US 12,460,016 B2
Plasma kallikrein binding proteins
Daniel J. Sexton, Melrose, MA (US); and Malini Viswanathan, Acton, MA (US)
Assigned to Takeda Pharmaceutical Company Limited, Osaka (JP)
Filed by Takeda Pharmaceutical Company Limited, Osaka (JP)
Filed on Oct. 4, 2022, as Appl. No. 17/937,795.
Application 14/339,053 is a division of application No. 12/985,914, filed on Jan. 6, 2011, granted, now 8,822,653.
Application 17/937,795 is a continuation of application No. 16/411,242, filed on May 14, 2019, granted, now 11,505,620.
Application 16/411,242 is a continuation of application No. 14/339,053, filed on Jul. 23, 2014, granted, now 10,336,832.
Claims priority of provisional application 61/292,614, filed on Jan. 6, 2010.
Prior Publication US 2023/0340150 A1, Oct. 26, 2023
Int. Cl. C07K 16/40 (2006.01); A61K 49/00 (2006.01); A61K 39/00 (2006.01)
CPC C07K 16/40 (2013.01) [A61K 49/0004 (2013.01); A61K 2039/505 (2013.01); C07K 2317/76 (2013.01); C07K 2317/92 (2013.01)] 8 Claims
 
1. An isolated antibody or antigen binding fragment thereof that binds plasma kallikrein (pKal), wherein the isolated antibody comprises:
(i) a heavy chain immunoglobulin variable domain (VH) sequence comprising a heavy chain complementarity determining region (HC CDR) 1 sequence of PYNMY (SEQ ID NO: 121), a HC CDR2 sequence of SIRPSGGGTVYADSVKG (SEQ ID NO: 157), a HC CDR3 sequence of GFIAARWYYFDY (SEQ ID NO: 193), a light chain immunoglobulin variable domain (VL) sequence comprising a complementarity determining region (LC CDR) 1 sequence of RASQSVSSSYLA (SEQ ID NO: 13), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 49), and a LC CDR3 sequence of QQYGSSPFT (SEQ ID NO: 85);
(ii) a VH sequence comprising a HC CDR1 sequence of WYTMV (SEQ ID NO: 122), a HC CDR2 sequence of RIYPSGGWTKYADSVKG (SEQ ID NO: 158), a HC CDR3 sequence of EGLLWFGENAFDI (SEQ ID NO: 194), a VL comprising a LC CDR1 sequence of SGDQLGDKYVG (SEQ ID NO: 14), a LC CDR2 sequence of QDTKRPS (SEQ ID NO: 50), and a LC CDR3 sequence of QAWDTSTAG (SEQ ID NO: 86);
(iii) a VH sequence comprising a HC CDR1 sequence of WYLMI (SEQ ID NO: 123), a HC CDR2 sequence of YIYPSGGFTYYADSVKG (SEQ ID NO: 159), a HC CDR3 sequence of TEGPLSWGYGMDV (SEQ ID NO: 195), a VL comprising a LC CDR1 sequence of SGDKLGDKYAC (SEQ ID NO: 15), a LC CDR2 sequence of QDSKRPS (SEQ ID NO: 51), and a LC CDR3 sequence of QAWDSSTGV (SEQ ID NO: 87);
(iv) a VH sequence comprising a HC CDR1 sequence of WYTMV (SEQ ID NO: 124), a HC CDR2 sequence of RIYPSGGWTKYADSVKG (SEQ ID NO: 160), a HC CDR3 sequence of EGLLWFGENAFDI (SEQ ID NO: 197), a VL comprising a LC CDR1 sequence of SGDQLGDKYVG (SEQ ID NO: 16), a LC CDR2 sequence of QDTKRPS (SEQ ID NO: 52), and a LC CDR3 sequence of QAWDTSTAG (SEQ ID NO: 88);
(v) a VH sequence comprising a HC CDR1 sequence of WYEMG (SEQ ID NO: 126), a HC CDR2 sequence of SIYSSGGGTMYADSVKG (SEQ ID NO: 162), a HC CDR3 sequence of NPQYSGYDRSLSDGAFDI (SEQ ID NO: 198), a VL comprising a LC CDR1 sequence of SGDNLGNKYNS (SEQ ID NO: 18), a LC CDR2 sequence of QDTKRPS (SEQ ID NO: 54), and a LC CDR3 sequence of QAWDGNVV (SEQ ID NO: 90);
