# US 10,766,969 B2 · Binding molecules for BCMA and CD3

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- Number: US 10,766,969 B2
- Document ID: US10766969B2
- Status: Granted
- Kind: B2
- Application number: 14/358,511
- Filed: 2012-11-15
- Published: 2015-01-22
- Granted: 2020-09-08
- Earliest claimed: 2011-11-15
- Assignees: Amgen Inc.
- Applicants: Amgen Research (Munich) GmbH; Boehringer Ingelheim International GmbH
- Inventors: Peter Kufer; Tobias Raum; Patrick Hoffmann; Roman Kischel; Ralf Lutterbuese; Doris Rau; Paul Adam; Eric Borges; Barbara Hebeis; Susanne Hipp
- Web page: https://patentgrep.com/patent/US10766969B2

## CPC

- C07K 16/468: {Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies}
- A61K 39/0005: {Vertebrate antigens (from snakes A61K39/38)}
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 17/00: Drugs for dermatological disorders
- A61P 19/00: Drugs for skeletal disorders
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/70578: {NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 (NGF-receptor C07K14/71, TNF-receptor C07K14/7151)}
- C07K 16/2809: {against the T-cell receptor (TcR)-CD3 complex}
- C07K 16/2875: {against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154 (against NGF C07K16/22, against TNF C07K16/241)}
- C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/575: {humoral response}
- C07K 2317/31: multispecific
- C07K 2317/33: Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/56: variable (Fv) region, i.e. VH and/or VL
- C07K 2317/565: Complementarity determining region [CDR]
- C07K 2317/622: Single chain antibody (scFv)
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- C07K 2319/00: Fusion polypeptide
- C07K 2319/21: containing a His-tag
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C07K 2319/31: fusions, other than Fc, for prolonged plasma life, e.g. albumin
- C07K 2319/43: containing a FLAG-tag
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a binding molecule which is at least bispecific comprising a first and a second binding domain, wherein the first binding domain is capable of binding to epitope cluster3 of BCMA, and the second binding domain is capable of binding to the Tcell CD3 receptor complex. Moreover, the invention provides a nucleic acid sequence encoding the binding molecule, a vector comprising said nucleic acid sequence and a host cell transformed or transfected with said vector. Furthermore, the invention provides a process for the production of the binding molecule of the invention, a medical use of said binding molecule and a kit comprising said binding molecule.

## Claims

### Claim 1

A binding molecule which is at least bispecific comprising a first and a second binding domain, wherein
(a) the first binding domain comprises a variable heavy chain and a variable light chain and binds to B cell maturation antigen (BCMA), wherein the first binding domain comprises a VH region comprising CDR-H1, CDR-H2, and CDR-H3 and a VL region comprising CDR-L1, CDR-L2, and CDR-L3, and at least five of the six CDRs selected from the group consisting of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 have sequences as follows:
(i) CDR-H1 as depicted in SEQ ID NO: 1, SEQ ID NO: 161, or SEQ ID NO: 311;
(ii) CDR-H2 as depicted in SEQ ID NO: 2, SEQ ID NO: 12, SEQ ID NO: 162, SEQ ID NO: 212, SEQ ID NO: 312, SEQ ID NO: 322, SEQ ID NO: 352, SEQ ID NO: 362, SEQ ID NO: 582, SEQ ID NO: 622, or SEQ OD NO: 752;
(iii) CDR-H3 as depicted in SEQ ID NO: 3, SEQ ID NO: 163, SEQ ID NO: 313, SEQ ID NO: 323, or SEQ ID NO: 623;
(iv) CDR-L1 as depicted in SEQ ID NO: 4, SEQ ID NO: 164, SEQ ID NO: 314, SEQ ID NO: 624, SEQ ID NO: 774, SEQ ID NO: 974, or SEQ ID NO: 994;
(v) CDR-L2 as depicted in SEQ ID NO: 5, SEQ ID NO: 165, SEQ ID NO: 315, or SEQ ID NO: 625; and
(vi) CDR-L3 as depicted in SEQ ID NO: 6, SEQ ID NO: 166, SEQ ID NO: 176, SEQ ID NO: 316, SEQ ID NO: 626, SEQ ID NO: 656, SEQ ID NO: 676, SEQ ID NO: 776, SEQ ID NO: 816, SEQ ID NO: 966, or SEQ ID NO: 996, and
wherein not more than one of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 has a sequence as follows:
(i) CDR-H1 comprises amino acid sequence X1X2X3X4X5 which has 80% or greater identity to a sequence selected from the group consisting of NYDMA (SEQ ID NO:1), NFDMA (SEQ ID NO:161), and NHIIH (SEQ ID NO:311), and where X1 is N; X2 is Y, F, or H; X3 is D or I; X4 is M or I; and X5 is A or H;
(ii) CDR-H2 comprises amino acid sequence X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20X21X22 which has 80% or greater identity to a sequence selected from the group consisting of: SIITSGDATYYRDSVKG (SEQ ID NO:2), SIITSGDMTYYRDSVKG (SEQ ID NO:12), SITTGADHAIYADSVKG (SEQ ID NO:162), SITTGADHAIYAESVKG (SEQ ID NO:212), SIITSGGDNYYRDSVKG (SEQ ID NO:582), SITTGGGDTYYADSVKG (SEQ ID NO:732), YINPYPGYHAYNEKFQG (SEQ ID NO:312), YINPYPGYHAYNQKFQG (SEQ ID NO:352), YINPYDGWGDYNEKFQG (SEQ ID NO:322), YINPYDGWGDYNQKFQG (SEQ ID NO:362), and SISTRGDITSYRDSVKG (SEQ ID NO: 622), and where X6 is S or Y; X7 is I; X8 is I, T, N, or S; X9 is T or P; X10 is S, Y, R, or G; is G, A, D, or P; X12 is D or G; X13 is A, M, H, D, Y, W or I; X14 is T, A, N, H, or G; X15 is Y, I, A, D or S; X16 is Y; X17 is R, A, or N; X18 is D, E, or Q; X19 is S or K; X20 is V or F; X21 is K or Q; and X22 is G;
(iii) CDR-H3 comprises amino acid sequence X23X24X25X26X27X28X29X30X31X32X33X34 which has 80% or greater identity to a sequence selected from the group consisting of: HDYYDGSYGFAY (SEQ ID NO:3), HGYYDGYHLFDY (SEQ ID NO:163), QDYYTDYMGFAY (SEQ ID NO:623), DGYYRDTDVLDY (SEQ ID NO:313), and DGYYRDADVLDY (SEQ ID NO:323), and where X23 is H, Q or D; X24 is D or G; X25 is Y; X26 is Y; X27 is D, T or R; X28 is G or D; X29 is S, Y, T or A; X30 is Y, H, M or D; X31 is G, L, or V; X32 is F or L; X33 is A or D; and X34 is Y;
(iv) CDR-L1 comprises amino acid sequence X35X36X37X38X39X40X41X42X43X44X45 which has 80% or greater identity to a sequence selected from the group consisting of: KASQSVGINVD (SEQ ID NO:4), RASQGISNYLN (SEQ ID NO:164), RASEDIYNGLA (SEQ ID NO:624), RASQGISNHLN (SEQ ID NO:774), RANQGISNNLN (SEQ ID NO:974), RASQGISNNLN (SEQ ID NO:994), and QASQDISNYLN (SEQ ID NO:314), and wherein X35 is K, R or Q; X36 is A; X37 is S or N; X38 is Q or E; X39 is S, G, or D; X40 is V or I; X41 is G, S, or Y; X42 is I or N; X43 is N, Y, G, or H; X44 is V or L; and X45 is D, N, or A;
(v) CDR-L2 comprises amino acid sequence X46X47X48X49X50X51X52 which has 80% or greater identity to a sequence selected from the group consisting of: GASNRHT (SEQ ID NO:5), YTSNLQS (SEQ ID NO:165), GASSLQD (SEQ ID NO:625), and YTSRLHT (SEQ ID NO:315), and wherein X46 is G or Y; X47 is A or T; X48 is S; X49 is N, S, or R; X50 is R or L; X51 is H or Q; and X52 is T, S, or D; or
(vi) CDR-L3 comprises amino acid sequence X53X54X55X56X57X58X59X60X61 which has 80% or greater identity to a sequence selected from the group consisting of: LQYGSIPFT (SEQ ID NO:6), QQYDISSYT (SEQ ID NO:166), MGQTISSYT (SEQ ID NO:176), QQGNTLPWT (SEQ ID NO:316), QQSYKYPLT (SEQ ID NO:626), AGPHKYPLT (SEQ ID NO:656), QQSRNYQQT (SEQ ID NO:676), QQYFDRPYT (SEQ ID NO:776), QQYSNLPYT (SEQ ID NO:816), QQFTSLPYT (SEQ ID NO:966), and QQFAHLPYT (SEQ ID NO:996), and wherein X53 is L, Q, M, or A; X54 is Q or G; X55 is G, P, Y, Q, S, or F; X56 is G, D, T, N, Y, H, R, F, S, or A; X57 is S, I, T, K, N, D, or H; X58 is I, S, L, Y, or R; X59 is P, S, or Q; X60 is F, Y, W, L, or Q and X61 is T; and
(b) the second binding domain comprises a variable heavy chain and a variable light chain and binds to the human T cell CD3 receptor complex.

