FGFR3 ANTIBODIES AND METHODS OF USE

Anti-FGFR3 antigen-binding proteins and antigen-binding binding fragments thereof are provided. Methods of inhibiting FGFR3 activity and methods of treating FGFR3-mediated diseases and disorders are also provided.

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Description
RELATED APPLICATIONS

This application is a division of U.S. patent application Ser. No. 17/407,774, filed Aug. 20, 2021, which claims the benefit of priority of U.S. Provisional Application No. 63/068,575, filed Aug. 21, 2020, the contents of which are incorporated by reference in their entirety for all purposes.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on Oct. 12, 2022, is named 734907 SA9-231DIV_ST26.xml, and is 572,730 bytes in size.

FIELD OF THE INVENTION

This disclosure relates to compositions of anti-fibroblast growth factor receptor 3 (anti-FGFR3) antigen-binding proteins or antigen-binding fragments thereof, such as antibodies and fragments thereof, and methods of using the same.

BACKGROUND

Fibroblast growth factor receptor 3 (FGFR3) is a protein involved, in part, in the negative regulation of bone development, being highly expressed in growth plate chondrocytes (Sarabipour et al. Biochim Biophys Acta. 1858(7 Pt A): 1436-1442. 2016). FGFR3 is a single-pass membrane receptor tyrosine kinase with 3 Ig-like domains (D1-D3). Binding of FGFR3 to an FGFR3-ligand, such as FGF18, triggers ligand-dependent receptor dimerization which leads to tyrosine kinase activation and downstream signal transduction. This signaling cascade regulates, among other things, chondrocyte proliferation and differentiation.

FGFR3 is a member of the fibroblast growth factor receptor family, which also includes FGFR1, FGFR2, and FGFR4. Each member of the receptor family is a single-pass membrane receptor tyrosine kinase and shares the feature of 3 Ig-like domains. Moreover, each member of the receptor family possesses a high degree of homology with the other members. Strategies to develop FGFR3-specific inhibitors have proven challenging for this reason. Nonetheless, it is important to develop FGFR3-specific inhibitors that do not cross-react with other fibroblast growth factor receptor family members to avoid unwanted side effects in the treatment of an FGFR3-mediate disease or disorder.

Accordingly, there is a need in the art to identify antigen-binding proteins or antigen-binding fragments thereof, that achieve effective inhibition of FGFR3 activity. Such antigen-binding proteins or antigen-binding fragments thereof may be useful in the treatment of FGFR3-mediated diseases and disorders.

SUMMARY

Disclosed herein are anti-FGFR3 antigen-binding proteins or antigen-binding fragments thereof, such as antibodies and antigen-binding fragments thereof. The antigen-binding proteins or antigen-binding fragments thereof, such as anti-FGFR3 antibodies and antigen-binding fragments thereof of the disclosure are suitable for treating FGFR3-mediated diseases and disorders.

In one aspect, the disclosure provides an antigen-binding protein or antigen-binding fragment thereof that specifically binds to fibroblast growth factor receptor 3 (FGFR3), comprising an antibody heavy chain variable (VH) domain and an antibody light chain variable (VL) domain, wherein: (a) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GX1TFTDX2E (SEQ ID NO: 157), wherein X1 comprises or consists of Y or D and X2 comprises or consists of F or Y; a CDR-H2 sequence comprising the amino acid sequence of IDPETGX3T (SEQ ID NO: 158), wherein X3 comprises or consists of G or S; or CDR-H2 sequence comprising the amino acid sequence of INPNNGX4T (SEQ ID NO: 159), wherein X4 comprises or consists of G or V; or CDR-H2 sequence comprising the amino acid sequence of VX5PETGGT (SEQ ID NO: 160), wherein X5 comprises or consists of D or E; a CDR-H3 sequence comprising the amino acid sequence of TRX6YX7GYX8X9X10X11DY (SEQ ID NO: 161), wherein X6 comprises or consists of T or N, X7 comprises D or E, X8 comprises or consists of S or P, X9 comprises or consists of Q, R, or Y, X10 comprises or consists of T or A, X11 comprises or consists of F or M; and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QS X12LYS X13N X14KNY (SEQ ID NO: 162), wherein X12 comprises or consists of L or V, X13 comprises or consists of N, D, or S, and X14 comprises or consists of Q or N; a CDR-L2 sequence comprising the amino acid sequence of X15AS (SEQ ID NO: 163), wherein X15 comprises or consists of W, Y, or F; a CDR-L3 sequence comprising the amino acid sequence of QQYYSYRT (SEQ ID NO: 75), LQYDNLLWT (SEQ ID NO: 81), or HQYLSX16YT (SEQ ID NO: 290) wherein X16 comprises or consists of P or S; (b) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTDYN (SEQ ID NOs: 76 and 82); a CDR-H2 sequence comprising the amino acid sequence of INPNNGGT (SEQ ID NOs: 77 and 83); a CDR-H3 sequence comprising the amino acid sequence of ARERDYDGAMDY (SEQ ID NO: 78); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDINKF (SEQ ID NOs: 79 and 85); a CDR-L2 sequence comprising the amino acid sequence of YTS (SEQ ID NOs: 80 and 86); a CDR-L3 sequence comprising the amino acid sequence of LQYDNLLWT (SEQ ID NOs: 81 and 87); (c) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTDYN (SEQ ID NOs: 76 and 82); a CDR-H2 sequence comprising the amino acid sequence of INPNNGGT (SEQ ID NOs: 77 and 83); a CDR-H3 sequence comprising the amino acid sequence of ARERDYDGSMDF (SEQ ID NO: 84); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDINKF (SEQ ID NOs: 79 and 85); a CDR-L2 sequence comprising the amino acid sequence of YTS (SEQ ID NOs: 80 and 86); a CDR-L3 sequence comprising the amino acid sequence of LQYDNLLWT (SEQ ID NOs: 81 and 87); (d) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTVTDYY (SEQ ID NO: 88); a CDR-H2 sequence comprising the amino acid sequence of INPNNGVT (SEQ ID NO: 89); a CDR-H3 sequence comprising the amino acid sequence of AREEDFDGFDY (SEQ ID NO: 90); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDVSTG (SEQ ID NO: 91); a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98 and 104); a CDR-L3 sequence comprising the amino acid sequence of QQHYSTPLT (SEQ ID NO: 93); (e) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GSTFSDFE (SEQ ID NO: 94); a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NOs: 71, 95, and 101); a CDR-H3 sequence comprising the amino acid sequence of TRNYDGYSQTX17DY (SEQ ID NO: 308), wherein X17 comprises M or F; and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVLYSX18NQKNY (SEQ ID NO: 309), wherein X18 comprises S or D; a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98 and 104); a CDR-L3 sequence comprising the amino acid sequence of or HQYLSSYT (SEQ ID NOs: 99 and 105); or (f) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GSTFTDFE (SEQ ID NO: 100); a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NOs: 71, 95, and 101); a CDR-H3 sequence comprising the amino acid sequence of TRNYDGYSQTX17DY (SEQ ID NO: 308), wherein X17 comprises M or F; and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVLYSX18NQKNY (SEQ ID NO: 309), wherein X18 comprises S or D; a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98 and 104); a CDR-L3 sequence comprising the amino acid sequence of or HQYLSSYT (SEQ ID NOs: 99 and 105).

In certain embodiments, (a) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GDTFTDFE (SEQ ID NO: 70), GDTFTDYE (SEQ ID NO: 295), or GYTFTDFE (SEQ ID NO: 296); a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NOs: 71, 95, and 101), VDPETGGT (SEQ ID NO: 297), IDPETGST (SEQ ID NO: 298), or VEPETGGT (SEQ ID NO: 299); a CDR-H3 sequence comprising the amino acid sequence of TRTYDGYPYAMDY (SEQ ID NO: 72), TRTYEGYPYAMDY (SEQ ID NO: 300), or TRTYDGYPYAFDY (SEQ ID NO: 301); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSLLYSNNQKNY (SEQ ID NO: 73), QSVLYSNNNKNY (SEQ ID NO: 302), or QSVLYSDNQKNY (SEQ ID NO: 306); a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104), YAS (SEQ ID NO: 303), or FAS (SEQ ID NO: 304); a CDR-L3 sequence comprising the amino acid sequence of QQYYSYRT (SEQ ID NO: 75); (b) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTDYN (SEQ ID NOs: 76 and 82); a CDR-H2 sequence comprising the amino acid sequence of INPNNGGT (SEQ ID NOs: 77 and 83); a CDR-H3 sequence comprising the amino acid sequence of ARERDYDGAMDY (SEQ ID NO: 78); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDINKF (SEQ ID NOs: 79 and 85); a CDR-L2 sequence comprising the amino acid sequence of YTS (SEQ ID NOs: 80 and 86); a CDR-L3 sequence comprising the amino acid sequence of LQYDNLLWT (SEQ ID NOs: 81 and 87); (c) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTDYN (SEQ ID NOs: 76 and 82); a CDR-H2 sequence comprising the amino acid sequence of INPNNGGT (SEQ ID NOs: 77 and 83); a CDR-H3 sequence comprising the amino acid sequence of ARERDYDGSMDF (SEQ ID NO: 84); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDINKF (SEQ ID NOs: 79 and 85); a CDR-L2 sequence comprising the amino acid sequence of YTS (SEQ ID NOs: 80 and 86); a CDR-L3 sequence comprising the amino acid sequence of LQYDNLLWT (SEQ ID NOs: 81 and 87); (d) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTVTDYY (SEQ ID NO: 88); a CDR-H2 sequence comprising the amino acid sequence of INPNNGVT (SEQ ID NO: 89); a CDR-H3 sequence comprising the amino acid sequence of AREEDFDGFDY (SEQ ID NO: 90); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDVSTG (SEQ ID NO: 91); a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104); a CDR-L3 sequence comprising the amino acid sequence of QQHYSTPLT (SEQ ID NO: 93); (e) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GSTFSDFE (SEQ ID NO: 94); a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NOs: 71, 95, and 101); a CDR-H3 sequence comprising the amino acid sequence of TRNYDGYSQTMDY (SEQ ID NO: 96) or TRNYDGYSQTFDY (SEQ ID NO: 305); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVLYSSNQKNY (SEQ ID NOs: 97 and 103) or QSVLYSDNQKNY (SEQ ID NO: 306); a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104); a CDR-L3 sequence comprising the amino acid sequence of or HQYLSSYT (SEQ ID NOs: 99 and 105); or (f) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GSTFTDFE (SEQ ID NO: 100); a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NOs: 71, 95, and 101); a CDR-H3 sequence comprising the amino acid sequence of TRNYDGYSRTMDY (SEQ ID NO: 102) or TRNYDGYSRTFDY (SEQ ID NO: 307); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVLYSSNQKNY(SEQ ID NOs: 97 and 103) or QSVLYSDNQKNY (SEQ ID NO: 306); a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104); a CDR-L3 sequence comprising the amino acid sequence of or HQYLSSYT (SEQ ID NOs: 99 and 105).

In certain embodiments, (a) the VH domain comprises the amino acid sequence selected from the group consisting of: SEQ ID NO: 6, SEQ ID NO: 18, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 10, SEQ ID NO: 110, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 57, and SEQ ID NO: 58; and the VL domain comprises the amino acid sequence selected from the group consisting of: SEQ ID NO: 7, SEQ ID NO: 19, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131, SEQ ID NO: 132, SEQ ID NO: 60, and SEQ ID NO: 61; (b) the VH domain comprises the amino acid sequence of SEQ ID NO: 8; and the VL domain comprises the amino acid sequence of SEQ ID NO: 9; (c) the VH domain comprises the amino acid sequence of SEQ ID NO: 10; and the VL domain comprises the amino acid sequence of SEQ ID NO: 11; (d) the VH domain comprises the amino acid sequence of SEQ ID NO: 12; and the VL domain comprises the amino acid sequence of SEQ ID NO: 13; (e) the VH domain comprises the amino acid sequence selected from the group consisting of: SEQ ID NO: 14, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, and SEQ ID NO: 23; and the VL domain comprises the amino acid sequence selected from the group consisting of: SEQ ID NO: 15, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27; (f) the VH domain comprises the amino acid sequence selected from the group consisting of: SEQ ID NO: 16, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, and SEQ ID NO: 31; the VL domain comprises the amino acid sequence selected from the group consisting of: SEQ ID NO: 17, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, and SEQ ID NO: 35.

In certain embodiments, the antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 63 or 65, and the antibody light chain comprises the amino acid sequence of SEQ ID NO: 67 or 69.

In certain embodiments, the VH domain is at least about 90% identical or at least about 95% identical to the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, or SEQ ID NO: 122, and wherein the VL domain is at least about 90% identical or at least about 95% identical to the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131, or SEQ ID NO: 132.

In certain embodiments, the antigen binding protein or fragment thereof of comprises an antibody heavy chain at least about 90% identical or at least about 95% identical to the amino acid sequence of SEQ ID NO: 63 or 65, and an antibody light chain at least about 90% identical or at least about 95% identical to the amino acid sequence of SEQ ID NO: 67 or 69.

In certain embodiments, (a) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GDTFTDFE (SEQ ID NO: 70), a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NO: 71), and a CDR-H3 sequence comprising the amino acid sequence of TRTYDGYPYAMDY (SEQ ID NO: 72); and (b) the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSLLYSNNQKNY (SEQ ID NO: 73), a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NO: 74), and a CDR-L3 sequence comprising the amino acid sequence of QQYYSYRT (SEQ ID NO: 75). In some embodiments thereof, the VH domain comprises the amino acid sequence of SEQ ID NO: 6, and the VL domain comprises the amino acid sequence of SEQ ID NO: 7.

In certain embodiments, (a) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTDYN (SEQ ID NO: 76), a CDR-H2 sequence comprising the amino acid sequence of INPNNGGT (SEQ ID NO: 77), and a CDR-H3 sequence comprising the amino acid sequence of ARERDYDGAMDY (SEQ ID NO: 78); and (b) the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDINKF (SEQ ID NO: 79), a CDR-L2 sequence comprising the amino acid sequence of YTS (SEQ ID NO: 80), and a CDR-L3 sequence comprising the amino acid sequence of LQYDNLLWT (SEQ ID NO: 81).

In certain embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 8, and the VL domain comprises the amino acid sequence of SEQ ID NO: 9.

In certain embodiments, (a) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTDYN (SEQ ID NO: 82), a CDR-H2 sequence comprising the amino acid sequence of INPNNGGT (SEQ ID NO: 83), and a CDR-H3 sequence comprising the amino acid sequence of ARERDYDGSMDF (SEQ ID NO: 84); and (b) the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDINKF (SEQ ID NO: 85), a CDR-L2 sequence comprising the amino acid sequence of YTS (SEQ ID NO: 86), and a CDR-L3 sequence comprising the amino acid sequence of LQYDNLLWT (SEQ ID NO: 87).

In certain embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 10, and the VL domain comprises the amino acid sequence of SEQ ID NO: 11.

In certain embodiments, (a) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTVTDYY (SEQ ID NO: 88), a CDR-H2 sequence comprising the amino acid sequence of INPNNGVT (SEQ ID NO: 89), and a CDR-H3 sequence comprising the amino acid sequence of AREEDFDGFDY (SEQ ID NO: 90); and (b) the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDVSTG (SEQ ID NO: 91), a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NO: 92), and a CDR-L3 sequence comprising the amino acid sequence of QQHYSTPLT (SEQ ID NO: 93).

In certain embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 12, and the VL domain comprises the amino acid sequence of SEQ ID NO: 13.

In certain embodiments, (a) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GSTFSDFE (SEQ ID NO: 94), a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NO: 95), and a CDR-H3 sequence comprising the amino acid sequence of TRNYDGYSQTMDY (SEQ ID NO: 96); and (b) the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVLYSSNQKNY (SEQ ID NO: 97), a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NO: 98), and a CDR-L3 sequence comprising the amino acid sequence of HQYLSSYT (SEQ ID NO: 99).

In certain embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 14, and the VL domain comprises the amino acid sequence of SEQ ID NO: 15.

In certain embodiments, (a) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GSTFTDFE (SEQ ID NO: 100), a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NO: 101), and a CDR-H3 sequence comprising the amino acid sequence of TRNYDGYSRTMDY (SEQ ID NO: 102); and (b) the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVLYSSNQKNY (SEQ ID NO: 103), a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NO: 104), and a CDR-L3 sequence comprising the amino acid sequence of HQYLSSYT (SEQ ID NO: 105).

In certain embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 16, and the VL domain comprises the amino acid sequence of SEQ ID NO: 17.

In certain embodiments, (a) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GDTFTDFE (SEQ ID NO: 70), a CDR-H2 sequence comprising the amino acid sequence of VDPETGGT (SEQ ID NO: 297), and a CDR-H3 sequence comprising the amino acid sequence of TRTYDGYPYAFDY (SEQ ID NO: 301); and (b) the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVLYSNNNKNY (SEQ ID NO: 302), a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, 104), and a CDR-L3 sequence comprising the amino acid sequence of QQYYSYRT (SEQ ID NO: 75).

In certain embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 57, and the VL domain comprises the amino acid sequence of SEQ ID NO: 19 or 59.

In certain embodiments, the antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 63, and the antibody light chain comprises the amino acid sequence of SEQ ID NO: 67.

In certain embodiments, (a) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GDTFTDFE (SEQ ID NO: 70), a CDR-H2 sequence comprising the amino acid sequence of VDPETGGT (SEQ ID NO: 297), and a CDR-H3 sequence comprising the amino acid sequence of TRTYDGYPYAFDY (SEQ ID NO: 301); and (b) the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVLYSDNQKNY (SEQ ID NO: 306), a CDR-L2 sequence comprising the amino acid sequence of FAS (SEQ ID NO: 304), and a CDR-L3 sequence comprising the amino acid sequence of QQYYSYRT (SEQ ID NO: 75).

In certain embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 57, and the VL domain comprises the amino acid sequence of SEQ ID NO: 61.

In certain embodiments, the antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 65, and the antibody light chain comprises the amino acid sequence of SEQ ID NO: 67.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof binds a human FGFR3 polypeptide comprising the amino acid sequence of SEQ ID NO: 133.

In certain embodiments, the antigen binding protein or antigen-binding fragment thereof binds a human FGFR3 polypeptide comprising the amino acid sequence of SEQ ID NO: 134.

In certain embodiments, the antigen binding protein or antigen-binding fragment thereof binds a region of human FGFR3 polypeptide comprising the amino acids D143 through L163 of SEQ ID NO: 133.

In certain embodiments, the antigen binding protein or antigen-binding fragment thereof binds a region of human FGFR3 polypeptide comprising the amino acids D143 through N170 of SEQ ID NO: 133.

In certain embodiments, the antigen binding protein or antigen-binding fragment thereof binds a region of human FGFR3 polypeptide comprising the amino acids D143 through D160 and G197 through L213 of SEQ ID NO: 133.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof is a chimeric or humanized antibody or antigen-binding binding fragment thereof.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof is a human antibody or antigen-binding binding fragment thereof.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof is a monoclonal antibody or antigen-binding binding fragment thereof.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof comprises one or more full-length antibody heavy chains comprising an Fc region.

In certain embodiments, the Fc region is a human IgG1 Fc region.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof comprises an antibody F(ab), F(ab′)2, Fab′-SH, Fv, or scFv fragment.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof comprises an antibody F(ab) fragment.

In certain embodiments, the antibody F(ab) fragment comprises SEQ ID NO: 56 and the first about 100 amino acids of SEQ ID NO: 54.

In certain embodiments, the antibody F(ab) fragment comprises SEQ ID NO: 57 and the first about 100 amino acids of SEQ ID NO: 54.

In certain embodiments, the antibody F(ab) fragment comprises SEQ ID NO: 58 and the first about 100 amino acids of SEQ ID NO: 54.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 141 and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 142.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 143 and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 144.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 145 and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 146.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 147 and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 148.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 149 and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 150.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 151 and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 152.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 153 and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 67.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 153 and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 154.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 153 and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 69.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 155 and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 67.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 155 and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 154.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 155 and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 69.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 156 and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 67.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 156 and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 154.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 156 and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 69.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof comprises cross-reactivity to mouse and cynomolgus FGFR3.

In certain embodiments, the antigen binding or antigen-binding binding fragment thereof protein does not bind to one or more of FGFR1, FGFR2, and FGFR4.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof does not bind to each of FGFR1, FGFR2, and FGFR4.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof binds to each of FGFR1, FGFR2, and FGFR4 with an affinity of 100 μM or greater.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof binds human FGFR3 with an equilibrium dissociation constant (KD) of 10 nM or less.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof binds human FGFR3 with an off rate (Kd) of 10−4 or greater.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof inhibits ligand-induced FGFR3 dimerization with IC50 of 5 μg/ml or less.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof inhibits FGFR3 receptor activation and downstream signaling with IC50 of 5 μg/ml or less.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof inhibits the activity of an FGFR3G380R mutant.

In certain embodiments, the antigen binding protein or antigen-binding fragment thereof is capable of penetrating a bone growth plate.

In certain embodiments, the antigen binding protein or antigen-binding fragment thereof is capable of decreasing binding of FGFR3 and its ligand in a bone growth plate.

In another aspect, the disclosure provides a pharmaceutical composition comprising the antigen binding protein or antigen-binding fragment thereof recited above, and a pharmaceutically acceptable carrier.

In another aspect, the disclosure provides an isolated nucleic acid molecule encoding the antigen binding protein or antigen-binding fragment thereof recited above.

In another aspect, the disclosure provides an expression vector comprising the nucleic acid molecule recited above.

In another aspect, the disclosure provides a host cell comprising the expression vector recited above.

In another aspect, the disclosure provides a method for treating a FGFR3-mediated disease or disorder in a subject, comprising administering to a subject in need thereof the antigen binding protein or antigen-binding fragment thereof recited above.

In certain embodiments, the FGFR3-mediated disease or disorder is achondroplasia.

In certain embodiments, the achondroplasia is FGFR3G380R+ achondroplasia.

In certain embodiments, the subject suffering from achondroplasia comprises one or more symptoms selected from the group consisting of shortened proximal limbs, brachydactyly, large head with prominent forehead frontal bossing, small midface with a flattened nasal bridge, spinal kyphosis, spinal lordosis, varus, valgus, ear infections, sleep apnea, and hydrocephalus.

In certain embodiments, the FGFR3-mediated disease or disorder is cancer.

In certain embodiments, the cancer is bladder cancer melanoma, urothelial cancer, and endometrial cancer.

In one aspect, the disclosure provides a method for treating achondroplasia in a subject, comprising administering to a subject in need thereof an antigen-binding protein fragment that specifically binds to FGFR3, wherein the antigen binding protein fragment does not bind to one or more of FGFR1, FGFR2, and FGFR4.

In one aspect, the disclosure provides a method for inhibiting one or both of FGFR3 activity and expression in a bone growth plate of a subject, comprising administering to a subject an antigen-binding protein fragment that specifically binds to FGFR3, wherein the antigen binding protein fragment does not bind to one or more of FGFR1, FGFR2, and FGFR4.

In one aspect, the disclosure provides an antigen-binding protein or antigen-binding fragment thereof that specifically binds to fibroblast growth factor receptor 3 (FGFR3), comprising an antibody heavy chain variable (VH) domain and an antibody light chain variable (VL) domain, wherein the antigen binding protein binds a human FGFR3 polypeptide comprising the amino acid sequence of SEQ ID NO: 134.

In certain embodiments, the antigen binding protein binds a region of human FGFR3 polypeptide comprising the amino acids D143 through L163 of SEQ ID NO: 133.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof binds a region of human FGFR3 polypeptide comprising the amino acids D143 through N170 of SEQ ID NO: 133.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof binds a region of human FGFR3 polypeptide comprising the amino acids D143 through D160 and G197 through L213 of SEQ ID NO: 133.

In one aspect, the disclosure provides an antigen-binding protein or antigen-binding fragment thereof with binding specificity to a fibroblast growth factor receptor 3 (FGFR3) epitope, comprising an antibody heavy chain variable (VH) domain and an antibody light chain variable (VL) domain, wherein the antigen binding protein or antigen-binding binding fragment thereof competes for binding to FGFR3 with an antibody comprising VH/VL domain amino acid sequence pairs selected from the group consisting of: SEQ ID NO: 6/SEQ ID NO: 7, SEQ ID NO: 8/SEQ ID NO: 9, SEQ ID NO: 10/SEQ ID NO: 11, SEQ ID NO: 12/SEQ ID NO: 13, SEQ ID NO: 14/SEQ ID NO: 15, and SEQ ID NO: 16/SEQ ID NO: 17.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof is a chimeric or humanized antibody or antigen-binding binding fragment thereof.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof is a human antibody or antigen-binding binding fragment thereof.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof is a monoclonal antibody or antigen-binding binding fragment thereof.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof comprises one or more full-length antibody heavy chains comprising an Fc region.

In certain embodiments, the Fc region is a human IgG1 Fc region.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof comprises an antibody F(ab), F(ab′)2, Fab′-SH, Fv, or scFv fragment.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof comprises an antibody F(ab) fragment.

In certain embodiments, the antibody F(ab) fragment comprises SEQ ID NO: 56 and the first about 100 amino acids of SEQ ID NO: 54.

In certain embodiments, the antibody F(ab) fragment comprises a heavy chain comprising SEQ ID NO: 57 and the first about 100 amino acids of SEQ ID NO: 54.

In certain embodiments, the antibody F(ab) fragment comprises a heavy chain comprising SEQ ID NO: 58 and the first about 100 amino acids of SEQ ID NO: 54.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 141, 164, 173, 182, 191, 200, 209, 218, 227, 236, 245, 254, 263, 272, or 281, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 142.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 143, 165, 174, 183, 192, 201, 210, 219, 228, 237, 246, 255, 264, 273, or 282, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 144.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 145, 166, 175, 184, 193, 202, 211, 220, 229, 238, 247, 256, 265, 274, or 283, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 146.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 147, 167, 176, 185, 194, 203, 212, 221, 230, 239, 248, 257, 266, 275, or 284, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 148.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 149, 168, 177, 186, 195, 204, 213, 222, 231, 240, 249, 258, 267, 276, or 285, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 150.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 151, 169, 178, 187, 196, 205, 214, 223, 232, 241, 250, 259, 268, 277, or 286, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 152.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 153, 170, 179, 188, 197, 206, 215, 224, 233, 242, 251, 260, 269, 278, or 287, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 67.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 153, 170, 179, 188, 197, 206, 215, 224, 233, 242, 251, 260, 269, 278, or 287, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 154.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 153, 170, 179, 188, 197, 206, 215, 224, 233, 242, 251, 260, 269, 278, or 287, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 69.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 155, 171, 180, 189, 198, 207, 216, 225, 234, 243, 252, 261, 270, 279, or 288, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 67.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 155, 171, 180, 189, 198, 207, 216, 225, 234, 243, 252, 261, 270, 279, or 288, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 154.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 155, 171, 180, 189, 198, 207, 216, 225, 234, 243, 252, 261, 270, 279, or 288, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 69.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 156, 172, 181, 190, 199, 208, 217, 226, 235, 244, 253, 262, 271, 280, or 289, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 67.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 156, 172, 181, 190, 199, 208, 217, 226, 235, 244, 253, 262, 271, 280, or 289, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 154.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 156, 172, 181, 190, 199, 208, 217, 226, 235, 244, 253, 262, 271, 280, or 289, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 69.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof comprises has cross-reactivity to mouse and cynomolgus FGFR3.

In certain embodiments, the antigen binding or antigen-binding binding fragment thereof protein does not bind to one or more of FGFR1, FGFR2, and FGFR4.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof does not bind to each of FGFR1, FGFR2, and FGFR4.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof binds to each of FGFR1, FGFR2, and FGFR4 with an affinity equilibrium dissociation constant (KD) of 100 μM or greater.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof binds human FGFR3 with an equilibrium dissociation constant (KD) of 10 nM or less.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof binds human FGFR3 with an off rate (Kd) of 10−4 or greater.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof inhibits ligand-induced FGFR3 dimerization with IC50 of 5 μg/ml or less.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof inhibits FGFR3 receptor activation and downstream signaling with IC50 of 5 μg/ml or less.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof inhibits the activity of an FGFR3G380R mutant.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof is capable of penetrating a bone growth plate.

In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof is capable of decreasing the binding of FGFR3 with its ligand in a bone growth plate. In certain embodiments, the antigen binding protein or antigen-binding binding fragment thereof is capable of decreasing the kinase activity of FGFR3 in a bone growth plate.

Also provided is a pharmaceutical composition comprising the antigen binding protein or antigen-binding fragment thereof as described herein. In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier.

Also provided is an isolated nucleic acid molecule encoding the antigen binding protein or antigen-binding fragment thereof as described herein. Also provided is an expression cassette comprising said nucleic acid molecule. Also provided is an expression vector comprising the isolated nucleic acid molecule. Further provided is a host cell comprising the expression vector, the expression cassette or the nucleic acid molecule.

Further provided is a method for treating a FGFR3-mediated disease or disorder in a subject. In certain embodiments, the method comprises administering to a subject in need thereof the antigen binding protein or antigen-binding fragment thereof as described herein. In certain embodiments, the FGFR3-mediated disease or disorder is achondroplasia. In certain embodiments, the achondroplasia is FGFR3G380R+ achondroplasia.

In certain embodiments, the FGFR3-mediated disease or disorder is cancer.

In certain embodiments, the cancer is bladder cancer melanoma, urothelial cancer, and endometrial cancer.

Also provided is a method for treating achondroplasia in a subject. In certain embodiments, the method comprises administering to a subject in need thereof an antigen-binding protein fragment that specifically binds to FGFR3, wherein the antigen binding protein fragment does not bind to one or more of FGFR1, FGFR2, and FGFR4.

Also provided is a method for inhibiting one or both of FGFR3 activity and expression in a bone growth plate of a subject. In certain embodiments, the method comprises administering to a subject an antigen-binding protein fragment that specifically binds to FGFR3, wherein the antigen binding protein fragment does not bind to one or more of FGFR1, FGFR2, and FGFR4.

In certain embodiments, the subject is a child. In certain embodiments, the child is an infant. In certain embodiments, the infant is a newborn.

Also provided is a method for preventing or alleviating one or more symptoms of achondroplasia in a subject. In certain embodiments, the method comprises administering to the subject an antigen-binding protein or an antigen-binding protein fragment thereof that specifically binds to FGFR3, wherein the antigen binding protein fragment does not bind to one or more of FGFR1, FGFR2, and FGFR4.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other features and advantages of the present disclosure will be more fully understood from the following detailed description of illustrative embodiments taken in conjunction with the accompanying drawings. The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided to the Office upon request and payment of the necessary fee.

FIG. 1 schematically depicts fibroblast growth factor receptor 3 (FGFR3) isoform IIIc.

FIG. 2 depicts heat maps generated with hydrogen deuterium exchange (HDX) mass spectrometry used to determine the epitopes on FGFR3 for select antibodies by measuring the amide hydrogen deuterium exchange on FGFR3.

FIG. 3 depicts fluorescent images from internalization assays to detect internalization of anti-FGFR3 antibodies in KMS-11 cells.

FIG. 4 graphically depicts the average amount of anti-FGFR3 antibody internalization relative to the total amount of antibody.

FIG. 5A-FIG. 5C graphically depict inhibition of FGFR3 dimerization by anti-FGFR3 antibody KC18 (FIG. 5A), KE58 (FIG. 5B), KE94 (FIG. 5C). Inhibition was evaluated by a chemiluminescent assay in U2OS cells co-expressing fusion protein of β-galactosidase-prolink (PK) and FGFR3 (FGFR3-PK) and β-galactosidase-enzyme acceptor (EA) and FGFR3 (FGFR3-EA).

FIG. 6 depicts an alignment of anti-FGFR3 antibodies KC18, KE63, and KE94.

FIG. 7 depicts an alignment of anti-FGFR3 antibody KC18_Hu18 with variants. Mutations of Hu18 residues are highlighted green or red.

FIG. 8A-FIG. 8C depict graphs demonstrating IC50 values for the inhibition of Erk phosphorylation by humanized anti-FGFR3 antibodies Hu18 (FIG. 8A), Hu44 (FIG. 8B), and Hu46 (FIG. 8C). Inhibition of Erk phosphorylation was determined by a homogenous time-resolved fluorescence (HTRF) assay.

FIG. 9A-FIG. 9B graphically depict relative Erk phosphorylation inhibition by anti-FGFR3 antibodies KC18 (FIG. 9A), KE63 (FIG. 9B), and KE94 (FIG. 9B) and their corresponding Fab fragments.

FIG. 10A-FIG. 10C graphically depict relative Erk phosphorylation inhibition by anti-FGFR3 antibody KC18 in different formats. FIG. 10A depicts inhibition effect of KC18 as a full-length antibody (KC18), a Fab fragment (Kc18 Fab), a one-armed, monovalent antibody (MetMab), and a PEGylated Fab fragment (PEG) in WT cells. FIG. 10B depicts inhibition effect of KC18 as a full-length antibody (IgG), a Fab fragment, a one-armed, monovalent antibody (MetMab), and a PEGylated Fab fragment (PEG) in Ach cells. FIG. 10C depicts KC18 fab fragments with half-life extension moieties using a human albumin nanobody conjugate (KC18 Fab-HLE), with and without human serum albumin (HSA) or mouse serum albumin (MSA). Erk phosphorylation was measured in an HTRF assay and compared to an isotype control (Iso).

FIG. 11 graphically depicts inhibition of Erk phosphorylation by humanized anti-FGFR3 antibodies Hu18, Hu44, and Hu46. Inhibition of Erk phosphorylation was determined using an HTRF assay.

FIG. 12A-FIG. 12B graphically depict femur (FIG. 12A) and tibia (FIG. 12B) length in an achondroplasia mouse model (Ach), which is a transgenic mouse that overexpresses the mouse FGFR3 protein with the G380R mutation under the collagen II promoter. Mice were administered the KC18 fab fragment subcutaneously from 3 days of age to 20 days of age.

FIG. 13A-FIG. 13B graphically depict vertebrae (FIG. 13A) and skull (FIG. 13B) length in the Ach mouse model. For skull measurements, NL=nasal length; FL=frontal length; and PL=parietal length.

FIG. 14 graphically depicts brain volume in the WT and Ach mouse model treated by saline or KC18 fab fragment.

FIG. 15A graphically depicts Kyphosis Index in the WT and Ach mouse model treated by saline or KC18 fab fragment. FIG. 15B depicts the calculation of Kyphotic Index using a mouse model.

FIG. 16A graphically depicts femur growth plate (GP) volume in Ach mouse model treated by vehicle or KC18 fab fragment. FIG. 16B depicts femur diameter in Ach mouse model treated by vehicle or KC18 fab fragment.

FIG. 17 graphically depicts increased secondary ossification center in tibia in Ach mouse model compared to those treated with vehicle.

 DETAILED DESCRIPTION

Antigen-binding proteins or antigen-binding fragments thereof are provided. Methods of inhibiting one or more FGFR3 activities, and methods of treating FGFR3-mediated diseases and disorders are also provided.

Generally, nomenclature used in connection with cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those well-known and commonly used in the art. The methods and techniques provided herein are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. Enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The nomenclature used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

Unless otherwise defined herein, scientific and technical terms used herein have the meanings that are commonly understood by those of ordinary skill in the art. In the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. The use of “or” means “and/or” unless stated otherwise. The use of the term “including,” as well as other forms, such as “includes” and “included,” is not limiting.

So that the disclosure may be more readily understood, certain terms are first defined.

Fibroblast Growth Factor Receptor 3 (FGFR3)

As used herein, the term “FGFR3” or “fibroblast growth factor receptor 3” or “CD333” refers to the FGFR3 protein encoded by the FGFR3 gene. FGFR3 belongs to a family of fibroblast growth factor receptors that also includes FGFR1, FGFR2, and FGFR4. Like the other fibroblast growth factor receptor family members, FGFR3 is a single-pass membrane receptor tyrosine kinase with 3 Ig-like domains (D1, D2, and D3). Ligand dependent receptor dimerization leads to tyrosine kinase activation and downstream signal transduction. FGFR3 undergoes alternative splicing leading to several isoforms, including isoform IIIb and isoform IIIc. IIIb and IIIc arise from alternative splicing of exons 8 and 9. IIIb and IIIc have identical Ig1 (D1) and Ig2 (D2) domains, but vary in the Ig3 (D3) domain. It is FGFR3 IIIc that is the major FGFR3 isoform in chondrocytes and mediates the anabolic effects of the FGFR3 ligand, FGF18, in articular cartilage. The structure and function of FGFR3 is described in further detail in Olsen et al. (PNAS. 101(4): 935-940. 2004), incorporated herein by reference in its entirety for all purposes.

The human FGFR3 isoform IIIc amino acid sequence is recited below.

(SEQ ID NO: 135) MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLV FGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNAS HEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGA PYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHR IGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSP HRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGP DGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHH SAWLVVLPAEEELVEADEAGSVYAGILSYGVGFFLFILVVAAVTLCRLRS PPKKGLGSPTVHKISRFPLKRQVSLESNASMSSNTPLVRIARLSSGEGPT LANVSELELPADPKWELSRARLTLGKPLGEGCFGQVVMAEAIGIDKDRAA KPVTVAVKMLKDDATDKDLSDLVSEMEMMKMIGKHKNIINLLGACTQGGP LYVLVEYAAKGNLREFLRARRPPGLDYSFDTCKPPEEQLTFKDLVSCAYQ VARGMEYLASQKCIHRDLAARNVLVTEDNVMKIADFGLARDVHNLDYYKK TTNGRLPVKWMAPEALFDRVYTHQSDVWSFGVLLWEIFTLGGSPYPGIPV EELFKLLKEGHRMDKPANCTHDLYMIMRECWHAAPSQRPTFKQLVEDLDR VLTVTSTDEYLDLSAPFEQYSPGGQDTPSSSSSGDDSVFAHDLLPPAPPS SGGSRT

Mutations in FGFR3 can lead to certain undesired conditions. A G380R mutation in the transmembrane domain of FGFR3 is associated with 98% of all achondroplasia cases. FGFR3 with a G380R mutation can be referred to as FGFR3G380R, and the sequence of the human FGFR3G380R isoform IIIc is recited below.

(SEQ ID NO: 133) MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLV FGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNAS HEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGA PYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHR IGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSP HRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGP DGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHH SAWLVVLPAEEELVEADEAGSVYAGILSYRVGFFLFILVVAAVTLCRLRS PPKKGLGSPTVHKISRFPLKRQVSLESNASMSSNTPLVRIARLSSGEGPT LANVSELELPADPKWELSRARLTLGKPLGEGCFGQVVMAEAIGIDKDRAA KPVTVAVKMLKDDATDKDLSDLVSEMEMMKMIGKHKNIINLLGACTQGGP LYVLVEYAAKGNLREFLRARRPPGLDYSFDTCKPPEEQLTFKDLVSCAYQ VARGMEYLASQKCIHRDLAARNVLVTEDNVMKIADFGLARDVHNLDYYKK TTNGRLPVKWMAPEALFDRVYTHQSDVWSFGVLLWEIFTLGGSPYPGIPV EELFKLLKEGHRMDKPANCTHDLYMIMRECWHAAPSQRPTFKQLVEDLDR VLTVTSTDEYLDLSAPFEQYSPGGQDTPSSSSSGDDSVFAHDLLPPAPPS SGGSRT

Antigen-Binding Proteins

As used herein, the term “antibody” or “antigen-binding protein” refers to an immunoglobulin molecule that specifically binds to, or is immunologically reactive with an antigen or epitope (e.g., a FGFR3 antigen or epitope), and includes both polyclonal and monoclonal antibodies, as well as functional antibody fragments thereof, including but not limited to fragment antigen-binding (Fab) fragments, F(ab′)2 fragments, Fab′ fragments, Fv fragments, recombinant IgG (rIgG) fragments, single chain variable fragments (scFv) and single domain antibodies (e.g., sdAb, sdFv, nanobody) fragments. The term “antibody” includes genetically engineered or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, meditope-enabled antibodies, heteroconjugate antibodies (e.g., bispecific antibodies, diabodies, triabodies, tetrabodies, tandem di-scFv, tandem tri-scFv) and the like. Unless otherwise stated, the term “antibody” should be understood to encompass functional antibody fragments thereof. As used herein, the term “functional antibody fragment” refers to an antibody fragment having at least 80%, at least 85%, at least 90%, or at least 95% affinity as the antibody of interest from which the fragment is derived from.

As used herein, the term “complementarity determining region” or “CDR” refers to sequences of amino acids within antibody variable regions, which confer antigen specificity and binding affinity. In general, there are three CDRs in each heavy chain variable region (CDR-H1, CDR-H2, CDR-H3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, CDR-L3). “Framework regions” or “FR” are known in the art to refer to the non-CDR portions of the variable regions of the heavy and light chains. In general, there are four FRs in each heavy chain variable region (FR-H1, FR-H2, FR-H3, and FR-H4), and four FRs in each light chain variable region (FR-L1, FR-L2, FR-L3, and FR-L4).

The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (“Kabat” numbering scheme), Al-Lazikani et al., (1997) JMB 273, 927-948 (“Chothia” numbering scheme), MacCallum et al., J. Mol. Biol. 262:732-745 (1996), “Antibody-antigen interactions: Contact analysis and binding site topography,” J. Mol. Biol. 262, 732-745. (“Contact” numbering scheme), Lefranc M P et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Dev Comp Immunol, 2003 January; 27(1):55-77 (“IMGT” numbering scheme), and Honegger A and Pluckthun A, “Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool,” J Mol Biol, 2001 Jun. 8; 309(3):657-70, (AHo numbering scheme).

The boundaries of a given CDR or FR may vary depending on the scheme used for identification. For example, the Kabat scheme is based structural alignments, while the Chothia scheme is based on structural information. Numbering for both the Kabat and Chothia schemes is based upon the most common antibody region sequence lengths, with insertions accommodated by insertion letters, for example, “30a,” and deletions appearing in some antibodies. The two schemes place certain insertions and deletions (“indels”) at different positions, resulting in differential numbering. The Contact scheme is based on analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme.

A “CDR” or “complementary determining region,” or individual specified CDRs (e.g., “CDR-H1,” “CDR-H2,” “CDR-H3”), of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) complementary determining region as defined by any of the known schemes. Likewise, an “FR” or “framework region,” or individual specified FRs (e.g., “FR-H1,” “FR-H2”) of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) framework region as defined by any of the known schemes. In some instances, the scheme for identification of a particular CDR or FR is specified, such as the CDR as defined by the IMGT, Kabat, Chothia, AbM, or Contact method. In other cases, the particular amino acid sequence of a CDR or FR is given. Unless otherwise specified, all particular CDR amino acid sequences mentioned in the disclosure are IMGT CDRs. However, alternative CDRs defined by other schemes are also encompassed by the present disclosure, such as those determined by abYsis Key Annotation (Website: abysis.org/abysis/sequence_input/key_annotation/key_annotation.cgi).

As used herein, the term “specifically binds,” “specifically binding,” “binding specificity” or “specifically recognized” refers that an antigen binding protein or antigen-binding fragment thereof that exhibits appreciable affinity for an antigen (e.g., an FGFR3 antigen) and does not exhibit significant cross reactivity to a target that is not an FGFR3 protein. As used herein, the term “affinity” refers to the strength of the interaction between an antigen binding protein or antigen-binding fragment thereof antigen binding site and the epitope to which it binds. As readily understood by those skilled in the art, an antigen binding protein affinity may be reported as a dissociation constant (KD) in molarity (M). The antigen binding protein or antigen-binding fragment thereof of the disclosure have KD values in the range of about 10−6 M to about 10−12 M (i.e., low micromolar to picomolar range), about 10−7 M to 10−11 M, about 10−8 M to about 10−10 M, about 10−9 M. In certain embodiments, the antigen binding protein or antigen-binding fragment thereof has a binding affinity of about 10−6 M, 10−7 M, 10−8 M, 10−9 M, 10−10 M, 10−11 M, or 10−12 M. In certain embodiments, the antigen binding protein or antigen-binding fragment thereof has a binding affinity of about 10−7 M to about 10−9 M (nanomolar range).

Specific binding can be determined according to any art-recognized means for determining such binding. In some embodiments, specific binding is determined by competitive binding assays (e.g. ELISA) or Biacore assays. In certain embodiments, the assay is conducted at about 20° C., 25° C., 30° C., or 37° C.

Anti-FGFR3 Antigen-Binding Proteins

In one aspect, the disclosure provides antigen binding proteins and antigen-binding fragments thereof with binding specificity to FGFR3.

Exemplary anti-FGFR3 antigen binding protein and antigen-binding fragment thereof CDRs are recited below in Table 1 and Table 4. Exemplary anti-FGFR3 antigen binding protein and antigen-binding fragment thereof variable heavy (VH) and variable light (VL) domains are recited below in Table 3, Table 8, Table 9, and Table 13. Exemplary anti-FGFR3 antigen binding protein full length heavy and light chains are recited below in Table 14.

