Antibodies for detecting urinary biomarkers

Abstract

The present invention provides isolated polypeptides capable of specifically binding to a protein target selected from LGALS9, CRP, BTLA, SAA, EGF, or FGA, or to a peptide thereof, especially under urinary conditions, which may be used for predicting in a urine sample of a subject suspected of having an infection whether the infection is a bacterial infection or a viral infection. The present invention further provides methods of diagnostics and treatment using the isolated polypeptides, and suitable diagnostic kits.

Description

[0001] ANTIBODIES FOR DETECTING URINARY BIOMARKERS

[0002] FIELD OF THE INVENTION

[0003] The present disclosure is generally directed to the reagents for the diagnostics of infectious diseases. Specifically, the invention relates to antibodies against urinary proteins and peptide fragments thereof for distinguishing between bacterial and viral infections.

[0004] BACKGROUND OF THE INVENTION

[0005] Antibiotic resistance has been largely attributed to the overuse and misuse of antibiotics. A major reason for this is incorrect diagnosis, often caused by the similar clinical features of infections caused by bacterial and by viral agents. While antibiotics is usually the treatment of choice to a bacterial infection, it is often at best useless when treating viral infections, and in worse scenarios may cause adverse effects and development of resistant bacteria. Nevertheless, when in doubt, prescribing antibiotics is usually the default, so as not to miss treating a bacterial infection. The rate of inappropriate antibiotic prescriptions in the hospital setting is estimated at 30 to 50%.

[0006] Typically, diagnostic tools today are based on specific microbiological diagnostic tests such as culture, serology and more recently nucleic acid-based tests usually directed at finding the causative agent. However, these tests involve challenges such as cases where the infection site is not readily accessible or unknown and so cannot be sampled, long times and expertise needed for microbiological laboratory assays, entailing dependency on health care professionals, and more.

[0007] Accordingly, fast, simple, and easy to use non-invasive diagnostic tests for infections could decrease morbidity and mortality by increasing early administration of antibiotics to patients with bacterial infections, and reducing unnecessary administration of antibiotics to patients without bacterial infections, such as those having a viral infection.

[0008] SUMMARY OF INVENTION

[0009] The following embodiments are described and illustrated in conjunction with compositions and methods which are meant to be exemplary and illustrative, not limiting in scope. In various embodiments, one or more of the above-described problems have been reduced or eliminated, while other embodiments are directed to other advantages or improvements.

[0010] In some embodiments, there is provided an isolated polypeptide capable of specifically binding a C-reactive protein (CRP) target or a peptide thereof under urinary conditions.

[0011] In some embodiments, the CRP peptide includes a sequence selected from sequences set forth in SEQ ID Nos. 861-866. In some embodiments, the isolated polypeptide includes a heavy chain variable (VH) region including three complementarity determining region (CDR) sequences (VH-CDR1, VH-CDR2, VH-CDR3) and a light chain variable (VL) region including three CDR sequences (VL-CDR1, VL-CDR2, and VL-CDR3), and the six CDR sequences are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences selected from: SEQ ID Nos. 181 and 182; SEQ ID Nos. 201 and 202; SEQ ID Nos. 221 and 222; SEQ ID Nos.

[0012] 241 and 242; SEQ ID Nos. 261 and 262; SEQ ID Nos. 281 and 282; SEQ ID Nos. 931 and 932; SEQ ID Nos. 971 and 972; SEQ ID Nos. 991 and 992; SEQ ID Nos. 1031 and 1032; SEQ ID Nos.

[0013] 1051 and 1052; SEQ ID Nos. 1091 and 1092; SEQ ID Nos. 1111 and 1112; SEQ ID Nos. 1131 and 1132; SEQ ID Nos. 1211 and 1212; SEQ ID Nos. 1231 and 1232; and SEQ ID Nos. 1311 and 1312.