### Claim 2 (depends on 1)

The binding molecule according to claim 1, wherein the first binding domain binds to macaque BCMA.

### Claim 3 (depends on 1)

The binding molecule according to claim 1 wherein the second binding domain binds to CD3 epsilon.

### Claim 4 (depends on 1)

The binding molecule according to claim 1, wherein the second binding domain binds to human CD3 and to macaque CD3.

### Claim 5 (depends on 1)

The binding molecule according to claim 1, wherein the binding molecule is selected from the group consisting of (scFv)2, diabodies and oligomers thereof.

### Claim 6 (depends on 1)

The binding molecule according to claim 1, wherein the binding molecule has an EC50 (pg/ml) of less than 350 in a cell-based cytotoxicity assay.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising any one of the binding molecule according to claim 1 and a pharmaceutically acceptable carrier.

### Claim 8 (depends on 1)

The binding molecule according to claim 1 for use in treatment or amelioration of a disease selected from the group consisting of plasma cell disorders, other B cell disorders that correlate with BCMA expression and autoimmune diseases.

### Claim 9 (depends on 1)

A kit comprising any one of the binding molecule as defined in claim 1.

### Claim 10 (depends on 1)

The binding molecule according to claim 1, wherein X2 is H, X3 is I, X4 is I, and X5 is H.

### Claim 11 (depends on 1)

The binding molecule according to claim 1, wherein X6 is Y, X8 is N, X9 is P, X10 is Y, X12 is G, X17 is N, X19 is K, X20 is F, and X21 is Q.

### Claim 12 (depends on 11)

The binding molecule according to claim 11, wherein X11 is P, X13 is Y, X14 is H, X15 is A, and X18 is E.

### Claim 13 (depends on 1)

The binding molecule according to claim 1, wherein X23 is D, X24 is G, X27 is R, X28 is D, X30 is D, X31 is V, X32 is L, and X33 is D.

### Claim 14 (depends on 13)

The binding molecule according to claim 13, wherein X29 is T.

### Claim 15 (depends on 1)

The binding molecule according to claim 1, wherein X37 is S, X38 is Q, X40 is I, X41 is S, X42 is N, X44 is L, and X45 is N.

### Claim 16 (depends on 15)

The binding molecule according to claim 15, wherein X35 is Q, X39 is D, and X43 is Y.

### Claim 17 (depends on 1)

The binding molecule according to claim 1 wherein X46 is Y, X47 is T, and X50 is L.

### Claim 18 (depends on 17)

The binding molecule according to claim 17 wherein X49 is R, X51 is H, and X52 is T.

### Claim 19 (depends on 1)

The binding molecule according to claim 1, wherein X53 is Q, X54 is Q, and X59 is P.

### Claim 20 (depends on 19)

The binding molecule according to claim 19, wherein X55 is G, X56 is N, X57 is T, X58 is L, and X60 is W.