TABLE 1 Antibody Heavy chain and Light chain CDR regions HEAVY Chain VH Chain ID HCDR1-IMGT HCDR2-IMGT HCDR3-IMGT KC18_VH GDTFTDFE IDPETGGT TRTYDGYPYAMDY (SEQ ID NO: 70) (SEQ ID NO: 71) (SEQ ID NO: 72) KE35_VH GYTFTDYN INPNNGGT ARERDYDGAMDY (SEQ ID NO: 76) (SEQ ID NO: 77) (SEQ ID NO: 78) KE42_VH GYTFTDYN INPNNGGT ARERDYDGSMDF (SEQ ID NO: 82) (SEQ ID NO: 83) (SEQ ID NO: 84) KE58_VH GYTVTDYY INPNNGVT AREEDFDGFDY (SEQ ID NO: 88) (SEQ ID NO: 89) (SEQ ID NO: 90) KE63_VH GSTFSDEE IDPETGGT TRNYDGYSQTMDY (SEQ ID NO: 94) (SEQ ID NO: 95) (SEQ ID NO: 96) KE94_VH GSTFTDEE IDPETGGT TRNYDGYSRTMDY (SEQ ID NO: 100) (SEQ ID NO: 101) (SEQ ID NO: 102) KC18 Hu18 VH GDTFTDFE VDPETGGT TRTYDGYPYAFDY (SEQ ID NO: 70) (SEQ ID NO: 297) (SEQ ID NO: 301) KC18Hrw1 GDTFTDFE IDPETGST TRTYDGYPYAMDY (SEQ ID NO: 70) (SEQ ID NO: 298) (SEQ ID NO: 72) KC18Hrw2 GDTFTDYE IDPETGST TRTYDGYPYAMDY (SEQ ID NO: 295) (SEQ ID NO: 298) (SEQ ID NO: 72) KC18Hrw3 GDTFTDYE IDPETGST TRTYDGYPYAMDY (SEQ ID NO: 295) (SEQ ID NO: 298) (SEQ ID NO: 72) KC18HV1-69rw2 GDTFTDFE VDPETGGT TRTYDGYPYAMDY (SEQ ID NO: 70) (SEQ ID NO: 297) (SEQ ID NO: 72) KC18HV1-69rw3 GDTFTDFE VDPETGGT TRTYEGYPYAMDY (SEQ ID NO: 70) (SEQ ID NO: 297) (SEQ ID NO: 300) KC18HV1-69rw4 GDTFTDFE VDPETGGT TRTYDGYPYAFDY (SEQ ID NO: 70) (SEQ ID NO: 297) (SEQ ID NO: 301) KC18_CL_VH1 GDTFTDFE IDPETGGT ARTYDGYPYAMDY (SEQ ID NO: 70) (SEQ ID NO: 95) (SEQ ID NO: 310) KC18_CL_VH1b GYTFTDFE VDPETGGT ARTYDGYPYAMDY (SEQ ID NO: 296) (SEQ ID NO: 297) (SEQ ID NO: 310) KC18_CL_VH1c GYTFTDFE VEPETGGT ARTYDGYPYAMDV (SEQ ID NO: 296) (SEQ ID NO: 299) (SEQ ID NO: 311) KC18_CL_VH2 GDTFTDFE IDPETGGT TRTYDGYPYAMDY (SEQ ID NO: 70) (SEQ ID NO: 95) (SEQ ID NO: 72) KC18_CL_VH3 GDTFTDFE IDPESGGT ARTYDGYPYAMDY (SEQ ID NO: 70) (SEQ ID NO: 312) (SEQ ID NO: 310) KC18_CL_VH3b GYTFTDFE IDPESGGT ARTYDGYPYAMDY (SEQ ID NO: 296) (SEQ ID NO: 312) (SEQ ID NO: 310) KC18_CL_VH3c GYTFTDFE IEPESGGT ARTYDGYPYAMDV (SEQ ID NO: 296) (SEQ ID NO: 313) (SEQ ID NO: 311) KC18_CL_VH4 GDTFTDFE IDPETGGT TRTYDGYPYAMDY (SEQ ID NO: 70) (SEQ ID NO: 95) (SEQ ID NO: 72) KC18_VH_6 GDTFTDFE VDPETGGT TRTYDGYPYAFDY (SEQ ID NO: 70) (SEQ ID NO: 297) (SEQ ID NO: 301) KC18_VH_15 GDTFTDFE VDPETGGT TRTYDGYPYAFDY (SEQ ID NO: 70) (SEQ ID NO: 297) (SEQ ID NO: 301) KC18_VH_16 GDTFTDFE VDPETGGT TRTYDGYPYAFDY (SEQ ID NO: 70) (SEQ ID NO: 297) (SEQ ID NO: 301) KE63 Hu01 VH GSTFSDEE IDPETGGT TRNYDGYSQTFDY (SEQ ID NO: 94) (SEQ ID NO: 95) (SEQ ID NO: 305) KE63 Hu02 VH GSTFSDEE IDPETGGT TRNYDGYSQTFDY (SEQ ID NO: 94) (SEQ ID NO: 95) (SEQ ID NO: 305) KE63 Hu03 VH GSTFSDEE IDPETGGT TRNYDGYSQTFDY (SEQ ID NO: 94) (SEQ ID NO: 95) (SEQ ID NO: 305) KE63 Hu04 VH GSTFSDEE IDPETGGT TRNYDGYSQTFDY (SEQ ID NO: 94) (SEQ ID NO: 95) (SEQ ID NO: 305) KE94 Hu01 VH GSTFTDEE IDPETGGT TRNYDGYSRTFDY (SEQ ID NO: 100) (SEQ ID NO: 101) (SEQ ID NO: 307) KE94 Hu02 VH GSTFTDEE IDPETGGT TRNYDGYSRTFDY (SEQ ID NO: 100) (SEQ ID NO: 101) (SEQ ID NO: 307) KE94 Hu03 VH GSTFTDEE IDPETGGT TRNYDGYSRTFDY (SEQ ID NO: 100) (SEQ ID NO: 101) (SEQ ID NO: 307) KE94 Hu04 VH GSTFTDEE IDPETGGT TRNYDGYSRTFDY (SEQ ID NO: 100) (SEQ ID NO: 101) (SEQ ID NO: 307) LIGHT Chain VL Chain ID LCDR1-IMGT LCDR2-IMGT LCDR3-IMGT KC18_VL QSLLYSNNQKNY WAS QQYYSYRT (SEQ ID NO: 73) (SEQ ID NO: 74) (SEQ ID NO: 75) KE35_VL QDINKF YTS LQYDNLLWT (SEQ ID NO: 79) (SEQ ID NO: 80) (SEQ ID NO: 81) KE42_VL QDINKF YTS LQYDNLLWT (SEQ ID NO: 85) (SEQ ID NO: 86) (SEQ ID NO: 87) KE58_VL QDVSTG WAS QQHYSTPLT (SEQ ID NO: 91) (SEQ ID NO: 92) (SEQ ID NO: 93) KE63_VL QSVLYSSNQKNY WAS HQYLSSYT (SEQ ID NO: 97) (SEQ ID NO: 98) (SEQ ID NO: 99) KE94_VL QSVLYSSNQKNY WAS HQYLSSYT (SEQ ID NO: 103) (SEQ ID NO: 104) (SEQ ID NO: 105) KC18 Hu18 VL QSVLYSNNNKNY WAS QQYYSYRT (SEQ ID NO: 302) (SEQ ID NO: 74) (SEQ ID NO: 75) KC18Lrw1 QSLLYSNNQKNY WAS QQYYSYRT (SEQ ID NO: 73) (SEQ ID NO: 74) (SEQ ID NO: 75) KC18Lrw2 QSVLYSSNNKNY WAS QQYYSYRT (SEQ ID NO: X) (SEQ ID NO: 74) (SEQ ID NO: 75) KC18Lrw3 QSVLYSNNNKNY WAS QQYYSYRT (SEQ ID NO: 302) (SEQ ID NO: 74) (SEQ ID NO: 75) KC18_CL_VL1 QSVLYSSNQKNY WAS QQYYSYRT (SEQ ID NO: 97) (SEQ ID NO: 74) (SEQ ID NO: 75) KC18_CL_VL1b QSVLYSNNQKNY WAS QQYYSYRT (SEQ ID NO: 315) (SEQ ID NO: 74) (SEQ ID NO: 75) KC18_CL_VL1c QSVLYSSNQKNY WAS QQYYSYRT (SEQ ID NO: 97) (SEQ ID NO: 74) (SEQ ID NO: 75) KC18_CL_VL1d QSVLYSSNQKNY YAS QQYYSYRT (SEQ ID NO: 97) (SEQ ID NO: 303) (SEQ ID NO: 75) KC18_CL_VL2 QSLLYSNNQKNY WAS QQYYSYRT (SEQ ID NO: 73) (SEQ ID NO: 74) (SEQ ID NO: 75) KC18_CL_VL3 QSLLHSNNQKNY WGS QQYYSYRT (SEQ ID NO: 317) (SEQ ID NO: 316) (SEQ ID NO: 75) KC18_CL_VL3b QSLLYSNNQKNY WGS QQYYSYRT (SEQ ID NO: 73) (SEQ ID NO: 316) (SEQ ID NO: 75) KC18_CL_VL4 QSLLYSNNQKNY WGS QQYYSYRT (SEQ ID NO: 73) (SEQ ID NO: 316) (SEQ ID NO: 75) KC18_CL_VL5 QGISYSNNQKNY WAS QQYYSYRT (SEQ ID NO: X) (SEQ ID NO: 74) (SEQ ID NO: 75) KC18_CL_VL6 QSLLYSNNQKNY WAS QQYYSYRT (SEQ ID NO: 73) (SEQ ID NO: 74) (SEQ ID NO: 75) KC18_VL_3 QSVLYSNNNKNY WAS QQYYSYRT (SEQ ID NO: 302) (SEQ ID NO: 74) (SEQ ID NO: 75) KC18_VL_14 QSVLYSDNQKNY YAS QQYYSYRT (SEQ ID NO: 306) (SEQ ID NO: 303) (SEQ ID NO: 75) KC18_VL_15 QSVLYSDNQKNY FAS QQYYSYRT (SEQ ID NO: 306) (SEQ ID NO: 304) (SEQ ID NO: 75) KE63 Hu01 VL QSVLYSSNQKNY WAS HQYLSSYT (SEQ ID NO: 97) (SEQ ID NO: 98) (SEQ ID NO: 99) KE63 Hu02 VL QSVLYSSNQKNY WAS HQYLSPYT (SEQ ID NO: 97) (SEQ ID NO: 98) (SEQ ID NO: 314) KE63 Hu03 VL QSVLYSDNQKNY YAS HQYLSPYT (SEQ ID NO: 306) (SEQ ID NO: 303) (SEQ ID NO: 314) KE63 Hu04 VL QSVLYSDNQKNY FAS HQYLSPYT (SEQ ID NO: 306) (SEQ ID NO: 304) (SEQ ID NO: 314) KE94 Hu01 VL QSVLYSSNQKNY WAS HQYLSSYT (SEQ ID NO: 97) (SEQ ID NO: 104) (SEQ ID NO: 105) KE94 Hu02 VL QSVLYSSNQKNY WAS HQYLSPYT (SEQ ID NO: 97) (SEQ ID NO: 104) (SEQ ID NO: 314) KE94 Hu03 VL QSVLYSDNQKNY YAS HQYLSPYT (SEQ ID NO: 306) (SEQ ID NO: 303) (SEQ ID NO: 314) KE94 Hu04 VL QSVLYSDNQKNY FAS HQYLSPYT (SEQ ID NO: 306) (SEQ ID NO: 304) (SEQ ID NO: 314)

In certain embodiments, the anti-FGFR3 antigen binding proteins and antigen-binding fragments thereof comprise an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence, a CDR-H2 sequence, and a CDR-H3 sequence. The CDR-H1 sequence comprises the amino acid sequence of GX1TFTDX2E (SEQ ID NO: 157), wherein X1 comprises Y or D and X2 comprises F or Y; the CDR-H2 sequence comprises the amino acid sequence of IDPETGX3T (SEQ ID NO: 158), wherein X3 comprises G or S; or CDR-H2 sequence comprising the amino acid sequence of INPNNGX4T (SEQ ID NO: 159), wherein X4 comprises G or V; or CDR-H2 sequence comprising the amino acid sequence of VX5PETGGT (SEQ ID NO: 160), wherein X5 comprises D or E; and the CDR-H3 sequence comprises the amino acid sequence of TRX6YX7GYX8X9X10X11DY (SEQ ID NO: 161), wherein X6 comprises T or N, comprises D or E, X8 comprises S or P, X9 comprises Q, R, or Y, X19 comprises T or A, X11 comprises F or M.

In certain embodiments, the anti-FGFR3 antigen binding proteins and antigen-binding fragments thereof comprise an antibody light chain variable (VL) domain comprising a CDR-L1 sequence, a CDR-L2 sequence, and a CDR-L3 sequence. The CDR-L1 sequence comprises the amino acid sequence of QS X12LYS X13N X14KNY (SEQ ID NO: 162), wherein X12 comprises L or V, X13 comprises N, D, or S, and X14 comprises Q or N; the CDR-L2 sequence comprises the amino acid sequence of X15AS (SEQ ID NO: 163), wherein X15 comprises W, Y, or F; and the CDR-L3 sequence comprises the amino acid sequence of QQYYSYRT (SEQ ID NO: 75), LQYDNLLWT (SEQ ID NO: 81), or HQYLSX16YT (SEQ ID NO: 290), wherein X16 comprises P or S.

In one aspect, the disclosure provides an antigen-binding protein or fragment thereof that specifically binds to fibroblast growth factor receptor 3 (FGFR3), comprising an antibody heavy chain variable (VH) domain and an antibody light chain variable (VL) domain, wherein:

    • (a) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GX1TFTDX2E (SEQ ID NO: 157), wherein X1 comprises Y or D and X2 comprises F or Y; a CDR-H2 sequence comprising the amino acid sequence of IDPETGX3T (SEQ ID NO: 158), wherein X3 comprises G or S; or CDR-H2 sequence comprising the amino acid sequence of INPNNGX4T (SEQ ID NO: 159), wherein X4 comprises G or V; or CDR-H2 sequence comprising the amino acid sequence of VX5PETGGT (SEQ ID NO: 160), wherein X5 comprises D or E; a CDR-H3 sequence comprising the amino acid sequence of TRX6YX7GYX8X9X10X11DY (SEQ ID NO: 161), wherein X6 comprises T or N, X7 comprises D or E, X8 comprises S or P, X9 comprises Q, R, or Y, X10 comprises T or A, X11 comprises F or M; and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QS X12LYS X13N X14KNY (SEQ ID NO: 162), wherein X12 comprises L or V, X13 comprises N, D, or S, and X14 comprises Q or N; a CDR-L2 sequence comprising the amino acid sequence of X15AS (SEQ ID NO: 163), wherein X15 comprises W, Y, or F; a CDR-L3 sequence comprising the amino acid sequence of QQYYSYRT (SEQ ID NO: 75), LQYDNLLWT (SEQ ID NO: 81), or HQYLSX16YT (SEQ ID NO: 290) wherein X16 comprises P or S;
    • (b) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTDYN (SEQ ID NOs: 76 and 82); a CDR-H2 sequence comprising the amino acid sequence of INPNNGGT (SEQ ID NOs: 77 and 83); a CDR-H3 sequence comprising the amino acid sequence of ARERDYDGAMDY (SEQ ID NO: 78); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDINKF (SEQ ID NOs: 79 and 85); a CDR-L2 sequence comprising the amino acid sequence of YTS (SEQ ID NOs: 80 and 86); a CDR-L3 sequence comprising the amino acid sequence of LQYDNLLWT (SEQ ID NOs: 81 and 87);
    • (c) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTDYN (SEQ ID NOs: 76 and 82); a CDR-H2 sequence comprising the amino acid sequence of INPNNGGT (SEQ ID NOs: 77 and 83); a CDR-H3 sequence comprising the amino acid sequence of ARERDYDGSMDF (SEQ ID NO: 84); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDINKF (SEQ ID NOs: 79 and 85); a CDR-L2 sequence comprising the amino acid sequence of YTS (SEQ ID NOs: 80 and 86); a CDR-L3 sequence comprising the amino acid sequence of LQYDNLLWT (SEQ ID NOs: 81 and 87);
    • (d) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTVTDYY (SEQ ID NO: 88); a CDR-H2 sequence comprising the amino acid sequence of INPNNGVT (SEQ ID NO: 89); a CDR-H3 sequence comprising the amino acid sequence of AREEDFDGFDY (SEQ ID NO: 90); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDVSTG (SEQ ID NO: 91); a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104); a CDR-L3 sequence comprising the amino acid sequence of QQHYSTPLT (SEQ ID NO: 93);
    • (e) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GSTFSDFE (SEQ ID NO: 94); a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NOs: 71, 95, and 101); a CDR-H3 sequence comprising the amino acid sequence of TRNYDGYSQTX17DY (SEQ ID NO: 308), wherein X17 comprises M or F; and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVLYSX18NQKNY (SEQ ID NO: 309), wherein X18 comprises S or D; a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104); a CDR-L3 sequence comprising the amino acid sequence of or HQYLSSYT (SEQ ID NOs: 99 and 105); or
    • (f) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GSTFTDFE (SEQ ID NO: 100); a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NOs: 71, 95, and 101); a CDR-H3 sequence comprising the amino acid sequence of TRNYDGYSQTX17DY (SEQ ID NO: 308), wherein X17 comprises M or F; and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVLYSX18NQKNY (SEQ ID NO: 309), wherein X18 comprises S or D; a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104); a CDR-L3 sequence comprising the amino acid sequence of HQYLSSYT (SEQ ID NOs: 99 and 105).

In certain embodiments, the antigen binding protein or fragment thereof comprises a VH domain and a VL domain, wherein:

    • (a) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GDTFTDFE (SEQ ID NO: 70), GDTFTDYE (SEQ ID NO: 295), or GYTFTDFE (SEQ ID NO: 296); a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NOs: 71, 95, and 101), VDPETGGT (SEQ ID NO: 297), IDPETGST (SEQ ID NO: 298), or VEPETGGT (SEQ ID NO: 299); a CDR-H3 sequence comprising the amino acid sequence of TRTYDGYPYAMDY (SEQ ID NO: 72), TRTYEGYPYAMDY (SEQ ID NO: 300), or TRTYDGYPYAFDY (SEQ ID NO: 301); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSLLYSNNQKNY (SEQ ID NO: 73), QSVLYSNNNKNY (SEQ ID NO: 302), or QSVLYSDNQKNY (SEQ ID NO: 306); a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104), YAS (SEQ ID NO: 303), or FAS (SEQ ID NO: 304); a CDR-L3 sequence comprising the amino acid sequence of QQYYSYRT (SEQ ID NO: 75);
    • (b) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTDYN (SEQ ID NOs: 76 and 82); a CDR-H2 sequence comprising the amino acid sequence of INPNNGGT (SEQ ID NOs: 77 and 83); a CDR-H3 sequence comprising the amino acid sequence of ARERDYDGAMDY (SEQ ID NO: 78); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDINKF (SEQ ID NOs: 79 and 85); a CDR-L2 sequence comprising the amino acid sequence of YTS (SEQ ID NOs: 80 and 86); a CDR-L3 sequence comprising the amino acid sequence of LQYDNLLWT (SEQ ID NOs: 81 and 87);
    • (c) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTDYN (SEQ ID NOs: 76 and 82); a CDR-H2 sequence comprising the amino acid sequence of INPNNGGT (SEQ ID NOs: 77 and 83); a CDR-H3 sequence comprising the amino acid sequence of ARERDYDGSMDF (SEQ ID NO: 84); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDINKF (SEQ ID NOs: 79 and 85); a CDR-L2 sequence comprising the amino acid sequence of YTS (SEQ ID NOs: 80 and 86); a CDR-L3 sequence comprising the amino acid sequence of LQYDNLLWT (SEQ ID NOs: 81 and 87);
    • (d) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GYTVTDYY (SEQ ID NO: 88); a CDR-H2 sequence comprising the amino acid sequence of INPNNGVT (SEQ ID NO: 89); a CDR-H3 sequence comprising the amino acid sequence of AREEDFDGFDY (SEQ ID NO: 90); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QDVSTG (SEQ ID NO: 91); a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, 104); a CDR-L3 sequence comprising the amino acid sequence of QQHYSTPLT (SEQ ID NO: 93);
    • (e) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GSTFSDFE (SEQ ID NO: 94); a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NOs: 71, 95, and 101); a CDR-H3 sequence comprising the amino acid sequence of TRNYDGYSQTMDY (SEQ ID NO: 96) or TRNYDGYSQTFDY (SEQ ID NO: 305); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVLYSSNQKNY(SEQ ID NOs: 97 and 103) or QSVLYSDNQKNY (SEQ ID NO: 306); a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104); a CDR-L3 sequence comprising the amino acid sequence of or HQYLSSYT (SEQ ID NOs: 99 and 105); or
    • (f) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GSTFTDFE (SEQ ID NO: 100); a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NOs: 71, 95, and 101); a CDR-H3 sequence comprising the amino acid sequence of TRNYDGYSRTMDY (SEQ ID NO: 102) or TRNYDGYSRTFDY (SEQ ID NO: 307); and the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVLYSSNQKNY(SEQ ID NOs: 97 and 103) or QSVLYSDNQKNY (SEQ ID NO: 306); a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, 104); a CDR-L3 sequence comprising the amino acid sequence of or HQYLSSYT (SEQ ID NOs: 99 and 105).

In certain embodiments, the FGFR3 antigen binding proteins and antigen-binding fragments thereof comprise one VH domain and one VL domain recited in Table 3, 8, 9, or 13. In certain embodiments, exemplary antigen-binding proteins or antigen-binding fragments thereof are provided:

TABLE 1.1 Heavy chains and light chains of exemplary antigen-binding proteins or antigen-binding fragments No. Heavy Chain Light Chain 1 SEQ ID NO: 6 SEQ ID NO: 7 2 SEQ ID NO: 6 SEQ ID NO: 9 3 SEQ ID NO: 6 SEQ ID NO: 11 4 SEQ ID NO: 6 SEQ ID NO: 13 5 SEQ ID NO: 6 SEQ ID NO: 15 6 SEQ ID NO: 6 SEQ ID NO: 17 7 SEQ ID NO: 8 SEQ ID NO: 7 8 SEQ ID NO: 8 SEQ ID NO: 9 9 SEQ ID NO: 8 SEQ ID NO: 11 10 SEQ ID NO: 8 SEQ ID NO: 13 11 SEQ ID NO: 8 SEQ ID NO: 15 12 SEQ ID NO: 8 SEQ ID NO: 17 13 SEQ ID NO: 10 SEQ ID NO: 7 14 SEQ ID NO: 10 SEQ ID NO: 9 15 SEQ ID NO: 10 SEQ ID NO: 11 16 SEQ ID NO: 10 SEQ ID NO: 13 17 SEQ ID NO: 10 SEQ ID NO: 15 18 SEQ ID NO: 10 SEQ ID NO: 17 19 SEQ ID NO: 12 SEQ ID NO: 7 20 SEQ ID NO: 12 SEQ ID NO: 9 21 SEQ ID NO: 12 SEQ ID NO: 11 22 SEQ ID NO: 12 SEQ ID NO: 13 23 SEQ ID NO: 12 SEQ ID NO: 15 24 SEQ ID NO: 12 SEQ ID NO: 17 25 SEQ ID NO: 14 SEQ ID NO: 7 26 SEQ ID NO: 14 SEQ ID NO: 9 27 SEQ ID NO: 14 SEQ ID NO: 11 28 SEQ ID NO: 14 SEQ ID NO: 13 29 SEQ ID NO: 14 SEQ ID NO: 15 30 SEQ ID NO: 14 SEQ ID NO: 17 31 SEQ ID NO: 18 SEQ ID NO: 19 32 SEQ ID NO: 18 SEQ ID NO: 24 33 SEQ ID NO: 18 SEQ ID NO: 25 34 SEQ ID NO: 18 SEQ ID NO: 26 35 SEQ ID NO: 18 SEQ ID NO: 27 36 SEQ ID NO: 18 SEQ ID NO: 32 37 SEQ ID NO: 18 SEQ ID NO: 33 38 SEQ ID NO: 18 SEQ ID NO: 34 39 SEQ ID NO: 18 SEQ ID NO: 35 40 SEQ ID NO: 18 SEQ ID NO: 59 41 SEQ ID NO: 18 SEQ ID NO: 60 42 SEQ ID NO: 18 SEQ ID NO: 61 43 SEQ ID NO: 18 SEQ ID NO: 67 44 SEQ ID NO: 18 SEQ ID NO: 69 45 SEQ ID NO: 18 SEQ ID NO: 112 46 SEQ ID NO: 18 SEQ ID NO: 113 47 SEQ ID NO: 18 SEQ ID NO: 114 48 SEQ ID NO: 18 SEQ ID NO: 123 49 SEQ ID NO: 18 SEQ ID NO: 124 50 SEQ ID NO: 18 SEQ ID NO: 125 51 SEQ ID NO: 18 SEQ ID NO: 126 52 SEQ ID NO: 18 SEQ ID NO: 127 53 SEQ ID NO: 18 SEQ ID NO: 128 54 SEQ ID NO: 18 SEQ ID NO: 129 55 SEQ ID NO: 18 SEQ ID NO: 130 56 SEQ ID NO: 18 SEQ ID NO: 131 57 SEQ ID NO: 18 SEQ ID NO: 132 58 SEQ ID NO: 20 SEQ ID NO: 19 59 SEQ ID NO: 20 SEQ ID NO: 24 60 SEQ ID NO: 20 SEQ ID NO: 25 61 SEQ ID NO: 20 SEQ ID NO: 26 62 SEQ ID NO: 20 SEQ ID NO: 27 63 SEQ ID NO: 20 SEQ ID NO: 32 64 SEQ ID NO: 20 SEQ ID NO: 33 65 SEQ ID NO: 20 SEQ ID NO: 34 66 SEQ ID NO: 20 SEQ ID NO: 35 67 SEQ ID NO: 20 SEQ ID NO: 59 68 SEQ ID NO: 20 SEQ ID NO: 60 69 SEQ ID NO: 20 SEQ ID NO: 61 70 SEQ ID NO: 20 SEQ ID NO: 67 71 SEQ ID NO: 20 SEQ ID NO: 69 72 SEQ ID NO: 20 SEQ ID NO: 112 73 SEQ ID NO: 20 SEQ ID NO: 113 74 SEQ ID NO: 20 SEQ ID NO: 114 75 SEQ ID NO: 20 SEQ ID NO: 123 76 SEQ ID NO: 20 SEQ ID NO: 124 77 SEQ ID NO: 20 SEQ ID NO: 125 78 SEQ ID NO: 20 SEQ ID NO: 126 79 SEQ ID NO: 20 SEQ ID NO: 127 80 SEQ ID NO: 20 SEQ ID NO: 128 81 SEQ ID NO: 20 SEQ ID NO: 129 82 SEQ ID NO: 20 SEQ ID NO: 130 83 SEQ ID NO: 20 SEQ ID NO: 131 84 SEQ ID NO: 20 SEQ ID NO: 132 85 SEQ ID NO: 21 SEQ ID NO: 19 86 SEQ ID NO: 21 SEQ ID NO: 24 87 SEQ ID NO: 21 SEQ ID NO: 25 88 SEQ ID NO: 21 SEQ ID NO: 26 89 SEQ ID NO: 21 SEQ ID NO: 27 90 SEQ ID NO: 21 SEQ ID NO: 32 91 SEQ ID NO: 21 SEQ ID NO: 33 92 SEQ ID NO: 21 SEQ ID NO: 34 93 SEQ ID NO: 21 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NO: 23 SEQ ID NO: 114 156 SEQ ID NO: 23 SEQ ID NO: 123 157 SEQ ID NO: 23 SEQ ID NO: 124 158 SEQ ID NO: 23 SEQ ID NO: 125 159 SEQ ID NO: 23 SEQ ID NO: 126 160 SEQ ID NO: 23 SEQ ID NO: 127 161 SEQ ID NO: 23 SEQ ID NO: 128 162 SEQ ID NO: 23 SEQ ID NO: 129 163 SEQ ID NO: 23 SEQ ID NO: 130 164 SEQ ID NO: 23 SEQ ID NO: 131 165 SEQ ID NO: 23 SEQ ID NO: 132 166 SEQ ID NO: 28 SEQ ID NO: 19 167 SEQ ID NO: 28 SEQ ID NO: 24 168 SEQ ID NO: 28 SEQ ID NO: 25 169 SEQ ID NO: 28 SEQ ID NO: 26 170 SEQ ID NO: 28 SEQ ID NO: 27 171 SEQ ID NO: 28 SEQ ID NO: 32 172 SEQ ID NO: 28 SEQ ID NO: 33 173 SEQ ID NO: 28 SEQ ID NO: 34 174 SEQ ID NO: 28 SEQ ID NO: 35 175 SEQ ID NO: 28 SEQ ID NO: 59 176 SEQ ID NO: 28 SEQ ID NO: 60 177 SEQ ID NO: 28 SEQ ID NO: 61 178 SEQ ID NO: 28 SEQ ID NO: 67 179 SEQ ID NO: 28 SEQ ID NO: 69 180 SEQ ID NO: 28 SEQ ID NO: 112 181 SEQ ID NO: 28 SEQ ID NO: 113 182 SEQ ID NO: 28 SEQ ID NO: 114 183 SEQ ID NO: 28 SEQ ID NO: 123 184 SEQ ID NO: 28 SEQ ID NO: 124 185 SEQ ID NO: 28 SEQ ID NO: 125 186 SEQ ID NO: 28 SEQ ID NO: 126 187 SEQ ID NO: 28 SEQ ID NO: 127 188 SEQ ID NO: 28 SEQ ID NO: 128 189 SEQ ID NO: 28 SEQ ID NO: 129 190 SEQ ID NO: 28 SEQ ID NO: 130 191 SEQ ID NO: 28 SEQ ID NO: 131 192 SEQ ID NO: 28 SEQ ID NO: 132 193 SEQ ID NO: 29 SEQ ID NO: 19 194 SEQ ID NO: 29 SEQ ID NO: 24 195 SEQ ID NO: 29 SEQ ID NO: 25 196 SEQ ID NO: 29 SEQ ID NO: 26 197 SEQ ID NO: 29 SEQ ID NO: 27 198 SEQ ID NO: 29 SEQ ID NO: 32 199 SEQ ID NO: 29 SEQ ID NO: 33 200 SEQ ID NO: 29 SEQ ID NO: 34 201 SEQ ID NO: 29 SEQ ID NO: 35 202 SEQ ID NO: 29 SEQ ID NO: 59 203 SEQ ID NO: 29 SEQ ID NO: 60 204 SEQ ID NO: 29 SEQ ID NO: 61 205 SEQ ID NO: 29 SEQ ID NO: 67 206 SEQ ID NO: 29 SEQ ID NO: 69 207 SEQ ID NO: 29 SEQ ID NO: 112 208 SEQ ID NO: 29 SEQ ID NO: 113 209 SEQ ID NO: 29 SEQ ID NO: 114 210 SEQ ID NO: 29 SEQ ID NO: 123 211 SEQ ID NO: 29 SEQ ID NO: 124 212 SEQ ID NO: 29 SEQ ID NO: 125 213 SEQ ID NO: 29 SEQ ID NO: 126 214 SEQ ID NO: 29 SEQ ID NO: 127 215 SEQ ID NO: 29 SEQ ID NO: 128 216 SEQ ID NO: 29 SEQ ID NO: 129 217 SEQ ID NO: 29 SEQ ID NO: 130 218 SEQ ID NO: 29 SEQ ID NO: 131 219 SEQ ID NO: 29 SEQ ID NO: 132 220 SEQ ID NO: 30 SEQ ID NO: 19 221 SEQ ID NO: 30 SEQ ID NO: 24 222 SEQ ID NO: 30 SEQ ID NO: 25 223 SEQ ID NO: 30 SEQ ID NO: 26 224 SEQ ID NO: 30 SEQ ID NO: 27 225 SEQ ID NO: 30 SEQ ID NO: 32 226 SEQ ID NO: 30 SEQ ID NO: 33 227 SEQ ID NO: 30 SEQ ID NO: 34 228 SEQ ID NO: 30 SEQ ID NO: 35 229 SEQ ID NO: 30 SEQ ID NO: 59 230 SEQ ID NO: 30 SEQ ID NO: 60 231 SEQ ID NO: 30 SEQ ID NO: 61 232 SEQ ID NO: 30 SEQ ID NO: 67 233 SEQ ID NO: 30 SEQ ID NO: 69 234 SEQ ID NO: 30 SEQ ID NO: 112 235 SEQ ID NO: 30 SEQ ID NO: 113 236 SEQ ID NO: 30 SEQ ID NO: 114 237 SEQ ID NO: 30 SEQ ID NO: 123 238 SEQ ID NO: 30 SEQ ID NO: 124 239 SEQ ID NO: 30 SEQ ID NO: 125 240 SEQ ID NO: 30 SEQ ID NO: 126 241 SEQ ID NO: 30 SEQ ID NO: 127 242 SEQ ID NO: 30 SEQ ID NO: 128 243 SEQ ID NO: 30 SEQ ID NO: 129 244 SEQ ID NO: 30 SEQ ID NO: 130 245 SEQ ID NO: 30 SEQ ID NO: 131 246 SEQ ID NO: 30 SEQ ID NO: 132 247 SEQ ID NO: 31 SEQ ID NO: 19 248 SEQ ID NO: 31 SEQ ID NO: 24 249 SEQ ID NO: 31 SEQ ID NO: 25 250 SEQ ID NO: 31 SEQ ID NO: 26 251 SEQ ID NO: 31 SEQ ID NO: 27 252 SEQ ID NO: 31 SEQ ID NO: 32 253 SEQ ID NO: 31 SEQ ID NO: 33 254 SEQ ID NO: 31 SEQ ID NO: 34 255 SEQ ID NO: 31 SEQ ID NO: 35 256 SEQ ID NO: 31 SEQ ID NO: 59 257 SEQ ID NO: 31 SEQ ID NO: 60 258 SEQ ID NO: 31 SEQ ID NO: 61 259 SEQ ID NO: 31 SEQ ID NO: 67 260 SEQ ID NO: 31 SEQ ID NO: 69 261 SEQ ID NO: 31 SEQ ID NO: 112 262 SEQ ID NO: 31 SEQ ID NO: 113 263 SEQ ID NO: 31 SEQ ID NO: 114 264 SEQ ID NO: 31 SEQ ID NO: 123 265 SEQ ID NO: 31 SEQ ID NO: 124 266 SEQ ID NO: 31 SEQ ID NO: 125 267 SEQ ID NO: 31 SEQ ID NO: 126 268 SEQ ID NO: 31 SEQ ID NO: 127 269 SEQ ID NO: 31 SEQ ID NO: 128 270 SEQ ID NO: 31 SEQ ID NO: 129 271 SEQ ID NO: 31 SEQ ID NO: 130 272 SEQ ID NO: 31 SEQ ID NO: 131 273 SEQ ID NO: 31 SEQ ID NO: 132 274 SEQ ID NO: 56 SEQ ID NO: 19 275 SEQ ID NO: 56 SEQ ID NO: 24 276 SEQ ID NO: 56 SEQ ID NO: 25 277 SEQ ID NO: 56 SEQ ID NO: 26 278 SEQ ID NO: 56 SEQ ID NO: 27 279 SEQ ID NO: 56 SEQ ID NO: 32 280 SEQ ID NO: 56 SEQ ID NO: 33 281 SEQ ID NO: 56 SEQ ID NO: 34 282 SEQ ID NO: 56 SEQ ID NO: 35 283 SEQ ID NO: 56 SEQ ID NO: 59 284 SEQ ID NO: 56 SEQ ID NO: 60 285 SEQ ID NO: 56 SEQ ID NO: 61 286 SEQ ID NO: 56 SEQ ID NO: 67 287 SEQ ID NO: 56 SEQ ID NO: 69 288 SEQ ID NO: 56 SEQ ID NO: 112 289 SEQ ID NO: 56 SEQ ID NO: 113 290 SEQ ID NO: 56 SEQ ID NO: 114 291 SEQ ID NO: 56 SEQ ID NO: 123 292 SEQ ID NO: 56 SEQ ID NO: 124 293 SEQ ID NO: 56 SEQ ID NO: 125 294 SEQ ID NO: 56 SEQ ID NO: 126 295 SEQ ID NO: 56 SEQ ID NO: 127 296 SEQ ID NO: 56 SEQ ID NO: 128 297 SEQ ID NO: 56 SEQ ID NO: 129 298 SEQ ID NO: 56 SEQ ID NO: 130 299 SEQ ID NO: 56 SEQ ID NO: 131 300 SEQ ID NO: 56 SEQ ID NO: 132 301 SEQ ID NO: 57 SEQ ID NO: 19 302 SEQ ID NO: 57 SEQ ID NO: 24 303 SEQ ID NO: 57 SEQ ID NO: 25 304 SEQ ID NO: 57 SEQ ID NO: 26 305 SEQ ID NO: 57 SEQ ID NO: 27 306 SEQ ID NO: 57 SEQ ID NO: 32 307 SEQ ID NO: 57 SEQ ID NO: 33 308 SEQ ID NO: 57 SEQ ID NO: 34 309 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340 SEQ ID NO: 58 SEQ ID NO: 67 341 SEQ ID NO: 58 SEQ ID NO: 69 342 SEQ ID NO: 58 SEQ ID NO: 112 343 SEQ ID NO: 58 SEQ ID NO: 113 344 SEQ ID NO: 58 SEQ ID NO: 114 345 SEQ ID NO: 58 SEQ ID NO: 123 346 SEQ ID NO: 58 SEQ ID NO: 124 347 SEQ ID NO: 58 SEQ ID NO: 125 348 SEQ ID NO: 58 SEQ ID NO: 126 349 SEQ ID NO: 58 SEQ ID NO: 127 350 SEQ ID NO: 58 SEQ ID NO: 128 351 SEQ ID NO: 58 SEQ ID NO: 129 352 SEQ ID NO: 58 SEQ ID NO: 130 353 SEQ ID NO: 58 SEQ ID NO: 131 354 SEQ ID NO: 58 SEQ ID NO: 132 355 SEQ ID NO: 63 SEQ ID NO: 19 356 SEQ ID NO: 63 SEQ ID NO: 24 357 SEQ ID NO: 63 SEQ ID NO: 25 358 SEQ ID NO: 63 SEQ ID NO: 26 359 SEQ ID NO: 63 SEQ ID NO: 27 360 SEQ ID NO: 63 SEQ ID NO: 32 361 SEQ ID NO: 63 SEQ ID NO: 33 362 SEQ ID NO: 63 SEQ ID NO: 34 363 SEQ ID NO: 63 SEQ ID NO: 35 364 SEQ ID NO: 63 SEQ ID NO: 59 365 SEQ ID NO: 63 SEQ ID NO: 60 366 SEQ ID NO: 63 SEQ ID NO: 61 367 SEQ ID NO: 63 SEQ ID NO: 67 368 SEQ ID NO: 63 SEQ ID NO: 69 369 SEQ ID NO: 63 SEQ ID NO: 112 370 SEQ ID NO: 63 SEQ ID NO: 113 371 SEQ ID NO: 63 SEQ ID NO: 114 372 SEQ ID NO: 63 SEQ ID NO: 123 373 SEQ ID NO: 63 SEQ ID NO: 124 374 SEQ ID NO: 63 SEQ ID NO: 125 375 SEQ ID NO: 63 SEQ ID NO: 126 376 SEQ ID NO: 63 SEQ ID NO: 127 377 SEQ ID NO: 63 SEQ ID NO: 128 378 SEQ ID NO: 63 SEQ ID NO: 129 379 SEQ ID NO: 63 SEQ ID NO: 130 380 SEQ ID NO: 63 SEQ ID NO: 131 381 SEQ ID NO: 63 SEQ ID NO: 132 382 SEQ ID NO: 65 SEQ ID NO: 19 383 SEQ ID NO: 65 SEQ ID NO: 24 384 SEQ ID NO: 65 SEQ ID NO: 25 385 SEQ ID NO: 65 SEQ ID NO: 26 386 SEQ ID NO: 65 SEQ ID NO: 27 387 SEQ ID NO: 65 SEQ ID NO: 32 388 SEQ ID NO: 65 SEQ ID NO: 33 389 SEQ ID NO: 65 SEQ ID NO: 34 390 SEQ ID NO: 65 SEQ ID NO: 35 391 SEQ ID NO: 65 SEQ ID NO: 59 392 SEQ ID NO: 65 SEQ ID NO: 60 393 SEQ ID NO: 65 SEQ ID NO: 61 394 SEQ ID NO: 65 SEQ ID NO: 67 395 SEQ ID NO: 65 SEQ ID NO: 69 396 SEQ ID NO: 65 SEQ ID NO: 112 397 SEQ ID NO: 65 SEQ ID NO: 113 398 SEQ ID NO: 65 SEQ ID NO: 114 399 SEQ ID NO: 65 SEQ ID NO: 123 400 SEQ ID NO: 65 SEQ ID NO: 124 401 SEQ ID NO: 65 SEQ ID NO: 125 402 SEQ ID NO: 65 SEQ ID NO: 126 403 SEQ ID NO: 65 SEQ ID NO: 127 404 SEQ ID NO: 65 SEQ ID NO: 128 405 SEQ ID NO: 65 SEQ ID NO: 129 406 SEQ ID NO: 65 SEQ ID NO: 130 407 SEQ ID NO: 65 SEQ ID NO: 131 408 SEQ ID NO: 65 SEQ ID NO: 132 409 SEQ ID NO: 106 SEQ ID NO: 19 410 SEQ ID NO: 106 SEQ ID NO: 24 411 SEQ ID NO: 106 SEQ ID NO: 25 412 SEQ ID NO: 106 SEQ ID NO: 26 413 SEQ ID NO: 106 SEQ ID NO: 27 414 SEQ ID NO: 106 SEQ ID NO: 32 415 SEQ ID NO: 106 SEQ ID NO: 33 416 SEQ ID NO: 106 SEQ ID NO: 34 417 SEQ ID NO: 106 SEQ ID NO: 35 418 SEQ ID NO: 106 SEQ ID NO: 59 419 SEQ ID NO: 106 SEQ ID NO: 60 420 SEQ ID NO: 106 SEQ ID NO: 61 421 SEQ ID NO: 106 SEQ ID NO: 67 422 SEQ ID NO: 106 SEQ ID NO: 69 423 SEQ ID NO: 106 SEQ ID NO: 112 424 SEQ ID NO: 106 SEQ ID NO: 113 425 SEQ ID NO: 106 SEQ ID NO: 114 426 SEQ ID NO: 106 SEQ ID NO: 123 427 SEQ ID NO: 106 SEQ ID NO: 124 428 SEQ ID NO: 106 SEQ ID NO: 125 429 SEQ ID NO: 106 SEQ ID NO: 126 430 SEQ ID NO: 106 SEQ ID NO: 127 431 SEQ ID NO: 106 SEQ ID NO: 128 432 SEQ ID NO: 106 SEQ ID NO: 129 433 SEQ ID NO: 106 SEQ ID NO: 130 434 SEQ ID NO: 106 SEQ ID NO: 131 435 SEQ ID NO: 106 SEQ ID NO: 132 436 SEQ ID NO: 107 SEQ ID NO: 19 437 SEQ ID NO: 107 SEQ ID NO: 24 438 SEQ ID NO: 107 SEQ ID NO: 25 439 SEQ ID NO: 107 SEQ ID NO: 26 440 SEQ ID NO: 107 SEQ ID NO: 27 441 SEQ ID NO: 107 SEQ ID NO: 32 442 SEQ ID NO: 107 SEQ ID NO: 33 443 SEQ ID NO: 107 SEQ ID NO: 34 444 SEQ ID NO: 107 SEQ ID NO: 35 445 SEQ ID NO: 107 SEQ ID NO: 59 446 SEQ ID NO: 107 SEQ ID NO: 60 447 SEQ ID NO: 107 SEQ ID NO: 61 448 SEQ ID NO: 107 SEQ ID NO: 67 449 SEQ ID NO: 107 SEQ ID NO: 69 450 SEQ ID NO: 107 SEQ ID NO: 112 451 SEQ ID NO: 107 SEQ ID NO: 113 452 SEQ ID NO: 107 SEQ ID NO: 114 453 SEQ ID NO: 107 SEQ ID NO: 123 454 SEQ ID NO: 107 SEQ ID NO: 124 455 SEQ ID NO: 107 SEQ ID NO: 125 456 SEQ ID NO: 107 SEQ ID NO: 126 457 SEQ ID NO: 107 SEQ ID NO: 127 458 SEQ ID NO: 107 SEQ ID NO: 128 459 SEQ ID NO: 107 SEQ ID NO: 129 460 SEQ ID NO: 107 SEQ ID NO: 130 461 SEQ ID NO: 107 SEQ ID NO: 131 462 SEQ ID NO: 107 SEQ ID NO: 132 463 SEQ ID NO: 108 SEQ ID NO: 19 464 SEQ ID NO: 108 SEQ ID NO: 24 465 SEQ ID NO: 108 SEQ ID NO: 25 466 SEQ ID NO: 108 SEQ ID NO: 26 467 SEQ ID NO: 108 SEQ ID NO: 27 468 SEQ ID NO: 108 SEQ ID NO: 32 469 SEQ ID NO: 108 SEQ ID NO: 33 470 SEQ ID NO: 108 SEQ ID NO: 34 471 SEQ ID NO: 108 SEQ ID NO: 35 472 SEQ ID NO: 108 SEQ ID NO: 59 473 SEQ ID NO: 108 SEQ ID NO: 60 474 SEQ ID NO: 108 SEQ ID NO: 61 475 SEQ ID NO: 108 SEQ ID NO: 67 476 SEQ ID NO: 108 SEQ ID NO: 69 477 SEQ ID NO: 108 SEQ ID NO: 112 478 SEQ ID NO: 108 SEQ ID NO: 113 479 SEQ ID NO: 108 SEQ ID NO: 114 480 SEQ ID NO: 108 SEQ ID NO: 123 481 SEQ ID NO: 108 SEQ ID NO: 124 482 SEQ ID NO: 108 SEQ ID NO: 125 483 SEQ ID NO: 108 SEQ ID NO: 126 484 SEQ ID NO: 108 SEQ ID NO: 127 485 SEQ ID NO: 108 SEQ ID NO: 128 486 SEQ ID NO: 108 SEQ ID NO: 129 487 SEQ ID NO: 108 SEQ ID NO: 130 488 SEQ ID NO: 108 SEQ ID NO: 131 489 SEQ ID NO: 108 SEQ ID NO: 132 490 SEQ ID NO: 109 SEQ ID NO: 19 491 SEQ ID NO: 109 SEQ ID NO: 24 492 SEQ ID NO: 109 SEQ ID NO: 25 493 SEQ ID NO: 109 SEQ ID NO: 26 494 SEQ ID NO: 109 SEQ ID NO: 27 495 SEQ ID NO: 109 SEQ ID NO: 32 496 SEQ ID NO: 109 SEQ ID NO: 33 497 SEQ ID NO: 109 SEQ ID NO: 34 498 SEQ ID NO: 109 SEQ ID NO: 35 499 SEQ ID NO: 109 SEQ ID NO: 59 500 SEQ ID NO: 109 SEQ ID NO: 60 501 SEQ ID NO: 109 SEQ ID NO: 61 502 SEQ ID NO: 109 SEQ ID NO: 67 503 SEQ ID NO: 109 SEQ ID NO: 69 504 SEQ ID NO: 109 SEQ ID NO: 112 505 SEQ ID NO: 109 SEQ ID NO: 113 506 SEQ ID NO: 109 SEQ ID NO: 114 507 SEQ ID NO: 109 SEQ ID NO: 123 508 SEQ ID NO: 109 SEQ ID NO: 124 509 SEQ ID NO: 109 SEQ ID NO: 125 510 SEQ ID NO: 109 SEQ ID NO: 126 511 SEQ ID NO: 109 SEQ ID NO: 127 512 SEQ ID NO: 109 SEQ ID NO: 128 513 SEQ ID NO: 109 SEQ ID NO: 129 514 SEQ ID NO: 109 SEQ ID NO: 130 515 SEQ ID NO: 109 SEQ ID NO: 131 516 SEQ ID NO: 109 SEQ ID NO: 132 517 SEQ ID NO: 110 SEQ ID NO: 19 518 SEQ ID NO: 110 SEQ ID NO: 24 519 SEQ ID NO: 110 SEQ ID NO: 25 520 SEQ ID NO: 110 SEQ ID NO: 26 521 SEQ ID NO: 110 SEQ ID NO: 27 522 SEQ ID NO: 110 SEQ ID NO: 32 523 SEQ ID NO: 110 SEQ ID NO: 33 524 SEQ ID NO: 110 SEQ ID NO: 34 525 SEQ ID NO: 110 SEQ ID NO: 35 526 SEQ ID NO: 110 SEQ ID NO: 59 527 SEQ ID NO: 110 SEQ ID NO: 60 528 SEQ ID NO: 110 SEQ ID NO: 61 529 SEQ ID NO: 110 SEQ ID NO: 67 530 SEQ ID NO: 110 SEQ ID NO: 69 531 SEQ ID NO: 110 SEQ ID NO: 112 532 SEQ ID NO: 110 SEQ ID NO: 113 533 SEQ ID NO: 110 SEQ ID NO: 114 534 SEQ ID NO: 110 SEQ ID NO: 123 535 SEQ ID NO: 110 SEQ ID NO: 124 536 SEQ ID NO: 110 SEQ ID NO: 125 537 SEQ ID NO: 110 SEQ ID NO: 126 538 SEQ ID NO: 110 SEQ ID NO: 127 539 SEQ ID NO: 110 SEQ ID NO: 128 540 SEQ ID NO: 110 SEQ ID NO: 129 541 SEQ ID NO: 110 SEQ ID NO: 130 542 SEQ ID NO: 110 SEQ ID NO: 131 543 SEQ ID NO: 111 SEQ ID NO: 132 544 SEQ ID NO: 111 SEQ ID NO: 19 545 SEQ ID NO: 111 SEQ ID NO: 24 546 SEQ ID NO: 111 SEQ ID NO: 25 547 SEQ ID NO: 111 SEQ ID NO: 26 548 SEQ ID NO: 111 SEQ ID NO: 27 549 SEQ ID NO: 111 SEQ ID NO: 32 550 SEQ ID NO: 111 SEQ ID NO: 33 551 SEQ ID NO: 111 SEQ ID NO: 34 552 SEQ ID NO: 111 SEQ ID NO: 35 553 SEQ ID NO: 111 SEQ ID NO: 59 554 SEQ ID NO: 111 SEQ ID NO: 60 555 SEQ ID NO: 111 SEQ ID NO: 61 556 SEQ ID NO: 111 SEQ ID NO: 67 557 SEQ ID NO: 111 SEQ ID NO: 69 558 SEQ ID NO: 111 SEQ ID NO: 112 559 SEQ ID NO: 111 SEQ ID NO: 113 560 SEQ ID NO: 111 SEQ ID NO: 114 561 SEQ ID NO: 111 SEQ ID NO: 123 562 SEQ ID NO: 111 SEQ ID NO: 124 563 SEQ ID NO: 111 SEQ ID NO: 125 564 SEQ ID NO: 111 SEQ ID NO: 126 565 SEQ ID NO: 111 SEQ ID NO: 127 566 SEQ ID NO: 111 SEQ ID NO: 128 567 SEQ ID NO: 111 SEQ ID NO: 129 568 SEQ ID NO: 111 SEQ ID NO: 130 569 SEQ ID NO: 111 SEQ ID NO: 131 570 SEQ ID NO: 111 SEQ ID NO: 132 571 SEQ ID NO: 115 SEQ ID NO: 19 572 SEQ ID NO: 115 SEQ ID NO: 24 573 SEQ ID NO: 115 SEQ ID NO: 25 574 SEQ ID NO: 115 SEQ ID NO: 26 575 SEQ ID NO: 115 SEQ ID NO: 27 576 SEQ ID NO: 115 SEQ ID NO: 32 577 SEQ ID NO: 115 SEQ ID NO: 33 578 SEQ ID NO: 115 SEQ ID NO: 34 579 SEQ ID NO: 115 SEQ ID NO: 35 580 SEQ ID NO: 115 SEQ ID NO: 59 581 SEQ ID NO: 115 SEQ ID NO: 60 582 SEQ ID NO: 115 SEQ ID NO: 61 583 SEQ ID NO: 115 SEQ ID NO: 67 584 SEQ ID NO: 115 SEQ ID NO: 69 585 SEQ ID NO: 115 SEQ ID NO: 112 586 SEQ ID NO: 115 SEQ ID NO: 113 587 SEQ ID NO: 115 SEQ ID NO: 114 588 SEQ ID NO: 115 SEQ ID NO: 123 589 SEQ ID NO: 115 SEQ ID NO: 124 590 SEQ ID NO: 115 SEQ ID NO: 125 591 SEQ ID NO: 115 SEQ ID NO: 126 592 SEQ ID NO: 115 SEQ ID NO: 127 593 SEQ ID NO: 115 SEQ ID NO: 128 594 SEQ ID NO: 115 SEQ ID NO: 129 595 SEQ ID NO: 115 SEQ ID NO: 130 596 SEQ ID NO: 115 SEQ ID NO: 131 597 SEQ ID NO: 115 SEQ ID NO: 132 598 SEQ ID NO: 116 SEQ ID NO: 19 599 SEQ ID NO: 116 SEQ ID NO: 24 600 SEQ ID NO: 116 SEQ ID NO: 25 601 SEQ ID NO: 116 SEQ ID NO: 26 602 SEQ ID NO: 116 SEQ ID NO: 27 603 SEQ ID NO: 116 SEQ ID NO: 32 604 SEQ ID NO: 116 SEQ ID NO: 33 605 SEQ ID NO: 116 SEQ ID NO: 34 606 SEQ ID NO: 116 SEQ ID NO: 35 607 SEQ ID NO: 116 SEQ ID NO: 59 608 SEQ ID NO: 116 SEQ ID NO: 60 609 SEQ ID NO: 116 SEQ ID NO: 61 610 SEQ ID NO: 116 SEQ ID NO: 67 611 SEQ ID NO: 116 SEQ ID NO: 69 612 SEQ ID NO: 116 SEQ ID NO: 112 613 SEQ ID NO: 116 SEQ ID NO: 113 614 SEQ ID NO: 116 SEQ ID NO: 114 615 SEQ ID NO: 116 SEQ ID NO: 123 616 SEQ ID NO: 116 SEQ ID NO: 124 617 SEQ ID NO: 116 SEQ ID NO: 125 618 SEQ ID NO: 116 SEQ ID NO: 126 619 SEQ ID NO: 116 SEQ ID NO: 127 620 SEQ ID NO: 116 SEQ ID NO: 128 621 SEQ ID NO: 116 SEQ ID NO: 129 622 SEQ ID NO: 116 SEQ ID NO: 130 623 SEQ ID NO: 116 SEQ ID NO: 131 624 SEQ ID NO: 116 SEQ ID NO: 132 625 SEQ ID NO: 117 SEQ ID NO: 19 626 SEQ ID NO: 117 SEQ ID NO: 24 627 SEQ ID NO: 117 SEQ ID NO: 25 628 SEQ ID NO: 117 SEQ ID NO: 26 629 SEQ ID NO: 117 SEQ ID NO: 27 630 SEQ ID NO: 117 SEQ ID NO: 32 631 SEQ ID NO: 117 SEQ ID NO: 33 632 SEQ ID NO: 117 SEQ ID NO: 34 633 SEQ ID NO: 117 SEQ ID NO: 35 634 SEQ ID NO: 117 SEQ ID NO: 59 635 SEQ ID NO: 117 SEQ ID NO: 60 636 SEQ ID NO: 117 SEQ ID NO: 61 637 SEQ ID NO: 117 SEQ ID NO: 67 638 SEQ ID NO: 117 SEQ ID NO: 69 639 SEQ ID NO: 117 SEQ ID NO: 112 640 SEQ ID NO: 117 SEQ ID NO: 113 641 SEQ ID NO: 117 SEQ ID NO: 114 642 SEQ ID NO: 117 SEQ ID NO: 123 643 SEQ ID NO: 117 SEQ ID NO: 124 644 SEQ ID NO: 117 SEQ ID NO: 125 645 SEQ ID NO: 117 SEQ ID NO: 126 646 SEQ ID NO: 117 SEQ ID NO: 127 647 SEQ ID NO: 117 SEQ ID NO: 128 648 SEQ ID NO: 117 SEQ ID NO: 129 649 SEQ ID NO: 117 SEQ ID NO: 130 650 SEQ ID NO: 117 SEQ ID NO: 131 651 SEQ ID NO: 117 SEQ ID NO: 132 652 SEQ ID NO: 118 SEQ ID NO: 19 653 SEQ ID NO: 118 SEQ ID NO: 24 654 SEQ ID NO: 118 SEQ ID NO: 25 655 SEQ ID NO: 118 SEQ ID NO: 26 656 SEQ ID NO: 118 SEQ ID NO: 27 657 SEQ ID NO: 118 SEQ ID NO: 32 658 SEQ ID NO: 118 SEQ ID NO: 33 659 SEQ ID NO: 118 SEQ ID NO: 34 660 SEQ ID NO: 118 SEQ ID NO: 35 661 SEQ ID NO: 118 SEQ ID NO: 59 662 SEQ ID NO: 118 SEQ ID NO: 60 663 SEQ ID NO: 118 SEQ ID NO: 61 664 SEQ ID NO: 118 SEQ ID NO: 67 665 SEQ ID NO: 118 SEQ ID NO: 69 666 SEQ ID NO: 118 SEQ ID NO: 112 667 SEQ ID NO: 118 SEQ ID NO: 113 668 SEQ ID NO: 118 SEQ ID NO: 114 669 SEQ ID NO: 118 SEQ ID NO: 123 670 SEQ ID 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SEQ ID NO: 119 SEQ ID NO: 127 701 SEQ ID NO: 119 SEQ ID NO: 128 702 SEQ ID NO: 119 SEQ ID NO: 129 703 SEQ ID NO: 119 SEQ ID NO: 130 704 SEQ ID NO: 119 SEQ ID NO: 131 705 SEQ ID NO: 119 SEQ ID NO: 132 706 SEQ ID NO: 120 SEQ ID NO: 19 707 SEQ ID NO: 120 SEQ ID NO: 24 708 SEQ ID NO: 120 SEQ ID NO: 25 709 SEQ ID NO: 120 SEQ ID NO: 26 710 SEQ ID NO: 120 SEQ ID NO: 27 711 SEQ ID NO: 120 SEQ ID NO: 32 712 SEQ ID NO: 120 SEQ ID NO: 33 713 SEQ ID NO: 120 SEQ ID NO: 34 714 SEQ ID NO: 120 SEQ ID NO: 35 715 SEQ ID NO: 120 SEQ ID NO: 59 716 SEQ ID NO: 120 SEQ ID NO: 60 717 SEQ ID NO: 120 SEQ ID NO: 61 718 SEQ ID NO: 120 SEQ ID NO: 67 719 SEQ ID NO: 120 SEQ ID NO: 69 720 SEQ ID NO: 120 SEQ ID NO: 112 721 SEQ ID NO: 120 SEQ ID NO: 113 722 SEQ ID NO: 120 SEQ ID NO: 114 723 SEQ ID NO: 120 SEQ ID NO: 123 724 SEQ ID NO: 120 SEQ ID NO: 124 725 SEQ ID NO: 120 SEQ ID NO: 125 726 SEQ ID NO: 120 SEQ ID NO: 126 727 SEQ ID NO: 120 SEQ ID NO: 127 728 SEQ ID NO: 120 SEQ ID NO: 128 729 SEQ ID NO: 120 SEQ ID NO: 129 730 SEQ ID NO: 120 SEQ ID NO: 130 731 SEQ ID NO: 120 SEQ ID NO: 131 732 SEQ ID NO: 120 SEQ ID NO: 132 733 SEQ ID NO: 121 SEQ ID NO: 19 734 SEQ ID NO: 121 SEQ ID NO: 24 735 SEQ ID NO: 121 SEQ ID NO: 25 736 SEQ ID NO: 121 SEQ ID NO: 26 737 SEQ ID NO: 121 SEQ ID NO: 27 738 SEQ ID NO: 121 SEQ ID NO: 32 739 SEQ ID NO: 121 SEQ ID NO: 33 740 SEQ ID NO: 121 SEQ ID NO: 34 741 SEQ ID NO: 121 SEQ ID NO: 35 742 SEQ ID NO: 121 SEQ ID NO: 59 743 SEQ ID NO: 121 SEQ ID NO: 60 744 SEQ ID NO: 121 SEQ ID NO: 61 745 SEQ ID NO: 121 SEQ ID NO: 67 746 SEQ ID NO: 121 SEQ ID NO: 69 747 SEQ ID NO: 121 SEQ ID NO: 112 748 SEQ ID NO: 121 SEQ ID NO: 113 749 SEQ ID NO: 121 SEQ ID NO: 114 750 SEQ ID NO: 121 SEQ ID NO: 123 751 SEQ ID NO: 121 SEQ ID NO: 124 752 SEQ ID NO: 121 SEQ ID NO: 125 753 SEQ ID NO: 121 SEQ ID NO: 126 754 SEQ ID NO: 121 SEQ ID NO: 127 755 SEQ ID NO: 121 SEQ ID NO: 128 756 SEQ ID NO: 121 SEQ ID NO: 129 757 SEQ ID NO: 121 SEQ ID NO: 130 758 SEQ ID NO: 121 SEQ ID NO: 131 759 SEQ ID NO: 121 SEQ ID NO: 132 760 SEQ ID NO: 122 SEQ ID NO: 19 761 SEQ ID NO: 122 SEQ ID NO: 24 762 SEQ ID NO: 122 SEQ ID NO: 25 763 SEQ ID NO: 122 SEQ ID NO: 26 764 SEQ ID NO: 122 SEQ ID NO: 27 765 SEQ ID NO: 122 SEQ ID NO: 32 766 SEQ ID NO: 122 SEQ ID NO: 33 767 SEQ ID NO: 122 SEQ ID NO: 34 768 SEQ ID NO: 122 SEQ ID NO: 35 769 SEQ ID NO: 122 SEQ ID NO: 59 770 SEQ ID NO: 122 SEQ ID NO: 60 771 SEQ ID NO: 122 SEQ ID NO: 61 772 SEQ ID NO: 122 SEQ ID NO: 67 773 SEQ ID NO: 122 SEQ ID NO: 69 774 SEQ ID NO: 122 SEQ ID NO: 112 775 SEQ ID NO: 122 SEQ ID NO: 113 776 SEQ ID NO: 122 SEQ ID NO: 114 777 SEQ ID NO: 122 SEQ ID NO: 123 778 SEQ ID NO: 122 SEQ ID NO: 124 779 SEQ ID NO: 122 SEQ ID NO: 125 780 SEQ ID NO: 122 SEQ ID NO: 126 781 SEQ ID NO: 122 SEQ ID NO: 127 782 SEQ ID NO: 122 SEQ ID NO: 128 783 SEQ ID NO: 122 SEQ ID NO: 129 784 SEQ ID NO: 122 SEQ ID NO: 130 785 SEQ ID NO: 122 SEQ ID NO: 131 786 SEQ ID NO: 122 SEQ ID NO: 132 787 SEQ ID NO: 141 SEQ ID NO: 142 788 SEQ ID NO: 143 SEQ ID NO: 142 789 SEQ ID NO: 145 SEQ ID NO: 142 790 SEQ ID NO: 147 SEQ ID NO: 142 791 SEQ ID NO: 149 SEQ ID NO: 142 792 SEQ ID NO: 151 SEQ ID NO: 142 793 SEQ ID NO: 153 SEQ ID NO: 142 794 SEQ ID NO: 155 SEQ ID NO: 142 795 SEQ ID NO: 156 SEQ ID NO: 142 796 SEQ ID NO: 164 SEQ ID NO: 142 797 SEQ ID NO: 165 SEQ ID NO: 142 798 SEQ ID NO: 166 SEQ ID NO: 142 799 SEQ ID NO: 167 SEQ ID NO: 142 800 SEQ ID NO: 168 SEQ ID NO: 142 801 SEQ ID NO: 169 SEQ ID NO: 142 802 SEQ ID NO: 170 SEQ ID NO: 142 803 SEQ ID NO: 171 SEQ ID NO: 142 804 SEQ ID NO: 172 SEQ ID NO: 142 805 SEQ ID NO: 173 SEQ ID NO: 142 806 SEQ ID NO: 174 SEQ ID NO: 142 807 SEQ ID NO: 175 SEQ ID NO: 142 808 SEQ ID NO: 176 SEQ ID NO: 142 809 SEQ ID NO: 177 SEQ ID NO: 142 810 SEQ ID NO: 178 SEQ ID NO: 142 811 SEQ ID NO: 179 SEQ ID NO: 142 812 SEQ ID NO: 180 SEQ ID NO: 142 813 SEQ ID NO: 181 SEQ ID NO: 142 814 SEQ ID NO: 182 SEQ ID NO: 142 815 SEQ ID NO: 183 SEQ ID NO: 142 816 SEQ ID NO: 184 SEQ ID NO: 142 817 SEQ ID NO: 185 SEQ ID NO: 142 818 SEQ ID NO: 186 SEQ ID NO: 142 819 SEQ ID NO: 187 SEQ ID NO: 142 820 SEQ ID NO: 188 SEQ ID NO: 142 821 SEQ ID NO: 189 SEQ ID NO: 142 822 SEQ ID NO: 190 SEQ ID NO: 142 823 SEQ ID NO: 191 SEQ ID NO: 142 824 SEQ ID NO: 192 SEQ ID NO: 142 825 SEQ ID NO: 193 SEQ ID NO: 142 826 SEQ ID NO: 194 SEQ ID NO: 142 827 SEQ ID NO: 195 SEQ ID NO: 142 828 SEQ ID NO: 196 SEQ ID NO: 142 829 SEQ ID NO: 197 SEQ ID NO: 142 830 SEQ ID NO: 198 SEQ ID NO: 142 831 SEQ ID NO: 199 SEQ ID NO: 142 832 SEQ ID NO: 200 SEQ ID NO: 142 833 SEQ ID NO: 201 SEQ ID NO: 142 834 SEQ ID NO: 202 SEQ ID NO: 142 835 SEQ ID NO: 203 SEQ ID NO: 142 836 SEQ ID NO: 204 SEQ ID NO: 142 837 SEQ ID NO: 205 SEQ ID NO: 142 838 SEQ ID NO: 206 SEQ ID NO: 142 839 SEQ ID NO: 207 SEQ ID NO: 142 840 SEQ ID NO: 208 SEQ ID NO: 142 841 SEQ ID NO: 209 SEQ ID NO: 142 842 SEQ ID NO: 210 SEQ ID NO: 142 843 SEQ ID NO: 211 SEQ ID NO: 142 844 SEQ ID NO: 212 SEQ ID NO: 142 845 SEQ ID NO: 213 SEQ ID NO: 142 846 SEQ ID NO: 214 SEQ ID NO: 142 847 SEQ ID NO: 215 SEQ ID NO: 142 848 SEQ ID NO: 216 SEQ ID NO: 142 849 SEQ ID NO: 217 SEQ ID NO: 142 850 SEQ ID NO: 218 SEQ ID NO: 142 851 SEQ ID NO: 219 SEQ ID NO: 142 852 SEQ ID NO: 220 SEQ ID NO: 142 853 SEQ ID NO: 221 SEQ ID NO: 142 854 SEQ ID NO: 222 SEQ ID NO: 142 855 SEQ ID NO: 223 SEQ ID NO: 142 856 SEQ ID NO: 224 SEQ ID NO: 142 857 SEQ ID NO: 225 SEQ ID NO: 142 858 SEQ ID NO: 226 SEQ ID NO: 142 859 SEQ ID NO: 227 SEQ ID NO: 142 860 SEQ ID NO: 228 SEQ ID NO: 142 861 SEQ ID NO: 229 SEQ ID NO: 142 862 SEQ ID NO: 230 SEQ ID NO: 142 863 SEQ ID NO: 231 SEQ ID NO: 142 864 SEQ ID NO: 232 SEQ ID NO: 142 865 SEQ ID NO: 233 SEQ ID NO: 142 866 SEQ ID NO: 234 SEQ ID NO: 142 867 SEQ ID NO: 235 SEQ ID NO: 142 868 SEQ ID NO: 236 SEQ ID NO: 142 869 SEQ ID NO: 237 SEQ ID NO: 142 870 SEQ ID NO: 238 SEQ ID NO: 142 871 SEQ ID NO: 239 SEQ ID NO: 142 872 SEQ ID NO: 240 SEQ ID NO: 142 873 SEQ ID NO: 241 SEQ ID NO: 142 874 SEQ ID NO: 242 SEQ ID NO: 142 875 SEQ ID NO: 243 SEQ ID NO: 142 876 SEQ ID NO: 244 SEQ ID NO: 142 877 SEQ ID NO: 245 SEQ ID NO: 142 878 SEQ ID NO: 246 SEQ ID NO: 142 879 SEQ ID NO: 247 SEQ ID NO: 142 880 SEQ ID NO: 248 SEQ ID NO: 142 881 SEQ ID NO: 249 SEQ ID NO: 142 882 SEQ ID NO: 250 SEQ ID NO: 142 883 SEQ ID NO: 251 SEQ ID NO: 142 884 SEQ ID NO: 252 SEQ ID NO: 142 885 SEQ ID NO: 253 SEQ ID NO: 142 886 SEQ ID NO: 254 SEQ ID NO: 142 887 SEQ ID NO: 255 SEQ ID NO: 142 888 SEQ ID NO: 256 SEQ ID NO: 142 889 SEQ ID NO: 257 SEQ ID NO: 142 890 SEQ ID NO: 258 SEQ ID NO: 142 891 SEQ ID NO: 259 SEQ ID NO: 142 892 SEQ ID NO: 260 SEQ ID NO: 142 893 SEQ ID NO: 261 SEQ ID NO: 142 894 SEQ ID NO: 262 SEQ ID NO: 142 895 SEQ ID NO: 263 SEQ ID NO: 142 896 SEQ ID NO: 264 SEQ ID NO: 142 897 SEQ ID NO: 265 SEQ ID NO: 142 898 SEQ ID NO: 266 SEQ ID NO: 142 899 SEQ ID NO: 267 SEQ ID NO: 142 900 SEQ ID NO: 268 SEQ ID NO: 142 901 SEQ ID NO: 269 SEQ ID NO: 142 902 SEQ ID NO: 270 SEQ ID NO: 142 903 SEQ ID NO: 271 SEQ ID NO: 142 904 SEQ ID NO: 272 SEQ ID NO: 142 905 SEQ ID NO: 273 SEQ ID NO: 142 906 SEQ ID NO: 274 SEQ ID NO: 142 907 SEQ ID NO: 275 SEQ ID NO: 142 908 SEQ ID NO: 276 SEQ ID NO: 142 909 SEQ ID NO: 277 SEQ ID NO: 142 910 SEQ ID NO: 278 SEQ ID NO: 142 911 SEQ ID NO: 279 SEQ ID NO: 142 912 SEQ ID NO: 280 SEQ ID NO: 142 913 SEQ ID NO: 281 SEQ ID NO: 142 914 SEQ ID NO: 282 SEQ ID NO: 142 915 SEQ ID NO: 283 SEQ ID NO: 142 916 SEQ ID NO: 284 SEQ ID NO: 142 917 SEQ ID NO: 285 SEQ ID NO: 142 918 SEQ ID NO: 286 SEQ ID NO: 142 919 SEQ ID NO: 287 SEQ ID NO: 142 920 SEQ ID NO: 288 SEQ ID NO: 142 921 SEQ ID NO: 289 SEQ ID NO: 142 922 SEQ ID NO: 141 SEQ ID NO: 144 923 SEQ ID NO: 143 SEQ ID NO: 144 924 SEQ ID NO: 145 SEQ ID NO: 144 925 SEQ ID NO: 147 SEQ ID NO: 144 926 SEQ ID NO: 149 SEQ ID NO: 144 927 SEQ ID NO: 151 SEQ ID NO: 144 928 SEQ ID NO: 153 SEQ ID NO: 144 929 SEQ ID NO: 155 SEQ ID NO: 144 930 SEQ ID NO: 156 SEQ ID NO: 144 931 SEQ ID NO: 164 SEQ ID NO: 144 932 SEQ ID NO: 165 SEQ ID NO: 144 933 SEQ ID NO: 166 SEQ ID NO: 144 934 SEQ ID NO: 167 SEQ ID NO: 144 935 SEQ ID NO: 168 SEQ ID NO: 144 936 SEQ ID NO: 169 SEQ ID NO: 144 937 SEQ ID NO: 170 SEQ ID NO: 144 938 SEQ ID NO: 171 SEQ ID NO: 144 939 SEQ ID NO: 172 SEQ ID NO: 144 940 SEQ ID NO: 173 SEQ ID NO: 144 941 SEQ ID NO: 174 SEQ ID NO: 144 942 SEQ ID NO: 175 SEQ ID NO: 144 943 SEQ ID NO: 176 SEQ ID NO: 144 944 SEQ ID NO: 177 SEQ ID NO: 144 945 SEQ ID NO: 178 SEQ ID NO: 144 946 SEQ ID NO: 179 SEQ ID NO: 144 947 SEQ ID NO: 180 SEQ ID NO: 144 948 SEQ ID NO: 181 SEQ ID NO: 144 949 SEQ ID NO: 182 SEQ ID NO: 144 950 SEQ ID NO: 183 SEQ ID NO: 144 951 SEQ ID NO: 184 SEQ ID NO: 144 952 SEQ ID NO: 185 SEQ ID NO: 144 953 SEQ ID NO: 186 SEQ ID NO: 144 954 SEQ ID NO: 187 SEQ ID NO: 144 955 SEQ ID NO: 188 SEQ ID NO: 144 956 SEQ ID NO: 189 SEQ ID NO: 144 957 SEQ ID NO: 190 SEQ ID NO: 144 958 SEQ ID NO: 191 SEQ ID NO: 144 959 SEQ ID NO: 192 SEQ ID NO: 144 960 SEQ ID NO: 193 SEQ ID NO: 144 961 SEQ ID NO: 194 SEQ ID NO: 144 962 SEQ ID NO: 195 SEQ ID NO: 144 963 SEQ ID NO: 196 SEQ ID NO: 144 964 SEQ ID NO: 197 SEQ ID NO: 144 965 SEQ ID NO: 198 SEQ ID NO: 144 966 SEQ ID NO: 199 SEQ ID NO: 144 967 SEQ ID NO: 200 SEQ ID NO: 144 968 SEQ ID NO: 201 SEQ ID NO: 144 969 SEQ ID NO: 202 SEQ ID NO: 144 970 SEQ ID NO: 203 SEQ ID NO: 144 971 SEQ ID NO: 204 SEQ ID NO: 144 972 SEQ ID NO: 205 SEQ ID NO: 144 973 SEQ ID NO: 206 SEQ ID NO: 144 974 SEQ ID NO: 207 SEQ ID NO: 144 975 SEQ ID NO: 208 SEQ ID NO: 144 976 SEQ ID NO: 209 SEQ ID NO: 144 977 SEQ ID NO: 210 SEQ ID NO: 144 978 SEQ ID NO: 211 SEQ ID NO: 144 979 SEQ ID NO: 212 SEQ ID NO: 144 980 SEQ ID NO: 213 SEQ ID NO: 144 981 SEQ ID NO: 214 SEQ ID NO: 144 982 SEQ ID NO: 215 SEQ ID NO: 144 983 SEQ ID NO: 216 SEQ ID NO: 144 984 SEQ ID NO: 217 SEQ ID NO: 144 985 SEQ ID NO: 218 SEQ ID NO: 144 986 SEQ ID NO: 219 SEQ ID NO: 144 987 SEQ ID NO: 220 SEQ ID NO: 144 988 SEQ ID NO: 221 SEQ ID NO: 144 989 SEQ ID NO: 222 SEQ ID NO: 144 990 SEQ ID NO: 223 SEQ ID NO: 144 991 SEQ ID NO: 224 SEQ ID NO: 144 992 SEQ ID NO: 225 SEQ ID NO: 144 993 SEQ ID NO: 226 SEQ ID NO: 144 994 SEQ ID NO: 227 SEQ ID NO: 144 995 SEQ ID NO: 228 SEQ ID NO: 144 996 SEQ ID NO: 229 SEQ ID NO: 144 997 SEQ ID NO: 230 SEQ ID NO: 144 998 SEQ ID NO: 231 SEQ ID NO: 144 999 SEQ ID NO: 232 SEQ ID NO: 144 1000 SEQ ID NO: 233 SEQ ID NO: 144 1001 SEQ ID NO: 234 SEQ ID NO: 144 1002 SEQ ID NO: 235 SEQ ID NO: 144 1003 SEQ ID NO: 236 SEQ ID NO: 144 1004 SEQ ID NO: 237 SEQ ID NO: 144 1005 SEQ ID NO: 238 SEQ ID NO: 144 1006 SEQ ID NO: 239 SEQ ID NO: 144 1007 SEQ ID NO: 240 SEQ ID NO: 144 1008 SEQ ID NO: 241 SEQ ID NO: 144 1009 SEQ ID NO: 242 SEQ ID NO: 144 1010 SEQ ID NO: 243 SEQ ID NO: 144 1011 SEQ ID NO: 244 SEQ ID NO: 144 1012 SEQ ID NO: 245 SEQ ID NO: 144 1013 SEQ ID NO: 246 SEQ ID NO: 144 1014 SEQ ID NO: 247 SEQ ID NO: 144 1015 SEQ ID NO: 248 SEQ ID NO: 144 1016 SEQ ID NO: 249 SEQ ID NO: 144 1017 SEQ ID NO: 250 SEQ ID NO: 144 1018 SEQ ID NO: 251 SEQ ID NO: 144 1019 SEQ ID NO: 252 SEQ ID NO: 144 1020 SEQ ID NO: 253 SEQ ID NO: 144 1021 SEQ ID NO: 254 SEQ ID NO: 144 1022 SEQ ID NO: 255 SEQ ID NO: 144 1023 SEQ ID NO: 256 SEQ ID NO: 144 1024 SEQ ID NO: 257 SEQ ID NO: 144 1025 SEQ ID NO: 258 SEQ ID NO: 144 1026 SEQ ID NO: 259 SEQ ID NO: 144 1027 SEQ ID NO: 260 SEQ ID NO: 144 1028 SEQ ID NO: 261 SEQ ID NO: 144 1029 SEQ ID NO: 262 SEQ ID NO: 144 1030 SEQ ID NO: 263 SEQ ID NO: 144 1031 SEQ ID NO: 264 SEQ ID NO: 144 1032 SEQ ID NO: 265 SEQ ID NO: 144 1033 SEQ ID NO: 266 SEQ ID NO: 144 1034 SEQ ID NO: 267 SEQ ID NO: 144 1035 SEQ ID NO: 268 SEQ ID NO: 144 1036 SEQ ID NO: 269 SEQ ID NO: 144 1037 SEQ ID NO: 270 SEQ ID NO: 144 1038 SEQ ID NO: 271 SEQ ID NO: 144 1039 SEQ ID NO: 272 SEQ ID NO: 144 1040 SEQ ID NO: 273 SEQ ID NO: 144 1041 SEQ ID NO: 274 SEQ ID NO: 144 1042 SEQ ID NO: 275 SEQ ID NO: 144 1043 SEQ ID NO: 276 SEQ ID NO: 144 1044 SEQ ID NO: 277 SEQ ID NO: 144 1045 SEQ ID NO: 278 SEQ ID NO: 144 1046 SEQ ID NO: 279 SEQ ID NO: 144 1047 SEQ ID NO: 280 SEQ ID NO: 144 1048 SEQ ID NO: 281 SEQ ID NO: 144 1049 SEQ ID NO: 282 SEQ ID NO: 144 1050 SEQ ID NO: 283 SEQ ID NO: 144 1051 SEQ ID NO: 284 SEQ ID NO: 144 1052 SEQ ID NO: 285 SEQ ID NO: 144 1053 SEQ ID NO: 286 SEQ ID NO: 144 1054 SEQ ID NO: 287 SEQ ID NO: 144 1055 SEQ ID NO: 288 SEQ ID NO: 144 1056 SEQ ID NO: 289 SEQ ID NO: 144 1057 SEQ ID NO: 141 SEQ ID NO: 146 1058 SEQ ID NO: 143 SEQ ID NO: 146 1059 SEQ ID NO: 145 SEQ ID NO: 146 1060 SEQ ID NO: 147 SEQ ID NO: 146 1061 SEQ ID NO: 149 SEQ ID NO: 146 1062 SEQ ID NO: 151 SEQ ID NO: 146 1063 SEQ ID NO: 153 SEQ ID NO: 146 1064 SEQ ID NO: 155 SEQ ID NO: 146 1065 SEQ ID NO: 156 SEQ ID NO: 146 1066 SEQ ID NO: 164 SEQ ID NO: 146 1067 SEQ ID NO: 165 SEQ ID NO: 146 1068 SEQ ID NO: 166 SEQ ID NO: 146 1069 SEQ ID NO: 167 SEQ ID NO: 146 1070 SEQ ID NO: 168 SEQ ID NO: 146 1071 SEQ ID NO: 169 SEQ ID NO: 146 1072 SEQ ID NO: 170 SEQ ID NO: 146 1073 SEQ ID NO: 171 SEQ ID NO: 146 1074 SEQ ID NO: 172 SEQ ID NO: 146 1075 SEQ ID NO: 173 SEQ ID NO: 146 1076 SEQ ID NO: 174 SEQ ID NO: 146 1077 SEQ ID NO: 175 SEQ ID NO: 146 1078 SEQ ID NO: 176 SEQ ID NO: 146 1079 SEQ ID NO: 177 SEQ ID NO: 146 1080 SEQ ID NO: 178 SEQ ID NO: 146 1081 SEQ ID NO: 179 SEQ ID NO: 146 1082 SEQ ID NO: 180 SEQ ID NO: 146 1083 SEQ ID NO: 181 SEQ ID NO: 146 1084 SEQ ID NO: 182 SEQ ID NO: 146 1085 SEQ ID NO: 183 SEQ ID NO: 146 1086 SEQ ID NO: 184 SEQ ID NO: 146 1087 SEQ ID NO: 185 SEQ ID NO: 146 1088 SEQ ID NO: 186 SEQ ID NO: 146 1089 SEQ ID NO: 187 SEQ ID NO: 146 1090 SEQ ID NO: 188 SEQ ID NO: 146 1091 SEQ ID NO: 189 SEQ ID NO: 146 1092 SEQ ID NO: 190 SEQ ID NO: 146 1093 SEQ ID NO: 191 SEQ ID NO: 146 1094 SEQ ID NO: 192 SEQ ID NO: 146 1095 SEQ ID NO: 193 SEQ ID NO: 146 1096 SEQ ID NO: 194 SEQ ID NO: 146 1097 SEQ ID NO: 195 SEQ ID NO: 146 1098 SEQ ID NO: 196 SEQ ID NO: 146 1099 SEQ ID NO: 197 SEQ ID NO: 146 1100 SEQ ID NO: 198 SEQ ID NO: 146 1101 SEQ ID NO: 199 SEQ ID NO: 146 1102 SEQ ID NO: 200 SEQ ID NO: 146 1103 SEQ ID NO: 201 SEQ ID NO: 146 1104 SEQ ID NO: 202 SEQ ID NO: 146 1105 SEQ ID NO: 203 SEQ ID NO: 146 1106 SEQ ID NO: 204 SEQ ID NO: 146 1107 SEQ ID NO: 205 SEQ ID NO: 146 1108 SEQ ID NO: 206 SEQ ID NO: 146 1109 SEQ ID NO: 207 SEQ ID NO: 146 1110 SEQ ID NO: 208 SEQ ID NO: 146 1111 SEQ ID NO: 209 SEQ ID NO: 146 1112 SEQ ID NO: 210 SEQ ID NO: 146 1113 SEQ ID NO: 211 SEQ ID NO: 146 1114 SEQ ID NO: 212 SEQ ID NO: 146 1115 SEQ ID NO: 213 SEQ ID NO: 146 1116 SEQ ID NO: 214 SEQ ID NO: 146 1117 SEQ ID NO: 215 SEQ ID NO: 146 1118 SEQ ID NO: 216 SEQ ID NO: 146 1119 SEQ ID NO: 217 SEQ ID NO: 146 1120 SEQ ID NO: 218 SEQ ID NO: 146 1121 SEQ ID NO: 219 SEQ ID NO: 146 1122 SEQ ID NO: 220 SEQ ID NO: 146 1123 SEQ ID NO: 221 SEQ ID NO: 146 1124 SEQ ID NO: 222 SEQ ID NO: 146 1125 SEQ ID NO: 223 SEQ ID NO: 146 1126 SEQ ID NO: 224 SEQ ID NO: 146 1127 SEQ ID NO: 225 SEQ ID NO: 146 1128 SEQ ID NO: 226 SEQ ID NO: 146 1129 SEQ ID NO: 227 SEQ ID NO: 146 1130 SEQ ID NO: 228 SEQ ID NO: 146 1131 SEQ ID NO: 229 SEQ ID NO: 146 1132 SEQ ID NO: 230 SEQ ID NO: 146 1133 SEQ ID NO: 231 SEQ ID NO: 146 1134 SEQ ID NO: 232 SEQ ID NO: 146 1135 SEQ ID NO: 233 SEQ ID NO: 146 1136 SEQ ID NO: 234 SEQ ID NO: 146 1137 SEQ ID NO: 235 SEQ ID NO: 146 1138 SEQ ID NO: 236 SEQ ID NO: 146 1139 SEQ ID NO: 237 SEQ ID NO: 146 1140 SEQ ID NO: 238 SEQ ID NO: 146 1141 SEQ ID NO: 239 SEQ ID NO: 146 1142 SEQ ID NO: 240 SEQ ID NO: 146 1143 SEQ ID NO: 241 SEQ ID NO: 146 1144 SEQ ID NO: 242 SEQ ID NO: 146 1145 SEQ ID NO: 243 SEQ ID NO: 146 1146 SEQ ID NO: 244 SEQ ID NO: 146 1147 SEQ ID NO: 245 SEQ ID NO: 146 1148 SEQ ID NO: 246 SEQ ID NO: 146 1149 SEQ ID NO: 247 SEQ ID NO: 146 1150 SEQ ID NO: 248 SEQ ID NO: 146 1151 SEQ ID NO: 249 SEQ ID NO: 146 1152 SEQ ID NO: 250 SEQ ID NO: 146 1153 SEQ ID NO: 251 SEQ ID NO: 146 1154 SEQ ID NO: 252 SEQ ID NO: 146 1155 SEQ ID NO: 253 SEQ ID NO: 146 1156 SEQ ID NO: 254 SEQ ID NO: 146 1157 SEQ ID NO: 255 SEQ ID NO: 146 1158 SEQ ID NO: 256 SEQ ID NO: 146 1159 SEQ ID NO: 257 SEQ ID NO: 146 1160 SEQ ID NO: 258 SEQ ID NO: 146 1161 SEQ ID NO: 259 SEQ ID NO: 146 1162 SEQ ID NO: 260 SEQ ID NO: 146 1163 SEQ ID NO: 261 SEQ ID NO: 146 1164 SEQ ID NO: 262 SEQ ID NO: 146 1165 SEQ ID NO: 263 SEQ ID NO: 146 1166 SEQ ID NO: 264 SEQ ID NO: 146 1167 SEQ ID NO: 265 SEQ ID NO: 146 1168 SEQ ID NO: 266 SEQ ID NO: 146 1169 SEQ ID NO: 267 SEQ ID NO: 146 1170 SEQ ID NO: 268 SEQ ID NO: 146 1171 SEQ ID NO: 269 SEQ ID NO: 146 1172 SEQ ID NO: 270 SEQ ID NO: 146 1173 SEQ ID NO: 271 SEQ ID NO: 146 1174 SEQ ID NO: 272 SEQ ID NO: 146 1175 SEQ ID NO: 273 SEQ ID NO: 146 1176 SEQ ID NO: 274 SEQ ID NO: 146 1177 SEQ ID NO: 275 SEQ ID NO: 146 1178 SEQ ID NO: 276 SEQ ID NO: 146 1179 SEQ ID NO: 277 SEQ ID NO: 146 1180 SEQ ID NO: 278 SEQ ID NO: 146 1181 SEQ ID NO: 279 SEQ ID NO: 146 1182 SEQ ID NO: 280 SEQ ID NO: 146 1183 SEQ ID NO: 281 SEQ ID NO: 146 1184 SEQ ID NO: 282 SEQ ID NO: 146 1185 SEQ ID NO: 283 SEQ ID NO: 146 1186 SEQ ID NO: 284 SEQ ID NO: 146 1187 SEQ ID NO: 285 SEQ ID NO: 146 1188 SEQ ID NO: 286 SEQ ID NO: 146 1189 SEQ ID NO: 287 SEQ ID NO: 146 1190 SEQ ID NO: 288 SEQ ID NO: 146 1191 SEQ ID NO: 289 SEQ ID NO: 146 1192 SEQ ID NO: 141 SEQ ID NO: 148 1193 SEQ ID NO: 143 SEQ ID NO: 148 1194 SEQ ID NO: 145 SEQ ID NO: 148 1195 SEQ ID NO: 147 SEQ ID NO: 148 1196 SEQ ID NO: 149 SEQ ID NO: 148 1197 SEQ ID NO: 151 SEQ ID NO: 148 1198 SEQ ID NO: 153 SEQ ID NO: 148 1199 SEQ ID NO: 155 SEQ ID NO: 148 1200 SEQ ID NO: 156 SEQ ID NO: 148 1201 SEQ ID NO: 164 SEQ ID NO: 148 1202 SEQ ID NO: 165 SEQ ID NO: 148 1203 SEQ ID NO: 166 SEQ ID NO: 148 1204 SEQ ID NO: 167 SEQ ID NO: 148 1205 SEQ ID NO: 168 SEQ ID NO: 148 1206 SEQ ID NO: 169 SEQ ID NO: 148 1207 SEQ ID NO: 170 SEQ ID NO: 148 1208 SEQ ID NO: 171 SEQ ID NO: 148 1209 SEQ ID NO: 172 SEQ ID NO: 148 1210 SEQ ID NO: 173 SEQ ID NO: 148 1211 SEQ ID NO: 174 SEQ ID NO: 148 1212 SEQ ID NO: 175 SEQ ID NO: 148 1213 SEQ ID NO: 176 SEQ ID NO: 148 1214 SEQ ID NO: 177 SEQ ID NO: 148 1215 SEQ ID NO: 178 SEQ ID NO: 148 1216 SEQ ID NO: 179 SEQ ID NO: 148 1217 SEQ ID NO: 180 SEQ ID NO: 148 1218 SEQ ID NO: 181 SEQ ID NO: 148 1219 SEQ ID NO: 182 SEQ ID NO: 148 1220 SEQ ID NO: 183 SEQ ID NO: 148 1221 SEQ ID NO: 184 SEQ ID NO: 148 1222 SEQ ID NO: 185 SEQ ID NO: 148 1223 SEQ ID NO: 186 SEQ ID NO: 148 1224 SEQ ID NO: 187 SEQ ID NO: 148 1225 SEQ ID NO: 188 SEQ ID NO: 148 1226 SEQ ID NO: 189 SEQ ID NO: 148 1227 SEQ ID NO: 190 SEQ ID NO: 148 1228 SEQ ID NO: 191 SEQ ID NO: 148 1229 SEQ ID NO: 192 SEQ ID NO: 148 1230 SEQ ID NO: 193 SEQ ID NO: 148 1231 SEQ ID NO: 194 SEQ ID NO: 148 1232 SEQ ID NO: 195 SEQ ID NO: 148 1233 SEQ ID NO: 196 SEQ ID NO: 148 1234 SEQ ID NO: 197 SEQ ID NO: 148 1235 SEQ ID NO: 198 SEQ ID NO: 148 1236 SEQ ID NO: 199 SEQ ID NO: 148 1237 SEQ ID NO: 200 SEQ ID NO: 148 1238 SEQ ID NO: 201 SEQ ID NO: 148 1239 SEQ ID NO: 202 SEQ ID NO: 148 1240 SEQ ID NO: 203 SEQ ID NO: 148 1241 SEQ ID NO: 204 SEQ ID NO: 148 1242 SEQ ID NO: 205 SEQ ID NO: 148 1243 SEQ ID NO: 206 SEQ ID NO: 148 1244 SEQ ID NO: 207 SEQ ID NO: 148 1245 SEQ ID NO: 208 SEQ ID NO: 148 1246 SEQ ID NO: 209 SEQ ID NO: 148 1247 SEQ ID NO: 210 SEQ ID NO: 148 1248 SEQ ID NO: 211 SEQ ID NO: 148 1249 SEQ ID NO: 212 SEQ ID NO: 148 1250 SEQ ID NO: 213 SEQ ID NO: 148 1251 SEQ ID NO: 214 SEQ ID NO: 148 1252 SEQ ID NO: 215 SEQ ID NO: 148 1253 SEQ ID NO: 216 SEQ ID NO: 148 1254 SEQ ID NO: 217 SEQ ID NO: 148 1255 SEQ ID NO: 218 SEQ ID NO: 148 1256 SEQ ID NO: 219 SEQ ID NO: 148 1257 SEQ ID NO: 220 SEQ ID NO: 148 1258 SEQ ID NO: 221 SEQ ID NO: 148 1259 SEQ ID NO: 222 SEQ ID NO: 148 1260 SEQ ID NO: 223 SEQ ID NO: 148 1261 SEQ ID NO: 224 SEQ ID NO: 148 1262 SEQ ID NO: 225 SEQ ID NO: 148 1263 SEQ ID NO: 226 SEQ ID NO: 148 1264 SEQ ID NO: 227 SEQ ID NO: 148 1265 SEQ ID NO: 228 SEQ ID NO: 148 1266 SEQ ID NO: 229 SEQ ID NO: 148 1267 SEQ ID NO: 230 SEQ ID NO: 148 1268 SEQ ID NO: 231 SEQ ID NO: 148 1269 SEQ ID NO: 232 SEQ ID NO: 148 1270 SEQ ID NO: 233 SEQ ID NO: 148 1271 SEQ ID NO: 234 SEQ ID NO: 148 1272 SEQ ID NO: 235 SEQ ID NO: 148 1273 SEQ ID NO: 236 SEQ ID NO: 148 1274 SEQ ID NO: 237 SEQ ID NO: 148 1275 SEQ ID NO: 238 SEQ ID NO: 148 1276 SEQ ID NO: 239 SEQ ID NO: 148 1277 SEQ ID NO: 240 SEQ ID NO: 148 1278 SEQ ID NO: 241 SEQ ID NO: 148 1279 SEQ ID NO: 242 SEQ ID NO: 148 1280 SEQ ID NO: 243 SEQ ID NO: 148 1281 SEQ ID NO: 244 SEQ ID NO: 148 1282 SEQ ID NO: 245 SEQ ID NO: 148 1283 SEQ ID NO: 246 SEQ ID NO: 148 1284 SEQ ID NO: 247 SEQ ID NO: 148 1285 SEQ ID NO: 248 SEQ ID NO: 148 1286 SEQ ID NO: 249 SEQ ID NO: 148 1287 SEQ ID NO: 250 SEQ ID NO: 148 1288 SEQ ID NO: 251 SEQ ID NO: 148 1289 SEQ ID NO: 252 SEQ ID NO: 148 1290 SEQ ID NO: 253 SEQ ID NO: 148 1291 SEQ ID NO: 254 SEQ ID NO: 148 1292 SEQ ID NO: 255 SEQ ID NO: 148 1293 SEQ ID NO: 256 SEQ ID NO: 148 1294 SEQ ID NO: 257 SEQ ID NO: 148 1295 SEQ ID NO: 258 SEQ ID NO: 148 1296 SEQ ID NO: 259 SEQ ID NO: 148 1297 SEQ ID NO: 260 SEQ ID NO: 148 1298 SEQ ID NO: 261 SEQ ID NO: 148 1299 SEQ ID NO: 262 SEQ ID NO: 148 1300 SEQ ID NO: 263 SEQ ID NO: 148 1301 SEQ ID NO: 264 SEQ ID NO: 148 1302 SEQ ID NO: 265 SEQ ID NO: 148 1303 SEQ ID NO: 266 SEQ ID NO: 148 1304 SEQ ID NO: 267 SEQ ID NO: 148 1305 SEQ ID NO: 268 SEQ ID NO: 148 1306 SEQ ID NO: 269 SEQ ID NO: 148 1307 SEQ ID NO: 270 SEQ ID NO: 148 1308 SEQ ID NO: 271 SEQ ID NO: 148 1309 SEQ ID NO: 272 SEQ ID NO: 148 1310 SEQ ID NO: 273 SEQ ID NO: 148 1311 SEQ ID NO: 274 SEQ ID NO: 148 1312 SEQ ID NO: 275 SEQ ID NO: 148 1313 SEQ ID NO: 276 SEQ ID NO: 148 1314 SEQ ID NO: 277 SEQ ID NO: 148 1315 SEQ ID NO: 278 SEQ ID NO: 148 1316 SEQ ID NO: 279 SEQ ID NO: 148 1317 SEQ ID NO: 280 SEQ ID NO: 148 1318 SEQ ID NO: 281 SEQ ID NO: 148 1319 SEQ ID NO: 282 SEQ ID NO: 148 1320 SEQ ID NO: 283 SEQ ID NO: 148 1321 SEQ ID NO: 284 SEQ ID NO: 148 1322 SEQ ID NO: 285 SEQ ID NO: 148 1323 SEQ ID NO: 286 SEQ ID NO: 148 1324 SEQ ID NO: 287 SEQ ID NO: 148 1325 SEQ ID NO: 288 SEQ ID NO: 148 1326 SEQ ID NO: 289 SEQ ID NO: 148 1327 SEQ ID NO: 141 SEQ ID NO: 150 1328 SEQ ID NO: 143 SEQ ID NO: 150 1329 SEQ ID NO: 145 SEQ ID NO: 150 1330 SEQ ID NO: 147 SEQ ID NO: 150 1331 SEQ ID NO: 149 SEQ ID NO: 150 1332 SEQ ID NO: 151 SEQ ID NO: 150 1333 SEQ ID NO: 153 SEQ ID NO: 150 1334 SEQ ID NO: 155 SEQ ID NO: 150 1335 SEQ ID NO: 156 SEQ ID NO: 150 1336 SEQ ID NO: 164 SEQ ID NO: 150 1337 SEQ ID NO: 165 SEQ ID NO: 150 1338 SEQ ID NO: 166 SEQ ID NO: 150 1339 SEQ ID NO: 167 SEQ ID NO: 150 1340 SEQ ID NO: 168 SEQ ID NO: 150 1341 SEQ ID NO: 169 SEQ ID NO: 150 1342 SEQ ID NO: 170 SEQ ID NO: 150 1343 SEQ ID NO: 171 SEQ ID NO: 150 1344 SEQ ID NO: 172 SEQ ID NO: 150 1345 SEQ ID NO: 173 SEQ ID NO: 150 1346 SEQ ID NO: 174 SEQ ID NO: 150 1347 SEQ ID NO: 175 SEQ ID NO: 150 1348 SEQ ID NO: 176 SEQ ID NO: 150 1349 SEQ ID NO: 177 SEQ ID NO: 150 1350 SEQ ID NO: 178 SEQ ID NO: 150 1351 SEQ ID NO: 179 SEQ ID NO: 150 1352 SEQ ID NO: 180 SEQ ID NO: 150 1353 SEQ ID NO: 181 SEQ ID NO: 150 1354 SEQ ID NO: 182 SEQ ID NO: 150 1355 SEQ ID NO: 183 SEQ ID NO: 150 1356 SEQ ID NO: 184 SEQ ID NO: 150 1357 SEQ ID NO: 185 SEQ ID NO: 150 1358 SEQ ID NO: 186 SEQ ID NO: 150 1359 SEQ ID NO: 187 SEQ ID NO: 150 1360 SEQ ID NO: 188 SEQ ID NO: 150 1361 SEQ ID NO: 189 SEQ ID NO: 150 1362 SEQ ID NO: 190 SEQ ID NO: 150 1363 SEQ ID NO: 191 SEQ ID NO: 150 1364 SEQ ID NO: 192 SEQ ID NO: 150 1365 SEQ ID NO: 193 SEQ ID NO: 150 1366 SEQ ID NO: 194 SEQ ID NO: 150 1367 SEQ ID NO: 195 SEQ ID NO: 150 1368 SEQ ID NO: 196 SEQ ID NO: 150 1369 SEQ ID NO: 197 SEQ ID NO: 150 1370 SEQ ID NO: 198 SEQ ID NO: 150 1371 SEQ ID NO: 199 SEQ ID NO: 150 1372 SEQ ID NO: 200 SEQ ID NO: 150 1373 SEQ ID NO: 201 SEQ ID NO: 150 1374 SEQ ID NO: 202 SEQ ID NO: 150 1375 SEQ ID NO: 203 SEQ ID NO: 150 1376 SEQ ID NO: 204 SEQ ID NO: 150 1377 SEQ ID NO: 205 SEQ ID NO: 150 1378 SEQ ID NO: 206 SEQ ID NO: 150 1379 SEQ ID NO: 207 SEQ ID NO: 150 1380 SEQ ID NO: 208 SEQ ID NO: 150 1381 SEQ ID NO: 209 SEQ ID NO: 150 1382 SEQ ID NO: 210 SEQ ID NO: 150 1383 SEQ ID NO: 211 SEQ ID NO: 150 1384 SEQ ID NO: 212 SEQ ID NO: 150 1385 SEQ ID NO: 213 SEQ ID NO: 150 1386 SEQ ID NO: 214 SEQ ID NO: 150 1387 SEQ ID NO: 215 SEQ ID NO: 150 1388 SEQ ID NO: 216 SEQ ID NO: 150 1389 SEQ ID NO: 217 SEQ ID NO: 150 1390 SEQ ID NO: 218 SEQ ID NO: 150 1391 SEQ ID NO: 219 SEQ ID NO: 150 1392 SEQ ID NO: 220 SEQ ID NO: 150 1393 SEQ ID NO: 221 SEQ ID NO: 150 1394 SEQ ID NO: 222 SEQ ID NO: 150 1395 SEQ ID NO: 223 SEQ ID NO: 150 1396 SEQ ID NO: 224 SEQ ID NO: 150 1397 SEQ ID NO: 225 SEQ ID NO: 150 1398 SEQ ID NO: 226 SEQ ID NO: 150 1399 SEQ ID NO: 227 SEQ ID NO: 150 1400 SEQ ID NO: 228 SEQ ID NO: 150 1401 SEQ ID NO: 229 SEQ ID NO: 150 1402 SEQ ID NO: 230 SEQ ID NO: 150 1403 SEQ ID NO: 231 SEQ ID NO: 150 1404 SEQ ID NO: 232 SEQ ID NO: 150 1405 SEQ ID NO: 233 SEQ ID NO: 150 1406 SEQ ID NO: 234 SEQ ID NO: 150 1407 SEQ ID NO: 235 SEQ ID NO: 150 1408 SEQ ID NO: 236 SEQ ID NO: 150 1409 SEQ ID NO: 237 SEQ ID NO: 150 1410 SEQ ID NO: 238 SEQ ID NO: 150 1411 SEQ ID NO: 239 SEQ ID NO: 150 1412 SEQ ID NO: 240 SEQ ID NO: 150 1413 SEQ ID NO: 241 SEQ ID NO: 150 1414 SEQ ID NO: 242 SEQ ID NO: 150 1415 SEQ ID NO: 243 SEQ ID NO: 150 1416 SEQ ID NO: 244 SEQ ID NO: 150 1417 SEQ ID NO: 245 SEQ ID NO: 150 1418 SEQ ID NO: 246 SEQ ID NO: 150 1419 SEQ ID NO: 247 SEQ ID NO: 150 1420 SEQ ID NO: 248 SEQ ID NO: 150 1421 SEQ ID NO: 249 SEQ ID NO: 150 1422 SEQ ID NO: 250 SEQ ID NO: 150 1423 SEQ ID NO: 251 SEQ ID NO: 150 1424 SEQ ID NO: 252 SEQ ID NO: 150 1425 SEQ ID NO: 253 SEQ ID NO: 150 1426 SEQ ID NO: 254 SEQ ID NO: 150 1427 SEQ ID NO: 255 SEQ ID NO: 150 1428 SEQ ID NO: 256 SEQ ID NO: 150 1429 SEQ ID NO: 257 SEQ ID NO: 150 1430 SEQ ID NO: 258 SEQ ID NO: 150 1431 SEQ ID NO: 259 SEQ ID NO: 150 1432 SEQ ID NO: 260 SEQ ID NO: 150 1433 SEQ ID NO: 261 SEQ ID NO: 150 1434 SEQ ID NO: 262 SEQ ID NO: 150 1435 SEQ ID NO: 263 SEQ ID NO: 150 1436 SEQ ID NO: 264 SEQ ID NO: 150 1437 SEQ ID NO: 265 SEQ ID NO: 150 1438 SEQ ID NO: 266 SEQ ID NO: 150 1439 SEQ ID NO: 267 SEQ ID NO: 150 1440 SEQ ID NO: 268 SEQ ID NO: 150 1441 SEQ ID NO: 269 SEQ ID NO: 150 1442 SEQ ID NO: 270 SEQ ID NO: 150 1443 SEQ ID NO: 271 SEQ ID NO: 150 1444 SEQ ID NO: 272 SEQ ID NO: 150 1445 SEQ ID NO: 273 SEQ ID NO: 150 1446 SEQ ID NO: 274 SEQ ID NO: 150 1447 SEQ ID NO: 275 SEQ ID NO: 150 1448 SEQ ID NO: 276 SEQ ID NO: 150 1449 SEQ ID NO: 277 SEQ ID NO: 150 1450 SEQ ID NO: 278 SEQ ID NO: 150 1451 SEQ ID NO: 279 SEQ ID NO: 150 1452 SEQ ID NO: 280 SEQ ID NO: 150 1453 SEQ ID NO: 281 SEQ ID NO: 150 1454 SEQ ID NO: 282 SEQ ID NO: 150 1455 SEQ ID NO: 283 SEQ ID NO: 150 1456 SEQ ID NO: 284 SEQ ID NO: 150 1457 SEQ ID NO: 285 SEQ ID NO: 150 1458 SEQ ID NO: 286 SEQ ID NO: 150 1459 SEQ ID NO: 287 SEQ ID NO: 150 1460 SEQ ID NO: 288 SEQ ID NO: 150 1461 SEQ ID NO: 289 SEQ ID NO: 150 1462 SEQ ID NO: 141 SEQ ID NO: 152 1463 SEQ ID NO: 143 SEQ ID NO: 152 1464 SEQ ID NO: 145 SEQ ID NO: 152 1465 SEQ ID NO: 147 SEQ ID NO: 152 1466 SEQ ID NO: 149 SEQ ID NO: 152 1467 SEQ ID NO: 151 SEQ ID NO: 152 1468 SEQ ID NO: 153 SEQ ID NO: 152 1469 SEQ ID NO: 155 SEQ ID NO: 152 1470 SEQ ID NO: 156 SEQ ID NO: 152 1471 SEQ ID NO: 164 SEQ ID NO: 152 1472 SEQ ID NO: 165 SEQ ID NO: 152 1473 SEQ ID NO: 166 SEQ ID NO: 152 1474 SEQ ID NO: 167 SEQ ID NO: 152 1475 SEQ ID NO: 168 SEQ ID NO: 152 1476 SEQ ID NO: 169 SEQ ID NO: 152 1477 SEQ ID NO: 170 SEQ ID NO: 152 1478 SEQ ID NO: 171 SEQ ID NO: 152 1479 SEQ ID NO: 172 SEQ ID NO: 152 1480 SEQ ID NO: 173 SEQ ID NO: 152 1481 SEQ ID NO: 174 SEQ ID NO: 152 1482 SEQ ID NO: 175 SEQ ID NO: 152 1483 SEQ ID NO: 176 SEQ ID NO: 152 1484 SEQ ID NO: 177 SEQ ID NO: 152 1485 SEQ ID NO: 178 SEQ ID NO: 152 1486 SEQ ID NO: 179 SEQ ID NO: 152 1487 SEQ ID NO: 180 SEQ ID NO: 152 1488 SEQ ID NO: 181 SEQ ID NO: 152 1489 SEQ ID NO: 182 SEQ ID NO: 152 1490 SEQ ID NO: 183 SEQ ID NO: 152 1491 SEQ ID NO: 184 SEQ ID NO: 152 1492 SEQ ID NO: 185 SEQ ID NO: 152 1493 SEQ ID NO: 186 SEQ ID NO: 152 1494 SEQ ID NO: 187 SEQ ID NO: 152 1495 SEQ ID NO: 188 SEQ ID NO: 152 1496 SEQ ID NO: 189 SEQ ID NO: 152 1497 SEQ ID NO: 190 SEQ ID NO: 152 1498 SEQ ID NO: 191 SEQ ID NO: 152 1499 SEQ ID NO: 192 SEQ ID NO: 152 1500 SEQ ID NO: 193 SEQ ID NO: 152 1501 SEQ ID NO: 194 SEQ ID NO: 152 1502 SEQ ID NO: 195 SEQ ID NO: 152 1503 SEQ ID NO: 196 SEQ ID NO: 152 1504 SEQ ID NO: 197 SEQ ID NO: 152 1505 SEQ ID NO: 198 SEQ ID NO: 152 1506 SEQ ID NO: 199 SEQ ID NO: 152 1507 SEQ ID NO: 200 SEQ ID NO: 152 1508 SEQ ID NO: 201 SEQ ID NO: 152 1509 SEQ ID NO: 202 SEQ ID NO: 152 1510 SEQ ID NO: 203 SEQ ID NO: 152 1511 SEQ ID NO: 204 SEQ ID NO: 152 1512 SEQ ID NO: 205 SEQ ID NO: 152 1513 SEQ ID NO: 206 SEQ ID NO: 152 1514 SEQ ID NO: 207 SEQ ID NO: 152 1515 SEQ ID NO: 208 SEQ ID NO: 152 1516 SEQ ID NO: 209 SEQ ID NO: 152 1517 SEQ ID NO: 210 SEQ ID NO: 152 1518 SEQ ID NO: 211 SEQ ID NO: 152 1519 SEQ ID NO: 212 SEQ ID NO: 152 1520 SEQ ID NO: 213 SEQ ID NO: 152 1521 SEQ ID NO: 214 SEQ ID NO: 152 1522 SEQ ID NO: 215 SEQ ID NO: 152 1523 SEQ ID NO: 216 SEQ ID NO: 152 1524 SEQ ID NO: 217 SEQ ID NO: 152 1525 SEQ ID NO: 218 SEQ ID NO: 152 1526 SEQ ID NO: 219 SEQ ID NO: 152 1527 SEQ ID NO: 220 SEQ ID NO: 152 1528 SEQ ID NO: 221 SEQ ID NO: 152 1529 SEQ ID NO: 222 SEQ ID NO: 152 1530 SEQ ID NO: 223 SEQ ID NO: 152 1531 SEQ ID NO: 224 SEQ ID NO: 152 1532 SEQ ID NO: 225 SEQ ID NO: 152 1533 SEQ ID NO: 226 SEQ ID NO: 152 1534 SEQ ID NO: 227 SEQ ID NO: 152 1535 SEQ ID NO: 228 SEQ ID NO: 152 1536 SEQ ID NO: 229 SEQ ID NO: 152 1537 SEQ ID NO: 230 SEQ ID NO: 152 1538 SEQ ID NO: 231 SEQ ID NO: 152 1539 SEQ ID NO: 232 SEQ ID NO: 152 1540 SEQ ID NO: 233 SEQ ID NO: 152 1541 SEQ ID NO: 234 SEQ ID NO: 152 1542 SEQ ID NO: 235 SEQ ID NO: 152 1543 SEQ ID NO: 236 SEQ ID NO: 152 1544 SEQ ID NO: 237 SEQ ID NO: 152 1545 SEQ ID NO: 238 SEQ ID NO: 152 1546 SEQ ID NO: 239 SEQ ID NO: 152 1547 SEQ ID NO: 240 SEQ ID NO: 152 1548 SEQ ID NO: 241 SEQ ID NO: 152 1549 SEQ ID NO: 242 SEQ ID NO: 152 1550 SEQ ID NO: 243 SEQ ID NO: 152 1551 SEQ ID NO: 244 SEQ ID NO: 152 1552 SEQ ID NO: 245 SEQ ID NO: 152 1553 SEQ ID NO: 246 SEQ ID NO: 152 1554 SEQ ID NO: 247 SEQ ID NO: 152 1555 SEQ ID NO: 248 SEQ ID NO: 152 1556 SEQ ID NO: 249 SEQ ID NO: 152 1557 SEQ ID NO: 250 SEQ ID NO: 152 1558 SEQ ID NO: 251 SEQ ID NO: 152 1559 SEQ ID NO: 252 SEQ ID NO: 152 1560 SEQ ID NO: 253 SEQ ID NO: 152 1561 SEQ ID NO: 254 SEQ ID NO: 152 1562 SEQ ID NO: 255 SEQ ID NO: 152 1563 SEQ ID NO: 256 SEQ ID NO: 152 1564 SEQ ID NO: 257 SEQ ID NO: 152 1565 SEQ ID NO: 258 SEQ ID NO: 152 1566 SEQ ID NO: 259 SEQ ID NO: 152 1567 SEQ ID NO: 260 SEQ ID NO: 152 1568 SEQ ID NO: 261 SEQ ID NO: 152 1569 SEQ ID NO: 262 SEQ ID NO: 152 1570 SEQ ID NO: 263 SEQ ID NO: 152 1571 SEQ ID NO: 264 SEQ ID NO: 152 1572 SEQ ID NO: 265 SEQ ID NO: 152 1573 SEQ ID NO: 266 SEQ ID NO: 152 1574 SEQ ID NO: 267 SEQ ID NO: 152 1575 SEQ ID NO: 268 SEQ ID NO: 152 1576 SEQ ID NO: 269 SEQ ID NO: 152 1577 SEQ ID NO: 270 SEQ ID NO: 152 1578 SEQ ID NO: 271 SEQ ID NO: 152 1579 SEQ ID NO: 272 SEQ ID NO: 152 1580 SEQ ID NO: 273 SEQ ID NO: 152 1581 SEQ ID NO: 274 SEQ ID NO: 152 1582 SEQ ID NO: 275 SEQ ID NO: 152 1583 SEQ ID NO: 276 SEQ ID NO: 152 1584 SEQ ID NO: 277 SEQ ID NO: 152 1585 SEQ ID NO: 278 SEQ ID NO: 152 1586 SEQ ID NO: 279 SEQ ID NO: 152 1587 SEQ ID NO: 280 SEQ ID NO: 152 1588 SEQ ID NO: 281 SEQ ID NO: 152 1589 SEQ ID NO: 282 SEQ ID NO: 152 1590 SEQ ID NO: 283 SEQ ID NO: 152 1591 SEQ ID NO: 284 SEQ ID NO: 152 1592 SEQ ID NO: 285 SEQ ID NO: 152 1593 SEQ ID NO: 286 SEQ ID NO: 152 1594 SEQ ID NO: 287 SEQ ID NO: 152 1595 SEQ ID NO: 288 SEQ ID NO: 152 1596 SEQ ID NO: 289 SEQ ID NO: 152 1597 SEQ ID NO: 141 SEQ ID NO: 154 1598 SEQ ID NO: 143 SEQ ID NO: 154 1599 SEQ ID NO: 145 SEQ ID NO: 154 1600 SEQ ID NO: 147 SEQ ID NO: 154 1601 SEQ ID NO: 149 SEQ ID NO: 154 1602 SEQ ID NO: 151 SEQ ID NO: 154 1603 SEQ ID NO: 153 SEQ ID NO: 154 1604 SEQ ID NO: 155 SEQ ID NO: 154 1605 SEQ ID NO: 156 SEQ ID NO: 154 1606 SEQ ID NO: 164 SEQ ID NO: 154 1607 SEQ ID NO: 165 SEQ ID NO: 154 1608 SEQ ID NO: 166 SEQ ID NO: 154 1609 SEQ ID NO: 167 SEQ ID NO: 154 1610 SEQ ID NO: 168 SEQ ID NO: 154 1611 SEQ ID NO: 169 SEQ ID NO: 154 1612 SEQ ID NO: 170 SEQ ID NO: 154 1613 SEQ ID NO: 171 SEQ ID NO: 154 1614 SEQ ID NO: 172 SEQ ID NO: 154 1615 SEQ ID NO: 173 SEQ ID NO: 154 1616 SEQ ID NO: 174 SEQ ID NO: 154 1617 SEQ ID NO: 175 SEQ ID NO: 154 1618 SEQ ID NO: 176 SEQ ID NO: 154 1619 SEQ ID NO: 177 SEQ ID NO: 154 1620 SEQ ID NO: 178 SEQ ID NO: 154 1621 SEQ ID NO: 179 SEQ ID NO: 154 1622 SEQ ID NO: 180 SEQ ID NO: 154 1623 SEQ ID NO: 181 SEQ ID NO: 154 1624 SEQ ID NO: 182 SEQ ID NO: 154 1625 SEQ ID NO: 183 SEQ ID NO: 154 1626 SEQ ID NO: 184 SEQ ID NO: 154 1627 SEQ ID NO: 185 SEQ ID NO: 154 1628 SEQ ID NO: 186 SEQ ID NO: 154 1629 SEQ ID NO: 187 SEQ ID NO: 154 1630 SEQ ID NO: 188 SEQ ID NO: 154 1631 SEQ ID NO: 189 SEQ ID NO: 154 1632 SEQ ID NO: 190 SEQ ID NO: 154 1633 SEQ ID NO: 191 SEQ ID NO: 154 1634 SEQ ID NO: 192 SEQ ID NO: 154 1635 SEQ ID NO: 193 SEQ ID NO: 154 1636 SEQ ID NO: 194 SEQ ID NO: 154 1637 SEQ ID NO: 195 SEQ ID NO: 154 1638 SEQ ID NO: 196 SEQ ID NO: 154 1639 SEQ ID NO: 197 SEQ ID NO: 154 1640 SEQ ID NO: 198 SEQ ID NO: 154 1641 SEQ ID NO: 199 SEQ ID NO: 154 1642 SEQ ID NO: 200 SEQ ID NO: 154 1643 SEQ ID NO: 201 SEQ ID NO: 154 1644 SEQ ID NO: 202 SEQ ID NO: 154 1645 SEQ ID NO: 203 SEQ ID NO: 154 1646 SEQ ID NO: 204 SEQ ID NO: 154 1647 SEQ ID NO: 205 SEQ ID NO: 154 1648 SEQ ID NO: 206 SEQ ID NO: 154 1649 SEQ ID NO: 207 SEQ ID NO: 154 1650 SEQ ID NO: 208 SEQ ID NO: 154 1651 SEQ ID NO: 209 SEQ ID NO: 154 1652 SEQ ID NO: 210 SEQ ID NO: 154 1653 SEQ ID NO: 211 SEQ ID NO: 154 1654 SEQ ID NO: 212 SEQ ID NO: 154 1655 SEQ ID NO: 213 SEQ ID NO: 154 1656 SEQ ID NO: 214 SEQ ID NO: 154 1657 SEQ ID NO: 215 SEQ ID NO: 154 1658 SEQ ID NO: 216 SEQ ID NO: 154 1659 SEQ ID NO: 217 SEQ ID NO: 154 1660 SEQ ID NO: 218 SEQ ID NO: 154 1661 SEQ ID NO: 219 SEQ ID NO: 154 1662 SEQ ID NO: 220 SEQ ID NO: 154 1663 SEQ ID NO: 221 SEQ ID NO: 154 1664 SEQ ID NO: 222 SEQ ID NO: 154 1665 SEQ ID NO: 223 SEQ ID NO: 154 1666 SEQ ID NO: 224 SEQ ID NO: 154 1667 SEQ ID NO: 225 SEQ ID NO: 154 1668 SEQ ID NO: 226 SEQ ID NO: 154 1669 SEQ ID NO: 227 SEQ ID NO: 154 1670 SEQ ID NO: 228 SEQ ID NO: 154 1671 SEQ ID NO: 229 SEQ ID NO: 154 1672 SEQ ID NO: 230 SEQ ID NO: 154 1673 SEQ ID NO: 231 SEQ ID NO: 154 1674 SEQ ID NO: 232 SEQ ID NO: 154 1675 SEQ ID NO: 233 SEQ ID NO: 154 1676 SEQ ID NO: 234 SEQ ID NO: 154 1677 SEQ ID NO: 235 SEQ ID NO: 154 1678 SEQ ID NO: 236 SEQ ID NO: 154 1679 SEQ ID NO: 237 SEQ ID NO: 154 1680 SEQ ID NO: 238 SEQ ID NO: 154 1681 SEQ ID NO: 239 SEQ ID NO: 154 1682 SEQ ID NO: 240 SEQ ID NO: 154 1683 SEQ ID NO: 241 SEQ ID NO: 154 1684 SEQ ID NO: 242 SEQ ID NO: 154 1685 SEQ ID NO: 243 SEQ ID NO: 154 1686 SEQ ID NO: 244 SEQ ID NO: 154 1687 SEQ ID NO: 245 SEQ ID NO: 154 1688 SEQ ID NO: 246 SEQ ID NO: 154 1689 SEQ ID NO: 247 SEQ ID NO: 154 1690 SEQ ID NO: 248 SEQ ID NO: 154 1691 SEQ ID NO: 249 SEQ ID NO: 154 1692 SEQ ID NO: 250 SEQ ID NO: 154 1693 SEQ ID NO: 251 SEQ ID NO: 154 1694 SEQ ID NO: 252 SEQ ID NO: 154 1695 SEQ ID NO: 253 SEQ ID NO: 154 1696 SEQ ID NO: 254 SEQ ID NO: 154 1697 SEQ ID NO: 255 SEQ ID NO: 154 1698 SEQ ID NO: 256 SEQ ID NO: 154 1699 SEQ ID NO: 257 SEQ ID NO: 154 1700 SEQ ID NO: 258 SEQ ID NO: 154 1701 SEQ ID NO: 259 SEQ ID NO: 154 1702 SEQ ID NO: 260 SEQ ID NO: 154 1703 SEQ ID NO: 261 SEQ ID NO: 154 1704 SEQ ID NO: 262 SEQ ID NO: 154 1705 SEQ ID NO: 263 SEQ ID NO: 154 1706 SEQ ID NO: 264 SEQ ID NO: 154 1707 SEQ ID NO: 265 SEQ ID NO: 154 1708 SEQ ID NO: 266 SEQ ID NO: 154 1709 SEQ ID NO: 267 SEQ ID NO: 154 1710 SEQ ID NO: 268 SEQ ID NO: 154 1711 SEQ ID NO: 269 SEQ ID NO: 154 1712 SEQ ID NO: 270 SEQ ID NO: 154 1713 SEQ ID NO: 271 SEQ ID NO: 154 1714 SEQ ID NO: 272 SEQ ID NO: 154 1715 SEQ ID NO: 273 SEQ ID NO: 154 1716 SEQ ID NO: 274 SEQ ID NO: 154 1717 SEQ ID NO: 275 SEQ ID NO: 154 1718 SEQ ID NO: 276 SEQ ID NO: 154 1719 SEQ ID NO: 277 SEQ ID NO: 154 1720 SEQ ID NO: 278 SEQ ID NO: 154 1721 SEQ ID NO: 279 SEQ ID NO: 154 1722 SEQ ID NO: 280 SEQ ID NO: 154 1723 SEQ ID NO: 281 SEQ ID NO: 154 1724 SEQ ID NO: 282 SEQ ID NO: 154 1725 SEQ ID NO: 283 SEQ ID NO: 154 1726 SEQ ID NO: 284 SEQ ID NO: 154 1727 SEQ ID NO: 285 SEQ ID NO: 154 1728 SEQ ID NO: 286 SEQ ID NO: 154 1729 SEQ ID NO: 287 SEQ ID NO: 154 1730 SEQ ID NO: 288 SEQ ID NO: 154 1731 SEQ ID NO: 289 SEQ ID NO: 154

