leu Ser Gln Lys Leu Cys Thr Leu Ala Trp Ser Ala His

35 40 45

Pro Leu Val Gly His Met Asp Leu Arg Glu Glu Gly Asp Glu Glu Thr

50 55 60

Thr Asn Asp Val Pro His Ile Gln Cys Gly Asp Gly Cys Asp Pro Gln

65 70 75 80

Gly Leu Arg Asp Asn Ser Gln Phe Cys Leu Gln Arg Ile His Gln Gly

85 90 95

Leu Ile Phe Tyr Glu Lys Leu Leu Gly Ser Asp Ile Phe Thr Gly Glu

100 105 110

Pro Ser Leu Leu Pro Asp Ser Pro Val Gly Gln Leu His Ala Ser Leu

115 120 125

Leu Gly Leu Ser Gln Leu Leu Gln Pro Glu Gly His His Trp Glu Thr

130 135 140

Gln Gln Ile Pro Ser Leu Ser Pro Ser Gln Pro Trp Gln Arg Leu Leu

145 150 155 160

Leu Arg Phe Lys Ile Leu Arg Ser Leu Gln Ala Phe Val Ala Val Ala

165 170 175

Ala Arg Val Phe Ala His Gly Ala Ala Thr Leu Ser Pro

180 185

<210> 34

<211> 288

<212> PRT

<213> Homo sapiens

<400> 34

Met Gln Ile Pro Gln Ala Pro Trp Pro Val Val Trp Ala Val Leu Gln

1 5 10 15

Leu Gly Trp Arg Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp

20 25 30

Asn Pro Pro Thr Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp

35 40 45

Asn Ala Thr Phe Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val

50 55 60

Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala

65 70 75 80

Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg

85 90 95

Val Thr Gln Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg

100 105 110

Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu

115 120 125

Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val

130 135 140

Thr Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro

145 150 155 160

Arg Pro Ala Gly Gln Phe Gln Thr Leu Val Val Gly Val Val Gly Gly

165 170 175

Leu Leu Gly Ser Leu Val Leu Leu Val Trp Val Leu Ala Val Ile Cys

180 185 190

Ser Arg Ala Ala Arg Gly Thr Ile Gly Ala Arg Arg Thr Gly Gln Pro

195 200 205

Leu Lys Glu Asp Pro Ser Ala Val Pro Val Phe Ser Val Asp Tyr Gly

210 215 220

Glu Leu Asp Phe Gln Trp Arg Glu Lys Thr Pro Glu Pro Pro Val Pro

225 230 235 240

Cys Val Pro Glu Gln Thr Glu Tyr Ala Thr Ile Val Phe Pro Ser Gly

245 250 255

Met Gly Thr Ser Ser Pro Ala Arg Arg Gly Ser Ala Asp Gly Pro Arg

260 265 270

Ser Ala Gln Pro Leu Arg Pro Glu Asp Gly His Cys Ser Trp Pro Leu

275 280 285

<210> 35

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<223> mAb-specific epitope

<400> 35

Cys Pro Tyr Ser Asn Pro Ser Leu Cys

1 5

<210> 36

<211> 24

<212> PRT

<213> Homo sapiens

<400> 36

Asn Ser Glu Leu Leu Ser Leu Ile Asn Asp Met Pro Ile Thr Asn Asp

1 5 10 15

Gln Lys Lys Leu Met Ser Asn Asn

20

<210> 37

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> mAb-specific epitope

<400> 37

Cys Gln Phe Asp Leu Ser Thr Arg Arg Leu Lys Cys

1 5 10

<210> 38

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> mAb-specific epitope

<400> 38

Cys Gln Tyr Asn Leu Ser Ser Arg Ala Leu Lys Cys

1 5 10

<210> 39

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> mAb-specific epitope

<400> 39

Cys Val Trp Gln Arg Trp Gln Lys Ser Tyr Val Cys

1 5 10

<210> 40

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> mAb-specific epitope

<400> 40

Cys Met Trp Asp Arg Phe Ser Arg Trp Tyr Lys Cys

1 5 10

<210> 41

<211> 25

<212> PRT

<213> Homo sapiens

<400> 41

Ser Phe Val Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp

1 5 10 15

Lys Leu Ala Ala Phe Pro Glu Asp Arg

20 25

<210> 42

<211> 19

<212> PRT

<213> Homo sapiens

<400> 42

Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu Ala Pro Lys Ala Gln

1 5 10 15

Ile Lys Glu

<210> 43

<211> 557

<212> PRT

<213> Rodents

<400> 43

Met Pro Pro Pro Arg Leu Leu Phe Phe Leu Leu Phe Leu Thr Pro Met

1 5 10 15

Glu Val Arg Pro Glu Glu Pro Leu Val Val Lys Val Glu Glu Gly Asp

20 25 30

Asn Ala Val Leu Gln Cys Leu Lys Gly Thr Ser Asp Gly Pro Thr Gln

35 40 45

Gln Leu Thr Trp Ser Arg Glu Ser Pro Leu Lys Pro Phe Leu Lys Leu

50 55 60

Ser Leu Gly Leu Pro Gly Leu Gly Ile His Met Arg Pro Leu Ala Ile

65 70 75 80

Trp Leu Phe Ile Phe Asn Val Ser Gln Gln Met Gly Gly Phe Tyr Leu

85 90 95

Cys Gln Pro Gly Pro Pro Ser Glu Lys Ala Trp Gln Pro Gly Trp Thr

100 105 110

Val Asn Val Glu Gly Ser Gly Glu Leu Phe Arg Trp Asn Val Ser Asp

115 120 125

Leu Gly Gly Leu Gly Cys Gly Leu Lys Asn Arg Ser Ser Glu Gly Pro

130 135 140

Ser Ser Pro Ser Gly Lys Leu Met Ser Pro Lys Leu Tyr Val Trp Ala

145 150 155 160

Lys Asp Arg Pro Glu Ile Trp Glu Gly Glu Pro Pro Cys Leu Pro Pro

165 170 175

Arg Asp Ser Leu Asn Gln Ser Leu Ser Gln Asp Leu Thr Met Ala Pro

180 185 190

Gly Ser Thr Leu Trp Leu Ser Cys Gly Val Pro Pro Asp Ser Val Ser

195 200 205

Arg Gly Pro Leu Ser Trp Thr His Val His Pro Lys Gly Pro Lys Ser

210 215 220

Leu Leu Ser Leu Glu Leu Lys Asp Asp Arg Pro Ala Arg Asp Met Trp

225 230 235 240

Val Met Glu Thr Gly Leu Leu Leu Pro Arg Ala Thr Ala Gln Asp Ala

245 250 255

Gly Lys Tyr Tyr Cys His Arg Gly Asn Leu Thr Met Ser Phe His Leu

260 265 270

Glu Ile Thr Ala Arg Pro Val Leu Trp His Trp Leu Leu Arg Thr Gly

275 280 285

Gly Trp Lys Val Ser Ala Val Thr Leu Ala Tyr Leu Ile Phe Cys Leu

290 295 300

Cys Ser Leu Val Gly Ile Leu His Leu Gln Arg Ala Leu Val Leu Arg

305 310 315 320

Arg Lys Arg Lys Arg Met Thr Asp Pro Thr Arg Arg Phe Phe Lys Val

325 330 335

Thr Pro Pro Pro Gly Ser Gly Pro Gln Asn Gln Tyr Gly Asn Val Leu

340 345 350

Ser Leu Pro Thr Pro Thr Ser Gly Leu Gly Arg Ala Gln Arg Trp Ala

355 360 365

Ala Gly Leu Gly Gly Thr Ala Pro Ser Tyr Gly Asn Pro Ser Ser Asp

370 375 380

Val Gln Ala Asp Gly Ala Leu Gly Ser Arg Ser Pro Pro Gly Val Gly

385 390 395 400

Pro Glu Glu Glu Glu Gly Glu Gly Tyr Glu Glu Pro Asp Ser Glu Glu

405 410 415

Asp Ser Glu Phe Tyr Glu Asn Asp Ser Asn Leu Gly Gln Asp Gln Leu

420 425 430

Ser Gln Asp Gly Ser Gly Tyr Glu Asn Pro Glu Asp Glu Pro Leu Gly

435 440 445

Pro Glu Asp Glu Asp Ser Phe Ser Asn Ala Glu Ser Tyr Glu Asn Glu

450 455 460

Asp Glu Glu Leu Thr Gln Pro Val Ala Arg Thr Met Asp Phe Leu Ser

465 470 475 480

Pro His Gly Ser Ala Trp Asp Pro Ser Arg Glu Ala Thr Ser Leu Ala

485 490 495

Gly Ser Gln Ser Tyr Glu Asp Met Arg Gly Ile Leu Tyr Ala Ala Pro

500 505 510

Gln Leu Arg Ser Ile Arg Gly Gln Pro Gly Pro Asn His Glu Glu Asp

515 520 525

Ala Asp Ser Tyr Glu Asn Met Asp Asn Pro Asp Gly Pro Asp Pro Ala

530 535 540

Trp Gly Gly Gly Gly Arg Met Gly Thr Trp Ser Thr Arg

545 550 555

<210> 44

<211> 300

<212> PRT

<213> Rodents

<400> 44

Met Ala Asn Cys Glu Phe Ser Pro Val Ser Gly Asp Lys Pro Cys Cys

1 5 10 15

Arg Leu Ser Arg Arg Ala Gln Leu Cys Leu Gly Val Ser Ile Leu Val

20 25 30

Leu Ile Leu Val Val Val Leu Ala Val Val Val Pro Arg Trp Arg Gln

35 40 45

Gln Trp Ser Gly Pro Gly Thr Thr Lys Arg Phe Pro Glu Thr Val Leu

50 55 60

Ala Arg Cys Val Lys Tyr Thr Glu Ile His Pro Glu Met Arg His Val

65 70 75 80

Asp Cys Gln Ser Val Trp Asp Ala Phe Lys Gly Ala Phe Ile Ser Lys

85 90 95

His Pro Cys Asn Ile Thr Glu Glu Asp Tyr Gln Pro Leu Met Lys Leu

100 105 110

Gly Thr Gln Thr Val Pro Cys Asn Lys Ile Leu Leu Trp Ser Arg Ile

115 120 125

Lys Asp Leu Ala His Gln Phe Thr Gln Val Gln Arg Asp Met Phe Thr

130 135 140

Leu Glu Asp Thr Leu Leu Gly Tyr Leu Ala Asp Asp Leu Thr Trp Cys

145 150 155 160

Gly Glu Phe Asn Thr Ser Lys Ile Asn Tyr Gln Ser Cys Pro Asp Trp

165 170 175

Arg Lys Asp Cys Ser Asn Asn Pro Val Ser Val Phe Trp Lys Thr Val

180 185 190

Ser Arg Arg Phe Ala Glu Ala Ala Cys Asp Val Val His Val Met Leu

195 200 205

Asn Gly Ser Arg Ser Lys Ile Phe Asp Lys Asn Ser Thr Phe Gly Ser

210 215 220

Val Glu Val His Asn Leu Gln Pro Glu Lys Val Gln Thr Leu Glu Ala

225 230 235 240

Trp Val Ile His Gly Gly Arg Glu Asp Ser Arg Asp Leu Cys Gln Asp

245 250 255

Pro Thr Ile Lys Glu Leu Glu Ser Ile Ile Ser Lys Arg Asn Ile Gln

260 265 270

Phe Ser Cys Lys Asn Ile Tyr Arg Pro Asp Lys Phe Leu Gln Cys Val

275 280 285

Lys Asn Pro Glu Asp Ser Ser Cys Thr Ser Glu Ile

290 295 300

<210> 45

<211> 378

<212> PRT

<213> Rodents

<400> 45

Met Val Leu Leu Trp Leu Thr Leu Leu Leu Ile Ala Leu Pro Cys Leu

1 5 10 15

Leu Gln Thr Lys Glu Asp Pro Asn Pro Pro Ile Thr Asn Leu Arg Met

20 25 30

Lys Ala Lys Ala Gln Gln Leu Thr Trp Asp Leu Asn Arg Asn Val Thr

35 40 45

Asp Ile Glu Cys Val Lys Asp Ala Asp Tyr Ser Met Pro Ala Val Asn

50 55 60

Asn Ser Tyr Cys Gln Phe Gly Ala Ile Ser Leu Cys Glu Val Thr Asn

65 70 75 80

Tyr Thr Val Arg Val Ala Asn Pro Pro Phe Ser Thr Trp Ile Leu Phe

85 90 95

Pro Glu Asn Ser Gly Lys Pro Trp Ala Gly Ala Glu Asn Leu Thr Cys

100 105 110

Trp Ile His Asp Val Asp Phe Leu Ser Cys Ser Trp Ala Val Gly Pro

115 120 125

Gly Ala Pro Ala Asp Val Gln Tyr Asp Leu Tyr Leu Asn Val Ala Asn

130 135 140

Arg Arg Gln Gln Tyr Glu Cys Leu His Tyr Lys Thr Asp Ala Gln Gly

145 150 155 160

Thr Arg Ile Gly Cys Arg Phe Asp Asp Ile Ser Arg Leu Ser Ser Gly

165 170 175

Ser Gln Ser Ser His Ile Leu Val Arg Gly Arg Ser Ala Ala Phe Gly

180 185 190

Ile Pro Cys Thr Asp Lys Phe Val Val Phe Ser Gln Ile Glu Ile Leu

195 200 205

Thr Pro Pro Asn Met Thr Ala Lys Cys Asn Lys Thr His Ser Phe Met

210 215 220

His Trp Lys Met Arg Ser His Phe Asn Arg Lys Phe Arg Tyr Glu Leu

225 230 235 240

Gln Ile Gln Lys Arg Met Gln Pro Val Ile Thr Glu Gln Val Arg Asp

245 250 255

Arg Thr Ser Phe Gln Leu Leu Asn Pro Gly Thr Tyr Thr Val Gln Ile

260 265 270

Arg Ala Arg Glu Arg Val Tyr Glu Phe Leu Ser Ala Trp Ser Thr Pro

275 280 285

Gln Arg Phe Glu Cys Asp Gln Glu Glu Gly Ala Asn Thr Arg Ala Trp

290 295 300

Arg Thr Ser Leu Leu Ile Ala Leu Gly Thr Leu Leu Ala Leu Val Cys

305 310 315 320

Val Phe Val Ile Cys Arg Arg Tyr Leu Val Met Gln Arg Leu Phe Pro

325 330 335

Arg Ile Pro His Met Lys Asp Pro Ile Gly Asp Ser Phe Gln Asn Asp

340 345 350

Lys Leu Val Val Trp Glu Ala Gly Lys Ala Gly Leu Glu Glu Cys Leu

355 360 365

Val Thr Glu Val Gln Val Val Gln Lys Thr

370 375

<210> 46

<211> 335

<212> PRT

<213> Rodents

<400> 46

Met Ala Gly Ser Pro Thr Cys Leu Thr Leu Ile Tyr Ile Leu Trp Gln

1 5 10 15

Leu Thr Gly Ser Ala Ala Ser Gly Pro Val Lys Glu Leu Val Gly Ser

20 25 30

Val Gly Gly Ala Val Thr Phe Pro Leu Lys Ser Lys Val Lys Gln Val

35 40 45

Asp Ser Ile Val Trp Thr Phe Asn Thr Thr Pro Leu Val Thr Ile Gln

50 55 60

Pro Glu Gly Gly Thr Ile Ile Val Thr Gln Asn Arg Asn Arg Glu Arg

65 70 75 80

Val Asp Phe Pro Asp Gly Gly Tyr Ser Leu Lys Leu Ser Lys Leu Lys

85 90 95

Lys Asn Asp Ser Gly Ile Tyr Tyr Val Gly Ile Tyr Ser Ser Ser Leu

100 105 110

Gln Gln Pro Ser Thr Gln Glu Tyr Val Leu His Val Tyr Glu His Leu

115 120 125

Ser Lys Pro Lys Val Thr Met Gly Leu Gln Ser Asn Lys Asn Gly Thr

130 135 140

Cys Val Thr Asn Leu Thr Cys Cys Met Glu His Gly Glu Glu Asp Val

145 150 155 160

Ile Tyr Thr Trp Lys Ala Leu Gly Gln Ala Ala Asn Glu Ser His Asn

165 170 175

Gly Ser Ile Leu Pro Ile Ser Trp Arg Trp Gly Glu Ser Asp Met Thr

180 185 190

Phe Ile Cys Val Ala Arg Asn Pro Val Ser Arg Asn Phe Ser Ser Pro

195 200 205

Ile Leu Ala Arg Lys Leu Cys Glu Gly Ala Ala Asp Asp Pro Asp Ser

210 215 220

Ser Met Val Leu Leu Cys Leu Leu Leu Val Pro Leu Leu Leu Ser Leu

225 230 235 240

Phe Val Leu Gly Leu Phe Leu Trp Phe Leu Lys Arg Glu Arg Gln Glu

245 250 255

Glu Tyr Ile Glu Glu Lys Lys Arg Val Asp Ile Cys Arg Glu Thr Pro

260 265 270

Asn Ile Cys Pro His Ser Gly Glu Asn Thr Glu Tyr Asp Thr Ile Pro

275 280 285

His Thr Asn Arg Thr Ile Leu Lys Glu Asp Pro Ala Asn Thr Val Tyr

290 295 300

Ser Thr Val Glu Ile Pro Lys Lys Met Glu Asn Pro His Ser Leu Leu

305 310 315 320

Thr Met Pro Asp Thr Pro Arg Leu Phe Ala Tyr Glu Asn Val Ile

325 330 335

<210> 47

<211> 184

<212> PRT

<213> Rodents

<400> 47

Met Leu Gln Met Ala Gly Gln Cys Ser Gln Asn Glu Tyr Phe Asp Ser

1 5 10 15

Leu Leu His Ala Cys Ile Pro Cys Gln Leu Arg Cys Ser Ser Asn Thr

20 25 30

Pro Pro Leu Thr Cys Gln Arg Tyr Cys Asn Ala Ser Val Thr Asn Ser

35 40 45

Val Lys Gly Thr Asn Ala Ile Leu Trp Thr Cys Leu Gly Leu Ser Leu

50 55 60

Ile Ile Ser Leu Ala Val Phe Val Leu Met Phe Leu Leu Arg Lys Ile

65 70 75 80

Asn Ser Glu Pro Leu Lys Asp Glu Phe Lys Asn Thr Gly Ser Gly Leu

85 90 95

Leu Gly Met Ala Asn Ile Asp Leu Glu Lys Ser Arg Thr Gly Asp Glu

100 105 110

Ile Ile Leu Pro Arg Gly Leu Glu Tyr Thr Val Glu Glu Cys Thr Cys

115 120 125

Glu Asp Cys Ile Lys Ser Lys Pro Lys Val Asp Ser Asp His Cys Phe

130 135 140

Pro Leu Pro Ala Met Glu Glu Gly Ala Thr Ile Leu Val Thr Thr Lys

145 150 155 160

Thr Asn Asp Tyr Cys Lys Ser Leu Pro Ala Ala Leu Ser Ala Thr Glu

165 170 175

Ile Glu Lys Ser Ile Ser Ala Arg

180

<210> 48

<211> 993

<212> PRT

<213> Rodents

<400> 48

Met Pro Ala Leu Ala Arg Asp Gly Gly Gln Leu Pro Leu Leu Val Val

1 5 10 15

Phe Ser Ala Met Ile Phe Gly Thr Ile Thr Asn Gln Asp Leu Pro Val

20 25 30

Ile Lys Cys Val Leu Ile Asn His Lys Asn Asn Asp Ser Ser Val Gly

35 40 45

Lys Ser Ser Ser Tyr Pro Met Val Ser Glu Ser Pro Glu Asp Leu Gly

50 55 60

Cys Ala Leu Arg Pro Gln Ser Ser Gly Thr Val Tyr Glu Ala Ala Ala

65 70 75 80

Val Glu Val Asp Val Ser Ala Ser Ile Thr Leu Gln Val Leu Val Asp

85 90 95

Ala Pro Gly Asn Ile Ser Cys Leu Trp Val Phe Lys His Ser Ser Leu

100 105 110

Asn Cys Gln Pro His Phe Asp Leu Gln Asn Arg Gly Val Val Ser Met

115 120 125

Val Ile Leu Lys Met Thr Glu Thr Gln Ala Gly Glu Tyr Leu Leu Phe

130 135 140

Ile Gln Ser Glu Ala Thr Asn Tyr Thr Ile Leu Phe Thr Val Ser Ile

145 150 155 160

Arg Asn Thr Leu Leu Tyr Thr Leu Arg Arg Pro Tyr Phe Arg Lys Met

165 170 175

Glu Asn Gln Asp Ala Leu Val Cys Ile Ser Glu Ser Val Pro Glu Pro

180 185 190

Ile Val Glu Trp Val Leu Cys Asp Ser Gln Gly Glu Ser Cys Lys Glu

195 200 205

Glu Ser Pro Ala Val Val Lys Lys Glu Glu Lys Val Leu His Glu Leu

210 215 220

Phe Gly Thr Asp Ile Arg Cys Cys Ala Arg Asn Glu Leu Gly Arg Glu

225 230 235 240

Cys Thr Arg Leu Phe Thr Ile Asp Leu Asn Gln Thr Pro Gln Thr Thr

245 250 255

Leu Pro Gln Leu Phe Leu Lys Val Gly Glu Pro Leu Trp Ile Arg Cys

260 265 270

Lys Ala Val His Val Asn His Gly Phe Gly Leu Thr Trp Glu Leu Glu

275 280 285

Asn Lys Ala Leu Glu Glu Gly Asn Tyr Phe Glu Met Ser Thr Tyr Ser

290 295 300

Thr Asn Arg Thr Met Ile Arg Ile Leu Phe Ala Phe Val Ser Ser Val

305 310 315 320

Ala Arg Asn Asp Thr Gly Tyr Tyr Thr Cys Ser Ser Ser Lys His Pro

325 330 335

Ser Gln Ser Ala Leu Val Thr Ile Val Glu Lys Gly Phe Ile Asn Ala

340 345 350

Thr Asn Ser Ser Glu Asp Tyr Glu Ile Asp Gln Tyr Glu Glu Phe Cys

355 360 365

Phe Ser Val Arg Phe Lys Ala Tyr Pro Gln Ile Arg Cys Thr Trp Thr

370 375 380

Phe Ser Arg Lys Ser Phe Pro Cys Glu Gln Lys Gly Leu Asp Asn Gly

385 390 395 400

Tyr Ser Ile Ser Lys Phe Cys Asn His Lys His Gln Pro Gly Glu Tyr