### Claim 21 (depends on 1)

The binding molecule according to claim 1, wherein the first binding domain comprises a VH region comprising
(a) CDR-H1 as depicted in SEQ ID NO: 1, SEQ ID NO: 161, or SEQ ID NO: 311;
(b) CDR-H2 as depicted in SEQ ID NO: 2, SEQ ID NO: 12, SEQ ID NO: 162, SEQ ID NO: 212, SEQ ID NO: 312, SEQ ID NO: 322, SEQ ID NO: 352, SEQ ID NO: 362, SEQ ID NO: 582, SEQ ID NO: 622, or SEQ OD NO: 752; and
(c) CDR-H3 as depicted in SEQ ID NO: 3, SEQ ID NO: 163, SEQ ID NO: 313, SEQ ID NO: 323, or SEQ ID NO: 623;
and a VL region comprising
(a) CDR-L1 as depicted in SEQ ID NO: 4, SEQ ID NO: 164, SEQ ID NO: 314, SEQ ID NO: 624, SEQ ID NO: 774, SEQ ID NO: 974, or SEQ ID NO: 994;
(b) CDR-L2 as depicted in SEQ ID NO: 5, SEQ ID NO: 165, SEQ ID NO: 315, or SEQ ID NO: 625; and
(c) CDR-L3 as depicted in SEQ ID NO: 6, SEQ ID NO: 166, SEQ ID NO: 176, SEQ ID NO: 316, SEQ ID NO: 626, SEQ ID NO: 656, SEQ ID NO: 676, SEQ ID NO: 776, SEQ ID NO: 816, SEQ ID NO: 966, or SEQ ID NO: 996.

### Claim 22 (depends on 1)

The binding molecule according to claim 1, wherein said CDR-H1 comprises the amino acid sequence depicted in SEQ ID NO: 311, said CDR-H2 comprises the amino acid sequence depicted in SEQ ID NO: 312, said CDR-H3 comprises the amino acid sequence depicted in SEQ ID NO: 313, said CDR-L1 comprises the amino acid sequence depicted in SEQ ID NO: 314, said CDR-L2 comprises the amino acid sequence depicted in SEQ ID NO: 315, and said CDR-L 3 comprises the amino acid sequence depicted in SEQ ID NO: 316.