[0014] In some embodiments, the six CDR sequences of the isolated polypeptide include sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 183, 184, 185, 186, 187, and 188; SEQ ID Nos. 203, 204, 205, 206, 207, and 208; SEQ ID Nos. 223, 224, 225, 226, 227, and 228; SEQ ID Nos. 243, 244, 245, 246, 247, and 248; SEQ ID Nos. 263, 264, 265, 266, 267, and 268; SEQ ID Nos. 283, 284, 285, 286, 287, and 288; SEQ ID Nos. 933, 934, 935, 936, 937, and 938; SEQ ID Nos. 973, 974, 975, 976, 977, and 978; SEQ ID Nos. 993, 994, 995, 996, 997, and 998; SEQ ID Nos. 1033, 1034, 1035, 1036, 1037, and 1038; SEQ ID Nos. 1053, 1054, 1055, 1056, 1057, and 1058; SEQ ID Nos. 1093, 1094, 1095, 1096, 1097, and 1098; SEQ ID Nos. 1113, 1114, 1115, 1116, 1117, and 1118; SEQ ID Nos. 1133, 1134, 1135, 1136, 1137, and 1138; SEQ ID Nos. 1213, 1214, 1215, 1216, 1217, and 1218; SEQ ID Nos. 1233, 1234, 1235, 1236, 1237, and 1238; and SEQ ID Nos. 1313, 1314, 1315, 1316, 1317, and 1318.

[0015] In some embodiments, the V region sequences of the isolated polypeptide include sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos. 181 and 182; SEQ ID Nos. 201 and 202; SEQ ID Nos. 221 and 222; SEQ ID Nos. 241 and 242; SEQ ID Nos. 261 and 262; SEQ ID Nos. 281 and 282; SEQ ID Nos. 931 and 932; SEQ ID Nos. 971 and 972; SEQ ID Nos. 991 and 992; SEQ ID Nos. 1031 and 1032; SEQ ID Nos. 1051 and 1052; SEQ ID Nos.

[0016] 1091 and 1092; SEQ ID Nos. 1111 and 1112; SEQ ID Nos. 1131 and 1132; SEQ ID Nos. 1211 and 1212; SEQ ID Nos. 1231 and 1232; and SEQ ID Nos. 1311 and 1312.

[0017] In some embodiments, the six CDR sequences of the isolated polypeptide, include sequences substantially identical to six CDR sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 193, 194, 195, 196, 197, and 198; SEQ ID Nos. 213, 214, 215, 216, 217, and 218; SEQ ID Nos. 233, 234, 235, 236, 237, and 238; SEQ ID Nos. 253, 254, 255, 256, 257, and 258; SEQ ID Nos. 273, 274, 275, 276, 277, and 278; SEQ ID Nos. 293, 294, 295, 296, 297, and 298; SEQ ID Nos. 943, 944, 945, 946, 947, and 948; SEQ ID Nos. 983, 984, 985, 986, 987, and 988; SEQ ID Nos. 1003, 1004, 1005, 1006, 1007, and 1008; SEQ ID Nos. 1043, 1044, 1045, 1046, 1047, and 1048; SEQ ID Nos. 1063, 1064, 1065, 1066, 1067, and 1068; SEQ ID Nos. 1103, 1104, 1105, 1106, 1107, and 1108; SEQ ID Nos. 1123, 1124, 1125, 1126, 1127, and 1128; SEQ ID Nos.

[0018] 1143, 1144, 1145, 1146, 1147, and 1148; SEQ ID Nos. 1223, 1224, 1225, 1226, 1227, and 1228; SEQ ID Nos. 1243, 1244, 1245, 1246, 1247, and 1248; and SEQ ID Nos. 1323, 1324, 1325, 1326, 1327, and 1328.

[0019] In some embodiments, the V region sequences of the isolated polypeptide include sequences substantially identical to VH and VL sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 191 and 192; SEQ ID Nos. 211 and 212; SEQ ID Nos. 231 and 232; SEQ ID Nos.

[0020] 251 and 252; SEQ ID Nos. 271 and 272; SEQ ID Nos. 291 and 292; SEQ ID Nos. 941 and 942; SEQ ID Nos. 981 and 982; SEQ ID Nos. 1001 and 1002; SEQ ID Nos. 1041 and 1042; SEQ ID Nos. 1061 and 1062; SEQ ID Nos. 1101 and 1102; SEQ ID Nos. 1121 and 1122; SEQ ID Nos.

[0021] 1141 and 1142; SEQ ID Nos. 1221 and 1222; SEQ ID Nos. 1241 and 1242; and SEQ ID Nos.