In certain embodiments, the anti-FGFR3 antigen binding protein or fragment thereof comprises a pair of heavy chain and light chain of Table 1.1 above.

In certain embodiments, the anti-FGFR3 antigen binding protein or fragment thereof comprises a VH domain and a VL domain, wherein:

    • (a) the VH domain comprises the amino acid sequence selected from the group consisting of: SEQ ID NO: 6, SEQ ID NO: 18, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, and SEQ ID NO: 122; and the VL domain comprises the amino acid sequence selected from the group consisting of: SEQ ID NO: 7, SEQ ID NO: 19, SEQ ID NO: 60, SEQ ID NO: 61 SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131, and SEQ ID NO: 132;
    • (b) the VH domain comprises the amino acid sequence of SEQ ID NO: 8; and the VL domain comprises the amino acid sequence of SEQ ID NO: 9;
    • (c) the VH domain comprises the amino acid sequence of SEQ ID NO: 10; and the VL domain comprises the amino acid sequence of SEQ ID NO: 11;
    • (d) the VH domain comprises the amino acid sequence of SEQ ID NO: 12; and the VL domain comprises the amino acid sequence of SEQ ID NO: 13;
    • (e) the VH domain comprises the amino acid sequence selected from the group consisting of: SEQ ID NO: 14, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, and SEQ ID NO: 23; and the VL domain comprises the amino acid sequence selected from the group consisting of: SEQ ID NO: 15, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27;
    • (f) the VH domain comprises the amino acid sequence selected from the group consisting of: SEQ ID NO: 16, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, and SEQ ID NO: 31; the VL domain comprises the amino acid sequence selected from the group consisting of: SEQ ID NO: 17, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, and SEQ ID NO: 35.

In certain embodiments, the antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 63 or 65, and the antibody light chain comprises the amino acid sequence of SEQ ID NO: 67 or 69.

Variants of the anti-FGFR3 antigen binding protein or fragment thereof as described herein are also provided. In certain embodiments, the VH domain of a variant is at least about 80%, at least at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90% identical, at least about 91% identical, at least about 92% identical, at least about 93% identical, at least about 94% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, or at least about 99% identical to the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, or SEQ ID NO: 122, and the VL domain of the variant is at least about 80%, at least at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90% identical, at least about 91% identical, at least about 92% identical, at least about 93% identical, at least about 94% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, or at least about 99% identical to the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131, or SEQ ID NO: 132. The amino acid sequence alignment for obtaining the identity can be any conventional amino acid sequence alignment tool, and the sequence alignment algorithms includes Needle-Wunsch algorithm, Smith-Waterman algorithm, or Karling & Altschul algorithm, but is not limited thereto; the amino acid sequence alignment tool includes BLAST (Basic Local Alignment Search Tool), BLAT (BLAST-like Alignment Tool), Grapped BLAST or FASTA, but is not limited thereto. In certain embodiments, the variant has all of the identical heavy chain CDRs and light chain CDRs of the anti-FGFR3 antigen binding protein or fragment thereof as described herein, with modifications in the constant region on the heavy chain and/or the light chain.

In certain embodiments, the anti-FGFR3 antigen binding protein or fragment thereof comprises an antibody heavy chain at least about 80%, at least at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90% identical, at least about 91% identical, at least about 92% identical, at least about 93% identical, at least about 94% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, or at least about 99% identical to the amino acid sequence of SEQ ID NO: 63 or 65, and an antibody light chain at least about 80%, at least at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90% identical, at least about 91% identical, at least about 92% identical, at least about 93% identical, at least about 94% identical, at least about 95% identical, at least about 96% identical, at least about 97% identical, at least about 98% identical, or at least about 99% identical to the amino acid sequence of SEQ ID NO: 67 or 69.

In certain embodiments, the anti-FGFR3 antigen binding protein or fragment thereof comprises a VH domain and a VL domain, wherein: (a) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GDTFTDFE (SEQ ID NO: 70), a CDR-H2 sequence comprising the amino acid sequence of VDPETGGT (SEQ ID NO: 297), and a CDR-H3 sequence comprising the amino acid sequence of TRTYDGYPYAFDY (SEQ ID NO: 301); and (b) the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVLYSNNNKNY (SEQ ID NO: 302), a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104), and a CDR-L3 sequence comprising the amino acid sequence of QQYYSYRT (SEQ ID NO: 75).

In certain embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 57, and the VL domain comprises the amino acid sequence of SEQ ID NO: 19 or 59.

In certain embodiments, the antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 63, and the antibody light chain comprises the amino acid sequence of SEQ ID NO: 67. In certain embodiments, the antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 65, and the antibody light chain comprises the amino acid sequence of SEQ ID NO: 69.

In certain embodiments, the anti-FGFR3 antigen binding protein or fragment thereof comprises a VH domain and a VL domain, wherein: (a) the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GDTFTDFE (SEQ ID NO: 70), a CDR-H2 sequence comprising the amino acid sequence of VDPETGGT (SEQ ID NO: 297), and a CDR-H3 sequence comprising the amino acid sequence of TRTYDGYPYAFDY (SEQ ID NO: 301); and (b) the VL domain comprises a CDR-L1 sequence comprising the amino acid sequence of QSVLYSDNQKNY (SEQ ID NO: 306), a CDR-L2 sequence comprising the amino acid sequence of FAS (SEQ ID NO: 304), and a CDR-L3 sequence comprising the amino acid sequence of QQYYSYRT (SEQ ID NO: 75).

In certain embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 57, and the VL domain comprises the amino acid sequence of SEQ ID NO: 61.

In certain embodiments, the antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 65, and the antibody light chain comprises the amino acid sequence of SEQ ID NO: 67.

In certain embodiments, the anti-FGFR3 antigen binding proteins and antigen-binding fragments thereof of the disclosure comprise one or more sequences with at least about 80%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% sequence identity to any of the sequences of Table 1, Table 3, Table 4, Table 8, Table 13, or Table 14, or protein sequences encoded by the nucleic acid sequences in Table 9.

Also provided herein are human framework regions for anti-FGFR3 antigen binding proteins and antigen-binding fragments thereof. Non-limiting examples of human framework regions are provided below.

TABLE 1.2 Human Framework regions of anti-FGFR3 antigen binding proteins and antigen-binding fragments thereof Framework type Sequence Note Heavy chain QVQLVQSGAEVKKPGASVKVSCKAS(X)n1IHWVRQAP X is any naturally occurring amino acid, and GQGLEWIGA(X)n2AYNQKFQGRVTITADKSTSTAYMEL n1, n2, and n3 are numbers at least 3, and less SSLRSEDTAVYYC(X)n3WGQGTLVTVSS than 50, each X can be the same or different SEQ ID NO: 318 amino acid as the amino acid next to it Heavy chain QVQLVQSGAEVKKPGASVKVSCKAS(X)n1IHWVRQAP GQGLEWIGA(X)n2AYNQKFQGRVTITADKSTSTAYMEL SSLRSEDTAVYYC(X)n3WGQGTLVTVSS SEQ ID NO: 319 Heavy chain QVQLVQSGAEVKKPGASVKVSCKAS(X)n1IHWVRQAP GQGLEWIGA(X)n2AYNQKFQGRVTITADKSTSTAYMEL SSLRSEDTAVYYC(X)n3WGQGTLVTVSS SEQ ID NO: 320 Heavy chain QVQLVQSGAEVKKPGASVKVSCKAS(X)n1IHWVRQAP GQGLEWIGA(X)n2AYNQKFQGRVTITADKSTSTAYMEL SSLRSEDTAVYYC(X)n3WGQGTLVTVSS SEQ ID NO: 321 Heavy chain QVQLVQSGAEVKKPGASVKVSCKAS(X)n1IHWVRQAP GQGLEWIGG(X)n2AYNQKFQGRVTITADRSTSTAYMEL SSLRSEDTAVYYC(X)n3WGQGTLVTVSS SEQ ID NO: 322 Heavy chain QVQLVQSGAEVKKPGASVKVSCKAS(X)n1IHWVRQAP GQGLEWIGG(X)n2AYNQKFQGRVTITADRSTSTAYMEL SSLRSEDTAVYYC(X)n3WGQGTLVTVSS SEQ ID NO: 323 Heavy chain QVQLVQSGAEVKKPGASVKVSCKAS(X)n1IHWVRQAP GQGLEWIGG(X)n2AYNQKFQGRVTITADRSTSTAYMEL SSLRSEDTAVYYC(X)n3WGQGTLVTVSS SEQ ID NO: 324 Heavy chain QVQLVQSGAEVKKPGASVKVSCKAS(X)n1IHWVRQAP GQGLEWIGG(X)n2AYNQKFQGRVTITADRSTSTAYMEL SSLRSEDTAVYYC(X)n3WGQGTLVTVSS SEQ ID NO: 325 Heavy chain EVQLVQSGAEVKKPGATVKLSCKAS(X)n1IHWVQQAPG KGLEWIGD(X)n2AYAEKFQGRATLTADRSTDTAYMELS SLRSEDTAVYYC(X)n3WGQGTLVTVSS SEQ ID NO: 326 Heavy chain EVQLVQSGAEVKKPGATVKLSCKAS(X)n1IHWVQQAPG KGLEWIGD(X)n2AYAEKFQGRATLTADRSTDTAYLELS SLRSEDTAVYYC(X)n3WGQGTLVTVSS SEQ ID NO: 327 Heavy chain EVQLVQSGAEVKKPGATVKLSCKAS(X)n1IHWVQQAPG KGLEWIGD(X)n2AYAEKFQGRATLTADRSTDTAYLELS SLRSEDTAVYYC(X)n3WGQGTLVTVSS SEQ ID NO: 328 Light chain DIVMTQSPDSLAVSLGERVTINCKSS(X)n1ILAWYQQKPG QSPKLLIY(X)n2TRESGVPDRFSGSGSGTDFTLTISSLQAE DVAVYYC(X)n3FGQGTKLEIK SEQ ID NO: 329 Light chain DIVMTQSPDSLAVSLGERVTINCKSS(X)n1LAWYQQKPG QSPKLLIY(X)n2TRESGVPDRFSGSGSGTDFTLTISSLQAE DVAVYYC(X)n3FGQGTKLEIK SEQ ID NO: 330 Light chain DIVMTQSPDSLAVSLGERVTINCKSS(X)n1LAWYQQKPG QSPKLLIY(X)n2TRESGVPDRFSGSGSGTDFTLTISSLQAE DVAVYYC(X)n3FGQGTKLEIK SEQ ID NO: 331 Light chain DIVMTQSPDSLAVSLGERVTINCKSS(X)n1LAWYQQKPG QSPKLLIY(X)n2TRESGVPDRFSGSGSGTDFTLTISSLQAE DVAVYYC(X)n3FGQGTKLEIK SEQ ID NO: 332 Light chain DIVMTQSPDSLAVSLGERVTINCKSS(X)n1LAWYQQKPG QSPKLLIY(X)n2TRESGVPDRFSGSGSGTDFTLTISSLQAE DVAVYYC(X)n3FGQGTKLEIK SEQ ID NO: 333 Light chain DIVMTQSPDSLAVSLGERVTINCKSS(X)n1LAWYQQKPG QSPKLLIY(X)n2TRESGVPDRFSGSGSGTDFTLTISSLQAE DVAVYYC(X)n3FGQGTKLEIK SEQ ID NO: 334 Light chain DIVMTQSPDSLAVSLGERVTINCKSS(X)n1LAWYQQKPG QSPKLLIY(X)n2TRESGVPDRFSGSGSGTDFTLTISSLQAE DVAVYYC(X)n3FGQGTKLEIK SEQ ID NO: 335 Light chain DIVMTQSPDSLAVSLGERVTINCKSS(X)n1LAWYQQKPG QSPKLLIY(X)n2TRESGVPDRFSGSGSGTDFTLTISSLQAE DVAVYYC(X)n3FGQGTKLEIK SEQ ID NO: 336 Light chain DIVMTQSPDSLAVSLGERATINCKSS(X)n1LAWYQQKPG QSPKLLIY(X)n2TRESGVPDRFSGSGSGTDFTLTISSVQA EDVAVYYC(X)n3FGGGTKVEIK SEQ ID NO: 337 Light chain DIVMTQSPDSLAVSLGERATINCKSS(X)n1LAWYQQKPG QSPKLLIY(X)n2TRESGVPDRFSGSGSGTDFTLTISSVQA EDVAVYYC(X)n3FGGGTKVEIK SEQ ID NO: 338 Light chain DIVMTQSPDSLAVSLGERVTINCKSS(X)n1LAWYQQKPG QSPKLLIY(X)n2TRESGVPDRFSGSGSGTDFTLTISSVQA EDVAVYYC(X)n3FGGGTKLEIK SEQ ID NO: 339

In some embodiments, the anti-FGFR3 antigen binding proteins and antigen-binding fragments comprise three heavy chain CDRs that bind to FGFR3, such as the three heavy chain CDRs of mouse antibody KC18, KE35, KE42, KE58, KE63, or KE94, and a human heavy chain variable region framework. In certain embodiments, the anti-FGFR3 antigen binding proteins and antigen-binding fragments further comprise three light chain CDRs that bind to FGFR3, such as the three light chain CDRs of mouse antibody KC18, KE35, KE42, KE58, KE63, or KE94, and a human light chain variable region framework. In certain embodiments, the human heavy chain variable region framework comprises any one of SEQ ID NOs: 318 to 328. In certain embodiments, the human light chain variable region framework comprises any one of SEQ ID NOs: 329 to 339. In certain embodiments, the human heavy chain variable region framework comprises a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more identity to any one of SEQ ID NOs: 318 to 328. In certain embodiments, the human light chain variable region framework comprises a sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more identity to any one of SEQ ID NOs: 329 to 339. In certain embodiments, such anti-FGFR3 antigen binding proteins and antigen-binding fragments bind human FGFR3 with an equilibrium dissociation constant (KD) of about 100 nM or less, about 90 nM or less, about 80 nM or less, about 70 nM or less, about 60 nM or less, about 50 nM or less, about 40 nM or less, about 30 nM or less, about 20 nM or less, about 10 nM or less, about 9 nM or less, about 8 nM or less, about 7 nM or less, about 6 nM or less, about 5 nM or less, about 4 nM or less, about 3 nM or less, about 2.89 nM or less, about 2 nM or less, about 1.5 or less, about 1.4 or less, about 1.23 or less, about 1.2 or less, or about 1 nM or less, about 0.8 or less, or about 0.6 or less. “X nM or less” therein includes the embodiment “less than X nM”. “Less” therein can mean e.g. to about 2.8 nM, to about 1.3 nM, to about 1.1 nM, to about 0.7 nM or to about 0.5 nM. These lower limits can be used to form ranges with any of the aforementioned upper limits, such as about 3 nM or <3 nM to about 2.8 nM, about 1.5 nM or <1.5 nM to about 1.3 nM, about 1.3 nM or <1.3 nM to about 1.1 nM, about 0.9 nM or <0.9 nM to about 0.7 nM, or about 0.7 nM or <0.7 nM to about 0.5 nM. “About X” therein can mean e.g. “X±5%”, “X±4%”, “X±4%”, “X±3%”, “X±2%”, “X±1%” or “X±0.5%”. In certain embodiments, the nM values are as obtained by a Surface Plasmon Resonance assay, such as the Biacore assay.

In certain embodiments, the anti-FGFR3 antigen binding proteins and antigen-binding fragments thereof of the disclosure are chimeric or humanized antibodies. In certain embodiments, the antigen binding protein is a humanized antibody.

In certain embodiments, the antigen binding protein is a monoclonal antibody.

In certain embodiments, the antigen binding protein comprises one or more full-length antibody heavy chains comprising an Fc region. In certain embodiments, the Fc region is a human IgG1 Fc region. In certain embodiments, the Fc region is a human IgG4 Fc region.

In certain embodiments, the antibody Fc region comprises one or more mutations that reduces Fc effector function. In certain embodiments, the one or more mutations reduces one or more of antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), or complement dependent cytotoxicity (CDC). In certain embodiments, the human IgG1 Fc region comprises a L234A and L235A mutation. In certain embodiments, the human IgG4 Fc region comprises a F234A and L235A mutation. These IgG1 and IgG4 mutations are also known as the “LALA” and “FALA” mutations, respectively, and are described in further detail in Xu et al. (Cell Immunol. 2000; 200:16-26). In certain embodiments, the human IgG4 Fc region comprises one or more stabilizing mutations, including, but limited to, mutations in the IgG4 hinge that reduce or prevent the formation of disulfide bonds and in vivo fab arm exchange (FAE). In certain embodiments, the human IgG4 Fc region comprises a S228P mutation. The IgG4 hinge mutation is described in further detail in Angal et al. (Mol. Immunol. 1993; 30:105-108). In certain embodiments, the human IgG4 Fc region comprises a S228P mutation and a L235A mutation. In certain embodiments, the human IgG1 Fc region comprises one or more mutations that alters antibody glycosylation. In certain embodiments, the human IgG1 Fc region comprises one or more of a S298N mutation, a T299A mutation, and a Y300S mutation. In certain embodiments, the human IgG1 Fc region comprises a S298N mutation, a T299A mutation, and a Y300S mutation. The Fc region amino acid positions referred to herein are based on EU antibody numbering.

In certain embodiments, the anti-FGFR3 antigen binding protein fragments of the disclosure comprise or consists of an antibody F(ab), F(ab′)2, Fab′-SH, Fv, or scFv fragment. In certain embodiments, the antigen binding protein fragment comprises an antibody F(ab) fragment.

The antibody F(ab) fragment can be modified with one or more serum half-life extending moieties. In certain embodiments, the antibody F(ab) fragment is conjugated to an antigen binding protein with binding specificity to serum albumin. In certain embodiments, the antigen binding protein with binding specificity to serum albumin is a nanobody. In certain embodiments, the serum albumin is human serum albumin or mouse serum albumin.

In certain embodiments, the antibody F(ab) fragment comprises a heavy chain and a light chain. In certain embodiments, the heavy chain of the F(ab) fragment comprises a heavy chain variable region disclosed herewith, and a light chain variable region disclosed herewith. In certain embodiments, the heavy chain variable region comprises or consists of any one of SEQ ID NOs: 6, 8, 10, 12, 14, 16, 18, 20, 21, 22, 23, 28, 29, 30, 31, 56, 57, 58, 106, 107, 108, 109, 110, 111, 115, 116, 117, 118, 119, 120, 121, or 112, or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identity to any of SEQ ID NOs: 6, 8, 10, 12, 14, 16, 18, 20, 21, 22, 23, 28, 29, 30, 31, 56, 57, 58, 106, 107, 108, 109, 110, 111, 115, 116, 117, 118, 119, 120, 121, or 112. In certain embodiments, the light chain variable region comprises or consists of any one of SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 24, 25, 26, 27, 32, 33, 34, 35, 59, 60, 61, 112, 113, 114, 123, 124, 125, 126, 127, 128, 129, 130, 131, or 132, or a or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or at least 99% identity to any of SEQ ID NOs: 7, 9, 11, 13, 15, 17, 19, 24, 25, 26, 27, 32, 33, 34, 35, 59, 60, 61, 112, 113, 114, 123, 124, 125, 126, 127, 128, 129, 130, 131, or 132.

In certain embodiments, the heavy chain of the F(ab) fragment comprises or consists of a heavy chain variable region disclosed herewith and a heavy chain constant region. In certain embodiments, the heavy chain constant region is derived from a human IgG1 Fc region, a human IgG2 Fc region, a human IgG3 Fc region, a human IgG4 Fc region, or a combination thereof. In certain embodiments, the heavy chain constant region is a fragment of a human IgG1 Fc region, a human IgG2 Fc region, a human IgG3 Fc region, a human IgG4 Fc region, or a combination thereof. In certain embodiments, the heavy chain constant region comprises or consists of the first 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 5, 36, 37, 38, 39, 40, 41, 44, 45, 46, 7, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224,225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, or 300 amino acids of a human IgG Fc region, such as the human IgG1 Fc region (SEQ ID NO: 54).

In certain embodiments, the light chain of the F(ab) fragment comprises or consists of a light chain variable region disclosed herewith, and a light chain constant region. In certain embodiments, the light chain constant region is derived from a human kappa (κ) chain, a human lambda (λ) chain, or a combination thereof. In certain embodiments, the light chain constant region comprises or consists of a part of IgG1 light constant region. In certain embodiments, the part of the IgG1 light constant region comprises or consists of the first 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 5, 36, 37, 38, 39, 40, 41, 44, 45, 46, 7, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, or 107 amino acids of SEQ ID NO: 55.

In certain embodiments, the F(ab) fragment comprises one or more point mutations in the C-terminus to reduce anti-Fab antibody binding.