### Claim 23

A binding molecule which is at least bispecific comprising a first and a second binding domain, wherein
(a) the first binding domain binds to B cell maturation antigen (BCMA) and comprises a VH region comprising CDR-H1, CDR-H2, and CDR-H3 and a VL region comprising CDR-L1, CDR-L2, and CDR-L, wherein said CDR-H1, CDR-H2, CDR-L1, CDR-L2 and CDR-L3 are selected from the group consisting of:
(1) CDR-H1 as depicted in SEQ ID NO: 1, CDR-H2 as depicted in SEQ ID NO: 2, CDR-H3 as depicted in SEQ ID NO: 3, CDR-L1 as depicted in SEQ ID NO: 4, CDR-L2 as depicted in SEQ ID NO: 5 and CDR-L3 as depicted in SEQ ID NO: 6;
(2) CDR-H1 as depicted in SEQ ID NO: 11, CDR-H2 as depicted in SEQ ID NO: 12, CDR-H3 as depicted in SEQ ID NO: 13, CDR-L1 as depicted in SEQ ID NO: 14, CDR-L2 as depicted in SEQ ID NO: 15 and CDR-L3 as depicted in SEQ ID NO: 16;
(3) CDR-H1 as depicted in SEQ ID NO: 21, CDR-H2 as depicted in SEQ ID NO: 22, CDR-H3 as depicted in SEQ ID NO: 23, CDR-L1 as depicted in SEQ ID NO: 24, CDR-L2 as depicted in SEQ ID NO: 25 and CDR-L3 as depicted in SEQ ID NO: 26;
(4) CDR-H1 as depicted in SEQ ID NO: 31, CDR-H2 as depicted in SEQ ID NO: 32, CDR-H3 as depicted in SEQ ID NO: 33, CDR-L1 as depicted in SEQ ID NO: 34, CDR-L2 as depicted in SEQ ID NO: 35 and CDR-L3 as depicted in SEQ ID NO: 36;
(5) CDR-H1 as depicted in SEQ ID NO: 41, CDR-H2 as depicted in SEQ ID NO: 42, CDR-H3 as depicted in SEQ ID NO: 43, CDR-L1 as depicted in SEQ ID NO: 44, CDR-L2 as depicted in SEQ ID NO: 45 and CDR-L3 as depicted in SEQ ID NO: 46;
(6) CDR-H1 as depicted in SEQ ID NO: 51, CDR-H2 as depicted in SEQ ID NO: 52, CDR-H3 as depicted in SEQ ID NO: 53, CDR-L1 as depicted in SEQ ID NO: 54, CDR-L2 as depicted in SEQ ID NO: 55 and CDR-L3 as depicted in SEQ ID NO: 56;
(7) CDR-H1 as depicted in SEQ ID NO: 61, CDR-H2 as depicted in SEQ ID NO: 62, CDR-H3 as depicted in SEQ ID NO: 63, CDR-L1 as depicted in SEQ ID NO: 64, CDR-L2 as depicted in SEQ ID NO: 65 and CDR-L3 as depicted in SEQ ID NO: 66;
(8) CDR-H1 as depicted in SEQ ID NO: 71, CDR-H2 as depicted in SEQ ID NO: 72, CDR-H3 as depicted in SEQ ID NO: 73, CDR-L1 as depicted in SEQ ID NO: 74, CDR-L2 as depicted in SEQ ID NO: 75 and CDR-L3 as depicted in SEQ ID NO: 76;
(9) CDR-H1 as depicted in SEQ ID NO: 161, CDR-H2 as depicted in SEQ ID NO: 162, CDR-H3 as depicted in SEQ ID NO: 163, CDR-L1 as depicted in SEQ ID NO: 164, CDR-L2 as depicted in SEQ ID NO: 165 and CDR-L3 as depicted in SEQ ID NO: 166;
(10) CDR-H1 as depicted in SEQ ID NO: 171, CDR-H2 as depicted in SEQ ID NO: 172, CDR-H3 as depicted in SEQ ID NO: 173, CDR-L1 as depicted in SEQ ID NO: 174, CDR-L2 as depicted in SEQ ID NO: 175 and CDR-L3 as depicted in SEQ ID NO: 176;
(11) CDR-H1 as depicted in SEQ ID NO: 181, CDR-H2 as depicted in SEQ ID NO: 182, CDR-H3 as depicted in SEQ ID NO: 183, CDR-L1 as depicted in SEQ ID NO: 184, CDR-L2 as depicted in SEQ ID NO: 185 and CDR-L3 as depicted in SEQ ID NO: 186;
(12) CDR-H1 as depicted in SEQ ID NO: 191, CDR-H2 as depicted in SEQ ID NO: 192, CDR-H3 as depicted in SEQ ID NO: 193, CDR-L1 as depicted in SEQ ID NO: 194, CDR-L2 as depicted in SEQ ID NO: 195 and CDR-L3 as depicted in SEQ ID NO: 196;
(13) CDR-H1 as depicted in SEQ ID NO: 201, CDR-H2 as depicted in SEQ ID NO: 202, CDR-H3 as depicted in SEQ ID NO: 203, CDR-L1 as depicted in SEQ ID NO: 204, CDR-L2 as depicted in SEQ ID NO: 205 and CDR-L3 as depicted in SEQ ID NO: 206;
(14) CDR-H1 as depicted in SEQ ID NO: 211, CDR-H2 as depicted in SEQ ID NO: 212, CDR-H3 as depicted in SEQ ID NO: 213, CDR-L1 as depicted in SEQ ID NO:214, CDR-L2 as depicted in SEQ ID NO: 215 and CDR-L3 as depicted in SEQ ID NO: 216;
(15) CDR-H1 as depicted in SEQ ID NO: 221, CDR-H2 as depicted in SEQ ID NO: 222, CDR-H3 as depicted in SEQ ID NO: 223, CDR-L1 as depicted in SEQ ID NO: 224, CDR-L2 as depicted in SEQ ID NO: 225 and CDR-L3 as depicted in SEQ ID NO: 226;
(16) CDR-H1 as depicted in SEQ ID NO: 311, CDR-H2 as depicted in SEQ ID NO: 312, CDR-H3 as depicted in SEQ ID NO: 313, CDR-L1 as depicted in SEQ ID NO: 314, CDR-L2 as depicted in SEQ ID NO: 315 and CDR-L3 as depicted in SEQ ID NO: 316;
(17) CDR-H1 as depicted in SEQ ID NO: 321, CDR-H2 as depicted in SEQ ID NO: 322, CDR-H3 as depicted in SEQ ID NO: 323, CDR-L1 as depicted in SEQ ID NO: 324, CDR-L2 as depicted in SEQ ID NO: 325 and CDR-L3 as depicted in SEQ ID NO: 326;
(18) CDR-H1 as depicted in SEQ ID NO: 331, CDR-H2 as depicted in SEQ ID NO: 332, CDR-H3 as depicted in SEQ ID NO: 333, CDR-L1 as depicted in SEQ ID NO: 334, CDR-L2 as depicted in SEQ ID NO: 335 and CDR-L3 as depicted in SEQ ID NO: 336;
(19) CDR-H1 as depicted in SEQ ID NO: 341, CDR-H2 as depicted in SEQ ID NO: 342, CDR-H3 as depicted in SEQ ID NO: 343, CDR-L1 as depicted in SEQ ID NO: 344, CDR-L2 as depicted in SEQ ID NO: 345 and CDR-L3 as depicted in SEQ ID NO: 346;
(20) CDR-H1 as depicted in SEQ ID NO: 351, CDR-H2 as depicted in SEQ ID NO: 352, CDR-H3 as depicted in SEQ ID NO: 353, CDR-L1 as depicted in SEQ ID NO: 354, CDR-L2 as depicted in SEQ ID NO: 355 and CDR-L3 as depicted in SEQ ID NO: 356;
(21) CDR-H1 as depicted in SEQ ID NO: 361, CDR-H2 as depicted in SEQ ID NO: 362, CDR-H3 as depicted in SEQ ID NO: 363, CDR-L1 as depicted in SEQ ID NO: 364, CDR-L2 as depicted in SEQ ID NO: 365 and CDR-L3 as depicted in SEQ ID NO: 366;
(22) CDR-H1 as depicted in SEQ ID NO: 371, CDR-H2 as depicted in SEQ ID NO: 372, CDR-H3 as depicted in SEQ ID NO: 373, CDR-L1 as depicted in SEQ ID NO: 374, CDR-L2 as depicted in SEQ ID NO: 375 and CDR-L3 as depicted in SEQ ID NO: 376;
(23) CDR-H1 as depicted in SEQ ID NO: 381, CDR-H2 as depicted in SEQ ID NO: 382, CDR-H3 as depicted in SEQ ID NO: 383, CDR-L1 as depicted in SEQ ID NO: 384, CDR-L2 as depicted in SEQ ID NO: 385 and CDR-L3 as depicted in SEQ ID NO: 386;
(24) CDR-H1 as depicted in SEQ ID NO: 581, CDR-H2 as depicted in SEQ ID NO: 582, CDR-H3 as depicted in SEQ ID NO: 583, CDR-L1 as depicted in SEQ ID NO: 584, CDR-L2 as depicted in SEQ ID NO: 585 and CDR-L3 as depicted in SEQ ID NO: 586;
(25) CDR-H1 as depicted in SEQ ID NO: 591, CDR-H2 as depicted in SEQ ID NO: 592, CDR-H3 as depicted in SEQ ID NO: 593, CDR-L1 as depicted in SEQ ID NO: 594, CDR-L2 as depicted in SEQ ID NO: 595 and CDR-L3 as depicted in SEQ ID NO: 596;
(26) CDR-H1 as depicted in SEQ ID NO: 601, CDR-H2 as depicted in SEQ ID NO: 602, CDR-H3 as depicted in SEQ ID NO: 603, CDR-L1 as depicted in SEQ ID NO: 604, CDR-L2 as depicted in SEQ ID NO: 605 and CDR-L3 as depicted in SEQ ID NO: 606;