(vi) a VH sequence comprising a HC CDR1 sequence of YYMMV (SEQ ID NO: 128), a HC CDR2 sequence of YIYSSGGHTVYADSVKG (SEQ ID NO: 164), a HC CDR3 sequence of DLFLYDFWSKGAFDI (SEQ ID NO: 200), a LC CDR1 sequence of SGEKLGDKYVS (SEQ ID NO: 20), a LC CDR2 sequence of EDSRRPS (SEQ ID NO: 56), and a LC CDR3 sequence of QAWDSSTAI (SEQ ID NO: 92);
(vii) a VH sequence comprising a HC CDR1 sequence of HYRMS (SEQ ID NO: 129), a HC CDR2 sequence of SIYPSGGRTVYADSVKG (SEQ ID NO: 165), a HC CDR3 sequence of DKFEWRLLFRGIGNDAFDI (SEQ ID NO: 201), a LC CDR1 sequence of SGDKLGDKYTS (SEQ ID NO: 21), a LC CDR2 sequence of QDIKRPS (SEQ ID NO: 57), and a LC CDR3 sequence of QAWDSPNARV (SEQ ID NO: 93);
(viii) a VH sequence comprising a HC CDR1 sequence of RYIMH (SEQ ID NO: 137), a HC CDR2 sequence of SISPSGGLTSYADSVKG (SEQ ID NO: 173), a HC CDR3 sequence of EFENAYHYYYYGMDV (SEQ ID NO: 209), a LC CDR1 sequence of RASGDIGNALG (SEQ ID NO: 29), a LC CDR2 sequence of DASTLQS (SEQ ID NO: 65), and a LC CDR3 sequence of LQGYNYPRT (SEQ ID NO: 101);
(ix) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1111), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1112), a HC CDR3 sequence of VARGIAARSRTSYFDY (SEQ ID NO: 1113), a LC CDR1 sequence of RAGRSISTYVN (SEQ ID NO: 1093), a LC CDR2 sequence of AASSLQS (SEQ ID NO 1099), and a LC CDR3 sequence of QQSQSTPYT (SEQ ID NO: 1105);
(x) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1111), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1112), a HC CDR3 sequence of VARGIAARSRTSYFDY (SEQ ID NO: 1113), a LC CDR1 sequence of RASQIVSSRYLA (SEQ ID NO: 1094), a LC CDR2 sequence of GAASRAT (SEQ ID NO: 1100), and a LC CDR3 sequence of QQTYSSPFT (SEQ ID NO: 1106);
(xi) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1111), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1112), a HC CDR3 sequence of VARGIAARSRTSYFDY (SEQ ID NO: 1113), a LC CDR1 sequence of RASQSISNYLN (SEQ ID NO: 1095), a LC CDR2 sequence of AASSLQS (SEQ ID NO: 1101), and a LC CDR3 sequence of QQSYTSPYT (SEQ ID NO: 1107);
(xii) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1111), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1112), a HC CDR3 sequence of VARGIAARSRTSYFDY (SEQ ID NO: 1113), a LC CDR1 sequence of RASQIVSSNYLA (SEQ ID NO: 1096), a LC CDR2 sequence of GASNRAT (SEQ ID NO: 1102), and a LC CDR3 sequence of QQSFNIPYT (SEQ ID NO: 1108);
(xiii) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1111), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1112), a HC CDR3 sequence of VARGIAARSRTSYFDY (SEQ ID NO: 1113), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1097), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1103), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1109);
(xiv) a VH sequence comprising a HC CDR1 sequence of HYIMM (SEQ ID NO: 1127), a HC CDR2 sequence of GIYSSGGITVYADSVKG (SEQ ID NO: 1209), a HC CDR3 sequence of QRTGVPRRDSFNI (SEQ ID NO: 1291), a LC CDR1 sequence of RASQSISSWLA (SEQ ID NO: 1124), a LC CDR2 sequence of KASTLES (SEQ ID NO: 1125), and a LC CDR3 sequence of QQYNTYWT (SEQ ID NO: 1126);