In certain embodiments, the antigen binding protein comprises cross-reactivity to one or both of mouse and cynomolgus FGFR3. In certain embodiments, the cynomolgus FGFR3 is encoded by SEQ ID NO: 136:

(SEQ ID NO: 136) ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCAGTGGCCATCGT GGCCGGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGC GAGTGGCAGAAGTGTCCGGCCCGGAGCCCAGCCAGCAGGAGCAGTTGGTC TTCGGCAGCGGGGACGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGG TCCCATGGGGCCCACTGTCTGGGTCAAGGATGGCGCAGGGCTGGTGCCCT CGGAGCGTGTCCTGGTGGGGCCCCAGCGGCTGCAGGTGCTGAATGCCTCC CACGAGGACTCTGGGGCCTACAGCTGCCGGCAGCGGCTCACACAGCTCGT ACTGTGCCACTTCAGTGTGCGGGTGACAGATGCTCCATCCTCGGGAGATG ACGAAGACGGGGAGGACGAGGCTGAGGACACAGGTGTGGACACAGGGGCC CCTTACTGGACTCGGCCCGAGCGGATGGACAAGAAGCTGCTGGCTGTGCC GGCCGCCAACACCGTCCGCTTCCGCTGCCCGGCTGCCGGCAACCCCACTC CCTCCATCTCCTGGCTGAAGAATGGCAAGGAGTTCCGCGGCGAGCACCGC ATTGGCGGCATCAAGCTTCGGCACCAGCAGTGGAGCCTGGTCATGGAAAG CGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTGGTGGAGAACAAGT TTGGCAGCATCCGGCAGACATACACGCTGGACGTGCTGGAGCGCTCCCCG CACCGGCCCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCT GGGCAGCGATGTGGAGTTTCACTGCAAGGTGTACAGTGATGCGCAGCCCC ACATCCAGTGGCTCAAGCACGTGGAGGTGAATGGCAGCAAGGTGGGCCCC GACGGCACACCCTACGTCACCGTGCTCAAGACGGCGGGCGCTAATACCAC CGACAAGGAGCTAGAGGTTCTGTCCTTGCACAACGTCACCTTTGAGGACG CCGGGGAGTACACCTGCCTGGCGGGCAATTCTATTGGGTTTTCCCATCAC TCTGCGTGGCTCGTGGTGCTGCCAGCTGAGGAGGAGCTGGTGGAGGCTGA CGAGGCGGGCAGTGTGTACGCAGGCATCCTCAGCTACGGGGTGGGCTTCT TCCTGTTCATCCTGGTGGTGGCGGCTGTGACGCTCTGCCGCCTGCGCAGC ACCCCCAAGAAAGGCCTGGGCTCCCCCACCGTGCACAAGATCTCCCGCTT CCCACTCAAGCGACAGGTGTCCCTGGAGTCCAACGCGTCCATGAGCTCCA ACACACCGCTGGTGCGCATCGCAAGGCTGTCCTCAGGGGAGGGTCCCACA CTGGCCAATGTCTCCGAGCTTGAGCTGCCTGCTGACCCCAAATGGGAGCT GTCTCGGGCCCGGCTGACCCTGGGCAAGCCCCTTGGGGAGGGCTGCTTTG GCCAGGTGGTCATGGCGGAGGCTATCGGCATTGACAAGGACCGGGCCGCC AAGCCTGTCACCGTAGCCGTGAAGATGCTGAAAGATGATGCCACTGACAA GGACCTGTCAGACCTGGTGTCTGAGATGGAGATGATGAAGATGATTGGGA AACACAAGAACATTATCAACCTGCTGGGCGCCTGCACGCAGGGCGGGCCC CTGTACGTGCTGGTGGAGTACGCGGCCAAGGGCAACCTGAGGGAGTTTCT GCGGGCGCGGCGGCCCCCGGGCCTGGACTACTCCTTCGACACCTGCAAGC CGCCTGAGGAGCAGCTCACCTTCAAGGACCTGGTGTCCTGTGCCTACCAG GTGGCCCGAGGCATGGAGTACCTCGCCTCCCAGAAGTGCATCCACAGGGA CCTGGCTGCTCGAAATGTGCTGGTGACCGAGGACAACGTGATGAAGATCG CAGACTTCGGGCTGGCCCGCGACGTGCACAACCTTGACTACTACAAGAAG ACAACCAACGGCCGGCTGCCCGTGAAGTGGATGGCGCCTGAGGCCCTGTT TGACCGAGTCTACACCCACCAGAGTGACGTCTGGTCCTTTGGGGTCCTGC TCTGGGAGATCTTCACGCTGGGGGGCTCTCCGTACCCCGGCATCCCTGTG GAGGAGCTCTTCAAGCTGCTGAAGGAGGGTCACCGGATGGACAAGCCGGC CAACTGCACACACGACCTGTACATGATCATGCGGGAGTGCTGGCATGCTG CGCCCTCCCAGAGGCCCACCTTCAAGCAGCTGGTGGAGGACCTGGACCGT GTCCTCACTGTGACGTCCACCGACGAGTACCTGGACCTGTCAGCGCCCTT CGAGCAGTACTCCCCCGGCGGCCAGGACACCCCGAGCTCCAGCTCCTCAG GGGATGACTCCGTGTTTGCCCACGACCTGCTGCCCCCGGCCCCACCCAGC AGTGGGGGCTCGCGGACGTGA

In certain embodiments, the cynomolgus FGFR3 is the IIIc isoform, comprising SEQ ID NO: 138, or its mutated version comprising the G380R mutation (SEQ ID NO: 139):

(SEQ ID NO: 138) MGAPACALALCVAVAIVAGASSESLGTEQRVVGRVAEVSGPEPSQQEQLV FGSGDAVELSCPPPGGGPMGPTVWVKDGAGLVPSERVLVGPQRLQVLNAS HEDSGAYSCRQRLTQLVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGA PYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGKEFRGEHR IGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSP HRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGP DGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHH SAWLVVLPAEEELVEADEAGSVYAGILSYGVGFFLFILVVAAVTLCRLRS TPKKGLGSPTVHKISRFPLKRQVSLESNASMSSNTPLVRIARLSSGEGPT LANVSELELPADPKWELSRARLTLGKPLGEGCFGQVVMAEAIGIDKDRAA KPVTVAVKMLKDDATDKDLSDLVSEMEMMKMIGKHKNIINLLGACTQGGP LYVLVEYAAKGNLREFLRARRPPGLDYSFDTCKPPEEQLTFKDLVSCAYQ VARGMEYLASQKCIHRDLAARNVLVTEDNVMKIADFGLARDVHNLDYYKK TTNGRLPVKWMAPEALFDRVYTHQSDVWSFGVLLWEIFTLGGSPYPGIPV EELFKLLKEGHRMDKPANCTHDLYMIMRECWHAAPSQRPTFKQLVEDLDR VLTVTSTDEYLDLSAPFEQYSPGGQDTPSSSSSGDDSVFAHDLLPPAPPS SGGSRT (SEQ ID NO: 139) MGAPACALALCVAVAIVAGASSESLGTEQRVVGRVAEVSGPEPSQQEQLV FGSGDAVELSCPPPGGGPMGPTVWVKDGAGLVPSERVLVGPQRLQVLNAS HEDSGAYSCRQRLTQLVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGA PYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGKEFRGEHR IGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSP HRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGP DGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHH SAWLVVLPAEEELVEADEAGSVYAGILSYRVGFFLFILVVAAVTLCRLRS TPKKGLGSPTVHKISRFPLKRQVSLESNASMSSNTPLVRIARLSSGEGPT LANVSELELPADPKWELSRARLTLGKPLGEGCFGQVVMAEAIGIDKDRAA KPVTVAVKMLKDDATDKDLSDLVSEMEMMKMIGKHKNIINLLGACTQGGP LYVLVEYAAKGNLREFLRARRPPGLDYSFDTCKPPEEQLTFKDLVSCAYQ VARGMEYLASQKCIHRDLAARNVLVTEDNVMKIADFGLARDVHNLDYYKK TTNGRLPVKWMAPEALFDRVYTHQSDVWSFGVLLWEIFTLGGSPYPGIPV EELFKLLKEGHRMDKPANCTHDLYMIMRECWHAAPSQRPTFKQLVEDLDR VLTVTSTDEYLDLSAPFEQYSPGGQDTPSSSSSGDDSVFAHDLLPPAPPS SGGSRT

In certain embodiments, the antigen binding protein comprises binding specificity for FGFR3 isoform IIIb and/or isoform IIIc.

In certain embodiments, the antigen binding protein specifically binds to FGFR3, and does not bind to one or more of FGFR1, FGFR2, and FGFR4, or does not have detectable binding to one or more of FGFR1, FGFR2, and FGFR4. In certain embodiments, the antigen binding protein does not bind to each of FGFR1, FGFR2, and FGFR4, or does not have detectable binding to each of FGFR1, FGFR2, and FGFR4. In certain embodiments, the antigen binding protein binds to each of FGFR1, FGFR2, and FGFR4 with an affinity of about 100 μM, 500 μM, 1000 μM, or greater. In certain embodiments, the antigen binding protein does not bind to one or more of FGFR1, FGFR2, and FGFR4 over a background measurement, as determined by a Biacore affinity analysis.

In certain embodiments, the antigen binding protein binds human FGFR3 with an equilibrium dissociation constant (KD) of about 100 nM or less, about 90 nM or less, about 80 nM or less, about 70 nM or less, about 60 nM or less, about 50 nM or less, about 40 nM or less, about 30 nM or less, about 20 nM or less, about 10 nM or less, about 9 nM or less, about 8 nM or less, about 7 nM or less, about 6 nM or less, about 5 nM or less, about 4 nM or less, about 3 nM or less, about 2.89 nM or less, about 2 nM or less, about 1.5 or less, about 1.4 or less, about 1.23 or less, about 1.2 or less, or about 1 nM or less, about 0.8 or less, or about 0.6 or less. “X nM or less” therein includes the embodiment “less than X nM”. “Less” therein can mean e.g. to about 2.8 nM, to about 1.3 nM, to about 1.1 nM, to about 0.7 nM or to about 0.5 nM. These lower limits can be used to form ranges with any of the aforementioned upper limits, such as about 3 nM or <3 nM to about 2.8 nM, about 1.5 nM or <1.5 nM to about 1.3 nM, about 1.3 nM or <1.3 nM to about 1.1 nM, about 0.9 nM or <0.9 nM to about 0.7 nM, or about 0.7 nM or <0.7 nM to about 0.5 nM. “About X” therein can mean e.g. “X±5%”, “X±4%”, “X±4%”, “X±3%”, “X±2%”, “X±1%” or “X±0.5%”. In certain embodiments, the nM values are as obtained by a Surface Plasmon Resonance assay, such as the Biacore assay. In certain embodiments, the Biacore assay is carried out at about 4° C., 10° C., 15° C., 20° C., 25° C., 30° C., or 37° C.

In certain embodiments, the antigen binding protein binds human FGFR3 with an off rate (Kd) of about 10−2 s−1 or less, about 5×10−3 s−1 or less, about 2×10−3 s−1 or less, about 10−3 s−1 or less, about 9×10−4 s−1 or less, about 8×10−4 s−1 or less, about 7×10−4 s−1 or less, about 6×10−4 s−1 or less, about 5×10−4 s−1 or less, about 4×10−4 s−1 or less, or about 3.5×10−4 s−1 or less. “Less” therein can mean e.g. to about 3×10−4 s−1. “About X” therein can mean e.g. “X±10%”, “X±5%”, “X±4%”, “X±4%”, “X±3%”, “X±2%”, “X±1%” or “X±0.5%”.

In certain embodiments, the antigen binding protein inhibits ligand-induced FGFR3 dimerization with IC50 of about 5 μg/ml or less, about 4 μg/ml or less, about 3 μg/ml or less, about 2 μg/ml or less, about 1 μg/ml or less, about 0.9 μg/ml or less, about 0.8 μg/ml or less, about 0.7 μg/ml or less, about 0.6 μg/ml or less, about 0.5 μg/ml or less, about 0.4 μg/ml or less, or about 0.3 μg/ml or less. “Less” therein can mean e.g. to about 0.25 μg/ml (or less, e.g. to about 0.2 μg/ml or about 0.1 μg/ml). “About X” therein can mean e.g. “X±10%”, “X±5%”, “X±4%”, “X±4%”, “X±3%”, “X±2%”, “X±1%” or “X±0.5%”. In certain embodiments, the nM values are as obtained by a Homogenous Time-Resolved Fluorescence (HTRF) assay at about 4° C., 10° C., 15° C., 20° C., 25° C., 30° C., or 37° C.

In certain embodiments, the antigen binding protein inhibits FGFR3 receptor activation and downstream signaling with IC50 of about 5 μg/ml or less, about 4 μg/ml or less, about 3 μg/ml or less, about 2 μg/ml or less, about 1 μg/ml or less, about 0.9 μg/ml or less, about 0.8 μg/ml or less, about 0.7 μg/ml or less, about 0.6 μg/ml or less, about 0.5 μg/ml or less, about 0.4 μg/ml or less, or about 0.3 μg/ml or less. “Less” therein can mean e.g. to about 0.25 μg/ml (or less, e.g. to about 0.2 μg/ml or about 0.1 μg/ml). About X” therein can mean e.g. “X±10%”, “X±5%”, “X±4%”, “X±4%”, “X±3%”, “X±2%”, “X±1%” or “X±0.5%”. %”. In certain embodiments, the nM values are as obtained by a homogenous time-resolved fluorescence (HTRF) assay.

Inhibition of FGFR3 receptor activation and downstream signaling can be determined by any means known in the art. In certain embodiments, inhibition of FGFR3 receptor activation and downstream signaling is measured by determining Erk phosphorylation. A decrease in Erk phosphorylation indicates inhibition of FGFR3 activation. Erk phosphorylation can be determined using a homogenous time-resolved fluorescence (HTRF) assay. In certain embodiments, the assay is performed in chondrocytes. In certain embodiments, the assay is performed in mouse primary rib chondrocytes.

In certain embodiments, the antigen binding protein inhibits the activity of an FGFR3G380R mutant. In certain embodiments, the antigen binding protein inhibits the activity of a human FGFR3G380R mutant, a mouse FGFR3G380R mutant, and/or a cynomolgus FGFR3G380R mutant. In certain embodiments, the human FGFR3G380R mutant is represented by the amino acid sequence set forth in SEQ ID NO: 133.

In certain embodiments, the antigen binding protein or fragment thereof is capable of penetrating a bone growth plate.

In certain embodiments, the antigen binding protein or fragment thereof is capable of decreasing the binding of FGFR3 with its ligand in a bone growth plate.

Anti-FGFR3 Antigen-Binding Protein Epitopes

In one aspect, the disclosure provides an antigen-binding protein or fragment thereof with binding specificity to a fibroblast growth factor receptor 3 (FGFR3) epitope, comprising an antibody heavy chain variable (VH) domain and an antibody light chain variable (VL) domain, wherein the antigen binding protein binds a human FGFR3 polypeptide comprising the amino acid sequence of SEQ ID NO: 134, recited below.

(SEQ ID NO: 134) DTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNG REFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYT LDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVE VNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAG NSIGFSHHSAWLVVLPAEEELVE

In certain embodiments, the anti-FGFR3 antigen binding proteins and antigen-binding fragments thereof of the disclosure bind a human FGFR3 polypeptide comprising the amino acid sequence of SEQ ID NO: 134, recited above. The amino acid sequence recited above corresponds to the D2D3 region of FGFR3 isoform IIIc, specifically to amino acid D143 to E365 of FGFR3 isoform IIIc.

In certain embodiments, the anti-FGFR3 antigen binding proteins and antigen-binding fragments thereof of the disclosure bind an epitope of human FGFR3 polypeptide comprising the N-terminus of the D2 region (amino acids D143 to L163) of SEQ ID NO: 133, shown above.

In certain embodiments, the anti-FGFR3 antigen binding proteins and antigen-binding fragments thereof of the disclosure bind an epitope of human FGFR3 polypeptide comprising the N-terminus of the D2 region (amino acids D143 to N170) of SEQ ID NO: 133, shown above.

In certain embodiments, the anti-FGFR3 antigen binding proteins and antigen-binding fragments thereof of the disclosure bind an epitope of human FGFR3 polypeptide comprising the N-terminus and middle of the D2 region (amino acids D143 to D160 and G197 to L213) of SEQ ID NO: 133, shown above.

In certain embodiments, the one or more epitopes of the anti-FGFR3 antigen binding proteins and antigen-binding fragments thereof of the disclosure are determined by hydrogen deuterium exchange (HDX) mass spectrometry. HDX is performed by measuring the amide hydrogen deuterium exchange on FGFR3 over time. HDX mass spectrometry is described in further detail in Prądzińska et al. (Amino Acids. 48: 2809-2820. 2016).

In certain embodiments, the anti-FGFR3 antigen binding proteins and antigen-binding fragments thereof of the disclosure compete with a reference binding protein for binding to the human FGFR3 polypeptide D2 region.

In one aspect, the disclosure provides an antigen-binding protein or fragment thereof with binding specificity to a fibroblast growth factor receptor 3 (FGFR3) epitope, comprising an antibody heavy chain variable (VH) domain and an antibody light chain variable (VL) domain, wherein the antigen binding protein competes for binding to FGFR3 with an antibody comprising VH/VL domain amino acid sequence pairs selected from the group consisting of: SEQ ID NO: 6/SEQ ID NO: 7, SEQ ID NO: 8/SEQ ID NO: 9, SEQ ID NO: 10/SEQ ID NO: 11, SEQ ID NO: 12/SEQ ID NO: 13, SEQ ID NO: 14/SEQ ID NO: 15, and SEQ ID NO: 16/SEQ ID NO: 17.

Expression of Antigen-Binding Proteins

In one aspect, polynucleotides encoding the binding proteins (e.g., antigen-binding proteins and antigen-binding fragments thereof) disclosed herein are provided. Methods of making binding proteins comprising expressing these polynucleotides are also provided.

Polynucleotides encoding the binding proteins disclosed herein are typically inserted in an expression vector for introduction into host cells that may be used to produce the desired quantity of the binding proteins. Accordingly, in certain aspects, the disclosure provides expression vectors comprising polynucleotides disclosed herein and host cells comprising these vectors and polynucleotides.

The term “vector” or “expression vector” is used herein to mean vectors used in accordance with the present disclosure as a vehicle for introducing into and expressing a desired gene in a cell. As known to those skilled in the art, such vectors may readily be selected from the group consisting of plasmids, phages, viruses and retroviruses. In general, vectors compatible with the disclosure will comprise a selection marker, appropriate restriction sites to facilitate cloning of the desired gene and the ability to enter and/or replicate in eukaryotic or prokaryotic cells.

Numerous expression vector systems may be employed for the purposes of this disclosure. For example, one class of vector utilizes DNA elements which are derived from animal viruses such as bovine papilloma virus, polyoma virus, adenovirus, vaccinia virus, baculovirus, retroviruses (RSV, MMTV or MOMLV), or SV40 virus. Others involve the use of polycistronic systems with internal ribosome binding sites. Additionally, cells which have integrated the DNA into their chromosomes may be selected by introducing one or more markers which allow selection of transfected host cells. The marker may provide for prototrophy to an auxotrophic host, biocide resistance (e.g., antibiotics) or resistance to heavy metals such as copper. The selectable marker gene can either be directly linked to the DNA sequences to be expressed, or introduced into the same cell by co-transformation. Additional elements may also be needed for optimal synthesis of mRNA. These elements may include signal sequences, splice signals, as well as transcriptional promoters, enhancers, and termination signals. In some embodiments, the cloned variable region genes are inserted into an expression vector along with the heavy and light chain constant region genes (e.g., human constant region genes) synthesized as discussed above.

In other embodiments, the binding proteins may be expressed using polycistronic constructs. In such expression systems, multiple gene products of interest such as heavy and light chains of antibodies may be produced from a single polycistronic construct. These systems advantageously use an internal ribosome entry site (IRES) to provide relatively high levels of polypeptides in eukaryotic host cells. Compatible IRES sequences are disclosed in U.S. Pat. No. 6,193,980, which is incorporated by reference herein in its entirety for all purposes. Those skilled in the art will appreciate that such expression systems may be used to effectively produce the full range of polypeptides disclosed in the instant application.

More generally, once a vector or DNA sequence encoding a binding protein, e.g. an antibody or fragment thereof, has been prepared, the expression vector may be introduced into an appropriate host cell. That is, the host cells may be transformed. Introduction of the plasmid into the host cell can be accomplished by various techniques well known to those of skill in the art. These include, but are not limited to, transfection (including electrophoresis and electroporation), protoplast fusion, calcium phosphate precipitation, cell fusion with enveloped DNA, microinjection, and infection with intact virus. See, Ridgway, A. A. G. “Mammalian Expression Vectors” Chapter 24.2, pp. 470-472 Vectors, Rodriguez and Denhardt, Eds. (Butterworths, Boston, Mass. 1988). Plasmid introduction into the host can be by electroporation. The transformed cells are grown under conditions appropriate to the production of the light chains and heavy chains, and assayed for heavy and/or light chain protein synthesis. Exemplary assay techniques include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), or fluorescence-activated cell sorter analysis (FACS), immunohistochemistry and the like.

As used herein, the term “transformation” shall be used in a broad sense to refer to the introduction of DNA into a recipient host cell that changes the genotype.

Along those same lines, “host cells” refers to cells that have been transformed with vectors constructed using recombinant DNA techniques and encoding at least one heterologous gene. In descriptions of processes for isolation of polypeptides from recombinant hosts, the terms “cell” and “cell culture” are used interchangeably to denote the source of antibody unless it is clearly specified otherwise. In other words, recovery of polypeptide from the “cells” may mean either from spun down whole cells, from supernatant of lysed cells culture, or from the cell culture containing both the medium and the suspended cells.

In one embodiment, a host cell line used for antibody expression is of mammalian origin. Those skilled in the art can determine particular host cell lines which are best suited for the desired gene product to be expressed therein. Exemplary host cell lines include, but are not limited to, DG44 and DUXB11 (Chinese Hamster Ovary lines, DHFR minus), HELA (human cervical carcinoma), CV-1 (monkey kidney line), COS (a derivative of CV-1 with SV40 T antigen), R1610 (Chinese hamster fibroblast) BALBC/3T3 (mouse fibroblast), HEK (human kidney line), SP2/O (mouse myeloma), BFA-1c1BPT (bovine endothelial cells), RAJI (human lymphocyte), 293 (human kidney). In one embodiment, the cell line provides for altered glycosylation, e.g., afucosylation, of the antibody expressed therefrom (e.g., PER.C6® (Crucell) or FUT8-knock-out CHO cell lines (POTELLIGENT® cells) (Biowa, Princeton, N.J.)). In one embodiment, NSO cells may be used. CHO cells are particularly useful. Host cell lines are typically available from commercial services, e.g., the American Tissue Culture Collection, or from authors of published literature.

In vitro production allows scale-up to give large amounts of the desired polypeptides. Techniques for mammalian cell cultivation under tissue culture conditions are known in the art and include homogeneous suspension culture, e.g., in an airlift reactor or in a continuous stirrer reactor, or immobilized or entrapped cell culture, e.g., in hollow fibers, microcapsules, on agarose microbeads or ceramic cartridges. If necessary and/or desired, the solutions of polypeptides can be purified by the customary chromatography methods, for example gel filtration, ion-exchange chromatography, chromatography over DEAE-cellulose and/or (immuno-) affinity chromatography.

Genes encoding the binding proteins featured in the disclosure can also be expressed in non-mammalian cells such as bacteria or yeast or plant cells. In this regard, it will be appreciated that various unicellular non-mammalian microorganisms such as bacteria can also be transformed, i.e., those capable of being grown in cultures or fermentation. Bacteria, which are susceptible to transformation, include members of the enterobacteriaceae, such as strains of Escherichia coli or Salmonella; Bacillaceae, such as Bacillus subtilis; Pneumococcus; Streptococcus, and Haemophilus influenzae. It will further be appreciated that, when expressed in bacteria, the binding proteins can become part of inclusion bodies. In some embodiments, the binding proteins are then isolated, purified and assembled into functional molecules. In some embodiments, the binding proteins of the disclosure are expressed in a bacterial host cell. In some embodiments, the bacterial host cell is transformed with an expression vector comprising a nucleic acid molecule encoding a binding protein of the disclosure.

In addition to prokaryotes, eukaryotic microbes may also be used. Saccharomyces cerevisiae, or common baker's yeast, is the most commonly used among eukaryotic microbes, although a number of other strains are commonly available. For expression in Saccharomyces, the plasmid YRp7, for example (Stinchcomb et al., Nature, 282:39 (1979); Kingsman et al., Gene, 7:141 (1979); Tschemper et al., Gene, 10:157 (1980)), is commonly used. This plasmid already contains the TRP1 gene which provides a selection marker for a mutant strain of yeast lacking the ability to grow in tryptophan, for example ATCC No. 44076 or PEP4-1 (Jones, Genetics, 85:12 (1977)). The presence of the trpl lesion as a characteristic of the yeast host cell genome then provides an effective environment for detecting transformation by growth in the absence of tryptophan.

Methods of Preparing/Administering Binding Proteins

Methods of preparing and administering binding proteins (e.g., antigen-binding proteins and antigen-binding fragments thereof disclosed herein) to a subject are also provided. The route of administration of the antigen binding proteins and antigen-binding fragments thereof of the current disclosure may be oral, parenteral, by inhalation or topical. The term parenteral as used herein includes intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, rectal or vaginal administration. While all these forms of administration are clearly contemplated as being within the scope of the current disclosure, a form for administration would be a solution for injection, e.g. for intravenous or intraarterial injection or drip. Usually, a suitable pharmaceutical composition for injection may comprise a buffer, a surfactant, optionally a stabilizer agent, etc. However, in other methods compatible with the teachings herein, the modified antibodies can be delivered directly to the site of the adverse cellular population thereby increasing the exposure of the diseased tissue to the therapeutic agent.

Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Other common parenteral vehicles include sodium phosphate solutions, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present such as for example, antimicrobials, antioxidants, chelating agents, and inert gases and the like. Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In such cases, the composition must be sterile and should be fluid to the extent that syringability for injection exists. It should be stable under the conditions of manufacture and storage, and should also be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium. The proper fluidity can be maintained, for example, by the use of a coating, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.

Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents. Isotonic agents, for example, sugars, polyalcohols, may also be included in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

In any case, sterile injectable solutions can be prepared by incorporating an active compound (e.g., a modified binding protein by itself or in combination with other active agents) in a required amount in an appropriate solvent with one or a combination of ingredients enumerated, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and any required other ingredients. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation typically include vacuum drying and freeze-drying, which yield a powder of an active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The preparations for injections are processed, filled into containers such as ampoules, bags, bottles, syringes or vials, and sealed under aseptic conditions according to methods known in the art. Further, the preparations may be packaged and sold in the form of a kit.

Effective doses of the compositions of the present disclosure, for the treatment of a disease or disorder vary depending upon many different factors, including means of administration, target site, physiological state of the subject, whether the subject is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic. Usually, the patient is a human, but non-human mammals including transgenic mammals can also be treated. Treatment dosages may be titrated to optimize safety and efficacy.

Binding proteins described herein can be administered on multiple occasions. Intervals between single dosages can be weekly, monthly or yearly. Intervals can also be irregular as indicated by measuring levels of binding protein or antigen in the subject. Alternatively, binding proteins can be administered as a sustained release formulation, in which case less frequent administration is required. For antibodies, dosage and frequency vary depending on the half-life of the antibody in the patient. In general, humanized antibodies show the longest half-life, followed by chimeric antibodies and non-human antibodies.

The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. In prophylactic applications, compositions containing the present binding protein are administered to a subject not already in the disease state to enhance the subject's resistance. In terms of achondroplasia, a prophylactic treatment is understood as a method of preventing or alleviating one or more symptoms of the disorder. In terms of cancer, a prophylactic treatment is understood as a method of preventing the happening of cancer, or alleviating one or more symptoms of the cancer. Such an amount is defined to be a “prophylactic effective dose.” In this use, the precise amounts again depend upon the subject's state of health and general immunity. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, or until the patient shows partial or complete amelioration of disease symptoms. Thereafter, the patient can be administered a prophylactic regime.

Binding proteins described herein can optionally be administered in combination with other agents that are effective in treating the disorder or condition in need of treatment (e.g., prophylactic or therapeutic).

While the binding proteins may be administered as described immediately above, it must be emphasized that in other embodiments binding proteins may be administered to otherwise healthy subjects as a first line therapy. In such embodiments the binding proteins may be administered to subjects that have not, and are not, undergoing one or more other therapies, or subjects that have, or are undergoing one or more other therapies. As used herein, the administration of binding proteins, e.g. antibodies or fragments thereof, in conjunction or combination with an adjunct therapy means the sequential, simultaneous, coextensive, concurrent, concomitant, or contemporaneous administration or application of the therapy and the disclosed binding proteins. The administration or application of the various components of the combined therapeutic regimen may be timed to enhance the overall effectiveness of the treatment.

As previously discussed, the binding proteins of the present disclosure may be administered in a pharmaceutically effective amount for the in vivo treatment of mammalian disorders.

Pharmaceutical compositions in accordance with the present disclosure typically include a pharmaceutically acceptable, non-toxic, sterile carrier such as physiological saline, buffers, preservatives and the like. For the purposes of the instant application, a pharmaceutically effective amount of the binding protein that, shall be held to mean an amount sufficient to achieve effective binding to an antigen and to achieve a benefit, e.g., to ameliorate symptoms of a disease or disorder. Of course, the pharmaceutical compositions of the present disclosure may be administered in single or multiple doses to provide for a pharmaceutically effective amount of the antigen-binding protein or antigen-binding fragment thereof.

In keeping with the scope of the present disclosure, the antigen-binding protein or antigen-binding fragment thereof may be administered to a human or other animal in accordance with the methods of treatment herein in an amount sufficient to produce a therapeutic or prophylactic effect. The binding proteins of the disclosure can be administered to such human or other animal in a conventional dosage form prepared by combining the binding protein with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. The form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. In some embodiments, a cocktail comprising one or more species of binding proteins described in the current disclosure may prove to be particularly effective.

Methods of Treatment and Inhibition of FGFR3 Activity

The anti-FGFR3 antigen binding proteins or fragments thereof are useful for the treatment of FGFR3-mediated diseases or disorders. As used herein, the term “FGFR3-mediated disease or disorder” refers to any disease or disorder that is the result of aberrant FGFR3 activity. In certain embodiments, the disease or disorder is caused by FGFR3 over activity or over expression. Non-limiting examples of FGFR3-mediated diseases or disorders include achondroplasia, hypochondroplasia, and cancer.

The anti-FGFR3 antigen binding proteins or fragments thereof are useful for the reduction of FGFR3 activity. As used herein, an “FGFR3 activity” refers to any signaling event associated with the dimerization of FGFR3 on the surface of a cell. The FGFR3 activity can be one or both of an extracellular activity and an intracellular activity. FGFR3 activities include, but are not limited to, FGFR3 dimerization, extracellular signal-regulated kinase (Erk) phosphorylation, mitogen-activated protein kinase kinase (MKK, MEK, or MAP2K) phosphorylation, FGFR3 cytoplasmic tyrosine kinase domain activity, and FGF ligand binding activity (e.g., FGF18 binding to FGFR3).

As used herein, the term “achondroplasia” refers to a genetic disorder caused by mutations in the FGFR3 gene that make the resulting protein overactive. The anti-FGFR3 antigen binding proteins or fragments thereof are useful for the reduction of one or more symptoms of achondroplasia. Achondroplasia symptoms include, but are not limited to, shortening of the proximal limbs, brachydactyly (i.e., short fingers and toes with trident hands), large head with prominent forehead frontal bossing, small midface with a flattened nasal bridge, spinal kyphosis (convex curvature) or lordosis (concave curvature), varus (i.e., bowleg) or valgus (i.e., knock knee, ear infections (due to Eustachian tube blockages)), sleep apnea (central or obstructive), and hydrocephalus. Achondroplasia may be diagnosed through the measurement of one or more of proximal limb length (e.g., femur and tibia length), finger and toe length, head circumference (e.g., skull length), and lumbar vertebrae length, although other anatomical measurements can be employed. Achondroplasia may be diagnosed through genetic testing to detect one or more mutations in the FGFR3 gene.

In one aspect, the disclosure provides a method for treating a FGFR3-mediated disease or disorder in a subject, comprising administering to a subject in need thereof the antigen binding protein or fragment thereof described herein.

As used herein, the term “subject,” “patient,” or “individual” refers to a human or non-human animal. The term “non-human animal” includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, cats, rabbits, ferrets, rodents such as mice, rats and guinea pigs, avian species (e.g., chickens), amphibians, and reptiles. In certain embodiments, the subject is a mammal such as a non-human primate, sheep, dog, cat, rabbit, ferret or rodent. In certain embodiments, the subject is a cynomolgus monkey. In certain embodiments, the subject is a human. In certain embodiments, the subject is a child. In certain embodiments, the subject is an adolescent.

In certain embodiments, the FGFR3-mediated disease or disorder is achondroplasia. In certain embodiments, the achondroplasia is FGFR3G380R+ achondroplasia, meaning the subject to be treated contains the G380R mutation in its FGFR3 gene, either homozygous or heterozygous.

In certain embodiments, a subject diagnosed as having achondroplasia or risk of achondroplasia is treated with a binding protein disclosed herewith. In certain embodiments, the treatment leads to one or more effects selected from the group consisting of increased bone length (e.g., femur length and/or tibia length), increased bone diameter (e.g., femur diameter), increased growth plate volume (e.g., femur growth plate volume), increased vertebrae length, increased skull length, increased bone volume, increased skull volume, corrected vertebral abnormalities (e.g., increased Kyphosis Index), and improved bone age (e.g., more developed secondary ossification center), as compared to a control subject not receiving the treatment that is of the same development stage.

Accordingly, a method of improving one or more bone features in a subject is also provided. In certain embodiments, the method comprises administrating a binding protein or an antigen-binding fragment thereof disclosed herewith to a subject in need. In certain embodiments, the improved bone feature is selected from the group consisting of bone length (e.g., femur length or tibia length), bone diameter (e.g., femur diameter), growth plate volume, vertebrae length, skull length, bone volume, skull volume, Kyphosis Index, and improved bone age.

In certain embodiments, the FGFR3-mediated disease or disorder is cancer. In certain embodiments, the cancer is selected from the group consisting of bladder cancer, melanoma, urothelial cancer, and endometrial cancer.

In another aspect, the disclosure provides a method for treating achondroplasia in a subject, comprising administering to a subject in need thereof an antigen binding protein or an antigen-binding fragment thereof with binding specificity to an FGFR3 epitope, wherein the antigen binding protein or the antigen binding fragment thereof does not bind to one or more of FGFR1, FGFR2, and FGFR4.

In another aspect, the disclosure provides a method for inhibiting one or both of FGFR3 activity and expression in a bone growth plate of a subject, comprising administering to a subject an antigen binding protein or an antigen binding fragment thereof with binding specificity to an FGFR3 epitope, wherein the antigen binding protein fragment does not bind to one or more of FGFR1, FGFR2, and FGFR4. In certain embodiments, an FGFR3 antibody as described herewith is used.

Therapeutic and Prophylactic Uses

The disclosure provides therapeutic uses of its binding proteins or an antigen binding protein fragment thereof with binding specificity to an FGFR3 epitope, wherein the antigen binding protein fragment does not bind to one or more of FGFR1, FGFR2, and FGFR4) corresponding to the methods of treatment disclosed above. For instance, the disclosure provides a binding protein or the antigen binding protein fragment thereof as described herein for use in medicine. In some embodiments, it provides a binding protein, or an antigen binding protein fragment thereof as described herein for use as an FGFR3-activity inhibiting medicament. In some embodiments, it provides a binding protein, or an antigen binding protein fragment thereof as described herein for use in treating an FGFR3-mediated disorder. Examples of such disorders are given herein. In some embodiments, it provides a binding protein, or antigen binding protein fragment thereof as described herein for use in preventing one or more symptoms of achondroplasia, as exemplified above. In some embodiments, it provides a binding protein, or antigen binding protein fragment thereof as described herein for use in preventing cancer, as exemplified above. Embodiments described herein regarding methods of treatment, administration, subjects and all other aspects relevant to therapy and prevention also apply to these uses of binding proteins.

It will be readily apparent to those skilled in the art that other suitable modifications and adaptations of the methods described herein may be made using suitable equivalents without departing from the scope of the embodiments disclosed herein. Having now described certain embodiments in detail, the same will be more clearly understood by reference to the following example, which is included for purposes of illustration only and is not intended to be limiting.

EXAMPLE Example 1—Generation of Anti-FGFR3 Antibodies

Generation of Immunogen

Anti-FGFR3 monoclonal antibodies were developed using 300.19 pre-B lymphoblast cells (ATCC, Manassas, VA) transformed with DNA encoding full-length human FGFR3 (see FIG. 1, GenBank ID NP_000133.1, FGFR3 isoform IIIc) with the mutation G380R (SEQ ID NO: 133) which was expressed on the cell surface (FGFR3G380R-300.19 cell). The FGFR3G380R open reading frame was subcloned into the pXL-MCS vector and transfected into 300.19 cells (Immunogen 1). Separately, DNA encoding the human FGFR3 extra cellular domain (ECD) protein (Immunogen 2) was subcloned into the pTT5 vector (Invitrogen), and was prepared using Expi293 cells (Invitrogen). FGFR3 extra cellular domain (ECD) protein (Immunogen 2):

(SEQ ID NO: 140) GGLNDIFEAQKIEWHEHHHHHHEDQVDPRLIDGKIQPEPESLGTEQRVVG RAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVP SERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGD DEDGEDEAEDTGVDTGAPYVVTRPERMDKKLLAVPAANTVRFRCPAAGNP TPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVEN KFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQ PHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFE DAGEYTCLAGNSIGFSHHSAWLVVLPAEEELVEADEAGSAS

FGFR3 expression on FGFR3G380R-300.19 cells was monitored and quantified by FACS analysis using the comparator antibody, GT184.6.1, described further in Yin et al. (Mol. Cancer Ther. 14(10): 2270-8. 2015). Anti-FGFR1 (MAB765), anti-FGFR2 (MAB6843), anti-FGFR3 (MAB766), and anti-FGFR4 (MAB6852) antibodies were used as negative controls (R&D Systems, Minneapolis, MN). The FGFR3 ECD protein was quantified using an enzyme-linked immunosorbent assay (ELISA) with the antibodies described further below.

The cells expressing FGFR3 were maintained at 37° C. under 5% CO2 in RPMI (Gibco) supplemented with heat inactivated fetal bovine serum (FBS) (Hyclone). Cells were prepared for injection by substituting the above culture medium with phosphate buffered (Ca—Mg free) saline (CMF-PBS) supplemented with 5 mM EDTA and harvesting the cells in that buffer. The harvested cells were pelleted by centrifugation at 500×g for 5 minutes, washed once by resuspending the pellet in CMF-PBS and centrifuging as before, counted and adjusted to the appropriate volume (such as 5×106 cells in 0.2 ml) for injection by resuspending the cell pellet in CMF-PBS. The FGFR3 ECD protein was used to boost antibody titers in animals before sacrificing the mouse.

Cells were maintained in RPMI medium by seeding about 3-5×105 cells per ml in a T75 flask and grown for approximately 24-48 hours with selection antibiotic to eliminate the cells not carrying FGFR3 plasmid. Cell surface expression of FGFR3 on cells was verified by FACS analysis prior to use as an immunogen.

Generation of Anti-FGFR3 Antibodies—Hybridoma Strategy

Six eight-week old female FGFR3 KO (C57BL/6mFGFR3−) mice from the Jackson Laboratory (Bar Harbor, ME) were immunized with the FGFR3-transfected cells (Immunogen 1). Separately, wild-type Balb/c mice were immunized with the FGFR3 ECD protein described above (Immunogen 2). A group of mice were primed intraperitoneally on day 0 with FGFR3-expressing cells, FGFR3G380R-300.19 cells, in PBS without adjuvants, administrated on days 14, 28, 42 and 56, followed by an intraperitoneal boost on day 77 with the FGFR3 ECD protein in PBS without adjuvants. Each injection was administrated with approximately 5×106 cells in a volume of 200 μl and 50 μg protein in a volume of 100 μl PBS. Immunizations were performed in two-week intervals and the IgG titer was evaluated by ELISA with FGFR3 ECD protein to assess immune response.

The mice were sacrificed for harvesting the spleen and placed in approximately 10 ml of pre-warmed serum-free DMEM (Hyclone) at 37° C. in a petri dish. The splenocytes were teased out of the capsule using forceps and transferred to a 15-ml conical tube. The cells were then washed three times with pre-warmed serum-free IMDM (Hyclone) and cells from multiple mice were pooled.

The fusion partner cell, FO B lymphoblasts (ATCC, Manassas, VA), for the immunized spleen cells was established with a hypoxanthine/aminopterin/thymidine (HAT)-sensitive and IgG non-secreting myeloma cell line. Prior to the fusion, FO B lymphoblasts were maintained in IMDM medium supplemented with 10% FBS (37° C., 7% CO2) ensuring that the cells were in logarithmic growth phase on the day of the fusion.

The fusion protocol was derived from Lerner (Yale J Biol Med, 1981, 54 (5) 387-402) and Gefter et al. (Somatic Cell Genet, 1977, 3 (2) 231-236). Before the fusion, the spleen cells and the logarithmic phase myeloma cells were washed three times with serum-free IMDM and counted. For each fusion, 1-1.5×108 spleen cells were mixed with 2-3×107 myeloma cells in a 50-ml conical polypropylene tube and cells were washed once with serum-free IMDM. The ratio of spleen cells to myeloma cells was 5:1. The tubes were centrifuged at 500×g for 10 minutes to pellet the cells. After aspiration of the supernatant, the pellets were gently resuspended by tapping the bottom of the tubes. The tubes were then placed in a beaker of 37° C. water. All subsequent fusion steps were carried out in the beaker of 37° C. water.

Next, 1 ml of polyethylene glycol 1500 (PEG) (Roche Applied Science, Indianapolis, IN) preheated to 37 C was slowly added to the cell pellet over the course of about 1 minute, while gently rocking the tube. The cells were incubated in the PEG for one minute followed by addition of 1 ml serum-free IMDM added dropwise to the pellet over the course of 30 seconds, and then 9 ml of serum-free IMDM were added to the pellet for one minute. The tube was then centrifuged at 500×g for 10 minutes at room temperature, and the supernatant was aspirated. The pellet was resuspended in 200 ml of filtered complete hybridoma production media, IMDM (Hyclone) supplemented with 10% FBS (Hyclone), 1× non-essential amino acid (Gibco), 1 mM sodium pyruvate (Gibco), 1× pen-strep (Gibco) and 1× HAT (Sigma). The resuspended cells were then seeded in ten 96-well flat-bottom microtiter plates, in a volume of about 200 μl/well. The plates were kept in an incubator at 37° C., 7% CO2.

A primary hybridoma screen was designed to select hybridoma clones producing antibodies which recognized native FGFR3 epitopes. Supernatants from wells growing clones, typically on days 10-14 post-fusion, were incubated with Chinese hamster ovary (CHO) cells stably expressing FGFR3 (FGFR3-CHO). Antibody binding was detected by FACS using a fluorescently labeled goat anti-mouse secondary antibody. Clones were considered positive if labeled supernatant samples were greater than 10-fold over background in the FACS analysis. Selected positive clones were transferred to 24-well flat bottom plates and expanded for a second screen to confirm selection. Supernatants from 24-well plates were incubated with hFGFR3G380R-300.19 cells and detected by a fluorescently labeled goat anti-mouse secondary antibody. More than 4,000 hybridomas were generated and screened by FACS assay described above. Only 25 clones were confirmed specific to FGFR3. Positive clones were expanded for purified antibody production, VH and VL gene sequencing and cryo-preservation.

Generation of Anti-FGFR3 Antibodies—Phage-Display Strategy

Three scFv phage libraries and two fab fragment phage libraries were screened, with 5 separate screening campaigns performed. A first campaign screened the scFv phage libraries against the hFGFR3 isoform IIIc dimer. 2,700 scFv antibodies were screened with only 13 antibodies identified as potential candidates. A second campaign screened fab and scFv libraries against the hFGFR3 isoform IIIc dimer. 1,940 antibodies were screened with only 13 antibodies identified as potential candidates. A third and fourth campaign screened fab and scFv libraries against the hFGFR3 isoform IIIc dimer, the hFGFR3 isoform IIIc his tagged monomer, and hFGFR3 isoform IIIc-expressing cells. 9,770 antibodies were screened with only 36 antibodies identified as potential candidates. A fifth campaign screened fab libraries against the hFGFR3 isoform IIIc monomer and mouse FGFR3 (mFGFR3) isoform IIIc monomer, and hFGFR3 isoform IIIc- and mFGFR3 isoform IIIc-expressing cells. 2,990 antibodies were screened with only 57 antibodies identified as potential candidates. Between the five screening campaigns, 17,400 antibodies were screened. Among those screened antibodies, only 48 were found to be cross-reactive between human, mouse, and cyno, and only 15 were found to block FGFR3 ligand binding.

FGFR family member proteins (human FGFR1α IIIb, FGFR1α IIIc, FGFR1β IIIb, FGFR1β Mc, FGFR2α IIIc, FGFR2β IIIb, FGFR3 IIIb, FGFR3 Mc, FGFR4; mouse FGFR3; and cynomolgus FGFR3 recombinant proteins) were purchased from R&D Systems (Minneapolis, MN) for identifying FGFR3 specific clones by ELISA. cDNA encoding the following proteins were all subcloned into the pTT5 vector (Invitrogen): partial ECD and chimeric ECD proteins of FGFR3; human D2D3 (hD2D3) and D3 (hD3) of human FGFR3; mouse D2D3 (mD2D3) and D3 (mD3) of mouse FGFR3; cynomolgus D2D3 (cyD2D3) and D3 (cyD3) of cynomolgus FGFR3; and hD1-cyD2D3 and hD1-mD2D3 recombinant proteins. Proteins were prepared by transient transfection using Lipofectamine 2000 (Invitrogen) in Expi293 cells (Invitrogen). Supernatants from the selected clones were incubated in 96-well plates coated with the recombinant FGFR proteins and detected with goat anti-mouse IgG horseradish peroxidase (Jackson Immunoresearch, West Grove, PA) followed by chemiluminescent detection.

Cell Based-Binding Assays for Anti-FGFR3 Antibodies

A cell-based binding assay was used to characterize the anti-FGFR3 antibodies generated above. Full-length human, mouse, and cynomolgus FGFR3 cDNAs were subcloned into different pcDNA 3.1 (Invitrogen) vectors and transfected into 300.19 cells (ATCC). The cDNA of FGFR3 Ig domains D2D3 was subcloned into pcDNA 3.1 and transfected into CHO (D2D3-CHO) (ATCC) cells. Full-length human FGFR3G380R, mouse FGFR3, and cynomolgus FGFR3G380R cDNAs were also subcloned into different pcDNA 3.1 vectors. Stable cell lines expressing FGFR3 were generated by transfection of human FGFR3G380R, mouse FGFR3, and cynomolgus FGFR3G380R cDNA plasmid constructs into CHO (hFGFR3G380R-CHO and cyFGFR3G380R-CHO) and human embryonic kidney (HEK, mFGFR3-HEK) (ATCC) cells using the Lipofectamine 2000 kit (Invitrogen). Cell lines were maintained in F-12K medium supplemented with 10% FBS for CHO cells and in DMEM supplemented with 10% FBS for HEK cells overnight, then cultured in the presence of geneticin (0.5 ml/ml) for 10-14 days. Isolated single colonies were picked and grown in separate wells until sufficient clonal cells were expanded. Stable clones resistant to geneticin and expressing high copies of FGFR3 protein were identified by FACS assay using GT184.6.1.

Cell-based antibody binding to wild-type FGFR3, mutant FGFR3, and D2D3 FGFR3 expressed on CHO and HEK cells was accessed by FACS analysis. Cells were incubated with anti-FGFR3 antibodies in 1% bovine serum albumin in PBS (BPBS). After three washes, the cells were incubated with a fluorescent-conjugated secondary antibody (Invitrogen).

The results indicated that several antibodies bind specifically to FGFR3 expressed on the cells. For example, clones KC18, KE35, KE42, KE58, KE63, and KE94, with mouse and human isotype controls as negative controls and GT184.6.1 as a positive control, were tested for binding to CHO, HEK and 300.19 cells transfected to express wild-type FGFR3, mutant FGFR3, and the ECD domain of FGFR3. All antibodies bound to the cells as described above, with similar binding profiles and titration kinetics. The negative control antibodies exhibited only background reactivities. The binding of anti-FGFR3 antibodies to mouse primary rib chondrocytes was also observed by FACS analysis.

The binding specificities of antibodies KC18, KE35, KE42, KE58, KE63, and KE94 were also tested using GT184.6.1 as positive control. Unlike GT184.6.1, which bound to both hFGFR2 and hFGFR3, KC18, KE35, KE42, KE58, KE63, and KE94 only bound to hFGFR3, indicating high FGFR3 specificities.