(27) CDR-H1 as depicted in SEQ ID NO: 611, CDR-H2 as depicted in SEQ ID NO: 612, CDR-H3 as depicted in SEQ ID NO: 613, CDR-L1 as depicted in SEQ ID NO: 614, CDR-L2 as depicted in SEQ ID NO: 615 and CDR-L3 as depicted in SEQ ID NO: 616;
(28) CDR-H1 as depicted in SEQ ID NO: 621, CDR-H2 as depicted in SEQ ID NO: 622, CDR-H3 as depicted in SEQ ID NO: 623, CDR-L1 as depicted in SEQ ID NO: 624, CDR-L2 as depicted in SEQ ID NO: 625 and CDR-L3 as depicted in SEQ ID NO: 626;
(29) CDR-H1 as depicted in SEQ ID NO: 631, CDR-H2 as depicted in SEQ ID NO: 632, CDR-H3 as depicted in SEQ ID NO: 633, CDR-L1 as depicted in SEQ ID NO: 634, CDR-L2 as depicted in SEQ ID NO: 635 and CDR-L3 as depicted in SEQ ID NO: 636;
(30) CDR-H1 as depicted in SEQ ID NO: 641, CDR-H2 as depicted in SEQ ID NO: 642, CDR-H3 as depicted in SEQ ID NO: 643, CDR-L1 as depicted in SEQ ID NO: 644, CDR-L2 as depicted in SEQ ID NO: 645 and CDR-L3 as depicted in SEQ ID NO: 646;
(31) CDR-H1 as depicted in SEQ ID NO: 651, CDR-H2 as depicted in SEQ ID NO: 652, CDR-H3 as depicted in SEQ ID NO: 653, CDR-L1 as depicted in SEQ ID NO: 654, CDR-L2 as depicted in SEQ ID NO: 655 and CDR-L3 as depicted in SEQ ID NO: 656;
(32) CDR-H1 as depicted in SEQ ID NO: 661, CDR-H2 as depicted in SEQ ID NO: 662, CDR-H3 as depicted in SEQ ID NO: 663, CDR-L1 as depicted in SEQ ID NO: 664, CDR-L2 as depicted in SEQ ID NO: 665 and CDR-L3 as depicted in SEQ ID NO: 666;
(33) CDR-H1 as depicted in SEQ ID NO: 671, CDR-H2 as depicted in SEQ ID NO: 672, CDR-H3 as depicted in SEQ ID NO: 673, CDR-L1 as depicted in SEQ ID NO: 674, CDR-L2 as depicted in SEQ ID NO: 675 and CDR-L3 as depicted in SEQ ID NO: 676;
(34) CDR-H1 as depicted in SEQ ID NO: 681, CDR-H2 as depicted in SEQ ID NO: 682, CDR-H3 as depicted in SEQ ID NO: 683, CDR-L1 as depicted in SEQ ID NO: 684, CDR-L2 as depicted in SEQ ID NO: 685 and CDR-L3 as depicted in SEQ ID NO: 686;
(35) CDR-H1 as depicted in SEQ ID NO: 691, CDR-H2 as depicted in SEQ ID NO: 692, CDR-H3 as depicted in SEQ ID NO: 693, CDR-L1 as depicted in SEQ ID NO: 694, CDR-L2 as depicted in SEQ ID NO: 695 and CDR-L3 as depicted in SEQ ID NO: 696;
(36) CDR-H1 as depicted in SEQ ID NO: 701, CDR-H2 as depicted in SEQ ID NO: 702, CDR-H3 as depicted in SEQ ID NO: 703, CDR-L1 as depicted in SEQ ID NO: 704, CDR-L2 as depicted in SEQ ID NO: 705 and CDR-L3 as depicted in SEQ ID NO: 706;
(37) CDR-H1 as depicted in SEQ ID NO: 711, CDR-H2 as depicted in SEQ ID NO: 712, CDR-H3 as depicted in SEQ ID NO: 713, CDR-L1 as depicted in SEQ ID NO: 714, CDR-L2 as depicted in SEQ ID NO: 715 and CDR-L3 as depicted in SEQ ID NO: 716;
(38) CDR-H1 as depicted in SEQ ID NO: 721, CDR-H2 as depicted in SEQ ID NO: 722, CDR-H3 as depicted in SEQ ID NO: 723, CDR-L1 as depicted in SEQ ID NO: 724, CDR-L2 as depicted in SEQ ID NO: 725 and CDR-L3 as depicted in SEQ ID NO: 726;
(39) CDR-H1 as depicted in SEQ ID NO: 731, CDR-H2 as depicted in SEQ ID NO: 732, CDR-H3 as depicted in SEQ ID NO: 733, CDR-L1 as depicted in SEQ ID NO: 734, CDR-L2 as depicted in SEQ ID NO: 735 and CDR-L3 as depicted in SEQ ID NO: 736;
(40) CDR-H1 as depicted in SEQ ID NO: 741, CDR-H2 as depicted in SEQ ID NO: 742, CDR-H3 as depicted in SEQ ID NO: 743, CDR-L1 as depicted in SEQ ID NO: 744, CDR-L2 as depicted in SEQ ID NO: 745 and CDR-L3 as depicted in SEQ ID NO: 746;
(41) CDR-H1 as depicted in SEQ ID NO: 751, CDR-H2 as depicted in SEQ ID NO: 752, CDR-H3 as depicted in SEQ ID NO: 753, CDR-L1 as depicted in SEQ ID NO: 754, CDR-L2 as depicted in SEQ ID NO: 755 and CDR-L3 as depicted in SEQ ID NO: 756;
(42) CDR-H1 as depicted in SEQ ID NO: 761, CDR-H2 as depicted in SEQ ID NO: 762, CDR-H3 as depicted in SEQ ID NO: 763, CDR-L1 as depicted in SEQ ID NO: 764, CDR-L2 as depicted in SEQ ID NO: 765 and CDR-L3 as depicted in SEQ ID NO: 766;
(43) CDR-H1 as depicted in SEQ ID NO: 771, CDR-H2 as depicted in SEQ ID NO: 772, CDR-H3 as depicted in SEQ ID NO: 773, CDR-L1 as depicted in SEQ ID NO: 774, CDR-L2 as depicted in SEQ ID NO: 775 and CDR-L3 as depicted in SEQ ID NO: 776;
(44) CDR-H1 as depicted in SEQ ID NO: 781, CDR-H2 as depicted in SEQ ID NO: 782, CDR-H3 as depicted in SEQ ID NO: 783, CDR-L1 as depicted in SEQ ID NO: 784, CDR-L2 as depicted in SEQ ID NO: 785 and CDR-L3 as depicted in SEQ ID NO: 786;
(45) CDR-H1 as depicted in SEQ ID NO: 791, CDR-H2 as depicted in SEQ ID NO: 792, CDR-H3 as depicted in SEQ ID NO: 793, CDR-L1 as depicted in SEQ ID NO: 794, CDR-L2 as depicted in SEQ ID NO: 795 and CDR-L3 as depicted in SEQ ID NO: 796;
(46) CDR-H1 as depicted in SEQ ID NO: 801, CDR-H2 as depicted in SEQ ID NO: 802, CDR-H3 as depicted in SEQ ID NO: 803, CDR-L1 as depicted in SEQ ID NO: 804, CDR-L2 as depicted in SEQ ID NO: 805 and CDR-L3 as depicted in SEQ ID NO: 806;
(47) CDR-H1 as depicted in SEQ ID NO: 811, CDR-H2 as depicted in SEQ ID NO: 812, CDR-H3 as depicted in SEQ ID NO: 813, CDR-L1 as depicted in SEQ ID NO: 814, CDR-L2 as depicted in SEQ ID NO: 815 and CDR-L3 as depicted in SEQ ID NO: 816;
(48) CDR-H1 as depicted in SEQ ID NO: 821, CDR-H2 as depicted in SEQ ID NO: 822, CDR-H3 as depicted in SEQ ID NO: 823, CDR-L1 as depicted in SEQ ID NO: 824, CDR-L2 as depicted in SEQ ID NO: 825 and CDR-L3 as depicted in SEQ ID NO: 826;
(49) CDR-H1 as depicted in SEQ ID NO: 831, CDR-H2 as depicted in SEQ ID NO: 832, CDR-H3 as depicted in SEQ ID NO: 833, CDR-L1 as depicted in SEQ ID NO: 834, CDR-L2 as depicted in SEQ ID NO: 835 and CDR-L3 as depicted in SEQ ID NO: 836;
(50) CDR-H1 as depicted in SEQ ID NO: 961, CDR-H2 as depicted in SEQ ID NO: 962, CDR-H3 as depicted in SEQ ID NO: 963, CDR-L1 as depicted in SEQ ID NO: 964, CDR-L2 as depicted in SEQ ID NO: 965 and CDR-L3 as depicted in SEQ ID NO: 966;
(51) CDR-H1 as depicted in SEQ ID NO: 971, CDR-H2 as depicted in SEQ ID NO: 972, CDR-H3 as depicted in SEQ ID NO: 973, CDR-L1 as depicted in SEQ ID NO: 974, CDR-L2 as depicted in SEQ ID NO: 975 and CDR-L3 as depicted in SEQ ID NO: 976;
(52) CDR-H1 as depicted in SEQ ID NO: 981, CDR-H2 as depicted in SEQ ID NO: 982, CDR-H3 as depicted in SEQ ID NO: 983, CDR-L1 as depicted in SEQ ID NO: 984, CDR-L2 as depicted in SEQ ID NO: 985 and CDR-L3 as depicted in SEQ ID NO: 986; and
(53) CDR-H1 as depicted in SEQ ID NO: 991, CDR-H2 as depicted in SEQ ID NO: 992, CDR-H3 as depicted in SEQ ID NO: 993, CDR-L1 as depicted in SEQ ID NO: 994, CDR-L2 as depicted in SEQ ID NO: 995 and CDR-L3 as depicted in SEQ ID NO: 996; and
(b) the second binding domain comprises a variable heavy chain and a variable light chain and binds to the human T cell CD3 receptor complex.