405 410 415

Ile Phe His Ala Glu Asn Asp Asp Ala Gln Phe Thr Lys Met Phe Thr

420 425 430

Leu Asn Ile Arg Arg Lys Pro Gln Val Leu Ala Glu Ala Ser Ala Ser

435 440 445

Gln Ala Ser Cys Phe Ser Asp Gly Tyr Pro Leu Pro Ser Trp Thr Trp

450 455 460

Lys Lys Cys Ser Asp Lys Ser Pro Asn Cys Thr Glu Glu Ile Thr Glu

465 470 475 480

Gly Val Trp Asn Arg Lys Ala Asn Arg Lys Val Phe Gly Gln Trp Val

485 490 495

Ser Ser Ser Thr Leu Asn Met Ser Glu Ala Ile Lys Gly Phe Leu Val

500 505 510

Lys Cys Cys Ala Tyr Asn Ser Leu Gly Thr Ser Cys Glu Thr Ile Leu

515 520 525

Leu Asn Ser Pro Gly Pro Phe Pro Phe Ile Gln Asp Asn Ile Ser Phe

530 535 540

Tyr Ala Thr Ile Gly Val Cys Leu Leu Phe Ile Val Val Leu Thr Leu

545 550 555 560

Leu Ile Cys His Lys Tyr Lys Lys Gln Phe Arg Tyr Glu Ser Gln Leu

565 570 575

Gln Met Val Gln Val Thr Gly Ser Ser Asp Asn Glu Tyr Phe Tyr Val

580 585 590

Asp Phe Arg Glu Tyr Glu Tyr Asp Leu Lys Trp Glu Phe Pro Arg Glu

595 600 605

Asn Leu Glu Phe Gly Lys Val Leu Gly Ser Gly Ala Phe Gly Lys Val

610 615 620

Met Asn Ala Thr Ala Tyr Gly Ile Ser Lys Thr Gly Val Ser Ile Gln

625 630 635 640

Val Ala Val Lys Met Leu Lys Glu Lys Ala Asp Ser Ser Glu Arg Glu

645 650 655

Ala Leu Met Ser Glu Leu Lys Met Met Thr Gln Leu Gly Ser His Glu

660 665 670

Asn Ile Val Asn Leu Leu Gly Ala Cys Thr Leu Ser Gly Pro Ile Tyr

675 680 685

Leu Ile Phe Glu Tyr Cys Cys Tyr Gly Asp Leu Leu Asn Tyr Leu Arg

690 695 700

Ser Lys Arg Glu Lys Phe His Arg Thr Trp Thr Glu Ile Phe Lys Glu

705 710 715 720

His Asn Phe Ser Phe Tyr Pro Thr Phe Gln Ser His Pro Asn Ser Ser

725 730 735

Met Pro Gly Ser Arg Glu Val Gln Ile His Pro Asp Ser Asp Gln Ile

740 745 750

Ser Gly Leu His Gly Asn Ser Phe His Ser Glu Asp Glu Ile Glu Tyr

755 760 765

Glu Asn Gln Lys Arg Leu Glu Glu Glu Glu Asp Leu Asn Val Leu Thr

770 775 780

Phe Glu Asp Leu Leu Cys Phe Ala Tyr Gln Val Ala Lys Gly Met Glu

785 790 795 800

Phe Leu Glu Phe Lys Ser Cys Val His Arg Asp Leu Ala Ala Arg Asn

805 810 815

Val Leu Val Thr His Gly Lys Val Val Lys Ile Cys Asp Phe Gly Leu

820 825 830

Ala Arg Asp Ile Met Ser Asp Ser Asn Tyr Val Val Arg Gly Asn Ala

835 840 845

Arg Leu Pro Val Lys Trp Met Ala Pro Glu Ser Leu Phe Glu Gly Ile

850 855 860

Tyr Thr Ile Lys Ser Asp Val Trp Ser Tyr Gly Ile Leu Leu Trp Glu

865 870 875 880

Ile Phe Ser Leu Gly Val Asn Pro Tyr Pro Gly Ile Pro Val Asp Ala

885 890 895

Asn Phe Tyr Lys Leu Ile Gln Asn Gly Phe Lys Met Asp Gln Pro Phe

900 905 910

Tyr Ala Thr Glu Glu Ile Tyr Ile Ile Met Gln Ser Cys Trp Ala Phe

915 920 925

Asp Ser Arg Lys Arg Pro Ser Phe Pro Asn Leu Thr Ser Phe Leu Gly

930 935 940

Cys Gln Leu Ala Asp Ala Glu Glu Ala Met Tyr Gln Asn Val Asp Gly

945 950 955 960

Arg Val Ser Glu Cys Pro His Thr Tyr Gln Asn Arg Arg Pro Phe Ser

965 970 975

Arg Glu Met Asp Leu Gly Leu Leu Ser Pro Gln Ala Gln Val Glu Asp

980 985 990

Ser

<210> 49

<211> 364

<212> PRT

<213> Rodents

<400> 49

Met Pro Leu Leu Leu Leu Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala

1 5 10 15

Met Asp Pro Asn Phe Trp Leu Gln Val Gln Glu Ser Val Thr Val Gln

20 25 30

Glu Gly Leu Cys Val Leu Val Pro Cys Thr Phe Phe His Pro Ile Pro

35 40 45

Tyr Tyr Asp Lys Asn Ser Pro Val His Gly Tyr Trp Phe Arg Glu Gly

50 55 60

Ala Ile Ile Ser Arg Asp Ser Pro Val Ala Thr Asn Lys Leu Asp Gln

65 70 75 80

Glu Val Gln Glu Glu Thr Gln Gly Arg Phe Arg Leu Leu Gly Asp Pro

85 90 95

Ser Arg Asn Asn Cys Ser Leu Ser Ile Val Asp Ala Arg Arg Arg Asp

100 105 110

Asn Gly Ser Tyr Phe Phe Arg Met Glu Arg Gly Ser Thr Lys Tyr Ser

115 120 125

Tyr Lys Ser Pro Gln Leu Ser Val His Val Thr Asp Leu Thr His Arg

130 135 140

Pro Lys Ile Leu Ile Pro Gly Thr Leu Glu Pro Gly His Ser Lys Asn

145 150 155 160

Leu Thr Cys Ser Val Ser Trp Ala Cys Glu Gln Gly Thr Pro Pro Ile

165 170 175

Phe Ser Trp Leu Ser Ala Ala Pro Thr Ser Leu Gly Pro Arg Thr Thr

180 185 190

His Ser Ser Val Leu Ile Ile Thr Pro Arg Pro Gln Asp His Gly Thr

195 200 205

Asn Leu Thr Cys Gln Val Lys Phe Ala Gly Ala Gly Val Thr Thr Glu

210 215 220

Arg Thr Ile Gln Leu Asn Val Thr Tyr Val Pro Gln Asn Pro Thr Thr

225 230 235 240

Gly Ile Phe Pro Gly Asp Gly Ser Gly Lys Gln Glu Thr Arg Ala Gly

245 250 255

Val Val His Gly Ala Ile Gly Gly Ala Gly Val Thr Ala Leu Leu Ala

260 265 270

Leu Cys Leu Cys Leu Ile Phe Phe Ile Val Lys Thr His Arg Arg Lys

275 280 285

Ala Ala Arg Thr Ala Val Gly Arg Asn Asp Thr His Pro Thr Thr Gly

290 295 300

Ser Ala Ser Pro Lys His Gln Lys Lys Ser Lys Leu His Gly Pro Thr

305 310 315 320

Glu Thr Ser Ser Cys Ser Gly Ala Ala Pro Thr Val Glu Met Asp Glu

325 330 335

Glu Leu His Tyr Ala Ser Leu Asn Phe His Gly Met Asn Pro Ser Lys

340 345 350

Asp Thr Ser Thr Glu Tyr Ser Glu Val Arg Thr Gln

355 360

<210> 50

<211> 193

<212> PRT

<213> Rodents

<400> 50

Met Pro Glu Glu Gly Ser Gly Cys Ser Val Arg Arg Arg Pro Tyr Gly

1 5 10 15

Cys Val Leu Arg Ala Ala Leu Val Pro Leu Val Ala Gly Leu Val Ile

20 25 30

Cys Leu Val Val Cys Ile Gln Arg Phe Ala Gln Ala Gln Gln Gln Leu

35 40 45

Pro Leu Glu Ser Leu Gly Trp Asp Val Ala Glu Leu Gln Leu Asn His

50 55 60

Thr Gly Pro Gln Gln Asp Pro Arg Leu Tyr Trp Gln Gly Gly Pro Ala

65 70 75 80

Leu Gly Arg Ser Phe Leu His Gly Pro Glu Leu Asp Lys Gly Gln Leu

85 90 95

Arg Ile His Arg Asp Gly Ile Tyr Met Val His Ile Gln Val Thr Leu

100 105 110

Ala Ile Cys Ser Ser Thr Thr Ala Ser Arg His His Pro Thr Thr Leu

115 120 125

Ala Val Gly Ile Cys Ser Pro Ala Ser Arg Ser Ile Ser Leu Leu Arg

130 135 140

Leu Ser Phe His Gln Gly Cys Thr Ile Ala Ser Gln Arg Leu Thr Pro

145 150 155 160

Leu Ala Arg Gly Asp Thr Leu Cys Thr Asn Leu Thr Gly Thr Leu Leu

165 170 175

Pro Ser Arg Asn Thr Asp Glu Thr Phe Phe Gly Val Gln Trp Val Arg

180 185 190

Pro

<210> 51

<211> 943

<212> PRT

<213> Rodents

<400> 51

Met Arg Pro Ser Gly Thr Ala Gly Ala Ala Leu Leu Ala Leu Leu Ala

1 5 10 15

Ala Leu Cys Pro Ala Ser Arg Ala Leu Glu Glu Lys Lys Gly Asn Tyr

20 25 30

Val Val Thr Asp His Gly Ser Cys Val Arg Ala Cys Gly Ala Asp Ser

35 40 45

Tyr Glu Met Glu Glu Asp Gly Val Arg Lys Cys Lys Lys Cys Glu Gly

50 55 60

Pro Cys Arg Lys Val Cys Asn Gly Ile Gly Ile Gly Glu Phe Lys Asp

65 70 75 80

Ser Leu Ser Ile Asn Ala Thr Asn Ile Lys His Phe Lys Asn Cys Thr

85 90 95

Ser Ile Ser Gly Asp Leu His Ile Leu Pro Val Ala Phe Arg Gly Asp

100 105 110

Ser Phe Thr His Thr Pro Pro Leu Asp Pro Gln Glu Leu Asp Ile Leu

115 120 125

Lys Thr Val Lys Glu Ile Thr Gly Phe Leu Leu Ile Gln Ala Trp Pro

130 135 140

Glu Asn Arg Thr Asp Leu His Ala Phe Glu Asn Leu Glu Ile Ile Arg

145 150 155 160

Gly Arg Thr Lys Gln His Gly Gln Phe Ser Leu Ala Val Val Ser Leu

165 170 175

Asn Ile Thr Ser Leu Gly Leu Arg Ser Leu Lys Glu Ile Ser Asp Gly

180 185 190

Asp Val Ile Ile Ser Gly Asn Lys Asn Leu Cys Tyr Ala Asn Thr Ile

195 200 205

Asn Trp Lys Lys Leu Phe Gly Thr Ser Gly Gln Lys Thr Lys Ile Ile

210 215 220

Ser Asn Arg Gly Glu Asn Ser Cys Lys Ala Thr Gly Gln Val Cys His

225 230 235 240

Ala Leu Cys Ser Pro Glu Gly Cys Trp Gly Pro Glu Pro Arg Asp Cys

245 250 255

Val Ser Cys Arg Asn Val Ser Arg Gly Arg Glu Cys Val Asp Lys Cys

260 265 270

Asn Leu Leu Glu Gly Glu Pro Arg Glu Phe Val Glu Asn Ser Glu Cys

275 280 285

Ile Gln Cys His Pro Glu Cys Leu Pro Gln Ala Met Asn Ile Thr Cys

290 295 300

Thr Gly Arg Gly Pro Asp Asn Cys Ile Gln Cys Ala His Tyr Ile Asp

305 310 315 320

Gly Pro His Cys Val Lys Thr Cys Pro Ala Gly Val Met Gly Glu Asn

325 330 335

Asn Thr Leu Val Trp Lys Tyr Ala Asp Ala Gly His Val Cys His Leu

340 345 350

Cys His Pro Asn Cys Thr Tyr Gly Cys Thr Gly Pro Gly Leu Glu Gly

355 360 365

Cys Pro Thr Asn Gly Pro Lys Ile Pro Ser Ile Ala Thr Gly Met Val

370 375 380

Gly Ala Leu Leu Leu Leu Leu Val Val Ala Leu Gly Ile Gly Leu Phe

385 390 395 400

Met Arg Arg Arg His Ile Val Arg Lys Arg Thr Leu Arg Arg Leu Leu

405 410 415

Gln Glu Arg Glu Leu Val Glu Pro Leu Thr Pro Ser Gly Glu Ala Pro

420 425 430

Asn Gln Ala Leu Leu Arg Ile Leu Lys Glu Thr Glu Phe Lys Lys Ile

435 440 445

Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys Gly Leu Trp

450 455 460

Ile Pro Glu Gly Glu Lys Val Lys Ile Pro Val Ala Ile Lys Glu Leu

465 470 475 480

Arg Glu Ala Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu Asp Glu Ala

485 490 495

Tyr Val Met Ala Ser Val Asp Asn Pro His Val Cys Arg Leu Leu Gly

500 505 510

Ile Cys Leu Thr Ser Thr Val Gln Leu Ile Thr Gln Leu Met Pro Phe

515 520 525

Gly Cys Leu Leu Asp Tyr Val Arg Glu His Lys Asp Asn Ile Gly Ser

530 535 540

Gln Tyr Leu Leu Asn Trp Cys Val Gln Ile Ala Lys Gly Met Asn Tyr

545 550 555 560

Leu Glu Asp Arg Arg Leu Val His Arg Asp Leu Ala Ala Arg Asn Val

565 570 575

Leu Val Lys Thr Pro Gln His Val Lys Ile Thr Asp Phe Gly Leu Ala

580 585 590

Lys Leu Leu Gly Ala Glu Glu Lys Glu Tyr His Ala Glu Gly Gly Lys

595 600 605

Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu His Arg Ile Tyr

610 615 620

Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val Trp Glu Leu

625 630 635 640

Met Thr Phe Gly Ser Lys Pro Tyr Asp Gly Ile Pro Ala Ser Glu Ile

645 650 655

Ser Ser Ile Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro Pro Ile Cys

660 665 670

Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met Ile Asp Ala

675 680 685

Asp Ser Arg Pro Lys Phe Arg Glu Leu Ile Ile Glu Phe Ser Lys Met

690 695 700

Ala Arg Asp Pro Gln Arg Tyr Leu Val Ile Gln Gly Asp Glu Arg Met

705 710 715 720

His Leu Pro Ser Pro Thr Asp Ser Asn Phe Tyr Arg Ala Leu Met Asp

725 730 735

Glu Glu Asp Met Asp Asp Val Val Asp Ala Asp Glu Tyr Leu Ile Pro

740 745 750

Gln Gln Gly Phe Phe Ser Ser Pro Ser Thr Ser Arg Thr Pro Leu Leu

755 760 765

Ser Ser Leu Ser Ala Thr Ser Asn Asn Ser Thr Val Ala Cys Ile Asp

770 775 780

Arg Asn Gly Leu Gln Ser Cys Pro Ile Lys Glu Asp Ser Phe Leu Gln

785 790 795 800

Arg Tyr Ser Ser Asp Pro Thr Gly Ala Leu Thr Glu Asp Ser Ile Asp

805 810 815

Asp Thr Phe Leu Pro Val Pro Glu Tyr Ile Asn Gln Ser Val Pro Lys

820 825 830

Arg Pro Ala Gly Ser Val Gln Asn Pro Val Tyr His Asn Gln Pro Leu

835 840 845

Asn Pro Ala Pro Ser Arg Asp Pro His Tyr Gln Asp Pro His Ser Thr

850 855 860

Ala Val Gly Asn Pro Glu Tyr Leu Asn Thr Val Gln Pro Thr Cys Val

865 870 875 880

Asn Ser Thr Phe Asp Ser Pro Ala His Trp Ala Gln Lys Gly Ser His

885 890 895

Gln Ile Ser Leu Asp Asn Pro Asp Tyr Gln Gln Asp Phe Phe Pro Lys

900 905 910

Glu Ala Lys Pro Asn Gly Ile Phe Lys Gly Ser Thr Ala Glu Asn Ala

915 920 925

Glu Tyr Leu Arg Val Ala Pro Gln Ser Ser Glu Phe Ile Gly Ala

930 935 940

<210> 52

<211> 497

<212> PRT

<213> Rodents

<400> 52

Met Gln Asp Pro Ala Ser Thr Cys Val Pro Glu Pro Ala Ser Gln His

1 5 10 15

Thr Leu Arg Ser Gly Pro Gly Cys Leu Gln Gln Pro Glu Gln Gln Gly

20 25 30

Val Arg Asp Pro Gly Gly Ile Trp Ala Lys Leu Gly Ala Ala Glu Ala

35 40 45

Ser Ala Glu Arg Leu Gln Gly Arg Arg Ser Arg Gly Ala Ser Gly Ser

50 55 60

Glu Pro Gln Gln Met Gly Ser Asp Val Arg Asp Leu Asn Ala Leu Leu

65 70 75 80

Pro Ala Val Pro Ser Leu Gly Gly Gly Gly Gly Cys Ala Leu Pro Val

85 90 95

Ser Gly Ala Ala Gln Trp Ala Pro Val Leu Asp Phe Ala Pro Pro Gly

100 105 110

Ala Ser Ala Tyr Gly Ser Leu Gly Gly Pro Ala Pro Pro Pro Ala Pro

115 120 125

Pro Pro Pro Pro Pro Pro Pro His Ser Phe Ile Lys Gln Glu Pro

130 135 140

Ser Trp Gly Gly Ala Glu Pro His Glu Glu Gln Cys Leu Ser Ala Phe

145 150 155 160

Thr Val His Phe Ser Gly Gln Phe Thr Gly Thr Ala Gly Ala Cys Arg

165 170 175

Tyr Gly Pro Phe Gly Pro Pro Pro Pro Ser Gln Ala Ser Ser Gly Gln

180 185 190

Ala Arg Met Phe Pro Asn Ala Pro Tyr Leu Pro Ser Cys Leu Glu Ser

195 200 205

Gln Pro Ala Ile Arg Asn Gln Gly Tyr Ser Thr Val Thr Phe Asp Gly

210 215 220

Thr Pro Ser Tyr Gly His Thr Pro Ser His His Ala Ala Gln Phe Pro

225 230 235 240

Asn His Ser Phe Lys His Glu Asp Pro Met Gly Gln Gln Gly Ser Leu

245 250 255

Gly Glu Gln Gln Tyr Ser Val Pro Pro Pro Val Tyr Gly Cys His Thr

260 265 270

Pro Thr Asp Ser Cys Thr Gly Ser Gln Ala Leu Leu Leu Arg Thr Pro

275 280 285

Tyr Ser Ser Asp Asn Leu Tyr Gln Met Thr Ser Gln Leu Glu Cys Met

290 295 300

Thr Trp Asn Gln Met Asn Leu Gly Ala Thr Leu Lys Gly His Ser Thr

305 310 315 320

Gly Tyr Glu Ser Asp Asn His Thr Thr Pro Ile Leu Cys Gly Ala Gln

325 330 335

Tyr Arg Ile His Thr His Gly Val Phe Arg Gly Ile Gln Asp Val Arg

340 345 350

Arg Val Pro Gly Val Ala Pro Thr Leu Val Arg Ser Ala Ser Glu Thr

355 360 365

Ser Glu Lys Arg Pro Phe Met Cys Ala Tyr Pro Gly Cys Asn Lys Arg

370 375 380

Tyr Phe Lys Leu Ser His Leu Gln Met His Ser Arg Lys His Thr Gly

385 390 395 400

Glu Lys Pro Tyr Gln Cys Asp Phe Lys Asp Cys Glu Arg Arg Phe Ser

405 410 415

Arg Ser Asp Gln Leu Lys Arg His Gln Arg Arg His Thr Gly Val Lys

420 425 430

Pro Phe Gln Cys Lys Thr Cys Gln Arg Lys Phe Ser Arg Ser Asp His

435 440 445

Leu Lys Thr His Thr Arg Thr His Thr Gly Glu Lys Pro Phe Ser Cys

450 455 460

Arg Trp Pro Ser Cys Gln Lys Lys Phe Ala Arg Ser Asp Glu Leu Val

465 470 475 480

Arg His His Asn Met His Gln Arg Asn Met Thr Lys Leu Gln Leu Ala

485 490 495

Leu

<210> 53

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<223> CD19-1 VH chain

<400> 53

Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln

1 5 10 15

Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr

20 25 30

Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Tyr Asn Ser Ala Leu Lys

50 55 60

Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu

65 70 75 80

Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala

85 90 95

Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val

115

<210> 54

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> CD19-1 VL chain

<400> 54

Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Ser Leu Ser Ala Ser Leu Gly

1 5 10 15

Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr

20 25 30

Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile

35 40 45

Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln

65 70 75 80

Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr

100 105

<210> 55

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<223> CD19-2 VH chain

<400> 55

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Ile 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 Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys 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 Gly Thr Tyr Tyr Tyr Gly Ser Arg Val Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Thr Leu Thr Val

115

<210> 56