Biacore Affinity Analysis

The N-terminal ECD proteins of FGFR3 from human and mouse were produced with a terminal avidin tag and used in a forward format Biacore assay where proteins were immobilized on a Biacore chip and then the kinetics of antibody interaction with the proteins on the chip were determined. The proteins were immobilized on a Biacore chip for approximately 10,000 response units (RU). Then the antibodies were exposed to the chip for kinetic measurements, following the manufacturer's recommendations (GE Healthcare). Sensorgrams were fit to a 1:1 binding model and analyzed using double-reference subtraction by T200 Evaluation software (GE Healthcare). Affinities of the tested antibodies are shown in Table 2.

TABLE 2 anti-FGFR3 antibodies binding specificities and affinities FGFR3 Selectivity Reactivity antibodies FGFR1 FGRF2 FGFR3 FGFR4 hFGFR3IIIc hFGFR3IIIb mFGFR3 cynoFGFR3 KC18 − − + − +++ +++ +++ +++ KE35 − − + − +++ +++ +++ +++ KE42 − − + − +++ +++ +++ +++ KE58 − − + − +++ +++ +++ +++ KE63 − − + − +++ +++ +++ +++ KE94 − − + − +++ +++ +++ +++ Control mAb: − + + − ++ ++ +++ +++ GT184 Affinity (hFGFR3) Affinity (mFGFR3) FGFR3 Ka Kd KD KD antibodies (M−1s−1) (s−1) (nM) Ka Kd (nM) KC18 7.92E+05 3.47E−04 1.4 1.74E+05 1.10E−03 6.30 KE35 4.14E+05 1.20E−03 2.89 5.71E+5  1.08E−03 1.89 KE42 4.60E+05 5.67E−04 1.23 7.39E+5  6.00E−04 0.81 KE58 1.15E+06 1.43E−03 1.2 1.67E+05 9.18E−04 5.50 KE63 8.87E+05 7.45E−04 0.8 4.36E+05 2.91E−03 6.70 KE94 9.40E+05 5.95E−04 0.6 7.05E+05 1.48E−03 2.10 Control mAb: 4.23E+05 1.20E−03 2.8 4.15E+05 1.52E−03 3.7 GT184

Sequence Analysis of Anti-FGFR3 Monoclonal Antibodies

Prior to sequence analyses, the isotype of each clone was determined using the IsoStrip Mouse Monoclonal Antibody Isotyping Kit (Roche Applied Science, Indianapolis, IN). The heavy (VH) and light (VL) chain variable regions of clones were sequenced using 5′ RACE (Rapid Amplification of cDNA Ends) Kit (Clontech, Mountain View, CA) as per the manufacturer's instruction. Total RNA was extracted from each hybridoma clone using the RNeasy Miniprep kit according to the manufacturer's instructions (Qiagen, Germantown, MD). Full-length first strand cDNAs containing 5′ ends were generated by polymerase chain reaction (PCR) using 5′RACE kits (Clontech). The VH and VL genes were amplified by TA cloning kit (Invitrogen) with primers, 5′ primer (5′RACE kit, Clontech), and 3′ primer of IgG isotype specific heavy chain and 3′ primer of kappa light chain.

IgG1 3′ Primer: (SEQ ID NO: 1) 5′-TATGCAAGGCTTACAACCACA-3′ IgG2b 3′ Primer: (SEQ ID NO: 2) 5′-GTTAGGAGCTGGGCATTTGTGACACTCC-3′ IgG2c 3′ Primer: (SEQ ID NO: 3) 5′-GTTAGGTGCTGGGCATTTGCATGGAGGACAGGG-3′ IgG3 3′ Primer: (SEQ ID NO: 4) 5′-GTTTGGTGGGCATGAAGAACCCGGGG-3′ Kappa light chain 3′Primer: (SEQ ID NO: 5) 5′-CTCATTCCTGTTGAAGCTCTTGAC-3′

The amplified cDNAs were cloned into pCR2.1 vectors (Invitrogen) and transformed using a TOPO-TA cloning kit (Invitrogen) as per the manufacturer's instructions. Plasmids were isolated from 2 ml of an LB culture, inoculated from a single colony and grown overnight, using QIAprep spin miniprep kit (Qiagen) and sequenced using M13 Forward and M13 Reverse primers included in the TOPO-TA cloning kit (Invitrogen). The VH and VL gene sequences were analyzed using the IMGT V-Quest web server to identify and confirm variable region sequences. VH and VL sequences of each antibody are provided below in Table 3:

TABLE 3 Antibody VH and VL amino acid sequences Antibody ID Sequence KC18 VH QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWIGDI DPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYCTRTYDG YPYAMDYWGQGTSVTVSS (SEQ ID NO: 6) KC18 VL DIVMSQSPSSLAVSVGEKVTMSCKSSQSLLYSNNQKNYLAWYQQKPGQSPK LLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYRTF GGGTKLEIK (SEQ ID NO: 7) KE35 VH EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWIGY INPNNGGTRYNQKFKGKATLTVNKSSSTAYMELRSLTSEDSAVYYCARERD YDGAMDYWGQGTSVTVSS (SEQ ID NO: 8) KE35 VL DIQMTQSPSSLSASLGGKVTITCKASQDINKFIAWYQHKPGKGPRLLIHYTST LQPGIPSRFSGSGSGRDYSFSISNLEPEDIATYYCLQYDNLLWTFGGGTKLEIK (SEQ ID NO: 9) KE42 VH EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLQWIG YINPNNGGTNYNQNFKDKATLTVNKSSTTAYMELRSLTSEDSAVYYCARER DYDGSMDFWGQGTSVTVSS (SEQ ID NO: 10) KE42 VL DIQMTQSPSSLSASLGGKVTITCKASQDINKFIAWYQHKPGKGPRLLIHYTST LQPGIPSRFSGSGSGRDYSFSISNLEPEDIATYFCLQYDNLLWTFGGGTKLEIK (SEQ ID NO: 11) KE58 VH EVQLQQSGPDLVKPGASVKISCKASGYTVTDYYMNWVKQSHGKSLEWIGD INPNNGVTTYNQKFKDKATLTVDKSSSTAYMELRSLTSEDSAVYYCAREED FDGFDYWGQGTTLTVSS (SEQ ID NO: 12) KE58 VL DIVMTQSHKFMSTSVGDRVSITCKASQDVSTGVAWYQQKPGQSPQLLIYWA STRHTGVPDRFTGSGSGTDYILTIRSVQAEDLALYYCQQHYSTPLTFGAGTK LELK (SEQ ID NO: 13) KE63 VH QVQLQQSGAELVRPGASVTLSCKASGSTFSDFEIHWVKQTPVHGLEWIGGID PETGGTAYNQKFKGKAILTADRSSSTAYMELRSLTSEDSAVYYCTRNYDGY SQTMDYWGQGTSVTVSS (SEQ ID NO: 14) KE63 VL NIMMTQSPSSLAVSAGEKVTMSCKSSQSVLYSSNQKNYLAWYQQKPGQSP KLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCHQYLSSYT FGGGTKLEMK (SEQ ID NO: 15) KE94 VH QVQLQQSGAELVRPGASVTLSCKASGSTFTDFEIHWVKQTPVHGLEWIGAID PETGGTAYNQKFKGKAILTAVKSSSTAYMGLRSLTSEDSAVYYCTRNYDGY SRTMDYWGQGTSVTVSS (SEQ ID NO: 16) KE94 VL NIMMTQSPSSLAVSAGEKVTMSCKSSQSVLYSSNQKNYLAWYQQKPGQSP KLLIYWASTRESGVPDRFTGSGSGTDFSLSISSVQTEDLAVYYCHQYLSSYTF GGGTRLEMK (SEQ ID NO: 17)

The CDR regions for the VH and VL sequences recited above are provided below in Table 4:

TABLE 4 Antibody Heavy chain and Light chain CDR regions HEAVY Chain VH Chain ID HCDR1-IMGT HCDR2-IMGT HCDR3-IMGT KC18_VH GDTFTDFE IDPETGGT TRTYDGYPYAMDY (SEQ ID NO: 70) (SEQ ID NO: 71) (SEQ ID NO: 72) KE35_VH GYTFTDYN INPNNGGT ARERDYDGAMDY (SEQ ID NO: 76) (SEQ ID NO: 77) (SEQ ID NO: 78) KE42_VH GYTFTDYN INPNNGGT ARERDYDGSMDF (SEQ ID NO: 82) (SEQ ID NO: 83) (SEQ ID NO: 84) KE58_VH GYTVTDYY INPNNGVT AREEDFDGFDY (SEQ ID NO: 88) (SEQ ID NO: 89) (SEQ ID NO: 90) KE63_VH GSTFSDEE IDPETGGT TRNYDGYSQTMDY (SEQ ID NO: 94) (SEQ ID NO: 95) (SEQ ID NO: 96) KE94_VH GSTFTDFE IDPETGGT TRNYDGYSRTMDY (SEQ ID NO: 100) (SEQ ID NO: 101) (SEQ ID NO: 102) LIGHT Chain VL Chain ID LCDR1-IMGT LCDR2-IMGT LCDR3-IMGT KC18_VL QSLLYSNNQKNY WAS QQYYSYRT (SEQ ID NO: 73) (SEQ ID NO: 74) (SEQ ID NO: 75) KE35_VL QDINKF YTS LQYDNLLWT (SEQ ID NO: 79) (SEQ ID NO: 80) (SEQ ID NO: 81) KE42_VL QDINKF YTS LQYDNLLWT (SEQ ID NO: 85) (SEQ ID NO: 86) (SEQ ID NO: 87) KE58_VL QDVSTG WAS QQHYSTPLT (SEQ ID NO: 91) (SEQ ID NO: 92) (SEQ ID NO: 93) KE63_VL QSVLYSSNQKNY WAS HQYLSSYT (SEQ ID NO: 97) (SEQ ID NO: 98) (SEQ ID NO: 99) KE94_VL QSVLYSSNQKNY WAS HQYLSSYT (SEQ ID NO: 103) (SEQ ID NO: 104) (SEQ ID NO: 105)

Inhibition of FGF1 Ligand Binding by Anti-FGFR3 Antibodies

To test if the isolated antibodies could inhibit the binding between FGF1 ligand and FGFR3, an FGF1 ligand blocking assay was conducted. For the FGFR1 ligand blocking assay, human FGFR3 cells, FGFR3-300.19 and FGFR3G380R-300.19, were pre-incubated with various concentration of anti-FGFR3 antibodies and isotype controls, prior to addition of human FGF1 ligand (R&D Systems). Binding of hFGF1 to FGFR3 expressed on the cells was determined by FACS assay using biotinylated anti-FGF1 antibody followed by incubation with a streptavidin-fluorescent secondary antibody. The anti-FGFR3 antibodies which bound to the EC domain, including KC18, KE35, KE42, KE58, KE63, and KE94, all blocked binding of FGF1 to FGFR3 on these cells.

An ELISA-based blocking assay using human and mouse FGF1 ligand was conducted. Each well of 96-well plates was coated with either human or mouse FGFR3 proteins to capture both/either anti-hFGFR3 antibody and/or FGF1 ligand, then incubated with various concentrations of anti-FGFR3 antibody and isotype controls, prior to addition of human FGF1 ligand. Binding of FGF1 ligand was determined by addition of a substrate to induce a quantifiable chemiluminescence reaction. Inhibition of FGF1 binding to human FGFR3 and mouse FGFR3 proteins by the anti-FGFR3 antibodies was detected by ELISA, respectively.

Epitope Binning of Anti-FGFR3 Antibodies

Using a Biacore T100 (GE Healthcare, Piscataway, NJ), anti-FGFR3 antibodies were immobilized on a Biacore CM5 chip and ECD proteins of FGFR3 were injected. Competition of second anti-FGFR3 antibodies (Ab2) bound to FGFR3 protein captured by immobilized anti-FGFR3 antibodies (Ab1) were determined. The anti-FGFR3 antibodies were immobilized on a Biacore chip for approximately 100 response units (RU). Flow cell 1 remained blank for reference subtraction on each chip. The ECD FGFR3 protein and mouse anti-FGFR3 antibodies (Ab2) prepared in HBS-EP+ running buffer were injected for 3 minutes and 5 minutes at a flow rate of 50 μl/min, respectively. The Ab1 surface was regenerated between cycles using 10 mM glycine-HCl (pH 2.0) at 50 μl/min for 1 minutes. Sensorgrams were fit to a 1:1 binding model and analyzed using double-reference subtraction by BiaEvaluation software (GE Healthcare). It was determined that anti-FGFR3 antibodies KC18, KE35, KE42, KE58, KE63, and KE94 competed for the same region on FGFR3 around the D2 domain.

Hydrogen deuterium exchange (HDX) mass spectrometry was also used to determine the epitopes on FGFR3 for these antibodies by measuring the amide hydrogen deuterium exchange on FGFR3. HDX mass spectrometry measured amide hydrogen deuterium exchange over time and quenched at 0° C. and pH 2.5 along with protease digestion. Briefly, the antibody to be tested and antigen were mixed such that about 90% of the antibody is bound to the antigen at room temperature. Deuterium exchange was performed with a 10-fold dilution into D20 at neutral pH. Quenching was then performed by holding the reaction mixture for 1 minute at about 0 to 1° C. to reduce disulfide bonds. Protease digestion was performed with protease XIII and pepsin. HDX mass spectrometry is described in further detail in Prądzińska et al. (Amino Acids. 48: 2809-2820. 2016). The FGFR3 sequence used in the HDX assay is recited below, and corresponds to the D2D3 region, corresponding to D143 to E365 of FGFR3 Isoform IIIc:

(SEQ ID NO: 134) DTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNG REFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYT LDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVE VNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAG NSIGFSHHSAWLVVLPAEEELVE

The results (FIG. 2) indicated that KE35 and KE58 bind to the N-terminus of the D2 region (D143 to L163); KE42 binds to N-terminus of the D2 region (D143 to N170); while KC18, KE94, and KE63 bind to N-terminus and middle of the D2 region (D143 to D160 and G197 to L213).

Internalization Assay

Internalization of anti-FGFR3 antibodies was evaluated in KMS-11 cells (JCRB cell bank, Japan). The KMS-11 cells were incubated with each antibody at a final concentration of 2 μg/ml for 30 minutes, 1, 2, 5, and 24 hours, then placed at 4° C. before washing the cells with PBS (Ca2+ and Mg2+). A subset of samples was washed with glycine-HCl buffer (pH 4) and fixed with 4% paraformaldehyde (Sigma). Another subset of samples was permeabilized with Triton X-100 (Sigma). The cells with immunofluorescence staining buffer, containing dye and fluorescent conjugated secondary antibody, were imaged by a PerkinElmer Opera high-throughput automated microscope and analyzed using the PerkinElmer Columbus image management system (PerkinElmer, Hopkinton, MA). Internalization of anti-FGFR3 antibodies was observed in KMS-11 cells treated with glycine-HCl and Triton X-100. The cell surface staining of each antibody was detected in a subset without treatment of glycine-HCl and Triton X-100 (FIG. 3). The ratio of the fluorescence signal for internalized antibody (+pH3/+TX100) to total antibody (−pH3/+TX100) then allows comparison of the degree of internalization for different antibodies (FIG. 4). The results indicate that the anti-FGFR3 antibodies were effectively internalized into the KMS-11 cells.

Dimerization of FGFR3 Assay

Inhibition of FGFR3 dimerization by anti-FGFR3 antibodies was evaluated by a chemiluminescent assay. U2OS cells co-expressing a fusion protein of β-galactosidase-prolink (PK) and FGFR3 (FGFR3-PK) and β-galactosidase-enzyme acceptor (EA) and FGFR3 (FGFR3-EA) were developed by DiscoveRx (Fremont, CA). β-galactosidase is in an inactive form and when dimerization occurs the prolink and enzyme acceptor come together and are cleaved by the now activated β-galactosidase. The cells were pre-incubated with anti-FGFR3 antibodies at various concentrations before addition of FGF18 ligand to induce dimerization of FGFR3 proteins, then incubated at 37° C. overnight. The substrate was added to the cells and chemiluminescent signal was measured by EnVision (PerkinElmer). Blocking of FGFR3 dimerization by anti-FGFR3 antibodies was observed (FIG. 5A-FIG. 5C).

Humanization

Humanized variants of KC18, KE63 and KE94 clones were generated as follows: 1) Structural models of the Fv regions of these antibodies in complex with FGFR3 were generated by the Molecular Operating Environment (MOE) from the Chemical Computing Group using KC18-FGFR3 complex structure as template given their high sequence similarity with KC18 (FIG. 6); 2) The VH and VL sequences were searched against the human germline sequence, and the most similar human germline Fv sequence and J region were identified. CDRs from KC18, KE63 and KE94 were then grafted onto the framework of the closest human germline genes; 3) Analysis was performed to identify amino acids that were likely to be important for the FGFR3 binding properties of the antibodies. Selected Vernier zone and key contact residues were mutated back to mouse residues after examination within the structural models; and 4) Potential liability sites were removed.

Heavy chain of KC18_Hrw1-3 and _HV1.69rw2-4, and light chain of KC18_Lrw1-3 were designed by the method described above. Further analysis to introduce back-mutations, stabilizing mutations and to eliminate other unwanted motifs, additional heavy and light chains of KC18 variants were identified KC18_VH1, VH1b-c, VH2-3, VH3b-c and VH4, and KC18_VL1, VL1b-d, VL2, VL3, VL3b, VL4, VL5 and VL6, respectively. Heavy chains KE63 VH1-6 and light chains KE63_VL1-4 were designed. Particularly, initial KE63 (KE63_VH1 and KE63_VL1) humanized constructs were designed, then further modifications to the heavy and light chain were designed (KE63_VH2-6 and KE63_VL2-4) to introduce back-mutations, stabilizing mutations and to eliminate other unwanted motifs. Similar methods were also used to design KE94 humanized constructs KE94_VH1-6. Notably, KE63 and KE94 share the same set of VL designs, namely KE63_VL1-4 here. Tables 5, 6, and 7 indicate the strategy used to pair the heavy and light chain variants for KC18, KE63 and KE94, respectively, including the human and mouse germline identity percentage.

TABLE 5 Human and mouse germline identity percentage of the designed KC18 variants KC18 Lrw1 Lrw2 Lrw3 VL1 VL1d VL1c Human 93.07% 96.04% 95.05% 95.05% 93.07% 94.06% Mouse 88.12% 87.13% 86.14% 88.12% 88.12% 89.11% Hrw1 83.67% 74.49% KC18_Hu1 KC18_Hu7  KC18_Hu13 Hrw2 84.73% 75.51% KC18_Hu2 KC18_Hu8  KC18_Hu14 Hrw3 84.69% 75.51% KC18_Hu3 KC18_Hu9  KC18_Hu15 HV1.69rw2 83.67% 72.45% KC18_Hu4 KC18_Hu10 KC18_Hu16 HV1.69rw3 83.67% 72.45% KC18_Hu5 KC18 Hu11 KC18_Hu17 HV1.69rw4 83.67% 72.45% KC18_Hu6 KC18_Hu12 KC18_Hu18 VH1 80.61% 75.51% KC18_Hu19 KC18_Hu23 VH1b 84.69% 73.47% VH1c 82.65% 73.47% KC18_Hu38 VH2 77.55% 78.57% VH3 84.69% 73.47% KC18_Hu20 KC18_Hu24 VH3b 85.71% 74.49% VH3c 84.69% 74.49% KC18_Hu39 VH4 78.57% 79.59% KC18 VL1b VL2 VL3 VL3b VL4 VL5 VL6 Human 94.06% 90.10% 86.14% 85.15% 81.19% 81.19% 81.19% Mouse 87.13% 91.09% 79.21% 80.20% 86.14% 81.19% 85.15% Hrw1 83.67% 74.49% Hrw2 84.73% 75.51% Hrw3 84.69% 75.51% HV1.69rw2 83.67% 72.45% HV1.69rw3 83.67% 72.45% HV1.69rw4 83.67% 72.45% VH1 80.61% 75.51% KC18_Hu29 VH1b 84.69% 73.47% KC18_Hu40 KC18_Hu31 KC18_Hu35 VH1c 82.65% 73.47% VH2 77.55% 78.57% KC18_Hu27 KC18_Hu35 KC18_Hu37 VH3 84.69% 73.47% KC18_Hu30 VH3b 85.71% 74.49% KC18_Hu41 KC18_Hu32 VH3c 84.69% 74.49% VH4 78.57% 79.59% KC18_Hu28 KC18_Hu34

TABLE 6 Human and mouse germline identity percentage of the designed KE63 variants KE63 KE63_VL1 KE63_VL2 KE63_VL3 KE63_VL4 Human 93.07% 93.07% 91.09% 91.09% Mouse 90.00% 89.00% 87.00% 87.00% KE63_VH1 83.67% 74.49% KE63_Hu1 KE63_Hu2 KE63_Hu3 KE63_Hu4 KE63_VH2 86.73% 73.47% KE63_Hu5 KE63_Hu6 KE63_Hu7 KE63_Hu8 KE63_VH3 85.71% 74.49% KE63_Hu9 KE63_Hu10 KE63_Hu11 KE63_Hu12 KE63_VH4 86.73% 73.47% KE63_Hu13 KE63_Hu14 KE63_Hu15 KE63_Hu16 KE63_VH5 82.65% 73.47% KE63_Hu17 KE63_Hu18 KE63_Hu19 KE63_Hu20 KE63_VH6 81.63% 72.45% KE63_Hu21 KE63_Hu22 KE63_Hu23 KE63_Hu24

TABLE 7 Human and mouse germline identity percentage of the designed KE94 variants KE94 KE94_VL1 KE94_VL2 KE94_VL3 KE94_VL4 Human 93.07% 93.07% 91.09% 91.09% Mouse 90.00% 89.00% 87.00% 87.00% KE94_VH1 82.65% 77.55% KE94_Hu1 KE94_Hu2 KE94_Hu3 KE94_Hu4 KE94_VH2 85.71% 76.53% KE94_Hu5 KE94_Hu6 KE94_Hu7 KE94_Hu8 KE94_VH3 84.69% 77.55% KE94_Hu9 KE94_Hu10 KE94_Hu11 KE94_Hu12 KE94_VH4 83.67% 78.57% KE94_Hu13 KE94_Hu14 KE94_Hu15 KE94_Hu16 KE94_VH5 82.65% 77.55% KE94_Hu17 KE94_Hu18 KE94_Hu19 KE94_Hu20 KE94_VH6 81.63% 76.53% KE94_Hu21 KE94_Hu22 KE94_Hu23 KE94_Hu24

Amino acid sequences for the humanized variants of KC18, KE64 and KE94, without the constant regions, are depicted below in Table 8. Nucleic acid sequences for the humanized variants of KC18, KE64 and KE94, without the constant regions, are depicted below in Table 9. The heavy and light constant regions are indicated in SEQ ID NO: 54 and SEQ ID NO: 55, respectively.

TABLE 8 Amino acid sequences of humanized variants of KC18, KE64 and KE94 Antibody ID Sequence KC18 Hu18 VH EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGL EWIGDVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDT AVYYCTRTYDGYPYAFDYWGQGTLVTVSS (SEQ ID NO: 18) KC18 Hu18 VL DIVMTQSPDSLAVSLGERATINCKSSQSVLYSNNNKNYLAWYQQKP GQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYY CQQYYSYRTFGGGTKVEIK (SEQ ID NO: 19) KE63 Hu01 VH QVQLVQSGAEVKKPGASVKVSCKASGSTFSDFEIHWVRQAPGQGL EWIGGIDPETGGTAYNQKFQGRVTITADRSTSTAYMELSSLRSEDTA VYYCTRNYDGYSQTFDYWGQGTLVTVSS (SEQ ID NO: 20) KE63 Hu02 VH QVQLVQSGAEVKKPGASVKVSCKASGSTFSDFEIHWVRQAPGQGL EWIGGIDPETGGTAYNQKFQGRVTITADRSTSTAYMELSSLRSEDTA VYYCTRNYDGYSQTFDYWGQGTLVTVSS (SEQ ID NO: 21) KE63 Hu03 VH QVQLVQSGAEVKKPGASVKVSCKASGSTFSDFEIHWVRQAPGQGL EWIGGIDPETGGTAYNQKFQGRVTITADRSTSTAYMELSSLRSEDTA VYYCTRNYDGYSQTFDYWGQGTLVTVSS (SEQ ID NO: 22) KE63 Hu04 VH QVQLVQSGAEVKKPGASVKVSCKASGSTFSDFEIHWVRQAPGQGL EWIGGIDPETGGTAYNQKFQGRVTITADRSTSTAYMELSSLRSEDTA VYYCTRNYDGYSQTFDYWGQGTLVTVSS (SEQ ID NO: 23) KE63 Hu01 VL DIVMTQSPDSLAVSLGERVTINCKSSQSVLYSSNQKNYLAWYQQKP GQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYY CHQYLSSYTFGQGTKLEIK (SEQ ID NO: 24) KE63 Hu02 VL DIVMTQSPDSLAVSLGERVTINCKSSQSVLYSSNQKNYLAWYQQKP GQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYY CHQYLSPYTFGQGTKLEIK (SEQ ID NO: 25) KE63 Hu03 VL DIVMTQSPDSLAVSLGERVTINCKSSQSVLYSDNQKNYLAWYQQKP GQSPKLLIYYASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYY CHQYLSPYTFGQGTKLEIK (SEQ ID NO: 26) KE63 Hu04 VL DIVMTQSPDSLAVSLGERVTINCKSSQSVLYSDNQKNYLAWYQQKP GQSPKLLIYFASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC HQYLSPYTFGQGTKLEIK (SEQ ID NO: 27) KE94 Hu01 VH QVQLVQSGAEVKKPGASVKVSCKASGSTFTDFEIHWVRQAPGQGL EWIGAIDPETGGTAYNQKFQGRVTITADKSTSTAYMELSSLRSEDTA VYYCTRNYDGYSRTFDYWGQGTLVTVSS (SEQ ID NO: 28) KE94 Hu02 VH QVQLVQSGAEVKKPGASVKVSCKASGSTFTDFEIHWVRQAPGQGL EWIGAIDPETGGTAYNQKFQGRVTITADKSTSTAYMELSSLRSEDTA VYYCTRNYDGYSRTFDYWGQGTLVTVSS (SEQ ID NO: 29) KE94 Hu03 VH QVQLVQSGAEVKKPGASVKVSCKASGSTFTDFEIHWVRQAPGQGL EWIGAIDPETGGTAYNQKFQGRVTITADKSTSTAYMELSSLRSEDTA VYYCTRNYDGYSRTFDYWGQGTLVTVSS (SEQ ID NO: 30) KE94 Hu04 VH QVQLVQSGAEVKKPGASVKVSCKASGSTFTDFEIHWVRQAPGQGL EWIGAIDPETGGTAYNQKFQGRVTITADKSTSTAYMELSSLRSEDTA VYYCTRNYDGYSR1FDYWGQGTLVTVSS (SEQ ID NO: 31) KE94 Hu01 VL DIVMTQSPDSLAVSLGERVTINCKSSQSVLYSSNQKNYLAWYQQKP GQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYY CHQYLSSYTFGQGTKLEIK (SEQ ID NO: 32) KE94 Hu02 VL DIVMTQSPDSLAVSLGERVTINCKSSQSVLYSSNQKNYLAWYQQKP GQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYY CHQYLSPYTFGQGTKLEIK (SEQ ID NO: 33) KE94 Hu03 VL DIVMTQSPDSLAVSLGERVTINCKSSQSVLYSDNQKNYLAWYQQKP GQSPKLLIYYASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYY CHQYLSPYTFGQGTKLEIK (SEQ ID NO: 34) KE94 Hu04 VL DIVMTQSPDSLAVSLGERVTINCKSSQSVLYSDNQKNYLAWYQQKP GQSPKLLIYFASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC HQYLSPYTFGQGTKLEIK (SEQ ID NO: 35) IgG1 Constant Heavy ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTK VDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYR VVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPG (SEQ ID NO: 54) IgG1 Constant Light RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNA LQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC (SEQ ID NO: 55) KC18Hrw1 QVQLVQSGAEVKKPGASVKVSCKASGDTFTDFEIHWVRQAPGQGL EWIGDIDPETGSTSYAQKFQGRATLTADRSTSTAYMELSSLRSEDTA VYYCTRTYDGYPYAMDYWGQGTLVTVSS (SEQ ID NO: 106) KC18Hrw2 QVQLVQSGAEVKKPGASVKVSCKASGDTFTDYEIHWVRQAPGQGL EWIGDIDPETGSTSYAQKFQGRATLTADRSTSTAYMELSSLRSEDTA VYYCTRTYDGYPYAMDYWGQGTLVTVSS (SEQ ID NO: 107) KC18Hrw3 QVQLVQSGAEVKKPGASVKVSCKASGDTFTDYEIHWVRQAPGQGL EWIGDIDPETGSTSYAQKFQGRATLTADRSTSTAYMELSSLRSEDTA VYYCTRTYDGYPYAMDYWGQGTSVTVSS (SEQ ID NO: 108) KC18HV1-69rw2 EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGL EWIGDVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDT AVYYCTRTYDGYPYAMDYWGQGTLVTVSS (SEQ ID NO: 109) KC18HV1-69rw3 EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGL EWIGDVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDT AVYYCTRTYEGYPYAMDYWGQGTLVTVSS (SEQ ID NO: 110) KC18HV1-69rw4 EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGL EWIGDVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDT AVYYCTRTYDGYPYAFDYWGQGTLVTVSS (SEQ ID NO: 111) KC18Lrw1 DIVMTQSPDSLAVSLGERATINCKSSQSLLYSNNQKNYLAWYQQKP GQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYY CQQYYSYRTFGGGTKVEIK (SEQ ID NO: 112) KC18Lrw2 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKP GQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYY CQQYYSYRTFGGGTKVEIK (SEQ ID NO: 113) KC18Lrw3 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSNNNKNYLAWYQQKP GQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYY CQQYYSYRTFGGGTKVEIK (SEQ ID NO: 114) KC18_CL_VH1 QVQLVQSGAEVVKPGATVKISCKASGDTFTDFEIHWVQQAPGKGL EWIGDIDPETGGTAYNEKFQGRATLTADRSTSTAYMELSSLRSEDT AVYYCARTYDGYPYAMDYWGQGTTVTVSS (SEQ ID NO: 115) KC18_CL_VH1b QVQLVQSGAEVVKPGATVKISCKASGYTFTDFEIHWVQQAPGKGL EWIGDVDPETGGTAYAEKFQGRATITADRSTSTAYMELSSLRSEDT AVYYCARTYDGYPYAMDYWGQGTTVTVSS (SEQ ID NO: 116) KC18_CL_VH1c QVQLVQSGAEVVKPGATVKISCKASGYTFTDFEIHWVQQAPGKGL EWIGDVEPETGGTAYAEKFQGRATITADRSTSTAYMELSSLRSEDA AVYYCARTYDGYPYAMDVWGQGTTVTVSS (SEQ ID NO: 117) KC18_CL_VH2 QVQLVQSGAEVVKPGATVKLSCKASGDTFTDFEIHWVKQAPGKGL EWIGDIDPETGGTAYNEKFQGRATLTADRSTSTAYMELSSLRSEDT AVYYCTRTYDGYPYAMDYWGQGTTVTVSS (SEQ ID NO: 118) KC18_CL_VH3 QVQLVQSGAEVVKPGASVKVSCKASGDTFTDFEIHWVKQAPGQGL EWIGDIDPESGGTAYNQKFQGRVTMTADRSISTAYMELSRLRSDDT AVYYCARTYDGYPYAMDYWGQGTTVTVSS (SEQ ID NO: 119) KC18_CL_VH3b QVQLVQSGAEVVKPGASVKVSCKASGYTFTDFEIHWVKQAPGQGL EWIGDIDPESGGTAYNQKFQGRVTMTADRSISTAYMELSRLRSDDT AVYYCARTYDGYPYAMDYWGQGTTVTVSS (SEQ ID NO: 120) KC18_CL_VH3c QVQLVQSGAEVVKPGASVKVSCKASGYTFTDFEIHWVKQAPGQGL EWIGDIEPESGGTAYNQKFQGRVTMTADRSISTAYMELSRLRSDDA AVYYCARTYDGYPYAMDVWGQGTTVTVSS (SEQ ID NO: 121) KC18_CL_VH4 QVQLVQSGAEVVKPGASVKLSCKASGDTFTDFEIHWVKQAPGQGL EWIGDIDPETGGTAYNQKFQGRATLTADRSSSTAYMELSRLRSDDT AVYYCTRTYDGYPYAMDYWGQGTTVTVSS (SEQ ID NO: 122) KC18_CL_VL1 DIVMTQSPDSLAVSLGERVTINCKSSQSVLYSSNQKNYLAWYQQKP GQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYY CQQYYSYRTFGGGTKLEIK (SEQ ID NO: 123) KC18_CL_VL1b DIVMTQSPDSLAVSLGERVTINCKSSQSVLYSNNQKNYLAWYQQKP GQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYY CQQYYSYRTFGGGTKLEIK (SEQ ID NO: 124) KC18_CL_VL1c DIVMTQSPDSLAVSLGERVTINCKSSQSVLYSSNQKNYLAWYQQKP GQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYY CQQYYSYRTFGGGTKLEIK (SEQ ID NO: 125) KC18_CL_VL1d DIVMTQSPDSLAVSLGERVTINCKSSQSVLYSSNQKNYLAWYQQKP GQSPKLLIYYASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYY CQQYYSYRTFGGGTKLEIK (SEQ ID NO: 126) KC18_CL_VL2 DIVMTQSPSSLAVSLGERVTMNCKSSQSLLYSNNQKNYLAWYQQK PGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVY YCQQYYSYRTFGGGTKLEIK (SEQ ID NO: 127) KC18_CL_VL3 DIVMTQSPLSLPVTVGEPVSISCRSSQSLLHSNNQKNYLAWYLQKPG QSPQLLIYWGSTRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC QQYYSYRTFGGGTKLEIK (SEQ ID NO: 128) KC18_CL_VL3b DIVMTQSPLSLPVTVGEPVSISCRSSQSLLYSNNQKNYLAWYLQKPG QSPQLLIYWGSTRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC QQYYSYRTFGGGTKLEIK (SEQ ID NO: 129) KC18_CL_VL4 DIVMTQSPLSLAVTVGEKVSISCRSSQSLLYSNNQKNYLAWYQQKP GQSPKLLIYWGSTRESGVPDRFSGSGSGTDFTLTISRVEAEDVGVYY CQQYYSYRTFGGGTKLEIK (SEQ ID NO: 130) KC18_CL_VL5 DIQMTQSPSSLSVSVGDRVTMTCRASQGISYSNNQKNYLAWYQQK PGKSPKLLIYWASTRQSGVPSRFSGSGSGTDFTLTISSVQAEDVAVY YCQQYYSYRTFGGGTKLEIK (SEQ ID NO: 131) KC18_CL_VL6 DIQMTQSPSSLSVSVGDRVTMTCRSSQSLLYSNNQKNYLAWYQQK PGKSPKLLIYWASTRQSGVPSRFSGSGSGTDFTLTISSVQAEDVAVY YCQQYYSYRTFGGGTKLEIK (SEQ ID NO: 132)