(xv) a VH sequence comprising a HC CDR1 sequence of IYSMH (SEQ ID NO: 1128), a HC CDR2 sequence of SIYPSRGMTWYADSVKG (SEQ ID NO: 1210), a HC CDR3 sequence of RRTGIPRRDAFDI (SEQ ID NO: 1292), a LC CDR1 sequence of RASQSISSWLA (SEQ ID NO: 1124), a LC CDR2 sequence of KASTLES (SEQ ID NO: 1125), and a LC CDR3 sequence of QQYNTYWT (SEQ ID NO: 1126);
(xvi) a VH sequence comprising a HC CDR1 sequence of VYNMH (SEQ ID NO: 1129), a HC CDR2 sequence of SIYPSGGMTYYADSVKG (SEQ ID NO: 1211), a HC CDR3 sequence of RRTGIPRRDAFDI (SEQ ID NO: 1293), a LC CDR1 sequence of RASQSISSWLA (SEQ ID NO: 1124), a LC CDR2 sequence of KASTLES (SEQ ID NO: 1125), and a LC CDR3 sequence of QQYNTYWT (SEQ ID NO: 1126);
(xvii) a VH sequence comprising a HC CDR1 sequence of HYIMM (SEQ ID NO: 1130), a HC CDR2 sequence of GIYSSGGITVYADSVKG (SEQ ID NO: 1212), a HC CDR3 sequence of RRIGVPRRDEFDI (SEQ ID NO: 1294), a LC CDR1 sequence of RASQSISSWLA (SEQ ID NO: 1124), a LC CDR2 sequence of KASTLES (SEQ ID NO: 1125), and a LC CDR3 sequence of QQYNTYWT (SEQ ID NO: 1126);
(xviii) a VH sequence comprising a HC CDR1 sequence of HYIMM (SEQ ID NO: 1131), a HC CDR2 sequence of GIYSSGGITVYADSVKG (SEQ ID NO: 1213), a HC CDR3 sequence of RRTGVPRWDDFDI (SEQ ID NO: 1295), a LC CDR1 sequence of RASQSISSWLA (SEQ ID NO: 1124), a LC CDR2 sequence of KASTLES (SEQ ID NO: 1125), and a LC CDR3 sequence of QQYNTYWT (SEQ ID NO: 1126);
(xix) a VH sequence comprising a HC CDR1 sequence of IYSMH (SEQ ID NO: 1132), a HC CDR2 sequence of SIYSSGGPTKYADSVKG (SEQ ID NO: 1214), a HC CDR3 sequence of RRTGIPRRDAFDI (SEQ ID NO: 1296), a LC CDR1 sequence of RASQSISSWLA (SEQ ID NO: 1124), a LC CDR2 sequence of KASTLES (SEQ ID NO: 1125), and a LC CDR3 sequence of QQYNTYWT (SEQ ID NO: 1126);
(xx) a VH sequence comprising a HC CDR1 sequence of HYIMM (SEQ ID NO: 1133), a HC CDR2 sequence of GIYSSGGITVYADSVKG (SEQ ID NO: 1215), a HC CDR3 sequence of RRIGVPRRDSFDM (SEQ ID NO: 1297), a LC CDR1 sequence of RASQSISSWLA (SEQ ID NO: 1124), a LC CDR2 sequence of KASTLES (SEQ ID NO: 1125), and a LC CDR3 sequence of QQYNTYWT (SEQ ID NO: 1126);
(xxi) a VH sequence comprising a HC CDR1 sequence of HYIMM (SEQ ID NO: 1135), a HC CDR2 sequence of GIYSSGGITVYADSVKG (SEQ ID NO: 1217), a HC CDR3 sequence of RRTGVPRRDEFDI (SEQ ID NO: 1299), a LC CDR1 sequence of RASQSISSWLA (SEQ ID NO: 1124), a LC CDR2 sequence of KASTLES (SEQ ID NO: 1125), and a LC CDR3 sequence of QQYNTYWT (SEQ ID NO: 1126);
(xxii) a VH sequence comprising a HC CDR1 sequence of HYIMM (SEQ ID NO: 1137), a HC CDR2 sequence of GIYSSGGITVYADSVKG (SEQ ID NO: 1219), a HC CDR3 sequence of RRIGVPRRDSFDI (SEQ ID NO: 1301), a LC CDR1 sequence of RASQSISSWLA (SEQ ID NO: 1124), a LC CDR2 sequence of KASTLES (SEQ ID NO: 1125), and a LC CDR3 sequence of QQYNTYWT (SEQ ID NO: 1126);
(xxiii) a VH sequence comprising a HC CDR1 sequence of VYNMH (SEQ ID NO: 1138), a HC CDR2 sequence of SIYPSGGMTTYADSVKG (SEQ ID NO: 1220), a HC CDR3 sequence of RRTGIPRRDAFDI (SEQ ID NO: 1302), a LC CDR1 sequence of RASQSISSWLA (SEQ ID NO: 1124), a LC CDR2 sequence of KASTLES (SEQ ID NO: 1125), and a LC CDR3 sequence of QQYNTYWT (SEQ ID NO: 1126);