### Claim 24 (depends on 1)

The binding molecule according to claim 1, wherein the first binding domain comprises a VH region selected from the group consisting of VH regions as depicted in SEQ ID NO: 7, SEQ ID NO: 17, SEQ ID NO: 27, SEQ ID NO: 37, SEQ ID NO: 47, SEQ ID NO: 57, SEQ ID NO: 67, SEQ ID NO: 77, SEQ ID NO: 167, SEQ ID NO: 177, SEQ ID NO: 187, SEQ ID NO: 197, SEQ ID NO: 207, SEQ ID NO: 217, SEQ ID NO: 227, SEQ ID NO: 317, SEQ ID NO: 327, SEQ ID NO: 337, SEQ ID NO: 347, SEQ ID NO: 357, SEQ ID NO: 367, SEQ ID NO: 377, SEQ ID NO: 387, SEQ ID NO: 587, SEQ ID NO: 597, SEQ ID NO: 607, SEQ ID NO: 617, SEQ ID NO: 627, SEQ ID NO: 637, SEQ ID NO: 647, SEQ ID NO: 657, SEQ ID NO: 667, SEQ ID NO: 677, SEQ ID NO: 687, SEQ ID NO: 697, SEQ ID NO: 707, SEQ ID NO: 717, SEQ ID NO: 727, SEQ ID NO: 737, SEQ ID NO: 747, SEQ ID NO: 757, SEQ ID NO: 767, SEQ ID NO: 777, SEQ ID NO: 787, SEQ ID NO: 797, SEQ ID NO: 807, SEQ ID NO: 817, SEQ ID NO: 827, SEQ ID NO: 837, SEQ ID NO: 967, SEQ ID NO: 977, SEQ ID NO: 987, and SEQ ID NO: 997.

### Claim 25 (depends on 1)

The binding molecule according to claim 1, wherein the first binding domain comprises a VL region selected from the group consisting of VL regions as depicted in SEQ ID NO: 8, SEQ ID NO: 18, SEQ ID NO: 28, SEQ ID NO: 38, SEQ ID NO: 48, SEQ ID NO: 58, SEQ ID NO: 68, SEQ ID NO: 78, SEQ ID NO: 168, SEQ ID NO: 178, SEQ ID NO: 188, SEQ ID NO: 198, SEQ ID NO: 208, SEQ ID NO: 218, SEQ ID NO: 228, SEQ ID NO: 318, SEQ ID NO: 328, SEQ ID NO: 338, SEQ ID NO: 348, SEQ ID NO: 358, SEQ ID NO: 368, SEQ ID NO: 378, SEQ ID NO: 388, SEQ ID NO: 588, SEQ ID NO: 598, SEQ ID NO: 608, SEQ ID NO: 618, SEQ ID NO: 628, SEQ ID NO: 638, SEQ ID NO: 648, SEQ ID NO: 658, SEQ ID NO: 668, SEQ ID NO: 678, SEQ ID NO: 688, SEQ ID NO: 698, SEQ ID NO: 708, SEQ ID NO: 718, SEQ ID NO: 728, SEQ ID NO: 738, SEQ ID NO: 748, SEQ ID NO: 758, SEQ ID NO: 768, SEQ ID NO: 778, SEQ ID NO: 788, SEQ ID NO: 798, SEQ ID NO: 808, SEQ ID NO: 818, SEQ ID NO: 828, SEQ ID NO: 838, SEQ ID NO: 968, SEQ ID NO: 978, SEQ ID NO: 988, and SEQ ID NO: 998.