TABLE 9 Nucleic acid sequences of humanized variants of KC18, KE64 and KE94 (HC: heavy chain; LC: light chain) Antibody ID Sequence KC18 Hu18 HC GAGGTACAACTTGTCCAGTCAGGTGCGGAGGTTAAAAAACCGGG GGCCACAGTTAAACTGAGCTGCAAGGCTAGCGGTGATACTTTTA CCGATTTTGAGATACACTGGGTTCAGCAGGCTCCGGGGAAAGGG CTTGAATGGATTGGTGATGTTGACCCCGAAACGGGCGGAACCGC GTATGCAGAGAAGTTTCAAGGTAGGGCAACGCTCACTGCGGACA GAAGCACAGACACGGCATACATGGAGCTTAGTTCTCTCCGCTCT GAGGATACCGCTGTTTATTATTGTACTAGAACCTATGATGGATAT CCATACGCATTCGATTATTGGGGGCAAGGGACTCTTGTCACAGT CAGCTCCGCTTCAACCAAGGGACCTTCTGTCTTTCCTCTGGCCCC TTCAAGCAAGAGCACTTCCGGAGGGACTGCCGCACTCGGGTGCC TTGTGAAAGATTACTTCCCAGAGCCTGTCACCGTCAGCTGGAATT CAGGCGCTCTGACTAGCGGAGTGCACACCTTCCCCGCTGTGCTTC AGTCCTCCGGACTCTACTCTCTGAGCAGCGTGGTGACCGTGCCGT CCTCTTCTCTGGGGACCCAGACTTATATCTGCAACGTCAATCATA AGCCTTCTAATACCAAGGTGGACAAGAAGGTGGAACCCAAATCA TGTGACAAGACCCACACCTGTCCGCCCTGTCCGGCACCCGAACT GCTGGGTGGCCCTTCCGTGTTCCTTTTCCCTCCAAAGCCGAAGGA CACTCTTATGATTTCTCGCACTCCCGAAGTGACTTGCGTCGTGGT GGATGTGTCCCATGAGGATCCAGAGGTCAAGTTCAACTGGTACG TGGACGGTGTGGAAGTCCACAACGCCAAGACTAAGCCGAGAGA GGAACAGTACAATTCAACCTATCGGGTGGTGAGCGTCCTGACCG TGCTGCACCAGGACTGGCTTAACGGAAAGGAGTACAAGTGCAA AGTGTCAAACAAGGCACTGCCCGCTCCGATCGAAAAGACCATTA GCAAAGCTAAGGGCCAGCCCAGAGAACCCCAAGTCTATACCCTT CCACCCAGCCGGGACGAGCTGACCAAAAACCAGGTGTCACTCAC TTGTCTCGTGAAGGGTTTCTACCCCTCAGACATCGCCGTCGAATG GGAGTCCAATGGTCAGCCAGAGAACAACTACAAAACCACCCCTC CCGTGCTGGACAGCGACGGGTCTTTCTTTCTCTACTCAAAGCTGA CCGTGGATAAGTCTCGCTGGCAGCAAGGGAATGTGTTTTCCTGTT CAGTGATGCATGAGGCCCTTCATAATCATTACACCCAAAAGTCA CTGAGCCTGTCTCCCGGA (SEQ ID NO: 36) KC18 Hu18 LC GACATAGTGATGACTCAATCCCCAGATTCACTCGCCGTATCACTC GGAGAAAGAGCCACAATTAATTGTAAGAGTAGTCAGTCAGTCCT TTACTCTAATAACAACAAAAATTACCTGGCCTGGTACCAACAGA AACCAGGTCAATCTCCTAAACTGCTTATCTACTGGGCTAGTACCC GAGAATCAGGAGTTCCCGATAGGTTTTCTGGGTCTGGGAGCGGC ACCGACTTCACACTCACAATCTCTAGCGTACAGGCTGAAGATGT AGCGGTGTATTACTGCCAACAGTATTATTCATACAGGACCTTCG GTGGTGGCACCAAAGTAGAAATCAAACGCACTGTGGCAGCCCCT TCTGTGTTTATCTTCCCACCCTCCGACGAGCAGCTCAAGTCCGGT ACCGCCTCTGTCGTCTGCCTGCTGAACAATTTCTACCCAAGAGAG GCCAAGGTGCAGTGGAAGGTGGACAACGCACTGCAAAGCGGTA ATTCACAAGAGTCAGTCACCGAACAAGACTCAAAGGACAGCAC CTACTCACTGTCATCCACCCTGACTCTCTCAAAGGCTGACTACGA AAAGCACAAAGTGTATGCTTGTGAAGTCACTCATCAGGGCCTTT CTAGCCCTGTGACCAAGAGCTTCAACAGAGGCGAATGC (SEQ ID NO: 37) KE63 Hu01 HC CAGGTACAGTTGGTACAGTCAGGAGCGGAGGTTAAAAAACCAG GGGCGTCTGTGAAAGTCTCATGTAAAGCGAGCGGAAGCACGTTT AGCGATTTCGAGATTCACTGGGTGAGACAAGCACCCGGTCAGGG CCTGGAATGGATTGGAGGGATCGACCCGGAAACAGGGGGTACA GCATATAACCAAAAGTTTCAGGGACGGGTCACTATAACGGCTGA CAGGAGCACGTCAACTGCGTATATGGAATTGTCCAGTTTGAGGT CAGAAGATACGGCAGTCTACTACTGCACAAGAAATTATGATGGA TACTCTCAAACGTTTGATTATTGGGGTCAGGGGACCCTGGTAAC AGTCAGCTCAGCTTCAACCAAGGGACCTTCTGTCTTTCCTCTGGC CCCTTCAAGCAAGAGCACTTCCGGAGGGACTGCCGCACTCGGGT GCCTTGTGAAAGATTACTTCCCAGAGCCTGTCACCGTCAGCTGG AATTCAGGCGCTCTGACTAGCGGAGTGCACACCTTCCCCGCTGT GCTTCAGTCCTCCGGACTCTACTCTCTGAGCAGCGTGGTGACCGT GCCGTCCTCTTCTCTGGGGACCCAGACTTATATCTGCAACGTCAA TCATAAGCCTTCTAATACCAAGGTGGACAAGAAGGTGGAACCCA AATCATGTGACAAGACCCACACCTGTCCGCCCTGTCCGGCACCC GAACTGCTGGGTGGCCCTTCCGTGTTCCTTTTCCCTCCAAAGCCG AAGGACACTCTTATGATTTCTCGCACTCCCGAAGTGACTTGCGTC GTGGTGGATGTGTCCCATGAGGATCCAGAGGTCAAGTTCAACTG GTACGTGGACGGTGTGGAAGTCCACAACGCCAAGACTAAGCCG AGAGAGGAACAGTACAATTCAACCTATCGGGTGGTGAGCGTCCT GACCGTGCTGCACCAGGACTGGCTTAACGGAAAGGAGTACAAGT GCAAAGTGTCAAACAAGGCACTGCCCGCTCCGATCGAAAAGACC ATTAGCAAAGCTAAGGGCCAGCCCAGAGAACCCCAAGTCTATAC CCTTCCACCCAGCCGGGACGAGCTGACCAAAAACCAGGTGTCAC TCACTTGTCTCGTGAAGGGTTTCTACCCCTCAGACATCGCCGTCG AATGGGAGTCCAATGGTCAGCCAGAGAACAACTACAAAACCAC CCCTCCCGTGCTGGACAGCGACGGGTCTTTCTTTCTCTACTCAAA GCTGACCGTGGATAAGTCTCGCTGGCAGCAAGGGAATGTGTTTT CCTGTTCAGTGATGCATGAGGCCCTTCATAATCATTACACCCAAA AGTCACTGAGCCTGTCTCCCGGA (SEQ ID NO: 38) KE63 Hu02 HC CAGGTACAGTTGGTACAGTCAGGAGCGGAGGTTAAAAAACCAG GGGCGTCTGTGAAAGTCTCATGTAAAGCGAGCGGAAGCACGTTT AGCGATTTCGAGATTCACTGGGTGAGACAAGCACCCGGTCAGGG CCTGGAATGGATTGGAGGGATCGACCCGGAAACAGGGGGTACA GCATATAACCAAAAGTTTCAGGGACGGGTCACTATAACGGCTGA CAGGAGCACGTCAACTGCGTATATGGAATTGTCCAGTTTGAGGT CAGAAGATACGGCAGTCTACTACTGCACAAGAAATTATGATGGA TACTCTCAAACGTTTGATTATTGGGGTCAGGGGACCCTGGTAAC AGTCAGCTCAGCTTCAACCAAGGGACCTTCTGTCTTTCCTCTGGC CCCTTCAAGCAAGAGCACTTCCGGAGGGACTGCCGCACTCGGGT GCCTTGTGAAAGATTACTTCCCAGAGCCTGTCACCGTCAGCTGG AATTCAGGCGCTCTGACTAGCGGAGTGCACACCTTCCCCGCTGT GCTTCAGTCCTCCGGACTCTACTCTCTGAGCAGCGTGGTGACCGT GCCGTCCTCTTCTCTGGGGACCCAGACTTATATCTGCAACGTCAA TCATAAGCCTTCTAATACCAAGGTGGACAAGAAGGTGGAACCCA AATCATGTGACAAGACCCACACCTGTCCGCCCTGTCCGGCACCC GAACTGCTGGGTGGCCCTTCCGTGTTCCTTTTCCCTCCAAAGCCG AAGGACACTCTTATGATTTCTCGCACTCCCGAAGTGACTTGCGTC GTGGTGGATGTGTCCCATGAGGATCCAGAGGTCAAGTTCAACTG GTACGTGGACGGTGTGGAAGTCCACAACGCCAAGACTAAGCCG AGAGAGGAACAGTACAATTCAACCTATCGGGTGGTGAGCGTCCT GACCGTGCTGCACCAGGACTGGCTTAACGGAAAGGAGTACAAGT GCAAAGTGTCAAACAAGGCACTGCCCGCTCCGATCGAAAAGACC ATTAGCAAAGCTAAGGGCCAGCCCAGAGAACCCCAAGTCTATAC CCTTCCACCCAGCCGGGACGAGCTGACCAAAAACCAGGTGTCAC TCACTTGTCTCGTGAAGGGTTTCTACCCCTCAGACATCGCCGTCG AATGGGAGTCCAATGGTCAGCCAGAGAACAACTACAAAACCAC CCCTCCCGTGCTGGACAGCGACGGGTCTTTCTTTCTCTACTCAAA GCTGACCGTGGATAAGTCTCGCTGGCAGCAAGGGAATGTGTTTT CCTGTTCAGTGATGCATGAGGCCCTTCATAATCATTACACCCAAA AGTCACTGAGCCTGTCTCCCGGA (SEQ ID NO: 39) KE63 Hu03 HC CAGGTACAGTTGGTACAGTCAGGAGCGGAGGTTAAAAAACCAG GGGCGTCTGTGAAAGTCTCATGTAAAGCGAGCGGAAGCACGTTT AGCGATTTCGAGATTCACTGGGTGAGACAAGCACCCGGTCAGGG CCTGGAATGGATTGGAGGGATCGACCCGGAAACAGGGGGTACA GCATATAACCAAAAGTTTCAGGGACGGGTCACTATAACGGCTGA CAGGAGCACGTCAACTGCGTATATGGAATTGTCCAGTTTGAGGT CAGAAGATACGGCAGTCTACTACTGCACAAGAAATTATGATGGA TACTCTCAAACGTTTGATTATTGGGGTCAGGGGACCCTGGTAAC AGTCAGCTCAGCTTCAACCAAGGGACCTTCTGTCTTTCCTCTGGC CCCTTCAAGCAAGAGCACTTCCGGAGGGACTGCCGCACTCGGGT GCCTTGTGAAAGATTACTTCCCAGAGCCTGTCACCGTCAGCTGG AATTCAGGCGCTCTGACTAGCGGAGTGCACACCTTCCCCGCTGT GCTTCAGTCCTCCGGACTCTACTCTCTGAGCAGCGTGGTGACCGT GCCGTCCTCTTCTCTGGGGACCCAGACTTATATCTGCAACGTCAA TCATAAGCCTTCTAATACCAAGGTGGACAAGAAGGTGGAACCCA AATCATGTGACAAGACCCACACCTGTCCGCCCTGTCCGGCACCC GAACTGCTGGGTGGCCCTTCCGTGTTCCTTTTCCCTCCAAAGCCG AAGGACACTCTTATGATTTCTCGCACTCCCGAAGTGACTTGCGTC GTGGTGGATGTGTCCCATGAGGATCCAGAGGTCAAGTTCAACTG GTACGTGGACGGTGTGGAAGTCCACAACGCCAAGACTAAGCCG AGAGAGGAACAGTACAATTCAACCTATCGGGTGGTGAGCGTCCT GACCGTGCTGCACCAGGACTGGCTTAACGGAAAGGAGTACAAGT GCAAAGTGTCAAACAAGGCACTGCCCGCTCCGATCGAAAAGACC ATTAGCAAAGCTAAGGGCCAGCCCAGAGAACCCCAAGTCTATAC CCTTCCACCCAGCCGGGACGAGCTGACCAAAAACCAGGTGTCAC TCACTTGTCTCGTGAAGGGTTTCTACCCCTCAGACATCGCCGTCG AATGGGAGTCCAATGGTCAGCCAGAGAACAACTACAAAACCAC CCCTCCCGTGCTGGACAGCGACGGGTCTTTCTTTCTCTACTCAAA GCTGACCGTGGATAAGTCTCGCTGGCAGCAAGGGAATGTGTTTT CCTGTTCAGTGATGCATGAGGCCCTTCATAATCATTACACCCAAA AGTCACTGAGCCTGTCTCCCGGA (SEQ ID NO: 40) KE63 Hu04 HC CAGGTACAGTTGGTACAGTCAGGAGCGGAGGTTAAAAAACCAG GGGCGTCTGTGAAAGTCTCATGTAAAGCGAGCGGAAGCACGTTT AGCGATTTCGAGATTCACTGGGTGAGACAAGCACCCGGTCAGGG CCTGGAATGGATTGGAGGGATCGACCCGGAAACAGGGGGTACA GCATATAACCAAAAGTTTCAGGGACGGGTCACTATAACGGCTGA CAGGAGCACGTCAACTGCGTATATGGAATTGTCCAGTTTGAGGT CAGAAGATACGGCAGTCTACTACTGCACAAGAAATTATGATGGA TACTCTCAAACGTTTGATTATTGGGGTCAGGGGACCCTGGTAAC AGTCAGCTCAGCTTCAACCAAGGGACCTTCTGTCTTTCCTCTGGC CCCTTCAAGCAAGAGCACTTCCGGAGGGACTGCCGCACTCGGGT GCCTTGTGAAAGATTACTTCCCAGAGCCTGTCACCGTCAGCTGG AATTCAGGCGCTCTGACTAGCGGAGTGCACACCTTCCCCGCTGT GCTTCAGTCCTCCGGACTCTACTCTCTGAGCAGCGTGGTGACCGT GCCGTCCTCTTCTCTGGGGACCCAGACTTATATCTGCAACGTCAA TCATAAGCCTTCTAATACCAAGGTGGACAAGAAGGTGGAACCCA AATCATGTGACAAGACCCACACCTGTCCGCCCTGTCCGGCACCC GAACTGCTGGGTGGCCCTTCCGTGTTCCTTTTCCCTCCAAAGCCG AAGGACACTCTTATGATTTCTCGCACTCCCGAAGTGACTTGCGTC GTGGTGGATGTGTCCCATGAGGATCCAGAGGTCAAGTTCAACTG GTACGTGGACGGTGTGGAAGTCCACAACGCCAAGACTAAGCCG AGAGAGGAACAGTACAATTCAACCTATCGGGTGGTGAGCGTCCT GACCGTGCTGCACCAGGACTGGCTTAACGGAAAGGAGTACAAGT GCAAAGTGTCAAACAAGGCACTGCCCGCTCCGATCGAAAAGACC ATTAGCAAAGCTAAGGGCCAGCCCAGAGAACCCCAAGTCTATAC CCTTCCACCCAGCCGGGACGAGCTGACCAAAAACCAGGTGTCAC TCACTTGTCTCGTGAAGGGTTTCTACCCCTCAGACATCGCCGTCG AATGGGAGTCCAATGGTCAGCCAGAGAACAACTACAAAACCAC CCCTCCCGTGCTGGACAGCGACGGGTCTTTCTTTCTCTACTCAAA GCTGACCGTGGATAAGTCTCGCTGGCAGCAAGGGAATGTGTTTT CCTGTTCAGTGATGCATGAGGCCCTTCATAATCATTACACCCAAA AGTCACTGAGCCTGTCTCCCGGA (SEQ ID NO: 41) KE63 Hu01 LC GATATAGTTATGACACAGAGCCCTGACTCTCTGGCTGTGAGTTTG GGCGAGCGAGTAACCATTAATTGTAAGAGTTCTCAATCCGTCCT CTACTCAAGCAACCAGAAAAATTACCTCGCGTGGTACCAGCAAA AACCAGGACAGAGCCCCAAACTCTTGATCTATTGGGCGTCCACC CGAGAGAGTGGCGTGCCAGATCGGTTTTCAGGTTCTGGATCTGG TACCGACTTCACCCTTACAATCTCAAGCCTGCAAGCAGAGGATG TCGCAGTTTATTATTGCCATCAGTACCTGAGCAGCTACACATTCG GACAAGGAACGAAACTGGAAATCAAACGCACTGTGGCAGCCCC TTCTGTGTTTATCTTCCCACCCTCCGACGAGCAGCTCAAGTCCGG TACCGCCTCTGTCGTCTGCCTGCTGAACAATTTCTACCCAAGAGA GGCCAAGGTGCAGTGGAAGGTGGACAACGCACTGCAAAGCGGT AATTCACAAGAGTCAGTCACCGAACAAGACTCAAAGGACAGCA CCTACTCACTGTCATCCACCCTGACTCTCTCAAAGGCTGACTACG AAAAGCACAAAGTGTATGCTTGTGAAGTCACTCATCAGGGCCTT TCTAGCCCTGTGACCAAGAGCTTCAACAGAGGCGAATGC (SEQ ID NO: 42) KE63 Hu02 LC GACATAGTAATGACCCAAAGTCCAGATTCTTTGGCCGTATCTTTG GGTGAGCGCGTTACCATCAACTGTAAGTCTTCCCAGTCTGTGTTG TACTCATCTAATCAAAAAAACTACCTCGCTTGGTACCAGCAGAA GCCAGGTCAAAGCCCGAAACTGCTTATTTATTGGGCGTCTACGC GAGAGTCTGGGGTCCCCGATCGGTTTTCAGGGTCAGGCTCTGGC ACTGATTTTACTCTGACTATTTCATCCCTCCAAGCCGAAGACGTG GCAGTGTATTACTGCCACCAGTATTTGAGCCCTTACACGTTTGGG CAGGGGACTAAACTTGAAATCAAGCGCACTGTGGCAGCCCCTTC TGTGTTTATCTTCCCACCCTCCGACGAGCAGCTCAAGTCCGGTAC CGCCTCTGTCGTCTGCCTGCTGAACAATTTCTACCCAAGAGAGGC CAAGGTGCAGTGGAAGGTGGACAACGCACTGCAAAGCGGTAAT TCACAAGAGTCAGTCACCGAACAAGACTCAAAGGACAGCACCT ACTCACTGTCATCCACCCTGACTCTCTCAAAGGCTGACTACGAA AAGCACAAAGTGTATGCTTGTGAAGTCACTCATCAGGGCCTTTC TAGCCCTGTGACCAAGAGCTTCAACAGAGGCGAATGC (SEQ ID NO: 43) KE63 Hu03 LC GATATTGTGATGACTCAGTCACCTGACAGTCTGGCGGTTTCTTTG GGCGAAAGAGTGACTATAAATTGCAAAAGCAGCCAGTCAGTTCT CTATTCCGACAATCAAAAGAACTATCTCGCATGGTATCAGCAGA AGCCAGGGCAATCCCCAAAATTGCTTATATACTATGCATCAACG CGCGAAAGCGGTGTACCCGATCGGTTTTCAGGAAGTGGCAGTGG GACCGACTTTACGCTGACAATCTCTTCCCTTCAAGCGGAGGATGT CGCGGTTTATTATTGTCATCAGTATCTGAGTCCTTACACCTTTGG TCAAGGGACGAAGTTGGAGATCAAACGCACTGTGGCAGCCCCTT CTGTGTTTATCTTCCCACCCTCCGACGAGCAGCTCAAGTCCGGTA CCGCCTCTGTCGTCTGCCTGCTGAACAATTTCTACCCAAGAGAGG CCAAGGTGCAGTGGAAGGTGGACAACGCACTGCAAAGCGGTAA TTCACAAGAGTCAGTCACCGAACAAGACTCAAAGGACAGCACCT ACTCACTGTCATCCACCCTGACTCTCTCAAAGGCTGACTACGAA AAGCACAAAGTGTATGCTTGTGAAGTCACTCATCAGGGCCTTTC TAGCCCTGTGACCAAGAGCTTCAACAGAGGCGAATGC (SEQ ID NO: 44) KE63 Hu04 LC GACATCGTAATGACCCAGTCCCCCGATAGTCTGGCTGTGTCTTTG GGCGAGAGGGTAACGATAAACTGTAAATCAAGTCAGTCAGTGCT TTACTCAGATAACCAGAAGAACTATCTTGCGTGGTATCAGCAAA AGCCCGGACAGTCTCCAAAACTTCTTATATATTTCGCTTCTACCA GAGAATCAGGTGTACCAGACCGCTTTTCTGGAAGCGGCTCTGGT ACTGACTTTACCCTGACAATTAGTAGCTTGCAAGCTGAAGATGTT GCGGTATATTATTGTCACCAATACTTGAGTCCCTATACTTTTGGC CAAGGGACAAAACTGGAAATAAAGCGCACTGTGGCAGCCCCTTC TGTGTTTATCTTCCCACCCTCCGACGAGCAGCTCAAGTCCGGTAC CGCCTCTGTCGTCTGCCTGCTGAACAATTTCTACCCAAGAGAGGC CAAGGTGCAGTGGAAGGTGGACAACGCACTGCAAAGCGGTAAT TCACAAGAGTCAGTCACCGAACAAGACTCAAAGGACAGCACCT ACTCACTGTCATCCACCCTGACTCTCTCAAAGGCTGACTACGAA AAGCACAAAGTGTATGCTTGTGAAGTCACTCATCAGGGCCTTTC TAGCCCTGTGACCAAGAGCTTCAACAGAGGCGAATGC (SEQ ID NO: 45) KE94 Hu01 HC CAGGTTCAGCTGGTACAATCTGGCGCGGAAGTCAAAAAGCCAGG CGCAAGTGTTAAAGTGTCTTGCAAGGCTTCAGGATCTACCTTTAC AGATTTTGAAATCCACTGGGTAAGACAAGCACCTGGCCAGGGGC TGGAATGGATTGGTGCCATAGACCCTGAGACGGGAGGAACCGC ATATAACCAGAAATTCCAAGGTCGAGTGACTATTACTGCGGACA AGTCAACATCAACTGCCTATATGGAGCTGTCTTCTTTGAGGTCAG AGGATACAGCAGTTTACTACTGCACTAGAAATTACGATGGTTAT TCACGGACCTTCGATTATTGGGGTCAAGGCACTCTGGTGACCGT GAGTTCCGCTTCAACCAAGGGACCTTCTGTCTTTCCTCTGGCCCC TTCAAGCAAGAGCACTTCCGGAGGGACTGCCGCACTCGGGTGCC TTGTGAAAGATTACTTCCCAGAGCCTGTCACCGTCAGCTGGAATT CAGGCGCTCTGACTAGCGGAGTGCACACCTTCCCCGCTGTGCTTC AGTCCTCCGGACTCTACTCTCTGAGCAGCGTGGTGACCGTGCCGT CCTCTTCTCTGGGGACCCAGACTTATATCTGCAACGTCAATCATA AGCCTTCTAATACCAAGGTGGACAAGAAGGTGGAACCCAAATCA TGTGACAAGACCCACACCTGTCCGCCCTGTCCGGCACCCGAACT GCTGGGTGGCCCTTCCGTGTTCCTTTTCCCTCCAAAGCCGAAGGA CACTCTTATGATTTCTCGCACTCCCGAAGTGACTTGCGTCGTGGT GGATGTGTCCCATGAGGATCCAGAGGTCAAGTTCAACTGGTACG TGGACGGTGTGGAAGTCCACAACGCCAAGACTAAGCCGAGAGA GGAACAGTACAATTCAACCTATCGGGTGGTGAGCGTCCTGACCG TGCTGCACCAGGACTGGCTTAACGGAAAGGAGTACAAGTGCAA AGTGTCAAACAAGGCACTGCCCGCTCCGATCGAAAAGACCATTA GCAAAGCTAAGGGCCAGCCCAGAGAACCCCAAGTCTATACCCTT CCACCCAGCCGGGACGAGCTGACCAAAAACCAGGTGTCACTCAC TTGTCTCGTGAAGGGTTTCTACCCCTCAGACATCGCCGTCGAATG GGAGTCCAATGGTCAGCCAGAGAACAACTACAAAACCACCCCTC CCGTGCTGGACAGCGACGGGTCTTTCTTTCTCTACTCAAAGCTGA CCGTGGATAAGTCTCGCTGGCAGCAAGGGAATGTGTTTTCCTGTT CAGTGATGCATGAGGCCCTTCATAATCATTACACCCAAAAGTCA CTGAGCCTGTCTCCCGGA (SEQ ID NO: 46) KE94 Hu02 HC CAGGTTCAGCTGGTACAATCTGGCGCGGAAGTCAAAAAGCCAGG CGCAAGTGTTAAAGTGTCTTGCAAGGCTTCAGGATCTACCTTTAC AGATTTTGAAATCCACTGGGTAAGACAAGCACCTGGCCAGGGGC TGGAATGGATTGGTGCCATAGACCCTGAGACGGGAGGAACCGC ATATAACCAGAAATTCCAAGGTCGAGTGACTATTACTGCGGACA AGTCAACATCAACTGCCTATATGGAGCTGTCTTCTTTGAGGTCAG AGGATACAGCAGTTTACTACTGCACTAGAAATTACGATGGTTAT TCACGGACCTTCGATTATTGGGGTCAAGGCACTCTGGTGACCGT GAGTTCCGCTTCAACCAAGGGACCTTCTGTCTTTCCTCTGGCCCC TTCAAGCAAGAGCACTTCCGGAGGGACTGCCGCACTCGGGTGCC TTGTGAAAGATTACTTCCCAGAGCCTGTCACCGTCAGCTGGAATT CAGGCGCTCTGACTAGCGGAGTGCACACCTTCCCCGCTGTGCTTC AGTCCTCCGGACTCTACTCTCTGAGCAGCGTGGTGACCGTGCCGT CCTCTTCTCTGGGGACCCAGACTTATATCTGCAACGTCAATCATA AGCCTTCTAATACCAAGGTGGACAAGAAGGTGGAACCCAAATCA TGTGACAAGACCCACACCTGTCCGCCCTGTCCGGCACCCGAACT GCTGGGTGGCCCTTCCGTGTTCCTTTTCCCTCCAAAGCCGAAGGA CACTCTTATGATTTCTCGCACTCCCGAAGTGACTTGCGTCGTGGT GGATGTGTCCCATGAGGATCCAGAGGTCAAGTTCAACTGGTACG TGGACGGTGTGGAAGTCCACAACGCCAAGACTAAGCCGAGAGA GGAACAGTACAATTCAACCTATCGGGTGGTGAGCGTCCTGACCG TGCTGCACCAGGACTGGCTTAACGGAAAGGAGTACAAGTGCAA AGTGTCAAACAAGGCACTGCCCGCTCCGATCGAAAAGACCATTA GCAAAGCTAAGGGCCAGCCCAGAGAACCCCAAGTCTATACCCTT CCACCCAGCCGGGACGAGCTGACCAAAAACCAGGTGTCACTCAC TTGTCTCGTGAAGGGTTTCTACCCCTCAGACATCGCCGTCGAATG GGAGTCCAATGGTCAGCCAGAGAACAACTACAAAACCACCCCTC CCGTGCTGGACAGCGACGGGTCTTTCTTTCTCTACTCAAAGCTGA CCGTGGATAAGTCTCGCTGGCAGCAAGGGAATGTGTTTTCCTGTT CAGTGATGCATGAGGCCCTTCATAATCATTACACCCAAAAGTCA CTGAGCCTGTCTCCCGGA (SEQ ID NO: 47) KE94 Hu03 HC CAGGTTCAGCTGGTACAATCTGGCGCGGAAGTCAAAAAGCCAGG CGCAAGTGTTAAAGTGTCTTGCAAGGCTTCAGGATCTACCTTTAC AGATTTTGAAATCCACTGGGTAAGACAAGCACCTGGCCAGGGGC TGGAATGGATTGGTGCCATAGACCCTGAGACGGGAGGAACCGC ATATAACCAGAAATTCCAAGGTCGAGTGACTATTACTGCGGACA AGTCAACATCAACTGCCTATATGGAGCTGTCTTCTTTGAGGTCAG AGGATACAGCAGTTTACTACTGCACTAGAAATTACGATGGTTAT TCACGGACCTTCGATTATTGGGGTCAAGGCACTCTGGTGACCGT GAGTTCCGCTTCAACCAAGGGACCTTCTGTCTTTCCTCTGGCCCC TTCAAGCAAGAGCACTTCCGGAGGGACTGCCGCACTCGGGTGCC TTGTGAAAGATTACTTCCCAGAGCCTGTCACCGTCAGCTGGAATT CAGGCGCTCTGACTAGCGGAGTGCACACCTTCCCCGCTGTGCTTC AGTCCTCCGGACTCTACTCTCTGAGCAGCGTGGTGACCGTGCCGT CCTCTTCTCTGGGGACCCAGACTTATATCTGCAACGTCAATCATA AGCCTTCTAATACCAAGGTGGACAAGAAGGTGGAACCCAAATCA TGTGACAAGACCCACACCTGTCCGCCCTGTCCGGCACCCGAACT GCTGGGTGGCCCTTCCGTGTTCCTTTTCCCTCCAAAGCCGAAGGA CACTCTTATGATTTCTCGCACTCCCGAAGTGACTTGCGTCGTGGT GGATGTGTCCCATGAGGATCCAGAGGTCAAGTTCAACTGGTACG TGGACGGTGTGGAAGTCCACAACGCCAAGACTAAGCCGAGAGA GGAACAGTACAATTCAACCTATCGGGTGGTGAGCGTCCTGACCG TGCTGCACCAGGACTGGCTTAACGGAAAGGAGTACAAGTGCAA AGTGTCAAACAAGGCACTGCCCGCTCCGATCGAAAAGACCATTA GCAAAGCTAAGGGCCAGCCCAGAGAACCCCAAGTCTATACCCTT CCACCCAGCCGGGACGAGCTGACCAAAAACCAGGTGTCACTCAC TTGTCTCGTGAAGGGTTTCTACCCCTCAGACATCGCCGTCGAATG GGAGTCCAATGGTCAGCCAGAGAACAACTACAAAACCACCCCTC CCGTGCTGGACAGCGACGGGTCTTTCTTTCTCTACTCAAAGCTGA CCGTGGATAAGTCTCGCTGGCAGCAAGGGAATGTGTTTTCCTGTT CAGTGATGCATGAGGCCCTTCATAATCATTACACCCAAAAGTCA CTGAGCCTGTCTCCCGGA (SEQ ID NO: 48) KE94 Hu04 HC CAGGTTCAGCTGGTACAATCTGGCGCGGAAGTCAAAAAGCCAGG CGCAAGTGTTAAAGTGTCTTGCAAGGCTTCAGGATCTACCTTTAC AGATTTTGAAATCCACTGGGTAAGACAAGCACCTGGCCAGGGGC TGGAATGGATTGGTGCCATAGACCCTGAGACGGGAGGAACCGC ATATAACCAGAAATTCCAAGGTCGAGTGACTATTACTGCGGACA AGTCAACATCAACTGCCTATATGGAGCTGTCTTCTTTGAGGTCAG AGGATACAGCAGTTTACTACTGCACTAGAAATTACGATGGTTAT TCACGGACCTTCGATTATTGGGGTCAAGGCACTCTGGTGACCGT GAGTTCCGCTTCAACCAAGGGACCTTCTGTCTTTCCTCTGGCCCC TTCAAGCAAGAGCACTTCCGGAGGGACTGCCGCACTCGGGTGCC TTGTGAAAGATTACTTCCCAGAGCCTGTCACCGTCAGCTGGAATT CAGGCGCTCTGACTAGCGGAGTGCACACCTTCCCCGCTGTGCTTC AGTCCTCCGGACTCTACTCTCTGAGCAGCGTGGTGACCGTGCCGT CCTCTTCTCTGGGGACCCAGACTTATATCTGCAACGTCAATCATA AGCCTTCTAATACCAAGGTGGACAAGAAGGTGGAACCCAAATCA TGTGACAAGACCCACACCTGTCCGCCCTGTCCGGCACCCGAACT GCTGGGTGGCCCTTCCGTGTTCCTTTTCCCTCCAAAGCCGAAGGA CACTCTTATGATTTCTCGCACTCCCGAAGTGACTTGCGTCGTGGT GGATGTGTCCCATGAGGATCCAGAGGTCAAGTTCAACTGGTACG TGGACGGTGTGGAAGTCCACAACGCCAAGACTAAGCCGAGAGA GGAACAGTACAATTCAACCTATCGGGTGGTGAGCGTCCTGACCG TGCTGCACCAGGACTGGCTTAACGGAAAGGAGTACAAGTGCAA AGTGTCAAACAAGGCACTGCCCGCTCCGATCGAAAAGACCATTA GCAAAGCTAAGGGCCAGCCCAGAGAACCCCAAGTCTATACCCTT CCACCCAGCCGGGACGAGCTGACCAAAAACCAGGTGTCACTCAC TTGTCTCGTGAAGGGTTTCTACCCCTCAGACATCGCCGTCGAATG GGAGTCCAATGGTCAGCCAGAGAACAACTACAAAACCACCCCTC CCGTGCTGGACAGCGACGGGTCTTTCTTTCTCTACTCAAAGCTGA CCGTGGATAAGTCTCGCTGGCAGCAAGGGAATGTGTTTTCCTGTT CAGTGATGCATGAGGCCCTTCATAATCATTACACCCAAAAGTCA CTGAGCCTGTCTCCCGGA (SEQ ID NO: 49) KE94 Hu01 LC GATATAGTTATGACACAGAGCCCTGACTCTCTGGCTGTGAGTTTG GGCGAGCGAGTAACCATTAATTGTAAGAGTTCTCAATCCGTCCT CTACTCAAGCAACCAGAAAAATTACCTCGCGTGGTACCAGCAAA AACCAGGACAGAGCCCCAAACTCTTGATCTATTGGGCGTCCACC CGAGAGAGTGGCGTGCCAGATCGGTTTTCAGGTTCTGGATCTGG TACCGACTTCACCCTTACAATCTCAAGCCTGCAAGCAGAGGATG TCGCAGTTTATTATTGCCATCAGTACCTGAGCAGCTACACATTCG GACAAGGAACGAAACTGGAAATCAAACGCACTGTGGCAGCCCC TTCTGTGTTTATCTTCCCACCCTCCGACGAGCAGCTCAAGTCCGG TACCGCCTCTGTCGTCTGCCTGCTGAACAATTTCTACCCAAGAGA GGCCAAGGTGCAGTGGAAGGTGGACAACGCACTGCAAAGCGGT AATTCACAAGAGTCAGTCACCGAACAAGACTCAAAGGACAGCA CCTACTCACTGTCATCCACCCTGACTCTCTCAAAGGCTGACTACG AAAAGCACAAAGTGTATGCTTGTGAAGTCACTCATCAGGGCCTT TCTAGCCCTGTGACCAAGAGCTTCAACAGAGGCGAATGC (SEQ ID NO: 50) KE94 Hu02 LC GACATAGTAATGACCCAAAGTCCAGATTCTTTGGCCGTATCTTTG GGTGAGCGCGTTACCATCAACTGTAAGTCTTCCCAGTCTGTGTTG TACTCATCTAATCAAAAAAACTACCTCGCTTGGTACCAGCAGAA GCCAGGTCAAAGCCCGAAACTGCTTATTTATTGGGCGTCTACGC GAGAGTCTGGGGTCCCCGATCGGTTTTCAGGGTCAGGCTCTGGC ACTGATTTTACTCTGACTATTTCATCCCTCCAAGCCGAAGACGTG GCAGTGTATTACTGCCACCAGTATTTGAGCCCTTACACGTTTGGG CAGGGGACTAAACTTGAAATCAAGCGCACTGTGGCAGCCCCTTC TGTGTTTATCTTCCCACCCTCCGACGAGCAGCTCAAGTCCGGTAC CGCCTCTGTCGTCTGCCTGCTGAACAATTTCTACCCAAGAGAGGC CAAGGTGCAGTGGAAGGTGGACAACGCACTGCAAAGCGGTAAT TCACAAGAGTCAGTCACCGAACAAGACTCAAAGGACAGCACCT ACTCACTGTCATCCACCCTGACTCTCTCAAAGGCTGACTACGAA AAGCACAAAGTGTATGCTTGTGAAGTCACTCATCAGGGCCTTTC TAGCCCTGTGACCAAGAGCTTCAACAGAGGCGAATGC (SEQ ID NO: 51) KE94 Hu03 LC GATATTGTGATGACTCAGTCACCTGACAGTCTGGCGGTTTCTTTG GGCGAAAGAGTGACTATAAATTGCAAAAGCAGCCAGTCAGTTCT CTATTCCGACAATCAAAAGAACTATCTCGCATGGTATCAGCAGA AGCCAGGGCAATCCCCAAAATTGCTTATATACTATGCATCAACG CGCGAAAGCGGTGTACCCGATCGGTTTTCAGGAAGTGGCAGTGG GACCGACTTTACGCTGACAATCTCTTCCCTTCAAGCGGAGGATGT CGCGGTTTATTATTGTCATCAGTATCTGAGTCCTTACACCTTTGG TCAAGGGACGAAGTTGGAGATCAAACGCACTGTGGCAGCCCCTT CTGTGTTTATCTTCCCACCCTCCGACGAGCAGCTCAAGTCCGGTA CCGCCTCTGTCGTCTGCCTGCTGAACAATTTCTACCCAAGAGAGG CCAAGGTGCAGTGGAAGGTGGACAACGCACTGCAAAGCGGTAA TTCACAAGAGTCAGTCACCGAACAAGACTCAAAGGACAGCACCT ACTCACTGTCATCCACCCTGACTCTCTCAAAGGCTGACTACGAA AAGCACAAAGTGTATGCTTGTGAAGTCACTCATCAGGGCCTTTC TAGCCCTGTGACCAAGAGCTTCAACAGAGGCGAATGC (SEQ ID NO: 52) KE94 Hu04 LC GACATCGTAATGACCCAGTCCCCCGATAGTCTGGCTGTGTCTTTG GGCGAGAGGGTAACGATAAACTGTAAATCAAGTCAGTCAGTGCT TTACTCAGATAACCAGAAGAACTATCTTGCGTGGTATCAGCAAA AGCCCGGACAGTCTCCAAAACTTCTTATATATTTCGCTTCTACCA GAGAATCAGGTGTACCAGACCGCTTTTCTGGAAGCGGCTCTGGT ACTGACTTTACCCTGACAATTAGTAGCTTGCAAGCTGAAGATGTT GCGGTATATTATTGTCACCAATACTTGAGTCCCTATACTTTTGGC CAAGGGACAAAACTGGAAATAAAGCGCACTGTGGCAGCCCCTTC TGTGTTTATCTTCCCACCCTCCGACGAGCAGCTCAAGTCCGGTAC CGCCTCTGTCGTCTGCCTGCTGAACAATTTCTACCCAAGAGAGGC CAAGGTGCAGTGGAAGGTGGACAACGCACTGCAAAGCGGTAAT TCACAAGAGTCAGTCACCGAACAAGACTCAAAGGACAGCACCT ACTCACTGTCATCCACCCTGACTCTCTCAAAGGCTGACTACGAA AAGCACAAAGTGTATGCTTGTGAAGTCACTCATCAGGGCCTTTC TAGCCCTGTGACCAAGAGCTTCAACAGAGGCGAATGC (SEQ ID NO: 53)

Affinities of the humanized KC18 antibodies to human and mouse FGFR3 were determined and are shown in Table 10 below. The affinities of these humanized antibodies are comparable to the parental KC18 antibody.

TABLE 10 Affinities to human and mouse FGFR3 of the humanized KC18 antibodies KC18 hFGFR3 mFGFR3 Variants ka kd KD ka kd KD Hu7 1.96E+05 1.06E−3 5.41E−09 1.98E+05 1.26E−3 6.36E−09 Hu10 2.78E+05 1.32E−3 4.73E−09 2.86E+05 1.47E−3 5.15E−09 Hu12 3.27E+05 5.27E−04 1.61E−09 3.37E+05 5.83E−04 1.73E−09 Hu13 1.89E+05 8.57E−04 4.52E−09 1.93E+05 1.02E−3 5.28E−09 Hu16 2.76E+05 1.04E−3 3.76E−09 2.78E+05 1.18E−3 4.23E−09 Hu18 3.34E+05 4.17E−04 1.25E−09 3.37E+05 4.79E−04 1.42E−09 Hu19 2.25E+05 6.75E−04 2.99E−09 2.35E+05 8.85E−04 3.78E−09 Hu23 2.41E+05 6.48E−04 2.68E−09 2.54E+05 8.50E−04 3.35E−09 Hu27 2.14E+05 8.34E−04 3.90E−09 2.20E+05 1.01E−3 4.60E−09 Hu28 2.13E+05 9.49E−04 4.46E−09 2.10E+05 1.14E−3 5.41E−09 Hu33 1.66E+05 1.14E−3 6.89E−09 1.68E+05 1.54E−3 9.15E−09 Hu34 1.55E+05 1.06E−3 6.85E−09 1.64E+05 1.34E−3 8.14E−09 KC18 2.13E+05 5.80E−04 2.73E−09 2.20E+05 8.32E−04 3.78E−09

Humanized antibodies KC18_Hu42 to KC18_49 were designed based on the sequence of KC_Hu18 to further remove liability sites, such as oxidation sites in FRWH3 and CDRH3, a deamidation site in CDRL1, and an oxidation site in CDRL2 (Table 11). At the end, two additional variants each for VH and VL were designed, which resulted in 8 more variants (KC18_Hu42-49) in addition to KC18_Hu18 (Table 12).

TABLE 11 Liability motifs in KC18_Hu18. The IMGT definition was used. Liability residues are underlined in the sequences. Liability Modi- Involved Proposed Motif fication Region Sequence in binding mutations W Oxidation HFW2 IHWVQQAPGKGLEWIGD No Y (SEQ ID NO: 340) M Oxidation HFW3 AYAEKFQGRATLTADRSTD No L TAYMELSSLRSEDTAVYYC (SEQ ID NO: 341) W Oxidation HFW4 WGQGTLVTVSS No Y (SEQ ID NO: 342) NNN Deamidation LCDR1 QSVLYSNNNKNY Yes DNQ (SEQ ID NO: 302) W Oxidation LCDR2 WAS (SEQ ID NO: 74) Yes Y and F

A sequence alignment of Hu18 and the newly designed variants (Hu42-49) is shown in FIG. 7. Mutations of Hu18 residues are underlined.

TABLE 12 Human and mouse germline identity percentage of the desiged KC18 variants. KC18_VL_3 KC18_VL_14 KC18_VL_15 KC18 (SEQ ID NO: 59) (SEQ ID NO: 60) (SEQ ID NO: 61) Human 95.05% 92.08% 92.08% Mouse 86.14% 87.13% 87.13% KC18_VH_6 83.67% 72.45% KC18_Hu18 KC18_Hu42 KC18_Hu43 (SEQ ID NO: 56) KC18_VH_15 82.65% 71.43% KC18_Hu44 KC18_Hu45 KC18_Hu46 (SEQ ID NO: 57) KC18_VH_16 81.63% 70.41% KC18_Hu47 KC18_Hu48 KC18_Hu49 (SEQ ID NO: 58)

TABLE 13 Designed KC18 variant amino acid sequences. Antibody ID Sequence KC18_VH_6 EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDTAVYYCTR TYDGYPYAFDYWGQGTLVTVSS (SEQ ID NO: 56) KC18_VH_15 EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYWGQGTLVTVSS (SEQ ID NO: 57) KC18_VH_16 EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEYIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYYGQGTLVTVSS (SEQ ID NO: 58) KC18_VL_3 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSNNNKNYLAWYQQKPGQSP KLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSY RTFGGGTKVEIK (SEQ ID NO: 59) KC18_VL_14 DIVMTQSPDSLAVSLGERVTINCKSSQSVLYSDNQKNYLAWYQQKPGQSP KLLIYYASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYR TFGGGTKLEIK (SEQ ID NO: 60) KC18_VL_15 DIVMTQSPDSLAVSLGERVTINCKSSQSVLYSDNQKNYLAWYQQKPGQSP KLLIYFASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYR TFGGGTKLEIK (SEQ ID NO: 61)

TABLE 14 Designed KC18 variant sequences. Antibody ID Sequence KC18 Hu44 GAGGTTCAGTTGGTGCAAAGTGGGGCCGAGGTTAAAAAACCAGGTGC Heavy chain AACCGTGAAACTGTCCTGCAAGGCGAGTGGTGATACATTTACAGATTT nucleic acids TGAAATTCATTGGGTACAGCAGGCACCCGGAAAGGGATTGGAATGGAT (with constant AGGAGATGTGGACCCGGAGACTGGCGGAACCGCGTACGCGGAGAAAT region) TTCAGGGCAGAGCCACTTTGACGGCGGATAGAAGTACGGATACTGCCT ACCTTGAACTGAGTTCCTTGCGGTCCGAAGATACGGCAGTTTACTATTG TACTCGCACGTATGATGGCTACCCATACGCTTTCGATTATTGGGGACAA GGCACTCTCGTGACCGTATCTTCAGCTTCAACCAAGGGACCTTCTGTCT TTCCTCTGGCCCCTTCAAGCAAGAGCACTTCCGGAGGGACTGCCGCAC TCGGGTGCCTTGTGAAAGATTACTTCCCAGAGCCTGTCACCGTCAGCTG GAATTCAGGCGCTCTGACTAGCGGAGTGCACACCTTCCCCGCTGTGCTT CAGTCCTCCGGACTCTACTCTCTGAGCAGCGTGGTGACCGTGCCGTCCT CTTCTCTGGGGACCCAGACTTATATCTGCAACGTCAATCATAAGCCTTC TAATACCAAGGTGGACAAGAAGGTGGAACCCAAATCATGTGACAAGA CCCACACCTGTCCGCCCTGTCCGGCACCCGAACTGCTGGGTGGCCCTTC CGTGTTCCTTTTCCCTCCAAAGCCGAAGGACACTCTTATGATTTCTCGC ACTCCCGAAGTGACTTGCGTCGTGGTGGATGTGTCCCATGAGGATCCA GAGGTCAAGTTCAACTGGTACGTGGACGGTGTGGAAGTCCACAACGCC AAGACTAAGCCGAGAGAGGAACAGTACAATTCAACCTATCGGGTGGT GAGCGTCCTGACCGTGCTGCACCAGGACTGGCTTAACGGAAAGGAGTA CAAGTGCAAAGTGTCAAACAAGGCACTGCCCGCTCCGATCGAAAAGA CCATTAGCAAAGCTAAGGGCCAGCCCAGAGAACCCCAAGTCTATACCC TTCCACCCAGCCGGGACGAGCTGACCAAAAACCAGGTGTCACTCACTT GTCTCGTGAAGGGTTTCTACCCCTCAGACATCGCCGTCGAATGGGAGT CCAATGGTCAGCCAGAGAACAACTACAAAACCACCCCTCCCGTGCTGG ACAGCGACGGGTCTTTCTTTCTCTACTCAAAGCTGACCGTGGATAAGTC TCGCTGGCAGCAAGGGAATGTGTTTTCCTGTTCAGTGATGCATGAGGC CCTTCATAATCATTACACCCAAAAGTCACTGAGCCTGTCTCCCGGA (SEQ ID NO: 62) KC18 Hu44 EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG Heavy Chain DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT amino acids YDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV (with constant KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT region) YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 63) KC18 Hu46 GAGGTTCAGTTGGTGCAAAGTGGGGCCGAGGTTAAAAAACCAGGTGC Heavy Chain AACCGTGAAACTGTCCTGCAAGGCGAGTGGTGATACATTTACAGATTT nucleic acids TGAAATTCATTGGGTACAGCAGGCACCCGGAAAGGGATTGGAATGGAT (with constant AGGAGATGTGGACCCGGAGACTGGCGGAACCGCGTACGCGGAGAAAT region) TTCAGGGCAGAGCCACTTTGACGGCGGATAGAAGTACGGATACTGCCT ACCTTGAACTGAGTTCCTTGCGGTCCGAAGATACGGCAGTTTACTATTG TACTCGCACGTATGATGGCTACCCATACGCTTTCGATTATTGGGGACAA GGCACTCTCGTGACCGTATCTTCAGCTTCAACCAAGGGACCTTCTGTCT TTCCTCTGGCCCCTTCAAGCAAGAGCACTTCCGGAGGGACTGCCGCAC TCGGGTGCCTTGTGAAAGATTACTTCCCAGAGCCTGTCACCGTCAGCTG GAATTCAGGCGCTCTGACTAGCGGAGTGCACACCTTCCCCGCTGTGCTT CAGTCCTCCGGACTCTACTCTCTGAGCAGCGTGGTGACCGTGCCGTCCT CTTCTCTGGGGACCCAGACTTATATCTGCAACGTCAATCATAAGCCTTC TAATACCAAGGTGGACAAGAAGGTGGAACCCAAATCATGTGACAAGA CCCACACCTGTCCGCCCTGTCCGGCACCCGAACTGCTGGGTGGCCCTTC CGTGTTCCTTTTCCCTCCAAAGCCGAAGGACACTCTTATGATTTCTCGC ACTCCCGAAGTGACTTGCGTCGTGGTGGATGTGTCCCATGAGGATCCA GAGGTCAAGTTCAACTGGTACGTGGACGGTGTGGAAGTCCACAACGCC AAGACTAAGCCGAGAGAGGAACAGTACAATTCAACCTATCGGGTGGT GAGCGTCCTGACCGTGCTGCACCAGGACTGGCTTAACGGAAAGGAGTA CAAGTGCAAAGTGTCAAACAAGGCACTGCCCGCTCCGATCGAAAAGA CCATTAGCAAAGCTAAGGGCCAGCCCAGAGAACCCCAAGTCTATACCC TTCCACCCAGCCGGGACGAGCTGACCAAAAACCAGGTGTCACTCACTT GTCTCGTGAAGGGTTTCTACCCCTCAGACATCGCCGTCGAATGGGAGT CCAATGGTCAGCCAGAGAACAACTACAAAACCACCCCTCCCGTGCTGG ACAGCGACGGGTCTTTCTTTCTCTACTCAAAGCTGACCGTGGATAAGTC TCGCTGGCAGCAAGGGAATGTGTTTTCCTGTTCAGTGATGCATGAGGC CCTTCATAATCATTACACCCAAAAGTCACTGAGCCTGTCTCCCGGA (SEQ ID NO: 64) KC18 Hu46 EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG Heavy Chain DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT amino acids YDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV (with constant KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT region) YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 65) KC18 Hu44 GACATTGTAATGACACAATCTCCCGACTCTCTTGCAGTCAGCTTGGGTG Light Chain AACGAGCAACTATAAATTGTAAAAGCAGCCAGTCTGTACTCTACTCTA nucleic acids ATAACAACAAGAACTACCTCGCATGGTATCAGCAGAAACCGGGGCAA (with constant AGTCCTAAACTTTTGATCTATTGGGCAAGTACCAGGGAGAGCGGAGTA region) CCCGACAGATTCAGCGGGTCTGGATCAGGCACCGATTTTACTCTCACC ATTTCTTCAGTTCAAGCTGAAGACGTCGCAGTCTACTACTGCCAGCAGT ATTACAGTTACCGAACTTTTGGCGGTGGAACAAAAGTGGAAATAAAGC GCACTGTGGCAGCCCCTTCTGTGTTTATCTTCCCACCCTCCGACGAGCA GCTCAAGTCCGGTACCGCCTCTGTCGTCTGCCTGCTGAACAATTTCTAC CCAAGAGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCACTGCAAAG CGGTAATTCACAAGAGTCAGTCACCGAACAAGACTCAAAGGACAGCA CCTACTCACTGTCATCCACCCTGACTCTCTCAAAGGCTGACTACGAAAA GCACAAAGTGTATGCTTGTGAAGTCACTCATCAGGGCCTTTCTAGCCCT GTGACCAAGAGCTTCAACAGAGGCGAATGC (SEQ ID NO: 66) KC18 Hu44 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSNNNKNYLAWYQQKPGQSP Light Chain KLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSY amino acids RTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV (with constant QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE region) VTHQGLSSPVTKSFNRGEC (SEQ ID NO: 67) KC18 Hu46 GACATAGTTATGACCCAGTCTCCAGACTCCCTCGCAGTTTCTCTCGGCG Light Chain AGAGAGTAACAATCAACTGTAAGTCATCACAGTCCGTACTCTACTCTG nucleic acids ACAACCAAAAGAATTATTTGGCTTGGTATCAGCAAAAGCCAGGACAAA (with constant GCCCCAAACTTCTTATCTATTTTGCCAGCACTAGGGAGTCCGGGGTACC region) CGACCGCTTTAGTGGCTCAGGTTCTGGGACAGACTTTACACTGACCATT TCTAGCGTACAGGCTGAAGACGTTGCAGTCTACTACTGCCAGCAATAC TATTCTTACAGAACGTTTGGCGGGGGCACAAAGTTGGAGATCAAACGC ACTGTGGCAGCCCCTTCTGTGTTTATCTTCCCACCCTCCGACGAGCAGC TCAAGTCCGGTACCGCCTCTGTCGTCTGCCTGCTGAACAATTTCTACCC AAGAGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCACTGCAAAGCG GTAATTCACAAGAGTCAGTCACCGAACAAGACTCAAAGGACAGCACCT ACTCACTGTCATCCACCCTGACTCTCTCAAAGGCTGACTACGAAAAGC ACAAAGTGTATGCTTGTGAAGTCACTCATCAGGGCCTTTCTAGCCCTGT GACCAAGAGCTTCAACAGAGGCGAATGC (SEQ ID NO: 68) KC18 Hu46 DIVMTQSPDSLAVSLGERVTINCKSSQSVLYSDNQKNYLAWYQQKPGQSP Light Chain KLLIYFASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYR amino acids TFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ (with constant WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV region) THQGLSSPVTKSFNRGEC (SEQ ID NO: 69)