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> CD19-2 VL chain

<400> 56

Asp Ile Val Met Thr Gln Ala Ala Pro Ser Ile Pro Val Thr Pro Gly

1 5 10 15

Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu Asn Ser

20 25 30

Asn Gly Asn Thr Tyr Leu Tyr Trp Phe 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 Ala Phe Thr Leu Arg Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His

85 90 95

Leu Glu Tyr Pro Phe Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105 110

<210> 57

<211> 115

<212> PRT

<213> Rodents

<400> 57

Gln Val Gln Leu Gln Gln Pro 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 Ser Tyr

20 25 30

Trp Met Asn Trp Val Lys Gln Arg Pro Asp Gln Gly Leu Glu Trp Ile

35 40 45

Gly Arg Ile Asp Pro Tyr Asp Ser Glu Thr His Tyr Asn Gln Lys Phe

50 55 60

Lys Asp Lys Ala Ile 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 Gly Asn Trp Asp Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr

100 105 110

Val Ser Ser

115

<210> 58

<211> 107

<212> PRT

<213> Rodents

<400> 58

Asp Val Gln Ile Thr Gln Ser Pro Ser Tyr Leu Ala Ala Ser Pro Gly

1 5 10 15

Glu Thr Ile Thr Ile Asn Cys Arg Ala Ser Lys Ser Ile Ser Lys Asp

20 25 30

Leu Ala Trp Tyr Gln Glu Lys Pro Gly Lys Thr Asn Lys Leu Leu Ile

35 40 45

Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Met Tyr Tyr Cys Gln Gln His Asn Lys Tyr Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 59

<211> 118

<212> PRT

<213> Rodents

<400> 59

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe

50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Ser Val Thr Val Ser Ser

115

<210> 60

<211> 111

<212> PRT

<213> Rodents

<400> 60

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 Glu Ser Val Asp Asn Tyr

20 25 30

Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn

65 70 75 80

Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn

85 90 95

Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105 110

<210> 61

<211> 113

<212> PRT

<213> Rodents

<400> 61

Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser His Lys Phe Met

1 5 10 15

Ser Thr Ser Val Gly Asp Arg Val Asn Ile Thr Cys Lys Ala Ser Gln

20 25 30

Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro

50 55 60

Asp Arg Phe Thr Gly Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

65 70 75 80

Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln Tyr

85 90 95

Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

Arg

<210> 62

<211> 127

<212> PRT

<213> Rodents

<400> 62

Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr

20 25 30

Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu

35 40 45

Ala Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala

50 55 60

Ser Val Lys Gly Arg Phe Thr Leu Ser Arg Asp Asp Ser Gln Ser Ile

65 70 75 80

Leu Tyr Leu Gln Met Asn Ala Leu Arg Pro Glu Asp Ser Ala Thr Tyr

85 90 95

Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly

100 105 110

Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser

115 120 125

<210> 63

<211> 119

<212> PRT

<213> Rodents

<400> 63

Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser

1 5 10 15

Leu Ser Leu Thr Cys Ser Val Thr Asp Tyr Ser Ile Thr Ser Gly Tyr

20 25 30

Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met

35 40 45

Gly Tyr Ile Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ser

85 90 95

Arg Gly Glu Gly Phe Tyr Phe Asp Ser Trp Gly Gln Gly Thr Thr Leu

100 105 110

Thr Val Ser Ser Ala Arg Ser

115

<210> 64

<211> 113

<212> PRT

<213> Rodents

<400> 64

Asp Ile Met Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly

1 5 10 15

Glu Lys Phe Thr Met Thr Cys Lys Ser Ser Gln Ser Leu Phe Phe Gly

20 25 30

Ser Thr Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ala

65 70 75 80

Ile Ser Ser Val Met Pro Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln

85 90 95

Tyr Tyr Asn Tyr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile

100 105 110

Lys

<210> 65

<211> 115

<212> PRT

<213> Rodents

<400> 65

Glu 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 Thr Phe Thr Asp Tyr

20 25 30

Asn Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Tyr Pro Tyr Asn Gly Gly Thr Gly Tyr Asn Gln Lys Phe

50 55 60

Lys Ser Lys Ala Thr Leu Thr Val Asp Asn Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Asp Val Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Arg Pro Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val

100 105 110

Thr Val Ser

115

<210> 66

<211> 111

<212> PRT

<213> Rodents

<400> 66

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 Glu Ser Val Asp Asn Tyr

20 25 30

Gly Ile Ser Phe Met 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 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

Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 67

<211> 117

<212> PRT

<213> Rodents

<400> 67

Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Thr

1 5 10 15

Phe Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Asp Ile Asn Trp Val Asn Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Leu Gln Leu Asn Asn Leu Thr Ser Glu Asn Ser Ala Val Tyr Phe Cys

85 90 95

Ala Ser Gly Tyr Glu Asp Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser

100 105 110

Val Thr Val Ser Ser

115

<210> 68

<211> 108

<212> PRT

<213> Rodents

<400> 68

Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly

1 5 10 15

Glu Arg Val Ile Ile Asn Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr

20 25 30

Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile

35 40 45

Tyr Arg Ala Asn Arg Leu Val 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 Glu Tyr

65 70 75 80

Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Leu

85 90 95

Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg

100 105

<210> 69

<211> 120

<212> PRT

<213> Rodents

<400> 69

Glu Val Lys Leu Gln Glu 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 Lys Phe Thr Asp Tyr

20 25 30

Val Val His Trp Leu Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys 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 Val Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Tyr Arg Tyr Glu Val Tyr Gly Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 70

<211> 115

<212> PRT

<213> Rodents

<400> 70

Asp Ile Val Leu Thr Gln Ser Pro Thr Ile Met Ser Ala Ser Pro Gly

1 5 10 15

Glu Arg Val Thr Met Thr Cys Thr Ala Ser Ser Ser Val Asn Tyr Ile

20 25 30

His Trp Tyr Gln Gln Lys Ser Gly Asp Ser Pro Leu Arg Trp Ile Phe

35 40 45

Asp Thr Ser Lys Val 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 Thr Met Glu Ala Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Arg Ser Tyr Pro Leu Thr

85 90 95

Phe Gly Asp Gly Thr Arg Leu Glu Leu Lys Arg Ala Asp Ala Ala Pro

100 105 110

Thr Val Ser

115

<210> 71

<211> 118

<212> PRT

<213> Rodents

<400> 71

Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Val 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

Tyr Ile His Trp Ile Lys Gln Thr Pro Gly Gln Gly Leu Glu Trp Val

35 40 45

Gly Val Ile Tyr Pro Gly Asn Asp Asp Ile Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Thr 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 Glu Val Arg Leu Arg Tyr Phe Asp Val Trp Gly Ala Gly Thr

100 105 110

Thr Val Thr Val Ser Ser

115

<210> 72

<211> 113

<212> PRT

<213> Rodents

<400> 72

Asn Ile Met Leu Thr Gln Ser Pro Ser Ser Leu Ala Val Ser Ala Gly

1 5 10 15

Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Val Phe Phe Ser

20 25 30

Ser Ser Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Ile Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Val Gln Ser Glu Asp Leu Ala Ile Tyr Tyr Cys His Gln

85 90 95

Tyr Leu Ser Ser Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

Arg

<210> 73

<211> 115

<212> PRT

<213> Rodents

<400> 73

Glu 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 Thr Phe Thr Asp Tyr

20 25 30

Asn Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Tyr Pro Tyr Asn Gly Gly Thr Gly Tyr Asn Gln Lys Phe

50 55 60

Lys Ser Lys Ala Thr Leu Thr Val Asp Asn Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Asp Val Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Arg Pro Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val

100 105 110

Thr Val Ser

115

<210> 74

<211> 111

<212> PRT

<213> Rodents

<400> 74

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 Glu Ser Val Asp Asn Tyr

20 25 30

Gly Ile Ser Phe Met 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 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

Glu Val Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 75

<211> 117

<212> PRT

<213> Rodents

<400> 75

Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Thr

1 5 10 15

Phe Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Tyr

20 25 30

Asp Ile Asn Trp Val Asn Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Trp Ile Tyr Pro Gly Asp Gly Ser Thr Lys Tyr Asn Glu Lys Phe

50 55 60

Lys Ala Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Leu Gln Leu Asn Asn Leu Thr Ser Glu Asn Ser Ala Val Tyr Phe Cys

85 90 95

Ala Ser Gly Tyr Glu Asp Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser

100 105 110

Val Thr Val Ser Ser

115

<210> 76

<211> 108

<212> PRT

<213> Rodents

<400> 76

Asp Ile Lys Met Thr Gln Ser Pro Ser Ser Met Tyr Ala Ser Leu Gly

1 5 10 15

Glu Arg Val Ile Ile Asn Cys Lys Ala Ser Gln Asp Ile Asn Ser Tyr

20 25 30

Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile

35 40 45

Tyr Arg Ala Asn Arg Leu Val 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 Glu Tyr

65 70 75 80

Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Leu

85 90 95

Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg

100 105

<210> 77

<211> 120

<212> PRT

<213> Rodents

<400> 77

Glu 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 Ser Phe Thr Gly Tyr

20 25 30

Tyr Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Arg Ile Asn Pro Asn Asn Gly Val Thr Leu Tyr Asn Gln Lys Phe

50 55 60

Lys Asp Lys Ala Ile Leu Thr Val Asp Lys Ser Ser Thr 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

Ala Arg Ser Thr Met Ile Thr Asn Tyr Val Met Asp Tyr Trp Gly Gln

100 105 110

Val Thr Ser Val Thr Val Ser Ser

115 120

<210> 78

<211> 108

<212> PRT

<213> Rodents

<400> 78

Ser Ile Val Met Thr Gln Thr Pro Thr 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 Thr Leu Leu Ile

35 40 45

Ser Tyr Thr Ser Ser Arg Tyr Ala Gly Val Pro Asp Arg Phe Ile Gly

50 55 60

Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Leu Gln Ala

65 70 75 80

Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Asp Tyr Asn Ser Pro Pro

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg

100 105

<210> 79

<211> 119

<212> PRT

<213> Rodents

<400> 79

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Phe

20 25 30

Gly Met Asn Trp Val Lys Gln Gly Pro Gly Glu Gly Leu Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Asn Thr Gly Glu Pro Arg Tyr Ala Glu Glu Phe

50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Thr Ala Ser Thr Ala Tyr

65 70 75 80

Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Asp Trp Asp Gly Ala Tyr Phe Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Thr Leu Thr Val Ser Ser

115

<210> 80

<211> 107

<212> PRT

<213> Rodents

<400> 80

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

Asn Phe Ala Thr Asn Arg Tyr Thr Gly Val Pro Asn 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 Leu Tyr Phe Cys Gln Gln Asp Tyr Ser Ser Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 81

<211> 117

<212> PRT

<213> Rodents

<400> 81

Gln Val Gln Leu Gln Gln Ser Arg 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

Val Ile Ser Trp Val Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Tyr Pro Gly Ser Asn Ser Ile Tyr Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Arg 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

Ala Met Gly Gly Asn Tyr Gly Phe Asp Tyr Trp Gly Gln Gly Thr Thr

100 105 110

Leu Thr Val Ser Ser

115

<210> 82

<211> 108

<212> PRT

<213> Rodents

<400> 82

Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Leu Gly

1 5 10 15

Glu Arg Val Thr Leu Thr Cys Thr Ala Ser Ser Ser Ser Val Asn Ser Asn

20 25 30

Tyr Leu His Trp Tyr Gln Gln Lys Pro Gly Ser Ser Pro Lys Leu Trp

35 40 45

Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Ala Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu

65 70 75 80

Ala Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Tyr His Arg Ser Pro

85 90 95

Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 83

<211> 122

<212> PRT

<213> Rodents

<400> 83

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Lys Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Arg Ile Arg Ser Lys Ser Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp

50 55 60

Ser Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Gln Ser Met

65 70 75 80

Leu Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala Met Tyr

85 90 95

Tyr Cys Val Arg Gln Trp Asp Tyr Asp Val Arg Ala Met Asn Tyr Trp

100 105 110

Gly Gln Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 84

<211> 107

<212> PRT

<213> Rodents

<400> 84

Asp Ile Val Met Thr Gln Ser His Ile Phe Met Ser Thr Ser Val Gly

1 5 10 15

Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Asp Thr Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Trp Ala Ser Thr Arg Leu Thr Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser

65 70 75 80

Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 85

<211> 118

<212> PRT

<213> Rodents

<400> 85

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala

1 5 10 15

Ser Val Thr Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Asp Tyr

20 25 30

Glu Met His Trp Val Ile Gln Thr Pro Val His Gly Leu Glu Trp Ile

35 40 45

Gly Ala Ile Asp Pro Glu Thr Gly Gly Thr Ala Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Ile 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 Gly Tyr Tyr Asp Tyr Asp Ser Phe Thr Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ala

115

<210> 86

<211> 107

<212> PRT

<213> Rodents

<400> 86

Asp Ile Val Met Thr Gln Ser Gln Lys Ile Met Ser Thr Thr Val Gly

1 5 10 15

Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asn Val Asp Ala Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Ser Ala Ser Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Met Gln Ser

65 70 75 80

Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Asp Ile Tyr Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 87