[0022] 1321 and 1322.

[0023] In some embodiments, there is provided an isolated polypeptide capable of specifically binding a B- and T-lymphocyte attenuator (BTLA) protein target or a peptide thereof under urinary conditions.

[0024] In some embodiments, the BTLA peptide includes a sequence selected from sequences set forth in SEQ ID Nos. 867-869.

[0025] In some embodiments, the isolated polypeptide includes a heavy chain variable (VH) region including three complementarity determining region (CDR) sequences (VH-CDR1, VH-CDR2, VH-CDR3) and a light chain variable (VL) region including three CDR sequences (VL-CDR1, VL-CDR2, and VL-CDR3), and the six CDR sequences are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences selected from: SEQ ID Nos. 01 and 02; SEQ ID Nos. 21 and 22; SEQ ID Nos. 41 and 42; SEQ ID Nos. 61 and 62; SEQ ID Nos. 81 and 82; SEQ ID Nos. 101 and 102; SEQ ID Nos. 121 and 122; SEQ ID Nos.

[0026] 141 and 142; SEQ ID Nos. 161 and 162; SEQ ID Nos. 1351 and 1352; SEQ ID Nos. 1371 and 1372; SEQ ID Nos. 1391 and 1392; SEQ ID Nos. 1411 and 1412; SEQ ID Nos. 1431 and 1432; and SEQ ID Nos. 1451 and 1452.

[0027] In some embodiments, the six CDR sequences of the isolated polypeptide include sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 03, 04, 05, 06, 07, and 08; SEQ ID Nos. 23, 24, 25, 26, 27, and 28; SEQ ID Nos. 43, 44, 45, 46, 47, and 48; SEQ ID Nos.

[0028] 63, 64, 65, 66, 67, and 68; SEQ ID Nos. 83, 84, 85, 86, 87, and 88; SEQ ID Nos. 103, 104, 105, 106, 107, and 108; SEQ ID Nos. 123, 124, 125, 126, 127, and 128; SEQ ID Nos. 143, 144, 145, 146, 147, and 148; SEQ ID Nos. 163, 164, 165, 166, 167, and 168; SEQ ID Nos. 1353, 1354, 1355, 1356, 1357, and 1358; SEQ ID Nos. 1373, 1374, 1375, 1376, 1377, and 1378; SEQ ID Nos. 1393, 1394, 1395, 1396, 1397, and 1398; SEQ ID Nos. 1413, 1414, 1415, 1416, 1417, and 1418; SEQ ID Nos. 1433, 1434, 1435, 1436, 1437, and 1438; and SEQ ID Nos. 1453, 1454, 1455, 1456, 1457, and 1458.

[0029] In some embodiments, the V region sequences of the isolated polypeptide include sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos. 01 and 02; SEQ ID Nos. 21 and 22; SEQ ID Nos. 41 and 42; SEQ ID Nos. 61 and 62; SEQ ID Nos. 81 and 82; SEQ ID Nos. 101 and 102; SEQ ID Nos. 121 and 122; SEQ ID Nos. 141 and 142; SEQ ID Nos. 161 and 162; SEQ ID Nos. 1351 and 1352; SEQ ID Nos. 1371 and 1372; SEQ ID Nos. 1391 and 1392; SEQ ID Nos. 1411 and 1412; SEQ ID Nos. 1431 and 1432; and SEQ ID Nos. 1451 and 1452.

[0030] In some embodiments, the six CDR sequences of the isolated polypeptide include sequences substantially identical to six CDR sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 13, 14, 15, 16, 17, and 18; SEQ ID Nos. 33, 34, 35, 36, 37, and 38; SEQ ID Nos. 53, 54, 55, 56, 57, and 58; SEQ ID Nos. 73, 74, 75, 76, 77, and 78; SEQ ID Nos. 93, 94, 95, 96, 97, and 98; SEQ ID Nos. 113, 114, 115, 116, 117, and 118; SEQ ID Nos. 133, 134, 135, 136, 137, and 138; SEQ ID Nos. 153, 154, 155, 156, 157, and 158; SEQ ID Nos. 173, 174, 175, 176, 177, and 178; SEQ ID Nos. 1363, 1364, 1365, 1366, 1367, and 1368; SEQ ID Nos. 1383, 1384, 1385, 1386, 1387, and 1388; SEQ ID Nos. 1403, 1404, 1405, 1406, 1407, and 1408; SEQ ID Nos. 1423, 1424, 1425, 1426, 1427, and 1428; SEQ ID Nos. 1443, 1444, 1445, 1446, 1447, and 1448; and SEQ ID Nos. 1463, 1464, 1465, 1466, 1467, and 1468.