(xxiv) a VH sequence comprising a HC CDR1 sequence of HYIMM (SEQ ID NO: 1140), a HC CDR2 sequence of GIYSSGGITVYADSVKG (SEQ ID NO: 1222), a HC CDR3 sequence of RRTGVPRRDSFDI (SEQ ID NO: 1304), a LC CDR1 sequence of RASQSISSWLA (SEQ ID NO: 1124), a LC CDR2 sequence of KASTLES (SEQ ID NO: 1125), and a LC CDR3 sequence of QQYNTYWT (SEQ ID NO: 1126);
(xxv) a VH sequence comprising a HC CDR1 sequence of RYSMR (SEQ ID NO: 1142), a HC CDR2 sequence of VIYPSGGQTYYADSVKG (SEQ ID NO: 1224), a HC CDR3 sequence of RRTGIPRRDAFDI (SEQ ID NO: 1306), a LC CDR1 sequence of RASQSISSWLA (SEQ ID NO: 1124), a LC CDR2 sequence of KASTLES (SEQ ID NO: 1125), and a LC CDR3 sequence of QQYNTYWT (SEQ ID NO: 1126);
(xxvi) a VH sequence comprising a HC CDR1 sequence of HYIMM (SEQ ID NO: 1146), a HC CDR2 sequence of GIYSSGGITVYADSVKG (SEQ ID NO: 1228), a HC CDR3 sequence of RRTGVPRRDDFDI (SEQ ID NO: 1310), a LC CDR1 sequence of RASQSISSWLA (SEQ ID NO: 1124), a LC CDR2 sequence of KASTLES (SEQ ID NO: 1125), and a LC CDR3 sequence of QQYNTYWT (SEQ ID NO: 1126);
(xxvii) a VH sequence comprising a HC CDR1 sequence of HYIMM (SEQ ID NO: 1153), a HC CDR2 sequence of GIYSSGGITVYADSVKG (SEQ ID NO: 1235), a HC CDR3 sequence of RRIGVPRRDDFDI (SEQ ID NO: 1317), a LC CDR1 sequence of RASQSISSWLA (SEQ ID NO: 1124), a LC CDR2 sequence of KASTLES (SEQ ID NO: 1125), and a LC CDR3 sequence of QQYNTYWT (SEQ ID NO: 1126);
(xxviii) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1540), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1602), a HC CDR3 sequence of VARGIAARSRTSYLDQ (SEQ ID NO: 1664), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxix) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1541), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1603), a HC CDR3 sequence of VGQGIRGRSRTSYFAQ (SEQ ID NO: 1665), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxx) a VH sequence comprising a HC CDR1 sequence of DYMMA (SEQ ID NO: 1542), a HC CDR2 sequence of SIVPSGGHTHYADSVKG (SEQ ID NO: 1604), a HC CDR3 sequence of VARGIAARSRTSYFDY (SEQ ID NO: 1666), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxxi) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1543), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1605), a HC CDR3 sequence of VAQGIAARSRTSSVDQ (SEQ ID NO: 1667), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxxii) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1544), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1606), a HC CDR3 sequence of VARGIAARSRTSFFDY (SEQ ID NO: 1668), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxxiii) a VH sequence comprising a HC CDR1 sequence of QYLMA (SEQ ID NO: 1545), a HC CDR2 sequence of SIYPSGGWTKYADSVKG (SEQ ID NO: 1607), a HC CDR3 sequence of VARGIAARSRTSYFDY (SEQ ID NO: 1669), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxxiv) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1546), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1608), a HC CDR3 sequence of VARGIASRSRTRYCDY (SEQ ID NO: 1670), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxxv) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1547), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1609), a