Fgfr3 antibodies and methods of use

Abstract

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.

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 GX 1 TFTDX 2 E (SEQ ID NO: 157), wherein X 1  is Y or D and X 2  is F or Y;   a CDR-H2 sequence comprising the amino acid sequence of IDPETGX 3 T (SEQ ID NO: 158), wherein X 3  is G or S; or a CDR-H2 sequence comprising the amino acid sequence of INPNNGX 4 T (SEQ ID NO: 159), wherein X 4  is G or V; or a CDR-H2 sequence comprising the amino acid sequence of VX 5 PETGGT (SEQ ID NO: 160), wherein X 5  is D or E;   a CDR-H3 sequence comprising the amino acid sequence of TRX 6 YX 7 GYX 8 X 9 X 10 X 11 DY (SEQ ID NO: 161), wherein X 6  is T or N, X 7  is D or E, X 8  is S or P, X 9  is Q, R, or Y, X 10  is T or A, X 11  is F or M; and   the VL domain comprises   a CDR-L1 sequence comprising the amino acid sequence of QSX 12 LYSX 13 NX 14 KNY (SEQ ID NO: 162), wherein X 12  is L or V, X 13  is N, D, or S, and X 14  is Q or N;   a CDR-L2 sequence comprising the amino acid sequence of X 15 AS (SEQ ID NO: 163), wherein X 15  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 HQYLSX 16 YT (SEQ ID NO: 290) wherein X 16  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 TRNYDGYSQTX 17 DY (SEQ ID NO: 308), wherein X 17  is M or F; and   the VL domain comprises   a CDR-L1 sequence comprising the amino acid sequence of QSVLYSX 18 NQKNY (SEQ ID NO: 309, wherein X 18  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 TRNYDGYSQTX 17 DY (SEQ ID NO: 308), wherein X 17  is M or F; and   the VL domain comprises   a CDR-L1 sequence comprising the amino acid sequence of QSVLYSX 18 NQKNY (SEQ ID NO: 309), wherein X 18  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 GX 1 TFTDX 2 E (SEQ ID NO: 157), wherein X 1  is Y or D and X 2  is F or Y;   a CDR-H2 sequence comprising the amino acid sequence of IDPETGX 3 T (SEQ ID NO: 158), wherein X 3  is G or S; or a CDR-H2 sequence comprising the amino acid sequence of INPNNGX 4 T (SEQ ID NO: 159), wherein X 4  is G or V; or a CDR-H2 sequence comprising the amino acid sequence of VX 5 PETGGT (SEQ ID NO: 160), wherein X 5  is D or E;   a CDR-H3 sequence comprising the amino acid sequence of TRX 6 YX 7 GYX 8 X 9 X 10 X 11 DY (SEQ ID NO: 161), wherein X 6  is T or N, X 7  is D or E, X 8  is S or P, X 9  is Q, R, or Y, X 10  is T or A, X 11  is F or M; and   the VL domain comprises   a CDR-L1 sequence comprising the amino acid sequence of QSX 12 LYSX 13 NX 14 KNY (SEQ ID NO: 162), wherein X 12  is L or V, X 13  is N, D, or S, and X 14  is Q or N;   a CDR-L2 sequence comprising the amino acid sequence of X 15 AS (SEQ ID NO: 163), wherein X 15  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 HQYLSX 16 YT (SEQ ID NO: 290) wherein X 16  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 TRNYDGYSQTX 17 DY (SEQ ID NO: 308), wherein X 17  is M or F; and   the VL domain comprises   a CDR-L1 sequence comprising the amino acid sequence of QSVLYSX 18 NQKNY (SEQ ID NO: 309), wherein X 18  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 TRNYDGYSQTX 17 DY (SEQ ID NO: 308), wherein X 17  is M or F; and   the VL domain comprises   a CDR-L1 sequence comprising the amino acid sequence of QSVLYSX 18 NQKNY (SEQ ID NO: 309), wherein X 18  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 FGFR3 G380R+  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)