[0031] In some embodiments, the V region sequences of the isolated polypeptide include sequences substantially identical to VH and VL sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 11 and 12; SEQ ID Nos. 31 and 32; SEQ ID Nos. 51 and 52; SEQ ID Nos. 71 and 72; SEQ ID Nos. 91 and 92; SEQ ID Nos. 111 and 112; SEQ ID Nos. 131 and 132; SEQ ID Nos.

[0032] 151 and 152; SEQ ID Nos. 171 and 172; SEQ ID Nos. 1361 and 1362; SEQ ID Nos. 1381 and 1382; SEQ ID Nos. 1401 and 1402; SEQ ID Nos. 1421 and 1422; SEQ ID Nos. 1441 and 1442; and SEQ ID Nos. 1461 and 1462.

[0033] In some embodiments, there is provided an isolated polypeptide capable of specifically binding an epidermal growth factor (EGF) protein target or a peptide thereof under urinary conditions.

[0034] In some embodiments, the EGF peptide includes a sequence selected from sequences set forth in SEQ ID Nos. 870-875. In some embodiments, the isolated polypeptide includes a heavy chain variable (VH) region including three complementarity determining region (CDR) sequences (VH-CDR1, VH-CDR2, VH-CDR3) and a light chain variable (VL) region including three CDR sequences (VL-CDR1, VL-CDR2, and VL-CDR3), and the six CDR sequences are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences selected from: SEQ ID Nos. 301 and 302; SEQ ID Nos. 321 and 322; SEQ ID Nos. 341 and 342; SEQ ID Nos.

[0035] 361 and 362; SEQ ID Nos. 381 and 382; SEQ ID Nos. 401 and 402; SEQ ID Nos. 421 and 422; SEQ ID Nos. 441 and 442; and SEQ ID Nos. 461 and 462.

[0036] In some embodiments, the six CDR sequences of the isolated polypeptide include sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 303, 304, 305, 306, 307, and 308; SEQ ID Nos. 323, 324, 325, 326, 327, and 328; SEQ ID Nos. 343, 344, 345, 346, 347, and 348; SEQ ID Nos. 363, 364, 365, 366, 367, and 368; SEQ ID Nos. 383, 384, 385, 386, 387, and 388; SEQ ID Nos. 403, 404, 405, 406, 407, and 408; SEQ ID Nos. 423, 424, 425, 426, 427, and 428; SEQ ID Nos. 443, 444, 445, 446, 447, and 448; and SEQ ID Nos. 463, 464, 465, 466, 467, and 468.

[0037] In some embodiments, the V region sequences of the isolated polypeptide include sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos. 301 and 302; SEQ ID Nos. 321 and 322; SEQ ID Nos. 341 and 342; SEQ ID Nos. 361 and 362; SEQ ID Nos. 381 and 382; SEQ ID Nos. 401 and 402; SEQ ID Nos. 421 and 422; SEQ ID Nos. 441 and 442; and SEQ ID Nos. 461 and 462.

[0038] In some embodiments, the six CDR sequences of the isolated polypeptide include sequences substantially identical to six CDR sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 313, 314, 315, 316, 317, and 318; SEQ ID Nos. 333, 334, 335, 336, 337, and 338; SEQ ID Nos. 353, 354, 355, 356, 357, and 358; SEQ ID Nos. 373, 374, 375, 376, 377, and 378; SEQ ID Nos. 393, 394, 395, 396, 397, and 398; SEQ ID Nos. 413, 414, 415, 416, 417, and 418; SEQ ID Nos. 433, 434, 435, 436, 437, and 438; SEQ ID Nos. 453, 454, 455, 456, 457, and 458; and SEQ ID Nos. 473, 474, 475, 476, 477, and 478.