HC CDR3 sequence of VATGIVARSRTRYFDQ (SEQ ID NO: 1671), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxxvi) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1548), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1610), a HC CDR3 sequence of VARGIAARSRTRYFDY (SEQ ID NO: 1672), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxxvii) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1549), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1611), a HC CDR3 sequence of VAQGISARSRTSYFDY (SEQ ID NO: 1673), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxxviii) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1550), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1612), a HC CDR3 sequence of VAQGIVARSRTSYLHQ (SEQ ID NO: 1674), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxxix) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1552), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1614), a HC CDR3 sequence of VARGIAARSRTSYLDY (SEQ ID NO: 1676), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxxx) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1554), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1616), a HC CDR3 sequence of VARGIAARSRTRYFDQ (SEQ ID NO: 1678), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxxxi) a VH sequence comprising a HC CDR1 sequence of GYMMV (SEQ ID NO: 1555), a HC CDR2 sequence of RISPSGGPTIYADSVKG (SEQ ID NO: 1617), a HC CDR3 sequence of VARGIAARSRTSYFDY (SEQ ID NO: 1679), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxxxii) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1556), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1618), a HC CDR3 sequence of VARGIAARSRTSYFDQ (SEQ ID NO: 1680), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxxxiii) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1557), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1619), a HC CDR3 sequence of VARGIAARSRTILLDQ (SEQ ID NO: 1681), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxxxiv) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1558), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1620), a HC CDR3 sequence of VARGIAARSRTSFIDY (SEQ ID NO: 1682), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxxxv) a VH sequence comprising a HC CDR1 sequence of TYKMQ (SEQ ID NO: 1559), a HC CDR2 sequence of SISPSGGPTNYADSVKG (SEQ ID NO: 1621), a HC CDR3 sequence of VARGIAARSRTSYFDY (SEQ ID NO: 1683), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539);
(xxxxvi) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1560), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1622), a HC CDR3 sequence of VARGIAARSRTSYLDF (SEQ ID NO: 1684), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539); or
(xxxxvii) a VH sequence comprising a HC CDR1 sequence of HYLMT (SEQ ID NO: 1562), a HC CDR2 sequence of YISPSGGHTIYADSVKG (SEQ ID NO: 1624), a HC CDR3 sequence of VARGIAARSRTSYFNQ (SEQ ID NO: 1686), a LC CDR1 sequence of RTSQFVNSNYLA (SEQ ID NO: 1537), a LC CDR2 sequence of GASSRAT (SEQ ID NO: 1538), and a LC CDR3 sequence of QQSSRTPWT (SEQ ID NO: 1539).