<211> 119

<212> PRT

<213> Rodents

<400> 87

Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys 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

Ala Met Ser Trp Val Arg Gln Ile Pro Glu Lys Arg Leu Glu Trp Val

35 40 45

Ala Ser Ile Ser Arg Gly Gly Thr Thr Tyr Tyr Pro Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Val Arg Asn Ile Leu Tyr Leu

65 70 75 80

Gln Met Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr Tyr Cys Gly

85 90 95

Arg Tyr Asp Tyr Asp Gly Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Ser Val Thr Val Ser Ser

115

<210> 88

<211> 107

<212> PRT

<213> Rodents

<400> 88

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 Pro Asp Ile Asn Ser Tyr

20 25 30

Leu Ser Trp Phe Gln Gln Lys Pro Gly Lys Ser Pro Lys Thr Leu Ile

35 40 45

Tyr Arg Ala Asn Arg Leu Val Asp Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Gly Gly Ser Gly Gln Asp Tyr Ser Leu Thr Ile Asn Ser Leu Glu Tyr

65 70 75 80

Glu Asp Met Gly Ile Tyr Tyr Cys Leu Gln Tyr Asp Glu Phe Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Met Lys

100 105

<210> 89

<211> 117

<212> PRT

<213> Rodents

<400> 89

Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln

1 5 10 15

Thr Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ser Tyr

20 25 30

Gly Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Ala Gly Gly Phe Thr Asn Tyr Asn Ser Ala Leu Lys

50 55 60

Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Leu Leu

65 70 75 80

Lys Met Thr Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala

85 90 95

Arg Arg Gly Ser Ser Tyr Ser Met Asp Tyr Trp Gly Gln Gly Thr Ser

100 105 110

Val Thr Val Ser Ser

115

<210> 90

<211> 106

<212> PRT

<213> Rodents

<400> 90

Glu Ile Val Leu Ser Gln Ser Pro Ala Ile Thr Ala Ala Ser Leu Gly

1 5 10 15

Gln Lys Val Thr Ile Thr Cys Ser Ala Ser Ser Asn Val Ser Tyr Ile

20 25 30

His Trp Tyr Gln Gln Arg Ser Gly Thr Ser Pro Arg Pro Trp Ile Tyr

35 40 45

Glu Ile Ser Lys Leu Ala Ser Gly Val Pro Val Arg Phe Ser Gly Ser

50 55 60

Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Ala Glu

65 70 75 80

Asp Ala Ala Ile Tyr Tyr Cys Gln Gln Trp Asn Tyr Pro Leu Ile Thr

85 90 95

Phe Gly Ser Gly Thr Lys Leu Glu Ile Gln

100 105

<210> 91

<211> 116

<212> PRT

<213> Rodents

<400> 91

Glu Val Gln Val Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Gly Ser Ser Gly Trp Ser Glu Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 92

<211> 107

<212> PRT

<213> Rodents

<400> 92

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 Gly Ile Arg Asn Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile

35 40 45

Tyr Ala Ala Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Thr Gly

50 55 60

Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile Val Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His His Ser Tyr Pro Leu

85 90 95

Thr Ser Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 93

<211> 118

<212> PRT

<213> Rodents

<400> 93

Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Leu Lys Leu Ser Cys Val Thr Ser Gly Phe Thr Phe Arg Lys Phe

20 25 30

Gly Met Ser Trp Val Arg Gln Thr Ser Asp Lys Arg Leu Glu Trp Val

35 40 45

Ala Ser Ile Ser Thr Gly Gly Tyr Asn Thr Tyr Tyr Ser Asp Asn Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Thr Arg Gly Tyr Ser Ser Thr Ser Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Thr Val Thr Val

115

<210> 94

<211> 108

<212> PRT

<213> Rodents

<400> 94

Asp Ile Glu Leu Thr Gln Ser Pro Ala Ser Leu Ser Val Ala Thr Gly

1 5 10 15

Glu Lys Val Thr Ile Arg Cys Met Thr Ser Thr Asp Ile Asp Asp Asp

20 25 30

Met Asn Trp Tyr Gln Gln Lys Pro Gly Glu Pro Pro Lys Phe Leu Ile

35 40 45

Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Ser

50 55 60

Ser Gly Thr Gly Thr Asp Phe Val Phe Thr Ile Glu Asn Thr Leu Ser

65 70 75 80

Glu Asp Val Gly Asp Tyr Tyr Cys Leu Gln Ser Phe Asn Val Pro Leu

85 90 95

Thr Phe Gly Asp Gly Thr Lys Leu Glu Lys Ala Leu

100 105

<210> 95

<211> 119

<212> PRT

<213> Rodents

<400> 95

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 Ser Phe Pro Asp Tyr

20 25 30

Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe

50 55 60

Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Asn Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys

85 90 95

Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly

100 105 110

Thr Met Val Thr Val Ser Ser

115

<210> 96

<211> 112

<212> PRT

<213> Rodents

<400> 96

Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly

1 5 10 15

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe 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 Ile Tyr Tyr Cys Ser Gln Ser

85 90 95

Ser Ile Tyr Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 97

<211> 119

<212> PRT

<213> Rodents

<400> 97

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 Ser Phe Pro Asp Tyr

20 25 30

Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe

50 55 60

Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser 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

Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly

100 105 110

Thr Met Val Thr Val Ser Ser

115

<210> 98

<211> 112

<212> PRT

<213> Rodents

<400> 98

Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Ser Val Thr Pro Gly

1 5 10 15

Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Val His Ser

20 25 30

Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser

35 40 45

Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro

50 55 60

Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala Asp Phe Thr Leu Lys Ile

65 70 75 80

Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Glu Thr

85 90 95

Ser His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 99

<211> 117

<212> PRT

<213> Rodents

<400> 99

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Ser Ile Asn Trp Val Lys Arg Ala Pro Gly Lys Gly Leu Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Glu Thr Arg Glu Pro Ala Tyr Ala Tyr Asp Phe

50 55 60

Arg Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Leu Gln Ile Asn Asn Leu Lys Tyr Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Leu Asp Tyr Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser

100 105 110

Val Thr Val Ser Ser

115

<210> 100

<211> 111

<212> PRT

<213> Rodents

<400> 100

Asp Ile Val Leu Thr Gly Ser Pro Pro Ser Leu Ala Met Ser Leu Gly

1 5 10 15

Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Ile Leu

20 25 30

Gly Ser His Leu Ile His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Thr Leu Leu Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp

65 70 75 80

Pro Val Glu Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln Ser Arg

85 90 95

Thr Ile Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 101

<211> 117

<212> PRT

<213> Rodents

<400> 101

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr His Tyr

20 25 30

Ser Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met

35 40 45

Gly Arg Ile Asn Thr Glu Thr Gly Glu Pro Leu Tyr Ala Asp Asp Phe

50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Leu Val Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Phe Phe Cys

85 90 95

Ser Asn Asp Tyr Leu Tyr Ser Cys Asp Tyr Trp Gly Arg Gly Thr Thr

100 105 110

Leu Thr Val Ser Ser

115

<210> 102

<211> 111

<212> PRT

<213> Rodents

<400> 102

Asp Ile Val Leu Thr Gln Ser Pro Pro Ser Leu Ala Met Ser Leu Gly

1 5 10 15

Lys Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Thr Ile Leu

20 25 30

Gly Ser His Leu Ile Tyr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Thr Leu Leu Ile Gln Leu Ala Ser Asn Val Gln Thr Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asp

65 70 75 80

Pro Val Glu Glu Asp Asp Val Ala Val Tyr Tyr Cys Leu Gln Ser Arg

85 90 95

Thr Ile Pro Arg Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 103

<211> 119

<212> PRT

<213> Rodents

<400> 103

Glu Val Lys Leu Leu 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 Asp Phe Ser Arg Tyr

20 25 30

Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn Pro Asp Ser Ser Thr Ile Asn Tyr Thr Pro Ser Leu

50 55 60

Lys Asp Lys Phe Ile Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Lys Val Arg Ser Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Arg Pro Asp Gly Asn Tyr Trp Tyr Phe Asp Val Trp Gly Ala Gly

100 105 110

Thr Thr Val Thr Val Ser Ser

115

<210> 104

<211> 107

<212> PRT

<213> Rodents

<400> 104

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 Gly Ile Ala

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Ile

35 40 45

Tyr Trp Ala Ser Thr Arg His Thr Gly Val Pro Asp Arg Phe Thr Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Asn Val Gln Ser

65 70 75 80

Glu Asp Leu Ala Asp Tyr Phe Cys Gln Gln Tyr Ser Ser Tyr Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 105

<211> 120

<212> PRT

<213> Rodents

<400> 105

Gln Val Gln Leu Gln Gln Pro Gly Ala Glu Leu Val Arg Pro Gly Ala

1 5 10 15

Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Thr Tyr

20 25 30

Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Met Ile His Pro Ser Asp Ser Glu Thr Arg Leu Asn Gln Lys Phe

50 55 60

Lys Asp Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Pro Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Thr Met Ile Ala Thr Arg Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 106

<211> 107

<212> PRT

<213> Rodents

<400> 106

Asp Ile Val Met Thr Gln Ser Gln Lys Ser Met Ser Thr Ser Val Gly

1 5 10 15

Asp Arg Val Ser Ile Thr Cys Lys Ala Ser Gln Asp Val Ile Thr Gly

20 25 30

Val Ala 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 Ser Asn Val Gln Ala

65 70 75 80

Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Leu

85 90 95

Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105

<210> 107

<211> 121

<212> PRT

<213> Rodents

<400> 107

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg 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 Gln Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Ala Ile Tyr Pro Gly Asp Gly Asp Thr Arg Tyr Thr 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 Gln Leu Ser Ser Leu Ala Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Lys Val Tyr Tyr Gly Ser Asn Pro Phe Ala Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ala

115 120

<210> 108

<211> 107

<212> PRT

<213> Rodents

<400> 108

Asp Ile Gln Met Thr Gln Ser Ser Ser Tyr Leu Ser Val Ser Leu Gly

1 5 10 15

Gly Arg Val Thr Ile Thr Cys Lys Ala Ser Asp His Ile Asn Asn Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Asn Ala Pro Arg Leu Leu Ile

35 40 45

Ser Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Lys Asp Tyr Thr Leu Ser Ile Thr Ser Leu Gln Thr

65 70 75 80

Glu Asp Val Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Ser Thr Pro Trp

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 109

<211> 120

<212> PRT

<213> Rodents

<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 Ser Ser

20 25 30

Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Lys 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 Val Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Ser Thr Met Ile Ala Thr Gly Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 110

<211> 107

<212> PRT

<213> Rodents

<400> 110

Glu Thr Thr Val Thr Gln Ser Pro Ala Ser Leu Ser Met Ala Ile Gly

1 5 10 15

Glu Lys Val Thr Ile Arg Cys Ile Thr Ser Thr Asp Ile Asp Asp Asp

20 25 30

Met Asn Trp Tyr Gln Gln Lys Pro Gly Glu Pro Pro Lys Leu Leu Ile

35 40 45

Ser Glu Gly Asn Thr Leu Arg Pro Gly Val Pro Ser Arg Phe Ser Ser

50 55 60

Ser Gly Tyr Gly Thr Asp Phe Val Phe Thr Ile Glu Asn Met Leu Ser

65 70 75 80

Glu Asp Val Ala Asp Tyr Tyr Cys Leu Gln Ser Asp Asn Leu Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 111

<211> 120

<212> PRT

<213> Rodents

<400> 111

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 Ser

20 25 30

Trp Met Asn Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Lys 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 Val Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Ser Thr Met Ile Ala Thr Gly Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser

115 120

<210> 112

<211> 108

<212> PRT

<213> Rodents

<400> 112

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

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 Ser Ser Val Gln Ala

65 70 75 80

Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln His Tyr Ser Thr Pro Pro

85 90 95

Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 113

<211> 141

<212> PRT

<213> Rodents

<400> 113

Met Gly Trp Ser Trp Ile Phe Leu Phe Leu Val Ser Gly Thr Gly Gly

1 5 10 15

Val Leu Ser Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys

20 25 30

Pro Gly Ala Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe

35 40 45

Thr Asp Tyr Tyr Met Lys Trp Val Lys Gln Ser His Gly Lys Ser Leu

50 55 60

Glu Trp Ile Gly Asp Ile Ile Pro Ser Asn Gly Ala Thr Phe Tyr Asn

65 70 75 80

Gln Lys Phe Lys Gly Lys Ala Thr Leu Thr Val Asp Arg Ser Ser Ser

85 90 95

Thr Ala Tyr Met His Leu Asn Ser Leu Thr Ser Glu Asp Ser Ala Val

100 105 110

Tyr Tyr Cys Thr Arg Ser His Leu Leu Arg Ala Ser Trp Phe Ala Tyr

115 120 125

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser

130 135 140

<210> 114

<211> 134

<212> PRT

<213> Rodents

<400> 114

Met Glu Ser Gln Thr Gln Val Leu Met Ser Leu Leu Phe Trp Val Ser

1 5 10 15

Gly Thr Cys Gly Asp Phe Val Met Thr Gln Ser Pro Ser Ser Leu Thr

20 25 30

Val Thr Ala Gly Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser

35 40 45

Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Leu Gln

50 55 60

Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg

65 70 75 80

Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp

85 90 95

Phe Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr

100 105 110

Tyr Cys Gln Asn Asp Tyr Ser Tyr Pro Tyr Thr Phe Gly Gly Gly Thr

115 120 125

Lys Leu Glu Ile Lys Arg

130

<210> 115

<211> 140

<212> PRT

<213> Rodents

<400> 115

Trp Thr Trp Arg Phe Leu Phe Val Val Ala Ala Ala Thr Gly Val Gln

1 5 10 15

Ser Gln Val Gln Leu Leu Gln Ser Gly Ala Glu Val Lys Lys Pro Gly

20 25 30

Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Thr

35 40 45

Tyr Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp

50 55 60

Met Gly Gly Ile Ile Pro Ile Phe Gly Ile Val Asn Tyr Ala Gln Lys

65 70 75 80

Phe Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala

85 90 95

Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr

100 105 110

Cys Ala Arg Gly Gly Gly Ser Gly Pro Asp Val Leu Asp Ile Trp Gly

115 120 125

Gln Gly Thr Met Val Thr Val Ser Ser Ala Ser Thr

130 135 140

<210> 116

<211> 132

<212> PRT

<213> Rodents

<400> 116

Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Pro Gly Ala Arg Cys Val Ile Trp Met Thr Gln Ser Pro Ser Leu

20 25 30

Leu Ser Ala Ser Thr Gly Asp Arg Val Thr Ile Ser Cys Arg Met Ser

35 40 45

Gln Gly Ile Arg Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys

50 55 60

Ala Pro Glu Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val

65 70 75 80

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

85 90 95

Ile Ser Ser Leu Gln Ser Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln

100 105 110

Tyr Tyr Ser Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile

115 120 125

Lys Arg Thr Val

130

<210> 117

<211> 115

<212> PRT

<213> Rodents

<400> 117

Gln Val Gln Leu Gln Gln Pro 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 Ser Tyr

20 25 30

Trp Met Asn Trp Val Lys Gln Arg Pro Asp Gln Gly Leu Glu Trp Ile

35 40 45

Gly Arg Ile Asp Pro Tyr Asp Ser Glu Thr His Tyr Asn Gln Lys Phe

50 55 60

Lys Asp Lys Ala Ile 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 Gly Asn Trp Asp Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr

100 105 110

Val Ser Ser

115

<210> 118

<211> 107

<212> PRT

<213> Rodents

<400> 118

Asp Val Gln Ile Thr Gln Ser Pro Ser Tyr Leu Ala Ala Ser Pro Gly

1 5 10 15

Glu Thr Ile Thr Ile Asn Cys Arg Ala Ser Lys Ser Ile Ser Lys Asp

20 25 30

Leu Ala Trp Tyr Gln Glu Lys Pro Gly Lys Thr Asn Lys Leu Leu Ile

35 40 45

Tyr Ser Gly Ser Thr Leu Gln Ser Gly Ile Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Met Tyr Tyr Cys Gln Gln His Asn Lys Tyr Pro Tyr

85 90 95

Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 119

<211> 118

<212> PRT

<213> Rodents

<400> 119

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe

50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Ser Val Thr Val Ser Ser

115

<210> 120

<211> 111

<212> PRT

<213> Rodents

<400> 120

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 Glu Ser Val Asp Asn Tyr

20 25 30

Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn

65 70 75 80

Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn

85 90 95

Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys

100 105 110

<210> 121

<211> 127

<212> PRT

<213> Rodents

<400> 121

Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Thr Asp Tyr

20 25 30

Tyr Met Ser Trp Val Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu

35 40 45

Ala Leu Ile Arg Ser Lys Ala Asp Gly Tyr Thr Thr Glu Tyr Ser Ala

50 55 60

Ser Val Lys Gly Arg Phe Thr Leu Ser Arg Asp Asp Ser Gln Ser Ile

65 70 75 80

Leu Tyr Leu Gln Met Asn Ala Leu Arg Pro Glu Asp Ser Ala Thr Tyr

85 90 95

Tyr Cys Ala Arg Asp Ala Ala Tyr Tyr Ser Tyr Tyr Ser Pro Glu Gly

100 105 110

Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser

115 120 125

<210> 122

<211> 113

<212> PRT

<213> Rodents

<400> 122

Met Ala Asp Tyr Lys Asp Ile Val Met Thr Gln Ser His Lys Phe Met

1 5 10 15

Ser Thr Ser Val Gly Asp Arg Val Asn Ile Thr Cys Lys Ala Ser Gln

20 25 30

Asn Val Asp Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser

35 40 45

Pro Lys Ala Leu Ile Tyr Ser Ala Ser Tyr Arg Tyr Ser Gly Val Pro

50 55 60

Asp Arg Phe Thr Gly Arg Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile

65 70 75 80

Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln Tyr

85 90 95

Tyr Ser Thr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys

100 105 110

Arg

<210> 123

<211> 119

<212> PRT

<213> Rodents

<400> 123

Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln Ser

1 5 10 15

Leu Ser Leu Thr Cys Ser Val Thr Asp Tyr Ser Ile Thr Ser Gly Tyr

20 25 30

Tyr Trp Asn Trp Ile Arg Gln Phe Pro Gly Asn Lys Leu Glu Trp Met

35 40 45

Gly Tyr Ile Ser Tyr Asp Gly Ser Asn Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Asn Arg Ile Ser Ile Thr Arg Asp Thr Ser Lys Asn Gln Phe Phe Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Thr Glu Asp Thr Ala Thr Tyr Tyr Cys Ser