### Claim 26 (depends on 1)

The binding molecule according to claim 1, wherein wherein the first binding domain comprises a VH region and a VL region selected from the group consisting of:
(1) a VH region as depicted in SEQ ID NO: 7, and a VL region as depicted in SEQ ID NO: 8;
(2) a VH region as depicted in SEQ ID NO: 17, and a VL region as depicted in SEQ ID NO: 18;
(3) a VH region as depicted in SEQ ID NO: 27, and a VL region as depicted in SEQ ID NO: 28;
(4) a VH region as depicted in SEQ ID NO: 37, and a VL region as depicted in SEQ ID NO: 38;
(5) a VH region as depicted in SEQ ID NO: 47, and a VL region as depicted in SEQ ID NO: 48;
(6) a VH region as depicted in SEQ ID NO: 57, and a VL region as depicted in SEQ ID NO: 58;
(7) a VH region as depicted in SEQ ID NO: 67, and a VL region as depicted in SEQ ID NO: 68;
(8) a VH region as depicted in SEQ ID NO: 77, and a VL region as depicted in SEQ ID NO: 78;
(9) a VH region as depicted in SEQ ID NO: 167, and a VL region as depicted in SEQ ID NO: 168;
(10) a VH region as depicted in SEQ ID NO: 177, and a VL region as depicted in SEQ ID NO: 178;
(11) a VH region as depicted in SEQ ID NO: 187, and a VL region as depicted in SEQ ID NO: 188;
(12) a VH region as depicted in SEQ ID NO: 197, and a VL region as depicted in SEQ ID NO: 198;
(13) a VH region as depicted in SEQ ID NO: 207, and a VL region as depicted in SEQ ID NO: 208;
(14) a VH region as depicted in SEQ ID NO: 217, and a VL region as depicted in SEQ ID NO: 218;
(15) a VH region as depicted in SEQ ID NO: 227, and a VL region as depicted in SEQ ID NO: 228;
(16) a VH region as depicted in SEQ ID NO: 317, and a VL region as depicted in SEQ ID NO: 318;
(17) a VH region as depicted in SEQ ID NO: 327, and a VL region as depicted in SEQ ID NO: 328;
(18) a VH region as depicted in SEQ ID NO: 337, and a VL region as depicted in SEQ ID NO: 338;
(19) a VH region as depicted in SEQ ID NO: 347, and a VL region as depicted in SEQ ID NO: 348;
(20) a VH region as depicted in SEQ ID NO: 357, and a VL region as depicted in SEQ ID NO: 358;
(21) a VH region as depicted in SEQ ID NO: 367, and a VL region as depicted in SEQ ID NO: 368;
(22) a VH region as depicted in SEQ ID NO: 377, and a VL region as depicted in SEQ ID NO: 378;
(23) a VH region as depicted in SEQ ID NO: 387, and a VL region as depicted in SEQ ID NO: 388;
(24) a VH region as depicted in SEQ ID NO: 587, and a VL region as depicted in SEQ ID NO: 588;
(25) a VH region as depicted in SEQ ID NO: 597, and a VL region as depicted in SEQ ID NO: 598;
(26) a VH region as depicted in SEQ ID NO: 607, and a VL region as depicted in SEQ ID NO: 608;
(27) a VH region as depicted in SEQ ID NO: 617, and a VL region as depicted in SEQ ID NO: 618;
(28) a VH region as depicted in SEQ ID NO: 627, and a VL region as depicted in SEQ ID NO: 628;
(29) a VH region as depicted in SEQ ID NO: 637, and a VL region as depicted in SEQ ID NO: 638;
(30) a VH region as depicted in SEQ ID NO: 647, and a VL region as depicted in SEQ ID NO: 648;
(31) a VH region as depicted in SEQ ID NO: 657, and a VL region as depicted in SEQ ID NO: 658;
(32) a VH region as depicted in SEQ ID NO: 667, and a VL region as depicted in SEQ ID NO: 668;
(33) a VH region as depicted in SEQ ID NO: 677, and a VL region as depicted in SEQ ID NO: 678;
(34) a VH region as depicted in SEQ ID NO: 687, and a VL region as depicted in SEQ ID NO: 688;
(35) a VH region as depicted in SEQ ID NO: 697, and a VL region as depicted in SEQ ID NO: 698;
(36) a VH region as depicted in SEQ ID NO: 707, and a VL region as depicted in SEQ ID NO: 708;
(37) a VH region as depicted in SEQ ID NO: 717, and a VL region as depicted in SEQ ID NO: 718;
(38) a VH region as depicted in SEQ ID NO: 727, and a VL region as depicted in SEQ ID NO: 728;
(39) a VH region as depicted in SEQ ID NO: 737, and a VL region as depicted in SEQ ID NO: 738;
(40) a VH region as depicted in SEQ ID NO: 747, and a VL region as depicted in SEQ ID NO: 748;
(41) a VH region as depicted in SEQ ID NO: 757, and a VL region as depicted in SEQ ID NO: 758;
(42) a VH region as depicted in SEQ ID NO: 767, and a VL region as depicted in SEQ ID NO: 768;
(43) a VH region as depicted in SEQ ID NO: 777, and a VL region as depicted in SEQ ID NO: 778;
(44) a VH region as depicted in SEQ ID NO: 787, and a VL region as depicted in SEQ ID NO: 788;
(45) a VH region as depicted in SEQ ID NO: 797, and a VL region as depicted in SEQ ID NO: 798;
(46) a VH region as depicted in SEQ ID NO: 807, and a VL region as depicted in SEQ ID NO: 808;
(47) a VH region as depicted in SEQ ID NO: 817, and a VL region as depicted in SEQ ID NO: 818;
(48) a VH region as depicted in SEQ ID NO: 827, and a VL region as depicted in SEQ ID NO: 828;
(49) a VH region as depicted in SEQ ID NO: 837, and a VL region as depicted in SEQ ID NO: 838;
(50) a VH region as depicted in SEQ ID NO: 967, and a VL region as depicted in SEQ ID NO: 968;
(51) a VH region as depicted in SEQ ID NO: 977, and a VL region as depicted in SEQ ID NO: 978;
(52) a VH region as depicted in SEQ ID NO: 987, and a VL region as depicted in SEQ ID NO: 988; and
(53) a VH region as depicted in SEQ ID NO: 997, and a VL region as depicted in SEQ ID NO: 998.