TABLE 15 Humanized Anti-FGFR3 Fab fragment heavy chain amino acid sequences. Antibody ID Sequence Fab Heavy chain QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWIGD IDPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYCTRTY DGYPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSC (SEQ ID NO: 141) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWI GYINPNNGGTRYNQKFKGKATLTVNKSSSTAYMELRSLTSEDSAVYYCA RERDYDGAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSC (SEQ ID NO: 143) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLQWI GYINPNNGGTNYNQNFKDKATLTVNKSSTTAYMELRSLTSEDSAVYYCA RERDYDGSMDFWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSC (SEQ ID NO: 145) EVQLQQSGPDLVKPGASVKISCKASGYTVTDYYMNWVKQSHGKSLEWIG DINPNNGVTTYNQKFKDKATLTVDKSSSTAYMELRSLTSEDSAVYYCARE EDFDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSC (SEQ ID NO: 147) QVQLQQSGAELVRPGASVTLSCKASGSTFSDFEIHWVKQTPVHGLEWIGG IDPETGGTAYNQKFKGKAILTADRSSSTAYMELRSLTSEDSAVYYCTRNY DGYSQTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSC (SEQ ID NO: 149) QVQLQQSGAELVRPGASVTLSCKASGSTFTDEEIHWVKQTPVHGLEWIGA IDPETGGTAYNQKFKGKAILTAVKSSSTAYMGLRSLTSEDSAVYYCTRNY DGYSRTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSC (SEQ ID NO: 151) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDTAVYYCTR TYDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSC (SEQ ID NO: 153) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSC (SEQ ID NO: 155) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEYIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYYGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSC (SEQ ID NO: 156) QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWIGD IDPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYCTRTY DGYPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKS (SEQ ID NO: 164) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWI GYINPNNGGTRYNQKFKGKATLTVNKSSSTAYMELRSLTSEDSAVYYCA RERDYDGAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKS (SEQ ID NO: 165) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLQWI GYINPNNGGTNYNQNFKDKATLTVNKSSTTAYMELRSLTSEDSAVYYCA RERDYDGSMDFWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKS (SEQ ID NO: 166) EVQLQQSGPDLVKPGASVKISCKASGYTVTDYYMNWVKQSHGKSLEWIG DINPNNGVTTYNQKFKDKATLTVDKSSSTAYMELRSLTSEDSAVYYCARE EDFDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKS (SEQ ID NO: 167) QVQLQQSGAELVRPGASVTLSCKASGSTFSDEEIHWVKQTPVHGLEWIGG IDPETGGTAYNQKFKGKAILTADRSSSTAYMELRSLTSEDSAVYYCTRNY DGYSQTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKS (SEQ ID NO: 168) QVQLQQSGAELVRPGASVTLSCKASGSTFTDNEIHWVKQTPVHGLEWIGA IDPETGGTAYNQKFKGKAILTAVKSSSTAYMGLRSLTSEDSAVYYCTRNY DGYSRTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKS (SEQ ID NO: 169) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDTAVYYCTR TYDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKS (SEQ ID NO: 170) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKS (SEQ ID NO: 171) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEYIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYYGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKS (SEQ ID NO: 172) QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWIGD IDPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYCTRTY DGYPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPK (SEQ ID NO: 173) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWI GYINPNNGGTRYNQKFKGKATLTVNKSSSTAYMELRSLTSEDSAVYYCA RERDYDGAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPK (SEQ ID NO: 174) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLQWI GYINPNNGGTNYNQNFKDKATLTVNKSSTTAYMELRSLTSEDSAVYYCA RERDYDGSMDFWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPK (SEQ ID NO: 175) EVQLQQSGPDLVKPGASVKISCKASGYTVTDYYMNWVKQSHGKSLEWIG DINPNNGVTTYNQKFKDKATLTVDKSSSTAYMELRSLTSEDSAVYYCARE EDFDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPK (SEQ ID NO: 176) QVQLQQSGAELVRPGASVTLSCKASGSTFSDFEIHWVKQTPVHGLEWIGG IDPETGGTAYNQKFKGKAILTADRSSSTAYMELRSLTSEDSAVYYCTRNY DGYSQTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPK (SEQ ID NO: 177) QVQLQQSGAELVRPGASVTLSCKASGSTFTDNEIHWVKQTPVHGLEWIGA IDPETGGTAYNQKFKGKAILTAVKSSSTAYMGLRSLTSEDSAVYYCTRNY DGYSRTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPK (SEQ ID NO: 178) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDTAVYYCTR TYDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPK (SEQ ID NO: 179) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPK (SEQ ID NO: 180) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEYIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYYGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPK (SEQ ID NO: 181) QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWIGD IDPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYCTRTY DGYPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEP (SEQ ID NO: 182) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWI GYINPNNGGTRYNQKFKGKATLTVNKSSSTAYMELRSLTSEDSAVYYCA RERDYDGAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEP (SEQ ID NO: 183) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLQWI GYINPNNGGTNYNQNFKDKATLTVNKSSTTAYMELRSLTSEDSAVYYCA RERDYDGSMDFWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEP (SEQ ID NO: 184) EVQLQQSGPDLVKPGASVKISCKASGYTVTDYYMNWVKQSHGKSLEWIG DINPNNGVTTYNQKFKDKATLTVDKSSSTAYMELRSLTSEDSAVYYCARE EDFDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEP (SEQ ID NO: 185) QVQLQQSGAELVRPGASVTLSCKASGSTFSDFEIHWVKQTPVHGLEWIGG IDPETGGTAYNQKFKGKAILTADRSSSTAYMELRSLTSEDSAVYYCTRNY DGYSQTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEP (SEQ ID NO: 186) QVQLQQSGAELVRPGASVTLSCKASGSTFTDFEIHWVKQTPVHGLEWIGA IDPETGGTAYNQKFKGKAILTAVKSSSTAYMGLRSLTSEDSAVYYCTRNY DGYSRTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEP (SEQ ID NO: 187) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDTAVYYCTR TYDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEP (SEQ ID NO: 188) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEP (SEQ ID NO: 189) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEYIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYYGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEP (SEQ ID NO: 190) QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWIGD IDPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYCTRTY DGYPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVE (SEQ ID NO: 191) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWI GYINPNNGGTRYNQKFKGKATLTVNKSSSTAYMELRSLTSEDSAVYYCA RERDYDGAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVE (SEQ ID NO: 192) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLQWI GYINPNNGGTNYNQNFKDKATLTVNKSSTTAYMELRSLTSEDSAVYYCA RERDYDGSMDFWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVE (SEQ ID NO: 193) EVQLQQSGPDLVKPGASVKISCKASGYTVTDYYMNWVKQSHGKSLEWIG DINPNNGVTTYNQKFKDKATLTVDKSSSTAYMELRSLTSEDSAVYYCARE EDFDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVE (SEQ ID NO: 194) QVQLQQSGAELVRPGASVTLSCKASGSTFSDFEIHWVKQTPVHGLEWIGG IDPETGGTAYNQKFKGKAILTADRSSSTAYMELRSLTSEDSAVYYCTRNY DGYSQTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVE (SEQ ID NO: 195) QVQLQQSGAELVRPGASVTLSCKASGSTFTDFEIHWVKQTPVHGLEWIGA IDPETGGTAYNQKFKGKAILTAVKSSSTAYMGLRSLTSEDSAVYYCTRNY DGYSRTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVE (SEQ ID NO: 196) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDTAVYYCTR TYDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVE (SEQ ID NO: 197) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVE (SEQ ID NO: 198) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEYIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYYGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVE (SEQ ID NO: 199) QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWIGD IDPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYCTRTY DGYPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKV (SEQ ID NO: 200) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWI GYINPNNGGTRYNQKFKGKATLTVNKSSSTAYMELRSLTSEDSAVYYCA RERDYDGAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKV (SEQ ID NO: 201) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLQWI GYINPNNGGTNYNQNFKDKATLTVNKSSTTAYMELRSLTSEDSAVYYCA RERDYDGSMDFWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKV (SEQ ID NO: 202) EVQLQQSGPDLVKPGASVKISCKASGYTVTDYYMNWVKQSHGKSLEWIG DINPNNGVTTYNQKFKDKATLTVDKSSSTAYMELRSLTSEDSAVYYCARE EDFDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKV (SEQ ID NO: 203) QVQLQQSGAELVRPGASVTLSCKASGSTFSDFEIHWVKQTPVHGLEWIGG IDPETGGTAYNQKFKGKAILTADRSSSTAYMELRSLTSEDSAVYYCTRNY DGYSQTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKV (SEQ ID NO: 204) QVQLQQSGAELVRPGASVTLSCKASGSTFTDFEIHWVKQTPVHGLEWIGA IDPETGGTAYNQKFKGKAILTAVKSSSTAYMGLRSLTSEDSAVYYCTRNY DGYSRTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKV (SEQ ID NO: 205) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDTAVYYCTR TYDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKV (SEQ ID NO: 206) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKV (SEQ ID NO: 207) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEYIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYYGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKV (SEQ ID NO: 208) QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWIGD IDPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYCTRTY DGYPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKK (SEQ ID NO: 209) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWI GYINPNNGGTRYNQKFKGKATLTVNKSSSTAYMELRSLTSEDSAVYYCA RERDYDGAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKK (SEQ ID NO: 210) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLQWI GYINPNNGGTNYNQNFKDKATLTVNKSSTTAYMELRSLTSEDSAVYYCA RERDYDGSMDFWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKK (SEQ ID NO: 211) EVQLQQSGPDLVKPGASVKISCKASGYTVTDYYMNWVKQSHGKSLEWIG DINPNNGVTTYNQKFKDKATLTVDKSSSTAYMELRSLTSEDSAVYYCARE EDFDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKK (SEQ ID NO: 212) QVQLQQSGAELVRPGASVTLSCKASGSTFSDFEIHWVKQTPVHGLEWIGG IDPETGGTAYNQKFKGKAILTADRSSSTAYMELRSLTSEDSAVYYCTRNY DGYSQTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKK (SEQ ID NO: 213) QVQLQQSGAELVRPGASVTLSCKASGSTFTDFEIHWVKQTPVHGLEWIGA IDPETGGTAYNQKFKGKAILTAVKSSSTAYMGLRSLTSEDSAVYYCTRNY DGYSRTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKK (SEQ ID NO: 214) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDTAVYYCTR TYDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKK (SEQ ID NO: 215) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKK (SEQ ID NO: 216) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEYIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYYGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKK (SEQ ID NO: 217) QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWIGD IDPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYCTRTY DGYPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDK (SEQ ID NO: 218) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWI GYINPNNGGTRYNQKFKGKATLTVNKSSSTAYMELRSLTSEDSAVYYCA RERDYDGAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDK (SEQ ID NO: 219) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLQWI GYINPNNGGTNYNQNFKDKATLTVNKSSTTAYMELRSLTSEDSAVYYCA RERDYDGSMDFWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDK (SEQ ID NO: 220) EVQLQQSGPDLVKPGASVKISCKASGYTVTDYYMNWVKQSHGKSLEWIG DINPNNGVTTYNQKFKDKATLTVDKSSSTAYMELRSLTSEDSAVYYCARE EDFDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDK (SEQ ID NO: 221) QVQLQQSGAELVRPGASVTLSCKASGSTFSDFEIHWVKQTPVHGLEWIGG IDPETGGTAYNQKFKGKAILTADRSSSTAYMELRSLTSEDSAVYYCTRNY DGYSQTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDK (SEQ ID NO: 222) QVQLQQSGAELVRPGASVTLSCKASGSTFTDFEIHWVKQTPVHGLEWIGA IDPETGGTAYNQKFKGKAILTAVKSSSTAYMGLRSLTSEDSAVYYCTRNY DGYSRTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDK (SEQ ID NO: 223) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDTAVYYCTR TYDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDK (SEQ ID NO: 224) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDK (SEQ ID NO: 225) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEYIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYYGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDK (SEQ ID NO: 226) QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWIGD IDPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYCTRTY DGYPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTHTCP (SEQ ID NO: 227) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWI GYINPNNGGTRYNQKFKGKATLTVNKSSSTAYMELRSLTSEDSAVYYCA RERDYDGAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTCP (SEQ ID NO: 228) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLQWI GYINPNNGGTNYNQNFKDKATLTVNKSSTTAYMELRSLTSEDSAVYYCA RERDYDGSMDFWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTCP (SEQ ID NO: 229) EVQLQQSGPDLVKPGASVKISCKASGYTVTDYYMNWVKQSHGKSLEWIG DINPNNGVTTYNQKFKDKATLTVDKSSSTAYMELRSLTSEDSAVYYCARE EDFDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHTCP (SEQ ID NO: 230) QVQLQQSGAELVRPGASVTLSCKASGSTFSDFEIHWVKQTPVHGLEWIGG IDPETGGTAYNQKFKGKAILTADRSSSTAYMELRSLTSEDSAVYYCTRNY DGYSQTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSCDKTHTCP (SEQ ID NO: 231) QVQLQQSGAELVRPGASVTLSCKASGSTFTDFEIHWVKQTPVHGLEWIGA IDPETGGTAYNQKFKGKAILTAVKSSSTAYMGLRSLTSEDSAVYYCTRNY DGYSRTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSCDKTHTCP (SEQ ID NO: 232) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDTAVYYCTR TYDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTCP (SEQ ID NO: 233) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTHTCP (SEQ ID NO: 234) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEYIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYYGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTHTCP (SEQ ID NO: 235) QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWIGD IDPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYCTRTY DGYPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTHTC (SEQ ID NO: 236) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWI GYINPNNGGTRYNQKFKGKATLTVNKSSSTAYMELRSLTSEDSAVYYCA RERDYDGAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTC (SEQ ID NO: 237) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLQWI GYINPNNGGTNYNQNFKDKATLTVNKSSTTAYMELRSLTSEDSAVYYCA RERDYDGSMDFWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTC (SEQ ID NO: 238) EVQLQQSGPDLVKPGASVKISCKASGYTVTDYYMNWVKQSHGKSLEWIG DINPNNGVTTYNQKFKDKATLTVDKSSSTAYMELRSLTSEDSAVYYCARE EDFDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHTC (SEQ ID NO: 239) QVQLQQSGAELVRPGASVTLSCKASGSTFSDFEIHWVKQTPVHGLEWIGG IDPETGGTAYNQKFKGKAILTADRSSSTAYMELRSLTSEDSAVYYCTRNY DGYSQTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSCDKTHTC (SEQ ID NO: 240) QVQLQQSGAELVRPGASVTLSCKASGSTFTDFEIHWVKQTPVHGLEWIGA IDPETGGTAYNQKFKGKAILTAVKSSSTAYMGLRSLTSEDSAVYYCTRNY DGYSRTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSCDKTHTC (SEQ ID NO: 241) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDTAVYYCTR TYDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHTC (SEQ ID NO: 242) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTHTC (SEQ ID NO: 243) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEYIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYYGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTHTC (SEQ ID NO: 244) QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWIGD IDPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYCTRTY DGYPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 245) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWI GYINPNNGGTRYNQKFKGKATLTVNKSSSTAYMELRSLTSEDSAVYYCA RERDYDGAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 246) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLQWI GYINPNNGGTNYNQNFKDKATLTVNKSSTTAYMELRSLTSEDSAVYYCA RERDYDGSMDFWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 247) EVQLQQSGPDLVKPGASVKISCKASGYTVTDYYMNWVKQSHGKSLEWIG DINPNNGVTTYNQKFKDKATLTVDKSSSTAYMELRSLTSEDSAVYYCARE EDFDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 248) QVQLQQSGAELVRPGASVTLSCKASGSTFSDFEIHWVKQTPVHGLEWIGG IDPETGGTAYNQKFKGKAILTADRSSSTAYMELRSLTSEDSAVYYCTRNY DGYSQTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 249) QVQLQQSGAELVRPGASVTLSCKASGSTFTDFEIHWVKQTPVHGLEWIGA IDPETGGTAYNQKFKGKAILTAVKSSSTAYMGLRSLTSEDSAVYYCTRNY DGYSRTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 250) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDTAVYYCTR TYDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 251) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 252) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEYIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYYGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTHT (SEQ ID NO: 253) QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWIGD IDPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYCTRTY DGYPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 254) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWI GYINPNNGGTRYNQKFKGKATLTVNKSSSTAYMELRSLTSEDSAVYYCA RERDYDGAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 255) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLQWI GYINPNNGGTNYNQNFKDKATLTVNKSSTTAYMELRSLTSEDSAVYYCA RERDYDGSMDFWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 256) EVQLQQSGPDLVKPGASVKISCKASGYTVTDYYMNWVKQSHGKSLEWIG DINPNNGVTTYNQKFKDKATLTVDKSSSTAYMELRSLTSEDSAVYYCARE EDFDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 257) QVQLQQSGAELVRPGASVTLSCKASGSTFSDFEIHWVKQTPVHGLEWIGG IDPETGGTAYNQKFKGKAILTADRSSSTAYMELRSLTSEDSAVYYCTRNY DGYSQTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 258) QVQLQQSGAELVRPGASVTLSCKASGSTFTDFEIHWVKQTPVHGLEWIGA IDPETGGTAYNQKFKGKAILTAVKSSSTAYMGLRSLTSEDSAVYYCTRNY DGYSRTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 259) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDTAVYYCTR TYDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 260) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 261) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEYIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYYGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTH (SEQ ID NO: 262) QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWIGD IDPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYCTRTY DGYPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKT (SEQ ID NO: 263) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWI GYINPNNGGTRYNQKFKGKATLTVNKSSSTAYMELRSLTSEDSAVYYCA RERDYDGAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKT (SEQ ID NO: 264) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLQWI GYINPNNGGTNYNQNFKDKATLTVNKSSTTAYMELRSLTSEDSAVYYCA RERDYDGSMDFWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKT (SEQ ID NO: 265) EVQLQQSGPDLVKPGASVKISCKASGYTVTDYYMNWVKQSHGKSLEWIG DINPNNGVTTYNQKFKDKATLTVDKSSSTAYMELRSLTSEDSAVYYCARE EDFDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKT (SEQ ID NO: 266) QVQLQQSGAELVRPGASVTLSCKASGSTFSDFEIHWVKQTPVHGLEWIGG IDPETGGTAYNQKFKGKAILTADRSSSTAYMELRSLTSEDSAVYYCTRNY DGYSQTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSCDKT (SEQ ID NO: 267) QVQLQQSGAELVRPGASVTLSCKASGSTFTDFEIHWVKQTPVHGLEWIGA IDPETGGTAYNQKFKGKAILTAVKSSSTAYMGLRSLTSEDSAVYYCTRNY DGYSRTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSCDKT (SEQ ID NO: 268) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDTAVYYCTR TYDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDKT (SEQ ID NO: 269) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKT (SEQ ID NO: 270) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEYIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYYGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKT (SEQ ID NO: 271) QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWIGD IDPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYCTRTY DGYPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDK (SEQ ID NO: 272) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWI GYINPNNGGTRYNQKFKGKATLTVNKSSSTAYMELRSLTSEDSAVYYCA RERDYDGAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDK (SEQ ID NO: 273) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLQWI GYINPNNGGTNYNQNFKDKATLTVNKSSTTAYMELRSLTSEDSAVYYCA RERDYDGSMDFWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDK (SEQ ID NO: 274) EVQLQQSGPDLVKPGASVKISCKASGYTVTDYYMNWVKQSHGKSLEWIG DINPNNGVTTYNQKFKDKATLTVDKSSSTAYMELRSLTSEDSAVYYCARE EDFDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDK (SEQ ID NO: 275) QVQLQQSGAELVRPGASVTLSCKASGSTFSDFEIHWVKQTPVHGLEWIGG IDPETGGTAYNQKFKGKAILTADRSSSTAYMELRSLTSEDSAVYYCTRNY DGYSQTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSCDK (SEQ ID NO: 276) QVQLQQSGAELVRPGASVTLSCKASGSTFTDFEIHWVKQTPVHGLEWIGA IDPETGGTAYNQKFKGKAILTAVKSSSTAYMGLRSLTSEDSAVYYCTRNY DGYSRTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSCDK (SEQ ID NO: 277) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDTAVYYCTR TYDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCDK (SEQ ID NO: 278) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDK (SEQ ID NO: 279) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEYIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYYGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDK (SEQ ID NO: 280) QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWIGD IDPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYCTRTY DGYPYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCD (SEQ ID NO: 281) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWI GYINPNNGGTRYNQKFKGKATLTVNKSSSTAYMELRSLTSEDSAVYYCA RERDYDGAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCD (SEQ ID NO: 282) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLQWI GYINPNNGGTNYNQNFKDKATLTVNKSSTTAYMELRSLTSEDSAVYYCA RERDYDGSMDFWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCD (SEQ ID NO: 283) EVQLQQSGPDLVKPGASVKISCKASGYTVTDYYMNWVKQSHGKSLEWIG DINPNNGVTTYNQKFKDKATLTVDKSSSTAYMELRSLTSEDSAVYYCARE EDFDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCD (SEQ ID NO: 284) QVQLQQSGAELVRPGASVTLSCKASGSTFSDFEIHWVKQTPVHGLEWIGG IDPETGGTAYNQKFKGKAILTADRSSSTAYMELRSLTSEDSAVYYCTRNY DGYSQTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSCD (SEQ ID NO: 285) QVQLQQSGAELVRPGASVTLSCKASGSTFTDNEIHWVKQTPVHGLEWIGA IDPETGGTAYNQKFKGKAILTAVKSSSTAYMGLRSLTSEDSAVYYCTRNY DGYSRTMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTY ICNVNHKPSNTKVDKKVEPKSCD (SEQ ID NO: 286) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYMELSSLRSEDTAVYYCTR TYDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ TYICNVNHKPSNTKVDKKVEPKSCD (SEQ ID NO: 287) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEWIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCD (SEQ ID NO: 288) EVQLVQSGAEVKKPGATVKLSCKASGDTFTDFEIHWVQQAPGKGLEYIG DVDPETGGTAYAEKFQGRATLTADRSTDTAYLELSSLRSEDTAVYYCTRT YDGYPYAFDYYGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLV KDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCD (SEQ ID NO: 289)

TABLE 16 Humanized Anti-FGFR3 Fab fragment light chain amino acid sequences. Antibody ID Sequence Fab Light chain DIVMSQSPSSLAVSVGEKVTMSCKSSQSLLYSNNQKNYLAWYQQKPGQS PKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSY RTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC (SEQ ID NO: 142) DIQMTQSPSSLSASLGGKVTITCKASQDINKFIAWYQHKPGKGPRLLIHYTS TLQPGIPSRFSGSGSGRDYSFSISNLEPEDIATYYCLQYDNLLWTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC (SEQ ID NO: 144) DIQMTQSPSSLSASLGGKVTITCKASQDINKFIAWYQHKPGKGPRLLIHYTS TLQPGIPSRFSGSGSGRDYSFSISNLEPEDIATYFCLQYDNLLWTFGGGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC (SEQ ID NO: 146) DIVMTQSHKFMSTSVGDRVSITCKASQDVSTGVAWYQQKPGQSPQLLIY WASTRHTGVPDRFTGSGSGTDYILTIRSVQAEDLALYYCQQHYSTPLTFG AGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWK VDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC (SEQ ID NO: 148) NIMMTQSPSSLAVSAGEKVTMSCKSSQSVLYSSNQKNYLAWYQQKPGQS PKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCHQYLSS YTFGGGTKLEMKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAK VQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 150) NIMMTQSPSSLAVSAGEKVTMSCKSSQSVLYSSNQKNYLAWYQQKPGQS PKLLIYWASTRESGVPDRFTGSGSGTDFSLSISSVQTEDLAVYYCHQYLSS YTFGGGTRLEMKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC (SEQ ID NO: 152) DIVMTQSPDSLAVSLGERATINCKSSQSVLYSNNNKNYLAWYQQKPGQSP KLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSY RTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKV QWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC (SEQ ID NO: 67) DIVMTQSPDSLAVSLGERVTINCKSSQSVLYSDNQKNYLAWYQQKPGQSP KLLIYFASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYR TFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC (SEQ ID NO: 69) DIVMTQSPDSLAVSLGERVTINCKSSQSVLYSDNQKNYLAWYQQKPGQSP KLLIYYASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYR TFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC (SEQ ID NO: 154)

In certain embodiments, an anti-FGFR3 F(ab) fragment of the present application comprises a heavy chain of Table 15, and a light chain in Table 16.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 141, 164, 173, 182, 191, 200, 209, 218, 227, 236, 245, 254, 263, 272, or 281, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 142.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 143, 165, 174, 183, 192, 201, 210, 219, 228, 237, 246, 255, 264, 273, or 282, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 144.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 145, 166, 175, 184, 193, 202, 211, 220, 229, 238, 247, 256, 265, 274, or 283 and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 146.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 147, 167, 176, 185, 194, 203, 212, 221, 230, 239, 248, 257, 266, 275, or 284, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 148.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 149, 168, 177, 186, 195, 204, 213, 222, 231, 240, 249, 258, 267, 276, or 285, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 150.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 151, 169, 178, 187, 196, 205, 214, 223, 232, 241, 250, 259, 268, 277, or 286, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 152.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 153, 170, 179, 188, 197, 206, 215, 224, 233, 242, 251, 260, 269, 278, or 287, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 67.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 153, 170, 179, 188, 197, 206, 215, 224, 233, 242, 251, 260, 269, 278, or 287, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 154.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 153, 170, 179, 188, 197, 206, 215, 224, 233, 242, 251, 260, 269, 278, or 287, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 69.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 155, 171, 180, 189, 198, 207, 216, 225, 234, 243, 252, 261, 270, 279, or 288, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 67.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 155, 171, 180, 189, 198, 207, 216, 225, 234, 243, 252, 261, 270, 279, or 288, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 154.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 155, 171, 180, 189, 198, 207, 216, 225, 234, 243, 252, 261, 270, 279, or 288, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 69.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 156, 172, 181, 190, 199, 208, 217, 226, 235, 244, 253, 262, 271, 280, or 289, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 67.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 156, 172, 181, 190, 199, 208, 217, 226, 235, 244, 253, 262, 271, 280, or 289, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 154.

In certain embodiments, the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 156, 172, 181, 190, 199, 208, 217, 226, 235, 244, 253, 262, 271, 280, or 289, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 69.

In Vitro Analysis

Antibodies were screened for binding and specificity to FGFR3. Activity was assessed using a Homogenous Time-Resolved Fluorescence (HTRF) assay to evaluate the level of inhibition on Erk phosphorylation using mouse primary rib chondrocytes. Briefly, primary mouse rib chondrocyte cells isolated from the achondroplasia mouse model were pretreated for 2 hours with anti-FGFR3 antibodies with a concentration ranging from 0.016 μg/ml to 100 μg/ml. Cells were then stimulated with FGF18 for 5 minutes. The reaction was then stopped, total Erk was measured using the HTRF assay, and Phospho-Erk (Thr202/Tyr204) was measured in a separate HTRF assay. The percent inhibition of Erk phosphorylation was measured by taking the ratio of Phospho-Erk over total Erk and multiplying by 100. Particularly, mouse antibodies KC18, KE63, and KE94 and their corresponding Fab fragments were tested in the HTRF assay, all of which inhibited Erk phosphorylation (FIG. 9A and FIG. 9B).

To determine the effects of different mouse antibody formats on inhibition of Erk phosphorylation, KC18 mouse antibody in various formats, including full-length antibody (IgG), Fab, a one-armed, monovalent antibody (MetMab), and pegylated (PEG) Fab fragment were tested in the HTRF assay and compared to isotype control (Iso). Also, KC18 Fab with half-life extension using a human albumin nanobody (KC18 Fab-HLE) was tested, with and without human serum albumin (HSA) or mouse serum albumin (MSA).

The full-length KC18 mouse antibody has a heavy chain of SEQ ID NO: 291 (with mIgG2a Fc sequence), and a light chain of SEQ ID NO: 292. The KC18 mouse Fab antibody has a heavy chain of SEQ ID NO: 293, and a light chain of SEQ ID NO: 294.

(SEQ ID NO: 291) QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWI GDIDPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYC TRTYDGYPYAMDYWGQGTSVTVSSAKTTAPSVYPLAPVCGDTTGSSVT LGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTS STWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPPVAGP SVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHT AQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKGLPSSIER TISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWT NNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHE GLHNHHTTKSFSRTPGK (SEQ ID NO: 292) DIVMSQSPSSLAVSVGEKVTMSCKSSQSLLYSNNQKNYLAWYQQKPGQ SPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQ YYSYRTFGGGTKLEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNF YPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYE RHNSYTCEATHKTSTSPIVKSFNRNEC (SEQ ID NO: 293) QVQLQQSGAELVRPGASVTLSCKASGDTFTDFEIHWVKQTPVHGLEWI GDIDPETGGTAYNQKFRGRAMLTADRSSSTAYMELRSLTSEDSAVYYC TRTYDGYPYAMDYWGQGTSVTVSSAKTTAPSVYPLAPVCGDTTGSSVT LGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTS STWPSQSITCNVAHPASSTKVDKKI (SEQ ID NO: 294) DIVMSQSPSSLAVSVGEKVTMSCKSSQSLLYSNNQKNYLAWYQQKPGQ SPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQ YYSYRTFGGGTKLEIKRADAAPTVSIFPPSSEQLTSGGASVVCFLNNF YPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYE RHNSYTCEATHKTSTSPIVKSFNRNEC

All formats inhibited Erk phosphorylation (FIG. 10A to FIG. 10C). The antibody format referred to in FIG. 10A as “MetMab” is described in further detail in Merchant et al. (PNAS. 110(32): E2987-E2996. 2013).

Humanized FGFR3 antibodies, including Hu18, Hu44, and Hu46, were also tested in the HTRF assay, and found to inhibit Erk phosphorylation (FIG. 11). The IC50s of these humanized antibodies were determined, as well (FIG. 8A to FIG. 8C, respectively).

In Vivo Analysis

For in vivo evaluation of the antibodies, an achondroplasia mouse model (Ach) was used. The achondroplasia mouse is a transgenic mouse that overexpresses the mouse FGFR3 protein having the G380R mutation under control of the collagen II promoter (Shazeeb et al., (2018) Sci Rep 8, 469). The mice were genotyped at 1 day of age, and randomized to either a control (i.e., saline) group or an antibody dosed group. Achondroplasia mice (G380R) received a daily dose subcutaneously (SC) from 3 days of age to 20 days of age. The mice were then euthanized, and bones were collected at 21 days of age for microCT analysis. Tibias, femurs, vertebrae and skulls were used for the analysis, and lengths were measured using 3D microCT analysis. AMIRA (V6.0.1, FEI, Hillsboro, OR, USA) was used for all numerical analysis of bone lengths. The lengths of leg bones were measured using seed points along the bone, and a 3D length tool in AMIRA. The results indicated that achondroplasia (Ach) mice treated with KC18 Fab had a significantly increased tibia and femur length (FIG. 12A and FIG. 12B), a significantly increased vertebra and skull length (FIG. 13A and FIG. 13B), a significantly increased brain volume (FIG. 14), and corrected vertebral abnormalities as measured by Kyphosis Index (FIG. 15A-FIG. 15B). Ach mice treated with KC18 Fab also had several improved bone parameters, including femur growth plate volume, and femur diameter (FIG. 16A and FIG. 16B). Ach mice treated with KC18 Fab also had improved bone age as shown by more developed secondary ossification center in tibia (FIG. 17) compared to those treated with vehicle.

In summary, achondroplasia is the most common form of dwarfism due to activating mutations in the FGFR3 gene. FGFR3 protein is expressed in the growth plate and its function is to regulate proper growth. However, the activating mutations lead to excessive inhibition of chondrocyte proliferation and differentiation which is the main cause for the short stature and other skeletal deformities. The antibodies generated herein are specific to FGFR3 and inhibit FGFR3 activity. The mechanism of action of the antibody is to inhibit ligand binding and prevent activation of the receptor. The antibodies described herein can block ligand activation and subsequently inhibit downstream signaling measured by the decrease in Erk phosphorylation. This translates into inhibition of receptor activity. In vivo testing of anti-FGFR3 antibodies in the Ach mouse model demonstrated efficacy on the axial and appendicular skeleton. More specifically, a significant increase in femur and tibia length, skull length as well as lumbar length were observed.

Claims

1. An antigen-binding protein or antigen-binding fragment thereof that specifically binds to fibroblast growth factor receptor 3 (FGFR3), comprising an antibody heavy chain variable (VH) domain and an antibody light chain variable (VL) domain, wherein:

(a) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GX1TFTDX2E (SEQ ID NO: 157), wherein X1 is Y or D and X2 is F or Y;
a CDR-H2 sequence comprising the amino acid sequence of IDPETGX3T (SEQ ID NO: 158), wherein X3 is G or S; or a CDR-H2 sequence comprising the amino acid sequence of INPNNGX4T (SEQ ID NO: 159), wherein X4 is G or V; or a CDR-H2 sequence comprising the amino acid sequence of VX5PETGGT (SEQ ID NO: 160), wherein X5 is D or E;
a CDR-H3 sequence comprising the amino acid sequence of TRX6YX7GYX8X9X10X11DY (SEQ ID NO: 161), wherein X6 is T or N, X7 is D or E, X8 is S or P, X9 is Q, R, or Y, X10 is T or A, X11 is F or M; and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QSX12LYSX13NX14KNY (SEQ ID NO: 162), wherein X12 is L or V, X13 is N, D, or S, and X14 is Q or N;
a CDR-L2 sequence comprising the amino acid sequence of X15AS (SEQ ID NO: 163), wherein X15 is W, Y, or F;
a CDR-L3 sequence comprising the amino acid sequence of QQYYSYRT (SEQ ID NO: 75), LQYDNLLWT (SEQ ID NO: 81), or HQYLSX16YT (SEQ ID NO: 290) wherein X16 is P or S;
(b) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GYTFTDYN (SEQ ID NOs: 76 and 82);
a CDR-H2 sequence comprising the amino acid sequence of INPNNGGT (SEQ ID NOs: 77 and 83);
a CDR-H3 sequence comprising the amino acid sequence of ARERDYDGAMDY (SEQ ID NO: 78); and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QDINKF (SEQ ID NOs: 79 and 85);
a CDR-L2 sequence comprising the amino acid sequence of YTS (SEQ ID NOs: 80 and 86);
a CDR-L3 sequence comprising the amino acid sequence of LQYDNLLWT (SEQ ID NOs: 81 and 87);
(c) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GYTFTDYN (SEQ ID NOs: 76 and 82);
a CDR-H2 sequence comprising the amino acid sequence of INPNNGGT (SEQ ID NOs: 77 and 83);
a CDR-H3 sequence comprising the amino acid sequence of ARERDYDGSMDF (SEQ ID NO: 84); and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QDINKF (SEQ ID NOs: 79 and 85);
a CDR-L2 sequence comprising the amino acid sequence of YTS (SEQ ID NOs: 80 and 86);
a CDR-L3 sequence comprising the amino acid sequence of LQYDNLLWT (SEQ ID NOs: 81 and 87);
(d) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GYTVTDYY (SEQ ID NO: 88);
a CDR-H2 sequence comprising the amino acid sequence of INPNNGVT (SEQ ID NO: 89);
a CDR-H3 sequence comprising the amino acid sequence of AREEDFDGFDY (SEQ ID NO: 90); and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QDVSTG (SEQ ID NO: 91);
a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104);
a CDR-L3 sequence comprising the amino acid sequence of QQHYSTPLT (SEQ ID NO: 93);
(e) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GSTFSDFE (SEQ ID NO: 94);
a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NOs: 71, 95, and 101);
a CDR-H3 sequence comprising the amino acid sequence of TRNYDGYSQTX17DY (SEQ ID NO: 308), wherein X17 is M or F; and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QSVLYSX18NQKNY (SEQ ID NO: 309, wherein X18 is S or D;
a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104);
a CDR-L3 sequence comprising the amino acid sequence of or HQYLSSYT (SEQ ID NOs: 99 and 105); or
(f) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GSTFTDFE (SEQ ID NO: 100);
a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NOs: 71, 95, and 101);
a CDR-H3 sequence comprising the amino acid sequence of TRNYDGYSQTX17DY (SEQ ID NO: 308), wherein X17 is M or F; and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QSVLYSX18NQKNY (SEQ ID NO: 309), wherein X18 is S or D;
a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104);
a CDR-L3 sequence comprising the amino acid sequence of or HQYLSSYT (SEQ ID NOs: 99 and 105).

2. The antigen binding protein or antigen-binding fragment thereof of claim 1, wherein:

(a) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GDTFTDFE (SEQ ID NO: 70), GDTFTDYE (SEQ ID NO: 295), or GYTFTDFE (SEQ ID NO: 296);
a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NOs: 71, 95, and 101), VDPETGGT (SEQ ID NO: 297), IDPETGST (SEQ ID NO: 298), or VEPETGGT (SEQ ID NO: 299);
a CDR-H3 sequence comprising the amino acid sequence of TRTYDGYPYAMDY (SEQ ID NO: 72), TRTYEGYPYAMDY (SEQ ID NO: 300), or TRTYDGYPYAFDY (SEQ ID NO: 301); and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QSLLYSNNQKNY (SEQ ID NO: 73), QSVLYSNNNKNY (SEQ ID NO: 302), or QSVLYSDNQKNY (SEQ ID NO: 306);
a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, 104), YAS (SEQ ID NO: 303), or FAS (SEQ ID NO: 304);
a CDR-L3 sequence comprising the amino acid sequence of QQYYSYRT (SEQ ID NO: 75);
(b) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GYTFTDYN (SEQ ID NOs: 76 and 82);
a CDR-H2 sequence comprising the amino acid sequence of INPNNGGT (SEQ ID NOs: 77 and 83);
a CDR-H3 sequence comprising the amino acid sequence of ARERDYDGAMDY (SEQ ID NO: 78); and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QDINKF (SEQ ID NOs: 79 and 85);
a CDR-L2 sequence comprising the amino acid sequence of YTS (SEQ ID NOs: 80 and 86);
a CDR-L3 sequence comprising the amino acid sequence of LQYDNLLWT (SEQ ID NOs: 81 and 87);
(c) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GYTFTDYN (SEQ ID NOs: 76 and 82);
a CDR-H2 sequence comprising the amino acid sequence of INPNNGGT (SEQ ID NOs: 77 and 83);
a CDR-H3 sequence comprising the amino acid sequence of ARERDYDGSMDF (SEQ ID NO: 84); and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QDINKF (SEQ ID NOs: 79 and 85);
a CDR-L2 sequence comprising the amino acid sequence of YTS (SEQ ID NOs: 80 and 86);
a CDR-L3 sequence comprising the amino acid sequence of LQYDNLLWT (SEQ ID NOs: 81 and 87);
(d) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GYTVTDYY (SEQ ID NO: 88);
a CDR-H2 sequence comprising the amino acid sequence of INPNNGVT (SEQ ID NO: 89);
a CDR-H3 sequence comprising the amino acid sequence of AREEDFDGFDY (SEQ ID NO: 90); and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QDVSTG (SEQ ID NO: 91);
a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104);
a CDR-L3 sequence comprising the amino acid sequence of QQHYSTPLT (SEQ ID NO: 93);
(e) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GSTFSDFE (SEQ ID NO: 94);
a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NOs: 71, 95, and 101);
a CDR-H3 sequence comprising the amino acid sequence of TRNYDGYSQTMDY (SEQ ID NO: 96) or TRNYDGYSQTFDY (SEQ ID NO: 305); and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QSVLYSSNQKNY (SEQ ID NOs: 97 and 103) or QSVLYSDNQKNY (SEQ ID NO: 306);
a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104);
a CDR-L3 sequence comprising the amino acid sequence of or HQYLSSYT (SEQ ID NOs: 99 and 105); or
(f) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GSTFTDFE (SEQ ID NO: 100);
a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NOs: 71, 95, and 101);
a CDR-H3 sequence comprising the amino acid sequence of TRNYDGYSRTMDY (SEQ ID NO: 102) or TRNYDGYSRTFDY (SEQ ID NO: 307); and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QSVLYSSNQKNY (SEQ ID NOs: 97 and 103) or QSVLYSDNQKNY (SEQ ID NO: 306);
a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104);
a CDR-L3 sequence comprising the amino acid sequence of or HQYLSSYT (SEQ ID NOs: 99 and 105).

3. The antigen binding protein or antigen-binding fragment thereof of claim 1, wherein:

(a) the VH domain comprises an amino acid sequence selected from the group consisting of:
SEQ ID NO: 6, SEQ ID NO: 18, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 10, SEQ ID NO: 110, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, and SEQ ID NO: 122; and
the VL domain comprises an amino acid sequence selected from the group consisting of:
SEQ ID NO: 7, SEQ ID NO: 19, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131, and SEQ ID NO: 132;
(b) the VH domain comprises the amino acid sequence of SEQ ID NO: 8; and
the VL domain comprises the amino acid sequence of SEQ ID NO: 9;
(c) the VH domain comprises the amino acid sequence of SEQ ID NO: 10; and
the VL domain comprises the amino acid sequence of SEQ ID NO: 11;
(d) the VH domain comprises the amino acid sequence of SEQ ID NO: 12; and
the VL domain comprises the amino acid sequence of SEQ ID NO: 13;
(e) the VH domain comprises an amino acid sequence selected from the group consisting of:
SEQ ID NO: 14, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, and SEQ ID NO: 23; and
the VL domain comprises an amino acid sequence selected from the group consisting of:
SEQ ID NO: 15, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, and SEQ ID NO: 27;
(f) the VH domain comprises an amino acid sequence selected from the group consisting of:
SEQ ID NO: 16, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, and SEQ ID NO: 31;
the VL domain comprises an amino acid sequence selected from the group consisting of:
SEQ ID NO: 17, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, and SEQ ID NO: 35.

4. The antigen binding protein or antigen-binding fragment thereof of claim 1, wherein the antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 63 or 65, and the antibody light chain comprises the amino acid sequence of SEQ ID NO: 67 or 69.

5. The antigen binding protein or antigen-binding fragment thereof of claim 3, wherein the VH domain is at least about 90% identical or at least about 95% identical to the amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 8, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO: 18, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 63, SEQ ID NO: 65, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, or SEQ ID NO: 122, and

wherein the VL domain is at least about 90% identical or at least about 95% identical to the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, SEQ ID NO: 19, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 123, SEQ ID NO: 124, SEQ ID NO: 125, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, SEQ ID NO: 129, SEQ ID NO: 130, SEQ ID NO: 131, SEQ ID NO: 132.

6. The antigen binding protein or fragment thereof of claim 5, comprising an antibody heavy chain at least about 90% identical or at least about 95% identical to the amino acid sequence of SEQ ID NO: 63 or 65, and an antibody light chain at least about 90% identical or at least about 95% identical to the amino acid sequence of SEQ ID NO: 67 or 69.

7-32. (canceled)

33. The antigen binding protein or antigen-binding fragment thereof of claim 1, wherein the antigen binding protein or antigen-binding binding fragment thereof comprises one or more full-length antibody heavy chains comprising an Fc region, optionally wherein the Fc region is a human IgG1 Fc region.

34. (canceled)

35. The antigen binding protein or antigen-binding fragment thereof of claim 1, wherein the antigen binding protein or antigen-binding binding fragment thereof comprises an antibody F(ab), F(ab′)2, Fab′-SH, Fv, or scFv fragment.

36. The antigen binding protein or antigen-binding fragment thereof of claim 1, wherein the antigen binding protein or antigen-binding binding fragment thereof comprises an antibody F(ab) fragment.

37. The antigen binding protein or antigen-binding fragment thereof of claim 36, wherein the antibody F(ab) fragment comprises a heavy chain comprising SEQ ID NO: 56, SEQ ID NO: 57, or SEQ ID NO: 58 and the first about 100 amino acids of SEQ ID NO: 54.

38-39. (canceled)

40. The antigen binding protein or antigen-binding fragment thereof of claim 36, wherein the antibody F(ab) fragment is selected from the group consisting of:

(a) an antibody F(ab) fragment wherein the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 141, 164, 173, 182, 191, 200, 209, 218, 227, 236, 245, 254, 263, 272, or 281, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 142;
(b) an antibody F(ab) fragment wherein the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 143, 165, 174, 183, 192, 201, 210, 219, 228, 237, 246, 255, 264, 273, or 282, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 144;
(c) an antibody F(ab) fragment wherein the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 145, 166, 175, 184, 193, 202, 211, 220, 229, 238, 247, 256, 265, 274, or 283, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 146;
(d) an antibody F(ab) fragment wherein the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 147, 167, 176, 185, 194, 203, 212, 221, 230, 239, 248, 257, 266, 275, or 284, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 148;
(e) an antibody F(ab) fragment wherein the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 149, 168, 177, 186, 195, 204, 213, 222, 231, 240, 249, 258, 267, 276, or 285, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 150;
(f) an antibody F(ab) fragment wherein the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 151, 169, 178, 187, 196, 205, 214, 223, 232, 241, 250, 259, 268, 277, or 286, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 152;
(g) an antibody F(ab) fragment wherein the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 153, 170, 179, 188, 197, 206, 215, 224, 233, 242, 251, 260, 269, 278, or 287, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 67;
(h) an antibody F(ab) fragment wherein the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 153, 170, 179, 188, 197, 206, 215, 224, 233, 242, 251, 260, 269, 278, or 287, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 154;
(i) an antibody F(ab) fragment, wherein the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 153, 170, 179, 188, 197, 206, 215, 224, 233, 242, 251, 260, 269, 278, or 287, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 69;
(j) an antibody F(ab) fragment, wherein the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 155, 171, 180, 189, 198, 207, 216, 225, 234, 243, 252, 261, 270, 279, or 288, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 67;
(k) an antibody F(ab) fragment, wherein the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 155, 171, 180, 189, 198, 207, 216, 225, 234, 243, 252, 261, 270, 279, or 288, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 154;
(l) an antibody F(ab) fragment, wherein the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 155, 171, 180, 189, 198, 207, 216, 225, 234, 243, 252, 261, 270, 279, or 288, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 69;
(m) an antibody F(ab) fragment, wherein the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 156, 172, 181, 190, 199, 208, 217, 226, 235, 244, 253, 262, 271, 280, or 289, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 67;
(n) an antibody F(ab) fragment, wherein the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 156, 172, 181, 190, 199, 208, 217, 226, 235, 244, 253, 262, 271, 280, or 289, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 154; and
(o) an antibody F(ab) fragment, wherein the antibody F(ab) fragment heavy chain comprises the amino acid sequence of SEQ ID NO: 156, 172, 181, 190, 199, 208, 217, 226, 235, 244, 253, 262, 271, 280, or 289, and the antibody F(ab) fragment light chain comprises the amino acid sequence of SEQ ID NO: 69.

41-65. (canceled)

66. A pharmaceutical composition comprising the antigen binding protein or antigen-binding fragment of claim 1, and a pharmaceutically acceptable carrier.

67. An isolated nucleic acid molecule encoding the antigen binding protein or antigen-binding fragment thereof of claim 1.

68. An expression vector comprising the nucleic acid molecule of claim 67.

69. A host cell comprising the expression vector of claim 68.

70. A method for treating a FGFR3-mediated disease or disorder in a subject, comprising administering to a subject in need thereof the antigen binding protein or antigen-binding fragment thereof that specifically binds to fibroblast growth factor receptor 3 (FGFR3), comprising an antibody heavy chain variable (VH) domain and an antibody light chain variable (VL) domain, wherein:

(a) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GX1TFTDX2E (SEQ ID NO: 157), wherein X1 is Y or D and X2 is F or Y;
a CDR-H2 sequence comprising the amino acid sequence of IDPETGX3T (SEQ ID NO: 158), wherein X3 is G or S; or a CDR-H2 sequence comprising the amino acid sequence of INPNNGX4T (SEQ ID NO: 159), wherein X4 is G or V; or a CDR-H2 sequence comprising the amino acid sequence of VX5PETGGT (SEQ ID NO: 160), wherein X5 is D or E;
a CDR-H3 sequence comprising the amino acid sequence of TRX6YX7GYX8X9X10X11DY (SEQ ID NO: 161), wherein X6 is T or N, X7 is D or E, X8 is S or P, X9 is Q, R, or Y, X10 is T or A, X11 is F or M; and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QSX12LYSX13NX14KNY (SEQ ID NO: 162), wherein X12 is L or V, X13 is N, D, or S, and X14 is Q or N;
a CDR-L2 sequence comprising the amino acid sequence of X15AS (SEQ ID NO: 163), wherein X15 is W, Y, or F;
a CDR-L3 sequence comprising the amino acid sequence of QQYYSYRT (SEQ ID NO: 75), LQYDNLLWT (SEQ ID NO: 81), or HQYLSX16YT (SEQ ID NO: 290) wherein X16 is P or S;
(b) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GYTFTDYN (SEQ ID NOs: 76 and 82);
a CDR-H2 sequence comprising the amino acid sequence of INPNNGGT (SEQ ID NOs: 77 and 83);
a CDR-H3 sequence comprising the amino acid sequence of ARERDYDGAMDY (SEQ ID NO: 78); and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QDINKF (SEQ ID NOs: 79 and 85);
a CDR-L2 sequence comprising the amino acid sequence of YTS (SEQ ID NOs: 80 and 86);
a CDR-L3 sequence comprising the amino acid sequence of LQYDNLLWT (SEQ ID NOs: 81 and 87);
(c) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GYTFTDYN (SEQ ID NOs: 76 and 82);
a CDR-H2 sequence comprising the amino acid sequence of INPNNGGT (SEQ ID NOs: 77 and 83);
a CDR-H3 sequence comprising the amino acid sequence of ARERDYDGSMDF (SEQ ID NO: 84); and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QDINKF (SEQ ID NOs: 79 and 85);
a CDR-L2 sequence comprising the amino acid sequence of YTS (SEQ ID NOs: 80 and 86);
a CDR-L3 sequence comprising the amino acid sequence of LQYDNLLWT (SEQ ID NOs: 81 and 87);
(d) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GYTVTDYY (SEQ ID NO: 88);
a CDR-H2 sequence comprising the amino acid sequence of INPNNGVT (SEQ ID NO: 89);
a CDR-H3 sequence comprising the amino acid sequence of AREEDFDGFDY (SEQ ID NO: 90); and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QDVSTG (SEQ ID NO: 91);
a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104);
a CDR-L3 sequence comprising the amino acid sequence of QQHYSTPLT (SEQ ID NO: 93);
(e) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GSTFSDFE (SEQ ID NO: 94);
a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NOs: 71, 95, and 101);
a CDR-H3 sequence comprising the amino acid sequence of TRNYDGYSQTX17DY (SEQ ID NO: 308), wherein X17 is M or F; and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QSVLYSX18NQKNY (SEQ ID NO: 309), wherein X18 is S or D;
a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104);
a CDR-L3 sequence comprising the amino acid sequence of or HQYLSSYT (SEQ ID NOs: 99 and 105); or
(f) the VH domain comprises
a CDR-H1 sequence comprising the amino acid sequence of GSTFTDFE (SEQ ID NO: 100);
a CDR-H2 sequence comprising the amino acid sequence of IDPETGGT (SEQ ID NOs: 71, 95, and 101);
a CDR-H3 sequence comprising the amino acid sequence of TRNYDGYSQTX17DY (SEQ ID NO: 308), wherein X17 is M or F; and
the VL domain comprises
a CDR-L1 sequence comprising the amino acid sequence of QSVLYSX18NQKNY (SEQ ID NO: 309), wherein X18 is S or D;
a CDR-L2 sequence comprising the amino acid sequence of WAS (SEQ ID NOs: 74, 92, 98, and 104);
a CDR-L3 sequence comprising the amino acid sequence of or HQYLSSYT (SEQ ID NOs: 99 and 105).

71. The method of claim 70, wherein the FGFR3-mediated disease or disorder is achondroplasia, optionally wherein:

the achondroplasia is FGFR3G380R+ achondroplasia; and/or
the subject suffering from achondroplasia comprises one or more symptoms selected from the group consisting of shortened proximal limbs, brachydactyly, large head with prominent forehead frontal bossing, small midface with a flattened nasal bridge, spinal kyphosis, spinal lordosis, varus, valgus, ear infections, sleep apnea, and hydrocephalus.

72-73. (canceled)

74. The method of claim 70, wherein the FGFR3-mediated disease or disorder is cancer, optionally wherein the cancer is bladder cancer melanoma, urothelial cancer, and endometrial cancer.

75. (canceled)

76. A method for treating achondroplasia in a subject or preventing or alleviating one or more symptoms of achondroplasia in a subject, comprising administering to a subject in need thereof an antigen-binding protein fragment that specifically binds to FGFR3, wherein the antigen binding protein fragment does not bind to one or more of FGFR1, FGFR2, and FGFR4.

77. A method for inhibiting one or both of FGFR3 activity and expression in a bone growth plate of a subject, comprising administering to a subject the antigen-binding protein fragment of claim 1.

78. The method of claim 77, wherein the subject is a child, optionally wherein the child is an infant, optionally wherein the infant is a newborn.

79-81. (canceled)

Patent History
Publication number: 20230303704
Type: Application
Filed: Oct 12, 2022
Publication Date: Sep 28, 2023
Inventors: Yves SABBAGH (Framingham, MA), Yangde CHEN (Wellesley, MA), William BRONDYK (Mansfield, MA), Huawei QIU (Westborough, MA), Sunghae PARK (Waban, MA), Ronnie WEI (Needham, MA), Yu QIU (Framingham, MA), Yanfeng ZHOU (Framingham, MA), Cendrine LEMOINE (Vitry-sur-Seine), HyunSuk CHO (Framingham, MA)
Application Number: 18/045,995
Classifications
International Classification: C07K 16/28 (20060101); A61P 19/08 (20060101);