85 90 95

Arg Gly Glu Gly Phe Tyr Phe Asp Ser Trp Gly Gln Gly Thr Thr Leu

100 105 110

Thr Val Ser Ser Ala Arg Ser

115

<210> 124

<211> 113

<212> PRT

<213> Rodents

<400> 124

Asp Ile Met Met Ser Gln Ser Pro Ser Ser Leu Ala Val Ser Val Gly

1 5 10 15

Glu Lys Phe Thr Met Thr Cys Lys Ser Ser Gln Ser Leu Phe Phe Gly

20 25 30

Ser Thr Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Ala

65 70 75 80

Ile Ser Ser Val Met Pro Glu Asp Leu Ala Val Tyr Tyr Cys Gln Gln

85 90 95

Tyr Tyr Asn Tyr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile

100 105 110

Lys

<210> 125

<211> 464

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 125

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser

130 135 140

Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser

145 150 155 160

Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg

165 170 175

Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg

180 185 190

Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg

195 200 205

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser

210 215 220

Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ala Pro

225 230 235 240

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

245 250 255

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

260 265 270

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile

275 280 285

Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val

290 295 300

Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe

305 310 315 320

Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly

325 330 335

Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg

340 345 350

Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln

355 360 365

Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp

370 375 380

Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro

385 390 395 400

Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp

405 410 415

Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg

420 425 430

Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr

435 440 445

Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu

450 455 460

<210> 126

<211> 498

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 126

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser

130 135 140

Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser

145 150 155 160

Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg

165 170 175

Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg

180 185 190

Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg

195 200 205

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser

210 215 220

Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp

225 230 235 240

Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu

245 250 255

Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys

260 265 270

Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

275 280 285

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

290 295 300

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

305 310 315 320

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

325 330 335

Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr

340 345 350

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu

355 360 365

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu

370 375 380

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln

385 390 395 400

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

405 410 415

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

420 425 430

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

435 440 445

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

450 455 460

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

465 470 475 480

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

485 490 495

Arg Glu

<210> 127

<211> 513

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 127

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser

130 135 140

Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser

145 150 155 160

Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg

165 170 175

Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg

180 185 190

Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg

195 200 205

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser

210 215 220

Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp

225 230 235 240

Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu

245 250 255

Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys

260 265 270

Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala

275 280 285

Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile

290 295 300

Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala

305 310 315 320

Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr

325 330 335

Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu

340 345 350

Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile

355 360 365

Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp

370 375 380

Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

385 390 395 400

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

405 410 415

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

420 425 430

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

435 440 445

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

450 455 460

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

465 470 475 480

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

485 490 495

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

500 505 510

Glu

<210> 128

<211> 522

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 128

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser

130 135 140

Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser

145 150 155 160

Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg

165 170 175

Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg

180 185 190

Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg

195 200 205

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser

210 215 220

Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp

225 230 235 240

Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu

245 250 255

Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser

260 265 270

Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys

275 280 285

Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro

290 295 300

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

305 310 315 320

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

325 330 335

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

340 345 350

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg

355 360 365

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

370 375 380

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

385 390 395 400

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

405 410 415

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

420 425 430

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

435 440 445

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

450 455 460

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

465 470 475 480

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

485 490 495

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

500 505 510

Leu His Met Gln Ala Leu Pro Pro Arg Glu

515 520

<210> 129

<211> 500

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 129

Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly

1 5 10 15

Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly

20 25 30

Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln

35 40 45

Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe

50 55 60

Ser Ser Tyr Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

65 70 75 80

Glu Trp Val Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Ala

85 90 95

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn

100 105 110

Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val

115 120 125

Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr

130 135 140

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

145 150 155 160

Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu

165 170 175

Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln

180 185 190

Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

195 200 205

Ala Pro Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile

210 215 220

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

225 230 235 240

Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln

245 250 255

Tyr Gln Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

260 265 270

Lys Ser Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

275 280 285

Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg

290 295 300

Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys

305 310 315 320

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

325 330 335

Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu

340 345 350

Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln

355 360 365

Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly

370 375 380

Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

385 390 395 400

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

405 410 415

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

420 425 430

Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu

435 440 445

Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys

450 455 460

Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu

465 470 475 480

Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu

485 490 495

Pro Pro Arg Glu

500

<210> 130

<211> 466

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 130

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser

115 120 125

Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu

130 135 140

Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val

145 150 155 160

Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

165 170 175

Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp

180 185 190

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

195 200 205

Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln

210 215 220

Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser

225 230 235 240

Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

245 250 255

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

260 265 270

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

275 280 285

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

290 295 300

Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr

305 310 315 320

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu

325 330 335

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu

340 345 350

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln

355 360 365

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

370 375 380

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

385 390 395 400

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

405 410 415

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

420 425 430

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

435 440 445

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

450 455 460

Arg Glu

465

<210> 131

<211> 472

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 131

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser

115 120 125

Leu Cys Ser Gly Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser

130 135 140

Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys

145 150 155 160

Arg Gly Gly Gln Ser Val Ser Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln

165 170 175

Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg

180 185 190

Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

195 200 205

Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr

210 215 220

Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr

225 230 235 240

Lys Val Glu Ile Lys Ser Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro

245 250 255

Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro

260 265 270

Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu

275 280 285

Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys

290 295 300

Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly

305 310 315 320

Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val

325 330 335

Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu

340 345 350

Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp

355 360 365

Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn

370 375 380

Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg

385 390 395 400

Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly

405 410 415

Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu

420 425 430

Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu

435 440 445

Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His

450 455 460

Met Gln Ala Leu Pro Pro Arg Glu

465 470

<210> 132

<211> 491

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 132

Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser

20 25 30

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

35 40 45

Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln

50 55 60

Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly

65 70 75 80

Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

85 90 95

Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg

100 105 110

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp

115 120 125

Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Cys

130 135 140

Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Ser Glu Ile Val Leu

145 150 155 160

Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

165 170 175

Leu Ser Cys Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp

180 185 190

Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala

195 200 205

Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser

210 215 220

Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe

225 230 235 240

Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly

245 250 255

Gln Gly Thr Lys Val Glu Ile Lys Ser Asp Pro Thr Thr Thr Pro Ala

260 265 270

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

275 280 285

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

290 295 300

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

305 310 315 320

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

325 330 335

Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

340 345 350

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

355 360 365

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

370 375 380

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

385 390 395 400

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

405 410 415

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

420 425 430

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

435 440 445

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

450 455 460

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

465 470 475 480

Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu

485 490

<210> 133

<211> 497

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 133

Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser

20 25 30

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

35 40 45

Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln

50 55 60

Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly

65 70 75 80

Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

85 90 95

Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg

100 105 110

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp

115 120 125

Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

130 135 140

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly

145 150 155 160

Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser

165 170 175

Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser

180 185 190

Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg

195 200 205

Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg

210 215 220

Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg

225 230 235 240

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser

245 250 255

Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp

260 265 270

Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile

275 280 285

Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala

290 295 300

Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr

305 310 315 320

Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu

325 330 335

Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile

340 345 350

Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp

355 360 365

Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

370 375 380

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

385 390 395 400

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

405 410 415

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

420 425 430

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

435 440 445

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

450 455 460

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

465 470 475 480

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490 495

Glu

<210> 134

<211> 490

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 134

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser

115 120 125

Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu

130 135 140

Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val

145 150 155 160

Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

165 170 175

Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp

180 185 190

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

195 200 205

Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln

210 215 220

Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser

225 230 235 240

Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser

245 250 255

Leu Cys Ser Gly Gly Gly Gly Ser Ala Pro Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg Glu

485 490

<210> 135

<211> 496

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 135

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser

115 120 125

Leu Cys Ser Gly Gly Gly Gly Gly Ser Glu Ile Val Leu Thr Gln Ser

130 135 140

Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys

145 150 155 160

Arg Gly Gly Gln Ser Val Ser Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln

165 170 175

Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg

180 185 190

Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

195 200 205

Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr

210 215 220

Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr

225 230 235 240

Lys Val Glu Ile Lys Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys

245 250 255

Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Ala Pro

260 265 270

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

275 280 285

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

290 295 300

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile

305 310 315 320

Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val

325 330 335

Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe

340 345 350

Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly

355 360 365

Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg

370 375 380

Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln

385 390 395 400

Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp

405 410 415

Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro

420 425 430

Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp

435 440 445

Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg

450 455 460

Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr

465 470 475 480

Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu

485 490 495

<210> 136

<211> 514

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 136

Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser

20 25 30

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

35 40 45

Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln

50 55 60

Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly

65 70 75 80

Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

85 90 95

Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg

100 105 110

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp

115 120 125

Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

130 135 140

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr

145 150 155 160

Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu

165 170 175

Ser Cys Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr

180 185 190

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala Ser

195 200 205

Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly

210 215 220

Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala

225 230 235 240

Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly Gln

245 250 255

Gly Thr Lys Val Glu Ile Lys Ser Asp Pro Gly Ser Gly Gly Gly Gly

260 265 270

Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser

275 280 285

Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

290 295 300

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

305 310 315 320

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

325 330 335

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

340 345 350

Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr

355 360 365

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu

370 375 380

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu

385 390 395 400

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln

405 410 415

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

420 425 430

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

435 440 445

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

450 455 460

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

465 470 475 480

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

485 490 495

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

500 505 510

Arg Glu

<210> 137

<211> 515

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 137

Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser

20 25 30

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

35 40 45

Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln

50 55 60

Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly

65 70 75 80

Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

85 90 95

Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg

100 105 110

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp

115 120 125

Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Ser Cys

130 135 140

Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Ser Glu Ile Val Leu

145 150 155 160

Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

165 170 175

Leu Ser Cys Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp

180 185 190

Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala

195 200 205

Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser

210 215 220

Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe

225 230 235 240

Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly

245 250 255

Gln Gly Thr Lys Val Glu Ile Lys Ser Asp Pro Gly Ser Gly Gly Gly

260 265 270

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly

275 280 285

Ser Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

290 295 300

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

305 310 315 320

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

325 330 335

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

340 345 350

Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu

355 360 365

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

370 375 380

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

385 390 395 400

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln

405 410 415

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

420 425 430

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

435 440 445

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

450 455 460

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

465 470 475 480

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

485 490 495

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

500 505 510

Pro Arg Glu

515

<210> 138

<211> 521

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 138

Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser

20 25 30

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

35 40 45

Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln

50 55 60

Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly

65 70 75 80

Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

85 90 95

Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg

100 105 110

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp

115 120 125

Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

130 135 140

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly

145 150 155 160

Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser

165 170 175

Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser

180 185 190

Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg

195 200 205

Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg

210 215 220

Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg

225 230 235 240

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser

245 250 255

Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp

260 265 270

Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu

275 280 285

Cys Ser Gly Gly Gly Gly Ser Ala Pro Thr Thr Thr Pro Ala Pro Arg

290 295 300

Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg

305 310 315 320

Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly

325 330 335

Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr

340 345 350

Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg

355 360 365

Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro

370 375 380

Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu

385 390 395 400

Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala

405 410 415

Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu

420 425 430

Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly

435 440 445

Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu

450 455 460

Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser

465 470 475 480

Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly

485 490 495

Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu

500 505 510

His Met Gln Ala Leu Pro Pro Arg Glu

515 520

<210> 139

<211> 504

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 139

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser

130 135 140

Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser

145 150 155 160

Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg

165 170 175

Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg

180 185 190

Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg

195 200 205

Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser

210 215 220

Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser Asp

225 230 235 240

Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu

245 250 255

Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys

260 265 270

Ser Gly Gly Gly Gly Ser Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro

275 280 285

Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro

290 295 300

Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu

305 310 315 320

Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys

325 330 335

Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly

340 345 350

Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val

355 360 365

Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu

370 375 380

Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp

385 390 395 400

Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn

405 410 415

Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg

420 425 430

Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly

435 440 445

Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu

450 455 460

Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu

465 470 475 480

Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His

485 490 495

Met Gln Ala Leu Pro Pro Arg Glu

500

<210> 140

<211> 547

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 140

Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Leu Glu Ser

20 25 30

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

35 40 45

Ala Ser Gly Phe Thr Phe Ser Ser Tyr Ala Met Asn Trp Val Arg Gln

50 55 60

Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Leu Ser Ser Gly

65 70 75 80

Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

85 90 95

Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg

100 105 110

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Pro Met Asp

115 120 125

Ile Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

130 135 140

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ile Val Leu Thr

145 150 155 160

Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr Leu

165 170 175

Ser Cys Arg Gly Gly Gln Ser Val Ser Ser Ser Tyr Leu Ala Trp Tyr

180 185 190

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Met Tyr Asp Ala Ser

195 200 205

Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly

210 215 220

Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro Glu Asp Phe Ala

225 230 235 240

Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro Leu Thr Phe Gly Gln

245 250 255

Gly Thr Lys Val Glu Ile Lys Ser Asp Pro Gly Ser Gly Gly Gly Gly

260 265 270

Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser

275 280 285

Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser

290 295 300

Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu

305 310 315 320

Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

325 330 335

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

340 345 350

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

355 360 365

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

370 375 380

Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu

385 390 395 400

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

405 410 415

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

420 425 430

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln

435 440 445

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

450 455 460

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

465 470 475 480

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

485 490 495

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

500 505 510

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

515 520 525

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

530 535 540

Pro Arg Glu

545

<210> 141

<211> 523

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 141

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser

115 120 125

Gly Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu

130 135 140

Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val

145 150 155 160

Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro

165 170 175

Arg Leu Leu Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp

180 185 190

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser

195 200 205

Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln

210 215 220

Ser Trp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Ser

225 230 235 240

Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser

245 250 255

Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe

260 265 270

Ser Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala

275 280 285

Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala

290 295 300

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

305 310 315 320

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

325 330 335

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

340 345 350

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

355 360 365

Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

370 375 380

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

385 390 395 400

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

405 410 415

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

420 425 430

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

435 440 445

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

450 455 460

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

465 470 475 480

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

485 490 495

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

500 505 510

Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu

515 520

<210> 142

<211> 467

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-CD123-CAR

<400> 142

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe

50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

115 120 125

Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu

130 135 140

Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu

145 150 155 160

Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys

165 170 175

Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu

180 185 190

Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe

195 200 205

Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr

210 215 220

Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys

225 230 235 240

Leu Glu Leu Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

245 250 255

Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg

260 265 270

Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys

275 280 285

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

290 295 300

Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu

305 310 315 320

Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln

325 330 335

Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly

340 345 350

Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

355 360 365

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

370 375 380

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

385 390 395 400

Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu

405 410 415

Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys

420 425 430

Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu

435 440 445

Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu

450 455 460

Pro Pro Arg

465

<210> 143

<211> 518

<212> PRT

<213> Artificial sequence

<220>

<223> CD123 protein

<400> 143

Met Thr Lys Glu Asp Pro Asn Pro Pro Ile Thr Asn Leu Arg Met Lys

1 5 10 15

Ala Lys Ala Gln Gln Leu Thr Trp Asp Leu Asn Arg Asn Val Thr Asp

20 25 30

Ile Glu Cys Val Lys Asp Ala Asp Tyr Ser Met Pro Ala Val Asn Asn

35 40 45

Ser Tyr Cys Gln Phe Gly Ala Ile Ser Leu Cys Glu Val Thr Asn Tyr

50 55 60

Thr Val Arg Val Ala Asn Pro Pro Phe Ser Thr Trp Ile Leu Phe Pro

65 70 75 80

Glu Asn Ser Gly Lys Pro Trp Ala Gly Ala Glu Asn Leu Thr Cys Trp

85 90 95

Ile His Asp Val Asp Phe Leu Ser Cys Ser Trp Ala Val Gly Pro Gly

100 105 110

Ala Pro Ala Asp Val Gln Tyr Asp Leu Tyr Leu Asn Val Ala Asn Arg

115 120 125

Arg Gln Gln Tyr Glu Cys Leu His Tyr Lys Thr Asp Ala Gln Gly Thr

130 135 140

Arg Ile Gly Cys Arg Phe Asp Asp Ile Ser Arg Leu Ser Ser Gly Ser

145 150 155 160

Gln Ser Ser His Ile Leu Val Arg Gly Arg Ser Ala Ala Phe Gly Ile

165 170 175

Pro Cys Thr Asp Lys Phe Val Val Phe Ser Gln Ile Glu Ile Leu Thr

180 185 190

Pro Pro Asn Met Thr Ala Lys Cys Asn Lys Thr His Ser Phe Met His

195 200 205

Trp Lys Met Arg Ser His Phe Asn Arg Lys Phe Arg Tyr Glu Leu Gln

210 215 220

Ile Gln Lys Arg Met Gln Pro Val Ile Thr Glu Gln Val Arg Asp Arg

225 230 235 240

Thr Ser Phe Gln Leu Leu Asn Pro Gly Thr Tyr Thr Val Gln Ile Arg

245 250 255

Ala Arg Glu Arg Val Tyr Glu Phe Leu Ser Ala Trp Ser Thr Pro Gln

260 265 270

Arg Phe Glu Cys Asp Gln Glu Glu Gly Ala Asn Thr Arg Ala Trp Arg

275 280 285

Gly Gly Gly Gly Ala Gly Gly Gly Gly Cys Lys Pro Cys Ile Cys Thr

290 295 300

Val Pro Glu Val Ser Ser Val Phe Ile Phe Pro Pro Lys Pro Lys Asp

305 310 315 320

Val Leu Thr Ile Thr Leu Thr Pro Lys Val Thr Cys Val Val Val Asp

325 330 335

Ile Ser Lys Asp Asp Pro Glu Val Gln Phe Ser Trp Phe Val Asp Asp

340 345 350

Val Glu Val His Thr Ala Gln Thr Gln Pro Arg Glu Glu Gln Phe Asn

355 360 365

Ser Thr Phe Arg Ser Val Ser Glu Leu Pro Ile Met His Gln Asp Trp

370 375 380

Leu Asn Gly Lys Glu Phe Lys Cys Arg Val Asn Ser Ala Ala Phe Pro

385 390 395 400

Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Arg Pro Lys Ala

405 410 415

Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys Glu Gln Met Ala Lys Asp

420 425 430

Lys Val Ser Leu Thr Cys Met Ile Thr Asp Phe Phe Pro Glu Asp Ile

435 440 445

Thr Val Glu Trp Gln Trp Asn Gly Gln Pro Ala Glu Asn Tyr Lys Asn

450 455 460

Thr Gln Pro Ile Met Asp Thr Asp Gly Ser Tyr Phe Val Tyr Ser Lys

465 470 475 480

Leu Asn Val Gln Lys Ser Asn Trp Glu Ala Gly Asn Thr Phe Thr Cys

485 490 495

Ser Val Leu His Glu Gly Leu His Asn His His Thr Glu Lys Ser Leu

500 505 510

Ser His Ser Pro Gly Lys

515

<210> 144

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> mAb-specific epitope

<400> 144

Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser

1 5 10 15

<210> 145

<211> 469

<212> PRT

<213> Artificial sequence

<220>

<223> Anti-BCMA-CAR

<400> 145

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 Ser Phe Pro Asp Tyr

20 25 30

Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe

50 55 60

Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser 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

Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly

100 105 110

Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu Ser

130 135 140

Leu Ser Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser

145 150 155 160

Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu

165 170 175

Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn

180 185 190

Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala

195 200 205

Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val

210 215 220

Tyr Tyr Cys Ala Glu Thr Ser His Val Pro Trp Thr Phe Gly Gln Gly

225 230 235 240

Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr

245 250 255

Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala

260 265 270

Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe

275 280 285

Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val

290 295 300

Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys

305 310 315 320

Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr

325 330 335

Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu

340 345 350

Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro

355 360 365

Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly

370 375 380

Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro

385 390 395 400

Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr

405 410 415

Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly

420 425 430

Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln

435 440 445

Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln

450 455 460

Ala Leu Pro Pro Arg

465

<210> 146

<211> 485

<212> PRT

<213> Artificial sequence

<220>

<223> BC30-LM

<400> 146

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 Ser Phe Pro Asp Tyr

20 25 30

Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe

50 55 60

Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser 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

Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly

100 105 110

Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu Ser

130 135 140

Leu Ser Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser

145 150 155 160

Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu

165 170 175

Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn

180 185 190

Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala

195 200 205

Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val

210 215 220

Tyr Tyr Cys Ala Glu Thr Ser His Val Pro Trp Thr Phe Gly Gln Gly

225 230 235 240

Thr Lys Leu Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr

245 250 255

Ser Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr

260 265 270

Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala

275 280 285

Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe

290 295 300

Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val

305 310 315 320

Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys

325 330 335

Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr

340 345 350

Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu

355 360 365

Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro

370 375 380

Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly

385 390 395 400

Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro

405 410 415

Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr

420 425 430

Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly

435 440 445

Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln

450 455 460

Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln

465 470 475 480

Ala Leu Pro Pro Arg

485

<210> 147

<211> 491

<212> PRT

<213> Artificial sequence

<220>

<223> BC30-LML

<400> 147

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 Ser Phe Pro Asp Tyr

20 25 30

Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe

50 55 60

Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser 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

Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly

100 105 110

Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu Ser

130 135 140

Leu Ser Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser

145 150 155 160

Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu

165 170 175

Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn

180 185 190

Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala

195 200 205

Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val

210 215 220

Tyr Tyr Cys Ala Glu Thr Ser His Val Pro Trp Thr Phe Gly Gln Gly

225 230 235 240

Thr Lys Leu Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr

245 250 255

Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Thr Thr Thr Pro

260 265 270

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

275 280 285

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

290 295 300

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

305 310 315 320

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

325 330 335

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

340 345 350

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

355 360 365

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

370 375 380

Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr

385 390 395 400

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

405 410 415

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

420 425 430

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

435 440 445

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

450 455 460

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

465 470 475 480

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

485 490

<210> 148

<211> 500

<212> PRT

<213> Artificial sequence

<220>

<223> BC30-LMLM

<400> 148

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 Ser Phe Pro Asp Tyr

20 25 30

Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe

50 55 60

Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser 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

Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly

100 105 110

Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu Ser

130 135 140

Leu Ser Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser

145 150 155 160

Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu

165 170 175

Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn

180 185 190

Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala

195 200 205

Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val

210 215 220

Tyr Tyr Cys Ala Glu Thr Ser His Val Pro Trp Thr Phe Gly Gln Gly

225 230 235 240

Thr Lys Leu Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr

245 250 255

Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser

260 265 270

Asn Pro Ser Leu Cys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

275 280 285

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

290 295 300

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

305 310 315 320

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

325 330 335

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

340 345 350

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

355 360 365

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

370 375 380

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

385 390 395 400

Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

405 410 415

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

420 425 430

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

435 440 445

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

450 455 460

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

465 470 475 480

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

485 490 495

Leu Pro Pro Arg

500

<210> 149

<211> 506

<212> PRT

<213> Artificial sequence

<220>

<223> BC30-LMLML

<400> 149

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 Ser Phe Pro Asp Tyr

20 25 30

Tyr Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Tyr Phe Ala Ser Gly Asn Ser Glu Tyr Asn Gln Lys Phe

50 55 60

Thr Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ser 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

Ala Ser Leu Tyr Asp Tyr Asp Trp Tyr Phe Asp Val Trp Gly Gln Gly

100 105 110

Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Gly Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Thr Pro Leu Ser

130 135 140

Leu Ser Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Lys Ser Ser

145 150 155 160

Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu

165 170 175

Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Lys Val Ser Asn

180 185 190

Arg Phe Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Ala

195 200 205

Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val

210 215 220

Tyr Tyr Cys Ala Glu Thr Ser His Val Pro Trp Thr Phe Gly Gln Gly

225 230 235 240

Thr Lys Leu Glu Ile Lys Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr

245 250 255

Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser

260 265 270

Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Thr Thr Thr Pro Ala

275 280 285

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

290 295 300

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

305 310 315 320

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

325 330 335

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

340 345 350

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

355 360 365

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

370 375 380

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg

385 390 395 400

Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn

405 410 415

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

420 425 430

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

435 440 445

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

450 455 460

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

465 470 475 480

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

485 490 495

Ala Leu His Met Gln Ala Leu Pro Pro Arg

500 505

<210> 150

<211> 136

<212> PRT

<213> Artificial sequence

<220>

<223> BC30-RQR8

<400> 150

Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu

1 5 10 15

Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser Pro

20 25 30

Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys

35 40 45

Ser Gly Gly Gly Gly Ser Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

50 55 60

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

65 70 75 80

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

85 90 95

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

100 105 110

Ser Leu Val Ile Thr Leu Tyr Cys Asn His Arg Asn Arg Arg Arg Val

115 120 125

Cys Lys Cys Pro Arg Pro Val Val

130 135

<210> 151

<211> 284

<212> PRT

<213> Artificial sequence

<220>

<223> BCMA protein

<400> 151

Met Leu Gln Met Ala Gly Gln Cys Ser Gln Asn Glu Tyr Phe Asp Ser

1 5 10 15

Leu Leu His Ala Cys Ile Pro Cys Gln Leu Arg Cys Ser Ser Asn Thr

20 25 30

Pro Pro Leu Thr Cys Gln Arg Tyr Cys Asn Ala Ser Val Thr Asn Ser

35 40 45

Val Lys Gly Thr Asn Ala Gly Gly Gly Gly Ala Gly Gly Gly Gly Cys

50 55 60

Lys Pro Cys Ile Cys Thr Val Pro Glu Val Ser Ser Val Phe Ile Phe

65 70 75 80

Pro Pro Lys Pro Lys Asp Val Leu Thr Ile Thr Leu Thr Pro Lys Val

85 90 95

Thr Cys Val Val Val Asp Ile Ser Lys Asp Asp Pro Glu Val Gln Phe

100 105 110

Ser Trp Phe Val Asp Asp Val Glu Val His Thr Ala Gln Thr Gln Pro

115 120 125

Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Ser Val Ser Glu Leu Pro

130 135 140

Ile Met His Gln Asp Trp Leu Asn Gly Lys Glu Phe Lys Cys Arg Val

145 150 155 160

Asn Ser Ala Ala Phe Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr

165 170 175

Lys Gly Arg Pro Lys Ala Pro Gln Val Tyr Thr Ile Pro Pro Pro Lys

180 185 190

Glu Gln Met Ala Lys Asp Lys Val Ser Leu Thr Cys Met Ile Thr Asp

195 200 205

Phe Phe Pro Glu Asp Ile Thr Val Glu Trp Gln Trp Asn Gly Gln Pro

210 215 220

Ala Glu Asn Tyr Lys Asn Thr Gln Pro Ile Met Asp Thr Asp Gly Ser

225 230 235 240

Tyr Phe Val Tyr Ser Lys Leu Asn Val Gln Lys Ser Asn Trp Glu Ala

245 250 255

Gly Asn Thr Phe Thr Cys Ser Val Leu His Glu Gly Leu His Asn His

260 265 270

His Thr Glu Lys Ser Leu Ser His Ser Pro Gly Lys

275 280

<210> 152

<211> 490

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 152

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe

50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

115 120 125

Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu

130 135 140

Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu

145 150 155 160

Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys

165 170 175

Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu

180 185 190

Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe

195 200 205

Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr

210 215 220

Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys

225 230 235 240

Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys

245 250 255

Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg Glu

485 490

<210> 153

<211> 496

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 153

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe

50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

115 120 125

Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu

130 135 140

Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu

145 150 155 160

Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys

165 170 175

Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu

180 185 190

Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe

195 200 205

Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr

210 215 220

Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys

225 230 235 240

Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys

245 250 255

Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Ala Pro

260 265 270

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

275 280 285

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

290 295 300

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile

305 310 315 320

Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val

325 330 335

Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe

340 345 350

Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly

355 360 365

Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg

370 375 380

Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln

385 390 395 400

Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp

405 410 415

Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro

420 425 430

Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp

435 440 445

Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg

450 455 460

Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr

465 470 475 480

Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu

485 490 495

<210> 154

<211> 505

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 154

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe

50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

115 120 125

Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu

130 135 140

Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu

145 150 155 160

Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys

165 170 175

Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu

180 185 190

Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe

195 200 205

Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr

210 215 220

Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys

225 230 235 240

Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys

245 250 255

Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro

260 265 270

Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg

275 280 285

Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg

290 295 300

Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly

305 310 315 320

Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr

325 330 335

Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg

340 345 350

Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro

355 360 365

Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu

370 375 380

Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala

385 390 395 400

Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu

405 410 415

Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly

420 425 430

Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu

435 440 445

Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser

450 455 460

Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly

465 470 475 480

Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu

485 490 495

His Met Gln Ala Leu Pro Pro Arg Glu

500 505

<210> 155

<211> 511

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 155

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe

50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

115 120 125

Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu

130 135 140

Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu

145 150 155 160

Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys

165 170 175

Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu

180 185 190

Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe

195 200 205

Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr

210 215 220

Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys

225 230 235 240

Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys

245 250 255

Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Cys Pro

260 265 270

Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Ala Pro Thr

275 280 285

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

290 295 300

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

305 310 315 320

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

325 330 335

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

340 345 350

Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

355 360 365

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

370 375 380

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

385 390 395 400

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn

405 410 415

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

420 425 430

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

435 440 445

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

450 455 460

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

465 470 475 480

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

485 490 495

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu

500 505 510

<210> 156

<211> 474

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 156

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe

50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Ser Val Thr Val Ser Ser Gly Gly Gly Cys Pro Tyr Ser Asn Pro Ser

115 120 125

Leu Cys Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala

130 135 140

Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala

145 150 155 160

Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln

165 170 175

Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn

180 185 190

Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr

195 200 205

Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr

210 215 220

Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly

225 230 235 240

Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro Ala Pro

245 250 255

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

260 265 270

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

275 280 285

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

290 295 300

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg

305 310 315 320

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

325 330 335

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

340 345 350

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

355 360 365

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

370 375 380

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

385 390 395 400

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

405 410 415

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

420 425 430

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

435 440 445

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

450 455 460

Leu His Met Gln Ala Leu Pro Pro Arg Glu

465 470

<210> 157

<211> 480

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 157

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe

50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Ser Val Thr Val Ser Ser Gly Gly Gly Gly Gly Gly Cys Pro Tyr Ser

115 120 125

Asn Pro Ser Leu Cys Gly Gly Gly Gly Gly Gly Gly Ser Asp Ile Val

130 135 140

Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala

145 150 155 160

Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr

165 170 175

Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu

180 185 190

Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser

195 200 205

Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu

210 215 220

Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro

225 230 235 240

Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro

245 250 255

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

260 265 270

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

275 280 285

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile

290 295 300

Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val

305 310 315 320

Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe

325 330 335

Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly

340 345 350

Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg

355 360 365

Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln

370 375 380

Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp

385 390 395 400

Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro

405 410 415

Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp

420 425 430

Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg

435 440 445

Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr

450 455 460

Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu

465 470 475 480

<210> 158

<211> 487

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 158

Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gln

1 5 10 15

Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr

20 25 30

Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr Gly

35 40 45

Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met Gly

50 55 60

Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe Lys

65 70 75 80

Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu

85 90 95

His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala

100 105 110

Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr Ser

115 120 125

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala

145 150 155 160

Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser

165 170 175

Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro

180 185 190

Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser

195 200 205

Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr

210 215 220

Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys

225 230 235 240

Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu

245 250 255

Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro

260 265 270

Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu

275 280 285

Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp

290 295 300

Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly

305 310 315 320

Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg

325 330 335

Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln

340 345 350

Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu

355 360 365

Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala

370 375 380

Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu

385 390 395 400

Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp

405 410 415

Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu

420 425 430

Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile

435 440 445

Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr

450 455 460

Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met

465 470 475 480

Gln Ala Leu Pro Pro Arg Glu

485

<210> 159

<211> 493

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 159

Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly

1 5 10 15

Gly Gly Gly Ser Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu

20 25 30

Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr

35 40 45

Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys

50 55 60

Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr

65 70 75 80

Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser

85 90 95

Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr

100 105 110

Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln

145 150 155 160

Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser

165 170 175

Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His

180 185 190

Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg

195 200 205

Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly

210 215 220

Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp

225 230 235 240

Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe

245 250 255

Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr

260 265 270

Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro

275 280 285

Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val

290 295 300

His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro

305 310 315 320

Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu

325 330 335

Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro

340 345 350

Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys

355 360 365

Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe

370 375 380

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu

385 390 395 400

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

405 410 415

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

420 425 430

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

435 440 445

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

450 455 460

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

465 470 475 480

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu

485 490

<210> 160

<211> 502

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 160

Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly

1 5 10 15

Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Gly Gln Ile

20 25 30

Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr Val

35 40 45

Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr Gly Met

50 55 60

Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met Gly Trp

65 70 75 80

Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe Lys Gly

85 90 95

Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu His

100 105 110

Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg

115 120 125

Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr Ser Val

130 135 140

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

145 150 155 160

Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val

165 170 175

Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val

180 185 190

Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly

195 200 205

Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly

210 215 220

Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu

225 230 235 240

Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln

245 250 255

Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu

260 265 270

Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr

275 280 285

Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala

290 295 300

Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe

305 310 315 320

Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val

325 330 335

Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys

340 345 350

Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr

355 360 365

Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu

370 375 380

Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro

385 390 395 400

Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly

405 410 415

Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro

420 425 430

Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr

435 440 445

Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly

450 455 460

Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln

465 470 475 480

Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln

485 490 495

Ala Leu Pro Pro Arg Glu

500

<210> 161

<211> 508

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 161

Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly

1 5 10 15

Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly

20 25 30

Gly Gly Ser Gly Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys

35 40 45

Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile

50 55 60

Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser

65 70 75 80

Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr

85 90 95

Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala

100 105 110

Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala

115 120 125

Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp

130 135 140

Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

145 150 155 160

Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser

165 170 175

Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys

180 185 190

Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp

195 200 205

Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala

210 215 220

Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser

225 230 235 240

Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val

245 250 255

Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly

260 265 270

Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Thr Thr Thr Pro

275 280 285

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

290 295 300

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

305 310 315 320

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

325 330 335

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

340 345 350

Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

355 360 365

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

370 375 380

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

385 390 395 400

Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr

405 410 415

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

420 425 430

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

435 440 445

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

450 455 460

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

465 470 475 480

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

485 490 495

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu

500 505

<210> 162

<211> 558

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 162

Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Gln Gln Ser

20 25 30

Gly Pro Glu Leu Ile Lys Pro Gly Ala Ser Val Lys Met Ser Cys Lys

35 40 45

Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Val Met His Trp Val Lys Gln

50 55 60

Lys Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Tyr Asn

65 70 75 80

Asp Gly Thr Lys Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr

85 90 95

Ser Asp Lys Ser Ser Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Thr

100 105 110

Ser Glu Asp Ser Ala Val Tyr Tyr Cys Ala Arg Gly Thr Tyr Tyr Tyr

115 120 125

Gly Ser Arg Val Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu Thr Val

130 135 140

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

145 150 155 160

Ser Asp Ile Val Met Thr Gln Ala Ala Pro Ser Ile Pro Val Thr Pro

165 170 175

Gly Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu Asn

180 185 190

Ser Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln

195 200 205

Ser Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val

210 215 220

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg

225 230 235 240

Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln

245 250 255

His Leu Glu Tyr Pro Phe Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu

260 265 270

Lys Arg Ala Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser

275 280 285

Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln

290 295 300

Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr

305 310 315 320

Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr

325 330 335

Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln

340 345 350

Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala

355 360 365

Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala

370 375 380

Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr

385 390 395 400

Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln

405 410 415

Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser

420 425 430

Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys

435 440 445

Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln

450 455 460

Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu

465 470 475 480

Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg

485 490 495

Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met

500 505 510

Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly

515 520 525

Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp

530 535 540

Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Glu

545 550 555

<210> 163

<211> 536

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 163

Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Ile 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 Met His Trp Val Lys Gln Lys Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Asn Pro Tyr Asn Asp Gly Thr Lys 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 Gly Thr Tyr Tyr Tyr Gly Ser Arg Val Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Thr Leu Thr Val Ser Ser Ser Ser Gly Gly Ser Cys Pro

115 120 125

Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Ser Asp Ile Val Met Thr

130 135 140

Gln Ala Ala Pro Ser Ile Pro Val Thr Pro Gly Glu Ser Val Ser Ile

145 150 155 160

Ser Cys Arg Ser Ser Lys Ser Leu Leu Asn Ser Asn Gly Asn Thr Tyr

165 170 175

Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser Pro Gln Leu Leu Ile

180 185 190

Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro Asp Arg Phe Ser Gly

195 200 205

Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile Ser Arg Val Glu Ala

210 215 220

Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His Leu Glu Tyr Pro Phe

225 230 235 240

Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ala Asp Pro Gly

245 250 255

Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser

260 265 270

Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val

275 280 285

Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr

290 295 300

Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro

305 310 315 320

Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro

325 330 335

Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu

340 345 350

Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys

355 360 365

Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly

370 375 380

Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val

385 390 395 400

Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu

405 410 415

Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp

420 425 430

Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn

435 440 445

Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg

450 455 460

Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly

465 470 475 480

Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu

485 490 495

Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu

500 505 510

Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His

515 520 525

Met Gln Ala Leu Pro Pro Arg Glu

530 535

<210> 164

<211> 554

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 164

Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ile Gln Leu Val Gln Ser

20 25 30

Gly Pro Glu Leu Lys Lys Pro Gly Glu Thr Val Lys Ile Ser Cys Lys

35 40 45

Ala Ser Gly Tyr Ile Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln

50 55 60

Ala Pro Gly Lys Ser Phe Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr

65 70 75 80

Gly Glu Ser Thr Tyr Ser Ala Asp Phe Lys Gly Arg Phe Ala Phe Ser

85 90 95

Leu Glu Thr Ser Ala Ser Thr Ala Tyr Leu His Ile Asn Asp Leu Lys

100 105 110

Asn Glu Asp Thr Ala Thr Tyr Phe Cys Ala Arg Ser Gly Gly Tyr Asp

115 120 125

Pro Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile

145 150 155 160

Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg

165 170 175

Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn

180 185 190

Thr Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu

195 200 205

Leu Ile Tyr Arg Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe

210 215 220

Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu Thr Ile Asn Pro Val

225 230 235 240

Glu Ala Asp Asp Val Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp

245 250 255

Pro Pro Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp

260 265 270

Pro Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu

275 280 285

Cys Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser

290 295 300

Asn Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys

305 310 315 320

Pro Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro

325 330 335

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

340 345 350

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

355 360 365

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

370 375 380

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg

385 390 395 400

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

405 410 415

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

420 425 430

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

435 440 445

Ala Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu

450 455 460

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

465 470 475 480

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

485 490 495

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

500 505 510

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

515 520 525

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

530 535 540

Leu His Met Gln Ala Leu Pro Pro Arg Glu

545 550

<210> 165

<211> 532

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 165

Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ile Phe Thr Asn Tyr

20 25 30

Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Ser Phe Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Tyr Thr Gly Glu Ser Thr Tyr Ser Ala Asp Phe

50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr

65 70 75 80

Leu His Ile Asn Asp Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys

85 90 95

Ala Arg Ser Gly Gly Tyr Asp Pro Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Ser Val Thr Val Ser Ser Ser Ser Ser Gly Gly Ser Cys Pro Tyr Ser Asn