### Claim 27 (depends on 1)

The binding molecule according to claim 1, wherein the first binding domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 9, SEQ ID NO: 19, SEQ ID NO: 29, SEQ ID NO: 39, SEQ ID NO: 49, SEQ ID NO: 59, SEQ ID NO: 69, SEQ ID NO: 79, SEQ ID NO: 169, SEQ ID NO: 179, SEQ ID NO: 189, SEQ ID NO: 199, SEQ ID NO: 209, SEQ ID NO: 219, SEQ ID NO: 229, SEQ ID NO: 319, SEQ ID NO: 329, SEQ ID NO: 339, SEQ ID NO: 349, SEQ ID NO: 359, SEQ ID NO: 369, SEQ ID NO: 379, SEQ ID NO: 389, SEQ ID NO: 589, SEQ ID NO: 599, SEQ ID NO: 609, SEQ ID NO: 619, SEQ ID NO: 629, SEQ ID NO: 639, SEQ ID NO: 649, SEQ ID NO: 659, SEQ ID NO: 669, SEQ ID NO: 679, SEQ ID NO: 689, SEQ ID NO: 699, SEQ ID NO: 709, SEQ ID NO: 719, SEQ ID NO: 729, SEQ ID NO: 739, SEQ ID NO: 749, SEQ ID NO: 759, SEQ ID NO: 769, SEQ ID NO: 779, SEQ ID NO: 789, SEQ ID NO: 799, SEQ ID NO: 809, SEQ ID NO: 819, SEQ ID NO: 829, SEQ ID NO: 839, SEQ ID NO: 969, SEQ ID NO: 979, SEQ ID NO: 989, and SEQ ID NO: 999.

### Claim 28 (depends on 1)

The binding molecule according to claim 1, comprising the amino acid sequence shown in SEQ ID NO: 340 or SEQ ID NO: 980.

### Claim 29 (depends on 1)

The binding molecule according to claim 1 wherein not more than one of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 has a sequence as follows:
(i) CDR-H1 comprises amino acid sequence X1X2X3X4X5 having 100% identity to, or not more than one amino acid variation from, a sequence selected from the group consisting of NYDMA (SEQ ID NO:1), NFDMA (SEQ ID NO:161), and NHIIH (SEQ ID NO:311), and where X1 is N; X2 is Y, F, or H; X3 is D or I; X4 is M or I; and X5 is A or H;
(ii) CDR-H2 comprises amino acid sequence X6X7X8X9X10X11X12X13X14X15X16X17X18X19X20X21X22 having 100% identity to, or not more than one amino acid variation from, a sequence selected from the group consisting of: SIITSGDATYYRDSVKG (SEQ ID NO:2), SIITSGDMTYYRDSVKG (SEQ ID NO:12), SITTGADHAIYADSVKG (SEQ ID NO:162), SITTGADHAIYAESVKG (SEQ ID NO:212), SIITSGGDNYYRDSVKG (SEQ ID NO:582), SITTGGGDTYYADSVKG (SEQ ID NO:732), YINPYPGYHAYNEKFQG (SEQ ID NO:312), YINPYPGYHAYNQKFQG (SEQ ID NO:352), YINPYDGWGDYNEKFQG (SEQ ID NO:322), YINPYDGWGDYNQKFQG (SEQ ID NO:362), and SISTRGDITSYRDSVKG (SEQ ID NO: 622), and where X6 is S or Y; X7 is I; X8 is I, T, N, or S; X9 is T or P; X10 is S, Y, R, or G; X11 is G, A, D, or P; X12 is D or G; X13 is A, M, H, D, Y, W or I; X14 is T, A, N, H, or G; X15 is Y, I, A, D or S; X16 is Y; X17 is R, A, or N; X18 is D, E, or Q; X19 is S or K; X20 is V or F; X21 is K or Q; and X22 is G;
(iii) CDR-H3 comprises amino acid sequence X23X24X25X26X27X28X29X30X31X32X33X34 having 100% identity to, or not more than one amino acid variation from, a sequence selected from the group consisting of: HDYYDGSYGFAY (SEQ ID NO:3), HGYYDGYHLFDY (SEQ ID NO:163), QDYYTDYMGFAY (SEQ ID NO:623), DGYYRDTDVLDY (SEQ ID NO:313), and DGYYRDADVLDY (SEQ ID NO:323), and where X23 is H, Q or D; X24 is D or G; X25 is Y; X26 is Y; X27 is D, T or R; X28 is G or D; X29 is S, Y, T or A; X30 is Y, H, M or D; X31 is G, L, or V; X32 is F or L; X33 is A or D; and X34 is Y;
(iv) CDR-L1 comprises amino acid sequence X35X36X37X38X39X40X41X42X43X44X45 having 100% identity to, or not more than one amino acid variation from, a sequence selected from the group consisting of: KASQSVGINVD (SEQ ID NO:4), RASQGISNYLN (SEQ ID NO:164), RASEDIYNGLA (SEQ ID NO:624), RASQGISNHLN (SEQ ID NO:774), RANQGISNNLN (SEQ ID NO:974), RASQGISNNLN (SEQ ID NO:994), and QASQDISNYLN (SEQ ID NO:314), and wherein X35 is K, R or Q; X36 is A; X37 is S or N; X38 is Q or E; X39 is 5, G, or D; X40 is V or I; X41 is G, S, or Y; X42 is I or N; X43 is N, Y, G, or H; X44 is V or L; and X45 is D, N, or A;
(v) CDR-L2 comprises amino acid sequence X46X47X48X49X50X51X52 having 100% identity to, or not more than one amino acid variation from, a sequence selected from the group consisting of: GASNRHT (SEQ ID NO:5), YTSNLQS (SEQ ID NO:165), GASSLQD (SEQ ID NO:625), and YTSRLHT (SEQ ID NO:315), and wherein X46 is G or Y; X47 is A or T; X48 is S; X49 is N, S, or R; X50 is R or L; X51 is H or Q; and X52 is T, S, or D; or
(vi) CDR-L3 comprises amino acid sequence X53X54X55X56X57X58X59X60X61 having 100% identity to, or not more than one amino acid variation from, a sequence selected from the group consisting of: LQYGSIPFT (SEQ ID NO:6), QQYDISSYT (SEQ ID NO:166), MGQTISSYT (SEQ ID NO:176), QQGNTLPWT (SEQ ID NO:316), QQSYKYPLT (SEQ ID NO:626), AGPHKYPLT (SEQ ID NO:656), QQSRNYQQT (SEQ ID NO:676), QQYFDRPYT (SEQ ID NO:776), QQYSNLPYT (SEQ ID NO:816), QQFTSLPYT (SEQ ID NO:966), and QQFAHLPYT (SEQ ID NO:996), and wherein X53 is L, Q, M, or A; X54 is Q or G; X55 is G, P, Y, Q, S, or F; X56 is G, D, T, N, Y, H, R, F, S, or A; X57 is S, I, T, K, N, D, or H; X58 is I, S, L, Y, or R; X59 is P, S, or Q; X60 is F, Y, W, L, or Q and X61 is T.