[0039] In some embodiments, the V region sequences of the isolated polypeptide include sequences substantially identical to VH and VL sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 311 and 312; SEQ ID Nos. 331 and 332; SEQ ID Nos. 351 and 352; SEQ ID Nos.

[0040] 371 and 372; SEQ ID Nos. 391 and 392; SEQ ID Nos. 411 and 412; SEQ ID Nos. 431 and 432; SEQ ID Nos. 451 and 452; and SEQ ID Nos. 471 and 472. In some embodiments, there is provided an isolated polypeptide capable of specifically binding a fibrinogen alpha chain (FGA) protein target or a peptide thereof under urinary conditions.

[0041] In some embodiments, the FGA peptide includes a sequence selected from sequences set forth in SEQ ID Nos. 876-881.

[0042] In some embodiments, the isolated polypeptide includes a heavy chain variable (VH) region including three complementarity determining region (CDR) sequences (VH-CDR1, VH-CDR2, VH-CDR3) and a light chain variable (VL) region including three CDR sequences (VL-CDR1, VL-CDR2, and VL-CDR3), and the six CDR sequences are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences selected from: SEQ ID Nos. 481 and 482; SEQ ID Nos. 501 and 502; SEQ ID Nos. 521 and 522; SEQ ID Nos.

[0043] 541 and 542; SEQ ID Nos. 561 and 562; SEQ ID Nos. 581 and 582; SEQ ID Nos. 601 and 602; SEQ ID Nos. 621 and 622; and SEQ ID Nos. 641 and 642.

[0044] In some embodiments, the six CDR sequences of the isolated polypeptide include sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 483, 484, 485, 486, 487, and 488; SEQ ID Nos. 503, 504, 505, 506, 507, and 508; SEQ ID Nos. 523, 524, 525, 526, 527, and 528; SEQ ID Nos. 543, 544, 545, 546, 547, and 548; SEQ ID Nos. 563, 564, 565, 566, 567, and 568; SEQ ID Nos. 583, 584, 585, 586, 587, and 588; SEQ ID Nos. 603, 604, 605, 606, 607, and 608; SEQ ID Nos. 623, 624, 625, 626, 627, and 628; and SEQ ID Nos. 643, 644, 645, 646, 647, and 648.

[0045] In some embodiments, the V region sequences of the isolated polypeptide include sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos. 481 and 482; SEQ ID Nos. 501 and 502; SEQ ID Nos. 521 and 522; SEQ ID Nos. 541 and 542; SEQ ID Nos. 561 and 562; SEQ ID Nos. 581 and 582; SEQ ID Nos. 601 and 602; SEQ ID Nos. 621 and 622; and SEQ ID Nos. 641 and 642.

[0046] In some embodiments, the six CDR sequences of the isolated polypeptide include sequences substantially identical to six CDR sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 493, 494, 495, 496,497, and 498; SEQ ID Nos. 513, 514, 515,516, 517, and 518; SEQ ID Nos. 533, 534,535, 536,537, and 538; SEQ ID Nos. 553, 554, 555, 556, 557, and 558; SEQ ID Nos. 573, 574, 575, 576, 577, and 578; SEQ ID Nos. 593, 594, 595,596, 597, and 598; SEQ ID Nos. 613, 614, 615, 616,617, and 618; SEQ ID Nos. 633, 634, 635, 636, 637, and 638; and SEQ ID Nos. 653, 654, 655,656, 657, and 658.

[0047] In some embodiments, the V region sequences of the isolated polypeptide include sequences substantially identical to VH and VL sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 491 and 492; SEQ ID Nos. 511 and 512; SEQ ID Nos. 531 and 532; SEQ ID Nos.

[0048] 551 and 552; SEQ ID Nos. 571 and 572; SEQ ID Nos. 591 and 592; SEQ ID Nos. 611 and 612; SEQ ID Nos. 631 and 632; and SEQ ID Nos. 651 and 652.

[0049] In some embodiments, there is provided an isolated polypeptide capable of specifically binding a galectin 9 (LGALS9) protein target or a peptide thereof under urinary conditions.

[0050] In some embodiments, the LGALS9 peptide includes a sequence selected from sequences set forth in SEQ ID Nos. 882-888.