115 120 125

Pro Ser Leu Cys Ser Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro

130 135 140

Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg

145 150 155 160

Ala Ser Glu Ser Val Asp Asn Tyr Gly Asn Thr Phe Met His Trp Tyr

165 170 175

Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Arg Ala Ser

180 185 190

Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg

195 200 205

Thr Asp Phe Thr Leu Thr Ile Asn Pro Val Glu Ala Asp Asp Val Ala

210 215 220

Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Pro Thr Phe Gly Ala

225 230 235 240

Gly Thr Lys Leu Glu Leu Lys Arg Ser Asp Pro Gly Ser Gly Gly Gly

245 250 255

Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly

260 265 270

Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val

275 280 285

Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser

290 295 300

Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

305 310 315 320

Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg

325 330 335

Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys

340 345 350

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

355 360 365

Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu

370 375 380

Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln

385 390 395 400

Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly

405 410 415

Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

420 425 430

Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

435 440 445

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

450 455 460

Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu

465 470 475 480

Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys

485 490 495

Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu

500 505 510

Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu

515 520 525

Pro Pro Arg Glu

530

<210> 166

<211> 553

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 166

Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser

20 25 30

Gly Gly Gly Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala

35 40 45

Ala Ser Gly Phe Thr Phe Asn Asp Tyr Ala Met His Trp Val Arg Gln

50 55 60

Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Thr Ile Ser Trp Asn Ser

65 70 75 80

Gly Ser Ile Gly Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

85 90 95

Arg Asp Asn Ala Lys Lys Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg

100 105 110

Ala Glu Asp Thr Ala Leu Tyr Tyr Cys Ala Lys Asp Ile Gln Tyr Gly

115 120 125

Asn Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val Thr

130 135 140

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

145 150 155 160

Gly Ser Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser

165 170 175

Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser

180 185 190

Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu

195 200 205

Leu Ile Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe

210 215 220

Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu

225 230 235 240

Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp

245 250 255

Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Ser Asp Pro

260 265 270

Gly Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys

275 280 285

Ser Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn

290 295 300

Val Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro

305 310 315 320

Tyr Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg

325 330 335

Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg

340 345 350

Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly

355 360 365

Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr

370 375 380

Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg

385 390 395 400

Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro

405 410 415

Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu

420 425 430

Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala

435 440 445

Asp Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu

450 455 460

Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly

465 470 475 480

Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu

485 490 495

Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser

500 505 510

Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly

515 520 525

Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu

530 535 540

His Met Gln Ala Leu Pro Pro Arg Glu

545 550

<210> 167

<211> 531

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 167

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Asp Tyr

20 25 30

Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Thr Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr Tyr Cys

85 90 95

Ala Lys Asp Ile Gln Tyr Gly Asn Tyr Tyr Tyr Gly Met Asp Val Trp

100 105 110

Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ser Ser Ser Gly Gly Ser Cys

115 120 125

Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Ser Glu Ile Val Leu

130 135 140

Thr Gln Ser Pro Ala Thr Leu Ser Leu Ser Pro Gly Glu Arg Ala Thr

145 150 155 160

Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Tyr Leu Ala Trp Tyr

165 170 175

Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile Tyr Asp Ala Ser

180 185 190

Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly

195 200 205

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro Glu Asp Phe Ala

210 215 220

Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Ile Thr Phe Gly Gln

225 230 235 240

Gly Thr Arg Leu Glu Ile Lys Ser Asp Pro Gly Ser Gly Gly Gly Gly

245 250 255

Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser

260 265 270

Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser

275 280 285

Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu

290 295 300

Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

305 310 315 320

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

325 330 335

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

340 345 350

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

355 360 365

Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu

370 375 380

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

385 390 395 400

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

405 410 415

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln

420 425 430

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

435 440 445

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

450 455 460

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

465 470 475 480

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

485 490 495

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

500 505 510

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

515 520 525

Pro Arg Glu

530

<210> 168

<211> 552

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 168

Pro Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser

1 5 10 15

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Lys Leu Gln Glu

20 25 30

Ser Gly Pro Gly Leu Val Ala Pro Ser Gln Ser Leu Ser Val Thr Cys

35 40 45

Thr Val Ser Gly Val Ser Leu Pro Asp Tyr Gly Val Ser Trp Ile Arg

50 55 60

Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu Gly Val Ile Trp Gly Ser

65 70 75 80

Glu Thr Thr Tyr Tyr Asn Ser Ala Leu Lys Ser Arg Leu Thr Ile Ile

85 90 95

Lys Asp Asn Ser Lys Ser Gln Val Phe Leu Lys Met Asn Ser Leu Gln

100 105 110

Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala Lys His Tyr Tyr Tyr Gly

115 120 125

Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Ser Val Thr Val

130 135 140

Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

145 150 155 160

Ser Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu

165 170 175

Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys

180 185 190

Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu

195 200 205

Ile Tyr His Thr Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser

210 215 220

Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu

225 230 235 240

Gln Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro

245 250 255

Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Thr Ser Asp Pro Gly

260 265 270

Ser Gly Gly Gly Gly Ser Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ser

275 280 285

Gly Gly Gly Gly Ser Glu Leu Pro Thr Gln Gly Thr Phe Ser Asn Val

290 295 300

Ser Thr Asn Val Ser Pro Ala Lys Pro Thr Thr Thr Ala Cys Pro Tyr

305 310 315 320

Ser Asn Pro Ser Leu Cys Ala Pro Thr Thr Thr Pro Ala Pro Arg Pro

325 330 335

Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro

340 345 350

Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu

355 360 365

Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys

370 375 380

Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Arg Gly

385 390 395 400

Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val

405 410 415

Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu

420 425 430

Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp

435 440 445

Ala Pro Ala Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn

450 455 460

Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg

465 470 475 480

Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly

485 490 495

Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu

500 505 510

Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu

515 520 525

Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His

530 535 540

Met Gln Ala Leu Pro Pro Arg Glu

545 550

<210> 169

<211> 529

<212> PRT

<213> Artificial sequence

<220>

<223> Peptide

<400> 169

Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln

1 5 10 15

Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp Tyr

20 25 30

Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Tyr Asn Ser Ala Leu Lys

50 55 60

Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe Leu

65 70 75 80

Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Cys Ala

85 90 95

Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Ser Val Thr Val Ser Ser Ser Ser Gly Gly Ser Cys Pro Tyr

115 120 125

Ser Asn Pro Ser Leu Cys Ser Gly Gly Ser Asp Ile Gln Met Thr Gln

130 135 140

Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser

145 150 155 160

Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp Tyr Gln Gln

165 170 175

Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr His Thr Ser Arg Leu

180 185 190

His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

195 200 205

Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile Ala Thr Tyr

210 215 220

Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly Gly Gly Thr

225 230 235 240

Lys Leu Glu Ile Thr Ser Asp Pro Gly Ser Gly Gly Gly Gly Ser Cys

245 250 255

Pro Tyr Ser Asn Pro Ser Leu Cys Ser Gly Gly Gly Gly Ser Glu Leu

260 265 270

Pro Thr Gln Gly Thr Phe Ser Asn Val Ser Thr Asn Val Ser Pro Ala

275 280 285

Lys Pro Thr Thr Thr Ala Cys Pro Tyr Ser Asn Pro Ser Leu Cys Ala

290 295 300

Pro Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile

305 310 315 320

Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala

325 330 335

Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr

340 345 350

Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu

355 360 365

Val Ile Thr Leu Tyr Cys Arg Arg Gly Arg Lys Lys Leu Leu Tyr Ile

370 375 380

Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp

385 390 395 400

Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

405 410 415

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

420 425 430

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

435 440 445

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

450 455 460

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

465 470 475 480

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

485 490 495

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

500 505 510

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

Glu

<210> 170

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<223> Humanized F19 VH chain

<400> 170

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 Thr Ser Arg Tyr Thr Phe Thr Glu Tyr

20 25 30

Thr Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg Leu Glu Trp Ile

35 40 45

Gly Gly Ile Asn Pro Asn Asn Gly Ile Pro Asn Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Arg Val Thr Ile Thr Val Asp Thr 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 Arg Arg Ile Ala Tyr Gly Tyr Asp Glu Gly His Ala Met Asp

100 105 110

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 171

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> Humanized F19 VL chain

<400> 171

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 Tyr Ser

20 25 30

Arg Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Phe Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Phe Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln

85 90 95

Tyr Phe Ser Tyr Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

100 105 110

Lys

<210> 172

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<223> FAP5 VH chain

<400> 172

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Arg Pro Gly Ala

1 5 10 15

Ser Val Asn Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asn Asn

20 25 30

Gly Ile Asn Trp Leu Lys Gln Arg Thr Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Tyr Pro Arg Ser Thr Asn Thr Leu Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Arg Ser Ser Asn Thr Ala Tyr

65 70 75 80

Met Glu Thr Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr

85 90 95

Phe Cys Ala Arg Thr Leu Thr Ala Pro Phe Ala Phe Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ala

115

<210> 173

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<223> FAP5 VL chain

<400> 173

Gln Ile 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 Ser Ala Ser Ser Gly Val Asn Phe Met

20 25 30

His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Phe

35 40 45

Asp Thr Ser Lys 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 Ser Met Glu Ala Glu

65 70 75 80

Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Ser Phe Asn Pro Pro Thr

85 90 95

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg

100 105

<210> 174

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<223> mAb-specific epitope

<400> 174

Gly Gln Asn Asp Thr Ser Gln Thr Ser Ser Pro Ser

1 5 10

<210> 175

<211> 112

<212> PRT

<213> Artificial sequence

<220>

<223> CD3ζ intracellular signaling domain (ISD)

<400> 175

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Gln Gln Gly

1 5 10 15

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

20 25 30

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

35 40 45

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

50 55 60

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

65 70 75 80

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

85 90 95

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

100 105 110

<210> 176

<211> 42

<212> PRT

<213> Artificial sequence

<220>

<223> 41BB intracellular signaling domain (ISD)

<400> 176

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

1 5 10 15

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

20 25 30

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

35 40

<210> 177

<211> 42

<212> PRT

<213> Artificial sequence

<220>

<223> 41BB-IC (41BB co-stimulatory domain)

<400> 177

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

1 5 10 15

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

20 25 30

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

35 40

<210> 178

<211> 21

<212> PRT

<213> Artificial sequence

<220>

<223> CD8α signal peptide

<400> 178

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro

20

<210> 179

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<223> FcγRIIIα hinge

<400> 179

Gly Leu Ala Val Ser Thr Ile Ser Ser Phe Phe Pro Pro Gly Tyr Gln

1 5 10 15

<210> 180

<211> 45

<212> PRT

<213> Artificial sequence

<220>

<223> CD8α hinge

<400> 180

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

1 5 10 15

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

20 25 30

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

35 40 45

<210> 181

<211> 231

<212> PRT

<213> Artificial sequence

<220>

<223> IgG1 hinge

<400> 181

Glu Pro Lys Ser Pro Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala

1 5 10 15

Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

20 25 30

Asp Thr Leu Met Ile Ala Arg Thr Pro Glu Val Thr Cys Val Val Val

35 40 45

Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp

50 55 60

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr

65 70 75 80

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

85 90 95

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu

100 105 110

Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

115 120 125

Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys

130 135 140

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

145 150 155 160

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

165 170 175

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

180 185 190

Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser

195 200 205

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

210 215 220

Leu Ser Leu Ser Pro Gly Lys

225 230

<210> 182

<211> 24

<212> PRT

<213> Artificial sequence

<220>

<223> CD8α transmembrane (TM) domain

<400> 182

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

1 5 10 15

Ser Leu Val Ile Thr Leu Tyr Cys

20

<210> 183

<211> 52

<212> PRT

<213> Artificial sequence

<220>

<223> FcεRIα-TM-IC (FcεRIα chain transmembrane and intracellular domain)

<400> 183

Phe Phe Ile Pro Leu Leu Val Val Ile Leu Phe Ala Val Asp Thr Gly

1 5 10 15

Leu Phe Ile Ser Thr Gln Gln Gln Val Thr Phe Leu Leu Lys Ile Lys

20 25 30

Arg Thr Arg Lys Gly Phe Arg Leu Leu Asn Pro His Pro Lys Pro Asn

35 40 45

Pro Lys Asn Asn

50

<210> 184

<211> 215

<212> PRT

<213> Artificial sequence

<220>

<223> FcεRIβ-(-)ITAM (FcεRI β chain, no ITAM)

<400> 184

Met Asp Thr Glu Ser Asn Arg Arg Ala Asn Leu Ala Leu Pro Gln Glu

1 5 10 15

Pro Ser Ser Val Pro Ala Phe Glu Val Leu Glu Ile Ser Pro Gln Glu

20 25 30

Val Ser Ser Gly Arg Leu Leu Lys Ser Ala Ser Ser Pro Pro Leu His

35 40 45

Thr Trp Leu Thr Val Leu Lys Lys Glu Gln Glu Phe Leu Gly Val Thr

50 55 60

Gln Ile Leu Thr Ala Met Ile Cys Leu Cys Phe Gly Thr Val Val Cys

65 70 75 80

Ser Val Leu Asp Ile Ser His Ile Glu Gly Asp Ile Phe Ser Ser Phe

85 90 95

Lys Ala Gly Tyr Pro Phe Trp Gly Ala Ile Phe Phe Ser Ile Ser Gly

100 105 110

Met Leu Ser Ile Ile Ser Glu Arg Arg Asn Ala Thr Tyr Leu Val Arg

115 120 125

Gly Ser Leu Gly Ala Asn Thr Ala Ser Ser Ile Ala Gly Gly Thr Gly

130 135 140

Ile Thr Ile Leu Ile Ile Asn Leu Lys Lys Ser Leu Ala Tyr Ile His

145 150 155 160

Ile His Ser Cys Gln Lys Phe Phe Glu Thr Lys Cys Phe Met Ala Ser

165 170 175

Phe Ser Thr Glu Ile Val Val Met Met Leu Phe Leu Thr Ile Leu Gly

180 185 190

Leu Gly Ser Ala Val Ser Leu Thr Ile Cys Gly Ala Gly Glu Glu Leu

195 200 205

Lys Gly Asn Lys Val Pro Glu

210 215

<210> 185

<211> 41

<212> PRT

<213> Artificial sequence

<220>

<223> CD28-IC (CD28 co-stimulatory domain)

<400> 185

Arg Ser Lys Arg Ser Arg Gly Gly His Ser Asp Tyr Met Asn Met Thr

1 5 10 15

Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro

20 25 30

Pro Arg Asp Phe Ala Ala Tyr Arg Ser

35 40

<210> 186

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<223> BCMA VH

<400> 186

Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Leu Ser Ser Gly Gly Ser Thr Tyr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Pro Met Asp Ile Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val

<210> 187

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<223> BCMA VL

<400> 187

Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Gly Gly Gln Ser Val Ser Ser Ser

20 25 30

Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu

35 40 45

Met Tyr Asp Ala Ser Ile Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu

65 70 75 80

Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gln Ser Trp Pro

85 90 95

Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

Claims (72)

1. A chimeric antigen receptor (CAR) polypeptide comprising at least one extracellular binding domain, said extracellular binding domain comprising at least an antigen-specific VH chain and a VL chain forming an scFv, wherein said extracellular binding domain comprises at least one monoclonal antibody (mAb) specific epitope of SEQ ID NO 35. 2. The polypeptide according to claim 1, wherein the mAb-specific epitope is located between the VH chain and the VL chain. 3. The polypeptide according to claim 1 or 2, wherein the VH chain and VL chain, and the mAb-specific epitope are linked together by at least one linker and hinged to the transmembrane domain of the CAR. 4. The polypeptide of claim 3, wherein the mAb epitope is linked to the VH chain and the VL chain via two linkers. 5. The polypeptide according to claim 1, wherein the extracellular binding domain further comprises at least one monoclonal antibody (mAb) specific epitope of SEQ ID NO144. 6. The polypeptide of claim 1, wherein the extracellular binding domain comprises the following sequence V ₁ -L ₁ -V ₂ -(L) _x -tablet 1-(L) _x -； V ₁ -L ₁ -V ₂ -(L) _x -tablet 1-(L) _x -tablet 2-(L) _x -； V ₁ -L ₁ -V ₂ -(L) _x -tablet1-(L) _x -tablet2-(L) _x -tablet3-(L) _x -； (L) _x -tablet 1-(L) _x -V ₁ -L ₁ -V ₂ ; (L) _x - Epitope 1 - (L) _x - Epitope 2 - (L) _x - V ₁ - L ₁ - V ₂ ; Epitope 1-(L) _x - Epitope 2-(L) _x - Epitope 3-(L) _x - V ₁ - _{L 1} - V ₂ ; (L) _x - Epitope 1 - (L) _x - V ₁ - L ₁ - V ₂ - (L) _x - Epitope 2 - (L) _x ; (L) _x - Epitope 1 - (L) _x - V ₁ - L ₁ - V ₂ - (L) _x - Epitope 2 - (L) _x - Epitope 3 - (L) _x -; (L) _x - Epitope 1 - (L) _x - V ₁ - L ₁ - V ₂ - (L) _x - Epitope 2 - (L) _x - Epitope 3 - (L) _x - Epitope 4 - (L) _x -; (L) _x - Epitope 1 - (L) _x - Epitope 2 - (L) _x - V ₁ - L ₁ - V ₂ - (L) _x - Epitope 3 - (L) _x -; (L) _x - Epitope 1 - (L) _x - Epitope 2 - (L) _x - V ₁ - L ₁ - V ₂ - (L) _x - Epitope 3 - (L) _x - Epitope 4 - (L) _x -; _V1 -(L) _x -tablet1-(L) _{x -V2} ; V ₁ -(L) _x - Epitope 1 -(L) _{x -} V ₂ -(L) _x - Epitope 2 -(L) _x ； V ₁ -(L) _x - Epitope 1 -(L) _{x -} V ₂ -(L) _x - Epitope 2 -(L) _x - Epitope 3 -(L) _x ； V ₁ -(L) _x - Epitope 1 -(L) _{x -} V ₂ -(L) _x - Epitope 2 -(L) _x - Epitope 3 -(L) _x - Epitope 4 -(L) _x ; (L) _x -tablet 1 - (L) _x -V ₁ - (L) _x -tablet 2 - (L) _x -V ₂ ; or, (L) _x - Epitope 1 - (L) _x - V ₁ - (L) _x - Epitope 2 - (L) _x - V ₂ - (L) _x - Epitope 3 - (L) _x ; in, _V1 is _VL and _V2 is _VH or _V1 is _VH and _V2 is _VL ; _L1 is a connector suitable for connecting the _VH chain to the _VL chain; L is a linker containing glycine and serine residues, and each occurrence of L in the extracellular binding domain may be the same or different from other occurrences of L in the same extracellular binding domain, and, x is 0 or 1 and each occurrence of x is independently selected from the others; and, Epitopes 1, 2 and 4 are mAb-specific epitopes of SEQ ID NO 35; Epitope 3 is an mAb-specific epitope of SEQ ID NO 35 or SEQ ID NO 144. 7. The polypeptide of claim 6, wherein the extracellular binding domain comprises the following sequence: V ₁ -L ₁ -V ₂ -L-Tablet 1; V ₁ -L ₁ -V ₂ -L-Tablet 1-L; V ₁ -L ₁ -V ₂ -L-Tablet 1-L-Tablet 2; V ₁ -L ₁ -V ₂ -L-Tablet 1-L-Tablet 2-L; V ₁ -L ₁ -V ₂ -L-Tablet 1-L-Tablet 2-L-Tablet 3; V ₁ -L ₁ -V _{2 -L} -Tablet ₁ -L-Tablet ₂ -L-Tablet 3-L; V ₁ -L ₁ -V ₂ -Tablet 1; V ₁ -L ₁ -V ₂ -Tablet 1-L; V ₁ -L ₁ -V ₂ -Tablet 1-L-Tablet 2; V ₁ -L ₁ -V ₂ -Tablet 1-L-Tablet 2-L-Tablet 3; V ₁ -L ₁ -V ₂ -Tablet 1-L-Tablet 2-L-Tablet 3-L; Tablet 1-V ₁ -L ₁ -V ₂ ; Tablet 1-LV ₁ -L ₁ -V ₂ ; L-Tablet 1-V ₁ -L ₁ -V ₂ ; L-Tablet 1-LV ₁ -L ₁ -V ₂ ; Tablet 1-L-Tablet 2-V ₁ -L ₁ -V ₂ ; Tablet 1-L-Tablet 2-LV _{1 -L 1 -V 2 ;} L-Tablet 1-L-Tablet 2-V ₁ -L ₁ -V ₂ ; Tablet 1-L-Tablet 2-L-Tablet 3-V ₁ -L _{1 -V 2} ; Tablet 1-L- Tablet 2-L- Tablet 3-LV ₁ -L ₁ -V ₂ ; L- Tablet 1-L- Tablet 2-L- Tablet 3-V ₁ -L ₁ -V ₂ ; L- Tablet 1-L- Tablet 2-L- Tablet 3-LV ₁ -L ₁ -V ₂ ; V ₁ -L- Tablet 1-LV ₂ ; L- Tablet 1-LV ₁ -L- Tablet 2-LV ₂ ; V ₁ -L- Tablet 1-LV ₂ -L- Tablet 2-L; V ₁ -L- Tablet 1-LV ₂ -L- Tablet 2-L- Tablet 3 ; V ₁ -L- Tablet 1-LV ₂ -L- Tablet 2- Tablet 3 ; V ₁ -L- Tablet 1-LV ₂ -L- Tablet 2-L- Tablet 3- Tablet 4 ; L- Tablet 1-LV ₁ -L-tablet2- _LV2 -L-tablet3-L; Tablet1-LV1 _-L -tablet2-LV2 _-L -tablet3-L; L-tablet1-LV1 _-L -tablet2-LV2 -L-tablet3; L-tablet1-LV1 -L1 _{-V2 -L} -tablet2-L; L-tablet1- _{LV1 -L1} -V2 _-L - _tablet2 -L; L-tablet1- _LV1 -L1 -V2 _-L -tablet2-L-tablet3; _L -tablet1-LV1 _-L1 -V2 _-L -tablet2-tablet3; or Tablet1- _LV1 -L1 _-V2 -L-tablet2- _L -tablet3-tablet4, where _V1 is _VL and _V2 is _VH or _V1 is _VH and _V2 is _VL ; _L1 is any connector suitable for attaching the V _H chain to the V _L chain; L is a linker containing glycine and serine residues, and each occurrence of L in the extracellular binding domain may be the same as or different from other occurrences of L in the corresponding extracellular binding domains. Epitopes 1, 2 and 4 are mAb-specific epitopes of SEQ ID NO 35; Epitope 3 is an mAb-specific epitope of SEQ ID NO 35 or SEQ ID NO 144. 8. The polypeptide according to claim 6 or 7, wherein _L1 is a linker comprising glycine and/or serine. 9. The polypeptide of claim 8, wherein _L1 is a linker comprising the amino acid sequence (Gly-Gly-Gly-Ser) _n or (Gly-Gly-Gly-Gly-Ser) _n , wherein n is 1, 2, 3, 4 or 5 or a linker comprising the amino acid sequence (Gly ₄ Ser) ₄ or (Gly ₄ Ser) ₃ . 10. The polypeptide according to claim 6 or 7, wherein L is a linker comprising glycine and/or serine. 11. The polypeptide of claim 10, wherein L is a linker having an amino acid sequence selected from the following: SGG, GGS, SGGS, SSGGS, GGGG, SGGGG, GGGGS, SGGGGS, GGGGGS, SGGGGGS, SGGGGGGS, GSGGGGGS, GGGGGGGS, SGGGGGGGS, SGGGGGGGGS, or SGGGGSGGGGS. 12. The polypeptide according to claim 10, wherein L is SGGGG, GGGGS or SGGGGS. 13. The polypeptide of claim 1, wherein the VH and VL chains have an antigen target sequence that is more than 80% identical to the following: SEQ ID NO 43, SEQ ID NO 44, SEQ ID NO 45, SEQ ID NO 46, SEQ ID NO 47, SEQ ID NO 48, SEQ ID NO 49, SEQ ID NO 50, SEQ ID NO 51 and SEQ ID NO 52. 14. The polypeptide of claim 1, wherein the VH and VL chains have an antigen target sequence that is more than 90% identical to the following: SEQ ID NO 43, SEQ ID NO 44, SEQ ID NO 45, SEQ ID NO 46, SEQ ID NO 47, SEQ ID NO 48, SEQ ID NO 49, SEQ ID NO 50, SEQ ID NO 51 and SEQ ID NO 52. 15. The polypeptide of claim 1, wherein the VH and VL chains have an antigen target sequence that is more than 95% identical to the following: SEQ ID NO 43, SEQ ID NO 44, SEQ ID NO 45, SEQ ID NO 46, SEQ ID NO 47, SEQ ID NO 48, SEQ ID NO 49, SEQ ID NO 50, SEQ ID NO 51 and SEQ ID NO 52. 16. The polypeptide according to claim 1, wherein the antigen is a cell surface marker antigen. 17. The polypeptide according to claim 1, wherein the antigen is a tumor-associated surface antigen. 18. The polypeptide according to claim 1, wherein the antigen is selected from ErbB2 (HER2/neu), carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), epidermal growth factor receptor (EGFR, EGFR variant III (EGFRvIII), CD19, CD20, CD30, CD40, disialotetrahexosylganglioside GD2, GD3, C-type lectin-like molecule-1 (CLL-1), ductal epithelial mucin, gp36, TAG-72, glycosphingolipids, glioma-associated antigen, β-human chorionic gonadotropin, alpha-fetoprotein (AFP), lectin-reactive AFP, thyroglobulin, RAGE-1, MN-CAIX, human telomerase reverse transcriptase, RU1, RU2 (AS), intestinal carboxylesterase, mutase, etc. hsp70-2, M-CSF, prostate enzymes, prostate enzyme-specific antigen (PSA), PAP, NY-ESO-1, LAGA-1a, p53, prostate protein, PSMA, survivin and telomerase, prostate cancer tumor antigen-1 (PCTA-1), MAGE, ELF2M, neutrophil elastase, liver glycoside B2, CD22, insulin-like growth factor (IGF1)-I, IGF-II, IGFI receptor, mesothelin, major histocompatibility complex (MHC) molecule presenting tumor-specific peptide epitopes, 5T4, ROR1, Nkp30, NKG2D, tumor matrix antigen, extra domain A (EDA) and extra domain B (EDB) of fibronectin, and A1 domain (TnC) of tendinin-C. A1) and fibroblast-associated protein (fap), LRP6, melanoma-associated chondroitin sulfate proteoglycan (MCSP), CD38/CS1, MART1, WT1, MUC1, LMP2, idiotype, NY-ESO-1, Ras mutant, gp100, protease 3, bcr-abl, tyrosinase, hTERT, EphA2, ML-TAP, ERG, NA17, PAX3, ALK, androgen receptor; lineage-specific or tissue-specific antigens such as CD3, CD4, CD8, CD24, CD25, CD33, CD34, CD70, CD79, CD116, CD117, CD135, CD123, CD133, CD138, CTLA-4, B7-1 (CD80), B7-2 (CD86), endothelial glycoprotein, major histocompatibility complex (MHC) molecule, BCMA (CD269, TNFRSF) 17) or FLT-3. 19. The polypeptide according to claim 1, wherein VH and VL are selected from... VH of SEQ ID NO 65 and VL of SEQ ID NO 66; VH of SEQ ID NO 67 and VL of SEQ ID NO 68; VH of SEQ ID NO 69 and VL of SEQ ID NO 70; VH of SEQ ID NO 71 and VL of SEQ ID NO 72; VH of SEQ ID NO 77 and VL of SEQ ID NO 78; VH of SEQ ID NO 79 and VL of SEQ ID NO 80; VH of SEQ ID NO 81 and VL of SEQ ID NO 82; VH of SEQ ID NO 83 and VL of SEQ ID NO 84; VH of SEQ ID NO 85 and VL of SEQ ID NO 86; VH of SEQ ID NO 87 and VL of SEQ ID NO 88; VH of SEQ ID NO 89 and VL of SEQ ID NO 90; VH of SEQ ID NO 91 and VL of SEQ ID NO 92; SEQ ID NO VH of SEQ ID NO 93 and VL of SEQ ID NO 94; VH of SEQ ID NO 95 and VL of SEQ ID NO 96; VH of SEQ ID NO 97 and VL of SEQ ID NO 98; VH of SEQ ID NO 99 and VL of SEQ ID NO 100; VH of SEQ ID NO 101 and VL of SEQ ID NO 102; VH of SEQ ID NO 103 and VL of SEQ ID NO 104; VH of SEQ ID NO 105 and VL of SEQ ID NO 106; VH of SEQ ID NO 107 and VL of SEQ ID NO 108; VH of SEQ ID NO 109 and VL of SEQ ID NO 110; VH of SEQ ID NO 111 and VL of SEQ ID NO 112; VH of SEQ ID NO 113 and VL of SEQ ID NO 114; VH of SEQ ID NO 115 and VL of SEQ ID NO VL of SEQ ID NO 116; VH of SEQ ID NO 117 and VL of SEQ ID NO 118; VH of SEQ ID NO 119 and VL of SEQ ID NO 120; VH of SEQ ID NO 121 and VL of SEQ ID NO 122; or, VH of SEQ ID NO 123 and VL of SEQ ID NO 124; VH of SEQ ID NO 170 and VL of SEQ ID NO 171; VH of SEQ ID NO 172 and VL of SEQ ID NO 173; or VH of SEQ ID NO 186 and VL of SEQ ID NO 187. 20. The polypeptide of claim 1, wherein the polypeptide comprises an extracellular binding domain, wherein the extracellular binding domain further comprises a hinge, and the polypeptide further comprises... - Transmembrane structural domains, and, - Intracellular domain. 21. The polypeptide of claim 20, wherein the hinge comprises an IgG1 hinge, an IgG4 hinge, a CD8α hinge, or an FcγRIIIα hinge. 22. The polypeptide of claim 20, wherein the transmembrane domain comprises a transmembrane region of the α, β, or ζ chain of a T-cell receptor, PD-1, 4-1BB, OX40, ICOS, CTLA-4, LAG3, 2B4, BTLA4, TIM-3, TIGIT, SIRPA, CD28, CD3ε, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, or CD154. 23. The polypeptide of claim 20, wherein the transmembrane domain comprises a transmembrane region of PD-1 or CD8α. 24. The polypeptide of claim 20, wherein the transmembrane domain comprises a transmembrane region of CD8α. 25. The polypeptide of claim 20, wherein the intracellular domain comprises a CD3ζ signaling domain. 26. The polypeptide of claim 20, wherein the intracellular domain comprises a 4-1BB domain. 27. The polypeptide according to claim 1, wherein the CAR is a single-chain CAR. 28. The polypeptide of claim 1, wherein the polypeptide has more than 80% similarity to any of the following: SEQ ID NO 1 to 10 or SEQ ID NO 152 to 161, and comprises VH of SEQ ID NO 119 and VL of SEQ ID NO 120. 29. The polypeptide of claim 1, wherein the polypeptide has more than 90% similarity to any of the following: SEQ ID NO 1 to 10 or SEQ ID NO 152 to 161, and comprises VH of SEQ ID NO 119 and VL of SEQ ID NO 120. 30. The polypeptide of claim 1, wherein the polypeptide has more than 95% similarity to any of the following: SEQ ID NO 1 to 10 or SEQ ID NO 152 to 161, and comprises VH of SEQ ID NO 119 and VL of SEQ ID NO 120. 31. The polypeptide of claim 1, wherein the polypeptide is identical to any one of the following: SEQ ID NO 1 to 10 or SEQ ID NO 152 to 161. 32. The polypeptide of claim 1, wherein the polypeptide has more than 80% similarity to the following: SEQ ID NO 126 to 139, and comprises VH of SEQ ID NO 186 and VL of SEQ ID NO 187. 33. The polypeptide of claim 1, wherein the polypeptide has more than 90% similarity to the following: SEQ ID NO 126 to 139, and comprises VH of SEQ ID NO 186 and VL of SEQ ID NO 187. 34. The polypeptide of claim 1, wherein the polypeptide has more than 95% similarity to the following: SEQ ID NO 126 to 139, and comprises VH of SEQ ID NO 186 and VL of SEQ ID NO 187. 35. The polypeptide according to claim 1, wherein the polypeptide is identical to any one of the following: SEQ ID NO 126 to 139. 36. The polypeptide of claim 1, wherein the polypeptide has more than 80% similarity to SEQ ID NO 140 or 141, and comprises VH of SEQ ID NO 186 and VL of SEQ ID NO 187. 37. The polypeptide of claim 1, wherein the polypeptide has more than 90% similarity to SEQ ID NO 140 or 141, and comprises VH of SEQ ID NO 186 and VL of SEQ ID NO 187. 38. The polypeptide of claim 1, wherein the polypeptide has more than 95% similarity to SEQ ID NO 140 or 141 and comprises VH of SEQ ID NO 186 and VL of SEQ ID NO 187. 39. The polypeptide according to claim 1, wherein the polypeptide is identical to each of the following: SEQ ID NO 140 or 141. 40. The polypeptide of claim 1, wherein the polypeptide has more than 80% similarity to the following: SEQ ID NO 146 to 149, and comprises VH of SEQ ID NO 97 and VL of SEQ ID NO 98. 41. The polypeptide of claim 1, wherein the polypeptide has more than 90% similarity to the following: SEQ ID NO 146 to 149, and comprises VH of SEQ ID NO 97 and VL of SEQ ID NO 98. 42. The polypeptide of claim 1, wherein the polypeptide has more than 95% similarity to the following: SEQ ID NO 146 to 149, and comprises VH of SEQ ID NO 97 and VL of SEQ ID NO 98. 43. The polypeptide of claim 1, wherein the polypeptide is identical to any one of the following: SEQ ID NO 146 to 149. 44. The polypeptide of claim 1, wherein the polypeptide has more than 80% similarity to SEQ ID NO 162 or 163, and comprises VH of SEQ ID NO 55 and VL of SEQ ID NO 56. 45. The polypeptide of claim 1, wherein the polypeptide has more than 90% similarity to SEQ ID NO 162 or 163, and comprises VH of SEQ ID NO 55 and VL of SEQ ID NO 56. 46. The polypeptide of claim 1, wherein the polypeptide has more than 95% similarity to SEQ ID NO 162 or 163, and comprises VH of SEQ ID NO 55 and VL of SEQ ID NO 56. 47. The polypeptide according to claim 1, wherein the polypeptide is identical to each of the following: SEQ ID NO 162 or 163. 48. The polypeptide of claim 1, wherein the polypeptide has more than 80% similarity to SEQ ID NO 168 or 169, and comprises VH of SEQ ID NO 53 and VL of SEQ ID NO 54. 49. The polypeptide of claim 1, wherein the polypeptide has more than 90% similarity to SEQ ID NO 168 or 169, and comprises VH of SEQ ID NO 53 and VL of SEQ ID NO 54. 50. The polypeptide of claim 1, wherein the polypeptide has more than 95% similarity to SEQ ID NO 168 or 169, and comprises VH of SEQ ID NO 53 and VL of SEQ ID NO 54. 51. The polypeptide according to claim 1, wherein the polypeptide is identical to each of the following: SEQ ID NO 168 or 169. 52. The polypeptide of claim 1, wherein the polypeptide has more than 80% similarity to SEQ ID NO 164 or 165, and comprises VH of SEQ ID NO 119 and 120 of SEQ ID NO 56. 53. The polypeptide of claim 1, wherein the polypeptide has more than 90% similarity to SEQ ID NO 164 or 165, and comprises VH of SEQ ID NO 119 and 120 of SEQ ID NO 56. 54. The polypeptide of claim 1, wherein the polypeptide has more than 95% similarity to SEQ ID NO 164 or 165, and comprises VH of SEQ ID NO 119 and 120 of SEQ ID NO 56. 55. The polypeptide according to claim 1, wherein the polypeptide is identical to each of the following: SEQ ID NO 164 or 165. 56. The polypeptide according to claim 1, wherein the polypeptide is identical to SEQ ID NO 166 or 167. 57. The polypeptide according to claim 1, wherein the CAR is a multi-chain CAR. 58. A polynucleotide encoding a polypeptide according to any one of claims 1 to 57. 59. A polynucleotide encoding a polypeptide according to any one of claims 1 to 57, wherein the polypeptide comprises a CD3ζ signaling domain and a co-stimulatory domain from 4-1BB. 60. An expression vector comprising the polynucleotide of claim 58 or 59. 61. An engineered immune cell expressing the polypeptide of any one of claims 1 to 57 on its cell surface. 62. The engineered immune cell according to claim 61, wherein the cell is derived from inflammatory T lymphocytes, cytotoxic T lymphocytes, regulatory T lymphocytes, or helper T lymphocytes. 63. The use of the engineered immune cells according to claim 61 or 62 in the preparation of medicaments for treating diseases. 64. The application according to claim 63, wherein the disease is cancer. 65. The application according to claim 64, wherein the cancer is leukemia and lymphoma. 66. A method for engineering the in vitro immune cells of claim 61 or 62, comprising: (a) Provides immune cells; (b) Introducing at least one polynucleotide encoding the polypeptide of any one of claims 1 to 57 into the immune cells of step (a), (c) Express the polynucleotide in the immune cells described in step (b). 67. The method for engineered immune cells according to claim 66, wherein the immune cells are T cells. 68. Use of at least one epitope-specific monoclonal antibody (mAb) in the preparation of a medicament for eliminating engineered immune cells according to claim 61 or 62 in vivo in a patient, comprising contacting the engineered immune cells with the epitope-specific monoclonal antibody (mAb), wherein the epitope-specific monoclonal antibody (mAb) specifically recognizes the mAb-specific epitope of SEQ ID NO 35. 69. The application according to claim 68, wherein the epitope-specific mAb is rituximab. 70. The application according to claim 68, wherein the epitope-specific mAb binds to a molecule capable of activating the complement system. 71. The application according to claim 68, wherein the cytotoxic drug binds to the epitope-specific mAb. 72. The application according to claim 68, wherein the immune cell is a T cell.