[0051] In some embodiments, the isolated polypeptide includes a heavy chain variable (VH) region including three complementarity determining region (CDR) sequences (VH-CDR1, VH-CDR2, VH-CDR3) and a light chain variable (VL) region including three CDR sequences (VL-CDR1, VL-CDR2, and VL-CDR3), and the six CDR sequences are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences selected from: SEQ ID Nos. 661 and 662; SEQ ID Nos. 1471 and 1472; SEQ ID Nos. 1491 and 1492; SEQ ID Nos. 1511 and 1512; SEQ ID Nos. 1531 and 1532; SEQ ID Nos. 1551 and 1552; SEQ ID Nos.

[0052] 1571 and 1572; and SEQ ID Nos. 1591 and 1592.

[0053] In some embodiments, the six CDR sequences of the isolated polypeptide include sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 663, 664, 665, 666, 667, and 668; SEQ ID Nos. 1473, 1474, 1475, 1476, 1477, and 1478; SEQ ID Nos. 1493, 1494, 1495, 1496, 1497, and 1498; SEQ ID Nos. 1513, 1514, 1515, 1516, 1517, and 1518; SEQ ID Nos. 1533, 1534, 1535, 1536, 1537, and 1538; SEQ ID Nos. 1553, 1554, 1555, 1556, 1557, and 1558; SEQ ID Nos. 1573, 1574, 1575, 1576, 1577, and 1578; and SEQ ID Nos. 1593, 1594, 1595, 1596, 1597, and 1598.

[0054] In some embodiments, the V region sequences of the isolated polypeptide include sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos. 661 and 662; SEQ ID Nos. 1471 and 1472; SEQ ID Nos. 1491 and 1492; SEQ ID Nos. 1511 and 1512; SEQ ID Nos.

[0055] 1531 and 1532; SEQ ID Nos. 1551 and 1552; SEQ ID Nos. 1571 and 1572; and SEQ ID Nos.

[0056] 1591 and 1592.

[0057] In some embodiments, the six CDR sequences of the isolated polypeptide include sequences substantially identical to six CDR sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 673, 674, 675, 676, 677, and 678; SEQ ID Nos. 1483, 1484, 1485, 1486, 1487, and 1488; SEQ ID Nos. 1503, 1504, 1505, 1506, 1507, and 1508; SEQ ID Nos. 1523, 1524, 1525, 1526, 1527, and 1528; SEQ ID Nos. 1543, 1544, 1545, 1546, 1547, and 1548; SEQ ID Nos. 1563, 1564, 1565, 1566, 1567, and 1568; SEQ ID Nos. 1583, 1584, 1585, 1586, 1587, and 1588; and SEQ ID Nos. 1603, 1604, 1605, 1606, 1607, and 1608. In some embodiments, the V region sequences include sequences substantially identical to VH and VL sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 671 and 672; and SEQ ID Nos. 1481 and 1482; SEQ ID Nos. 1501 and 1502; SEQ ID Nos. 1521 and 1522; SEQ ID Nos. 1541 and 1542; SEQ ID Nos. 1561 and 1562; SEQ ID Nos. 1581 and 1582; and SEQ ID Nos. 1601 and 1602.

[0058] In some embodiments, there is provided an isolated polypeptide capable of specifically binding a serum amyloid A (SAA) protein target or a peptide thereof under urinary conditions.

[0059] In some embodiments, the SAA peptide includes a sequence selected from sequences set forth in SEQ ID Nos. 889-898.

[0060] In some embodiments, the isolated polypeptide includes a heavy chain variable (VH) region including three complementarity determining region (CDR) sequences (VH-CDR1, VH-CDR2, VH-CDR3) and a light chain variable (VL) region including three CDR sequences (VL-CDR1, VL-CDR2, and VL-CDR3), and the six CDR sequences are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences selected from: SEQ ID Nos. 681 and 682; SEQ ID Nos. 701 and 702; SEQ ID Nos. 721 and 722; SEQ ID Nos.

[0061] 741 and 742; SEQ ID Nos. 761 and 762; SEQ ID Nos. 781 and 782; SEQ ID Nos. 801 and 802; SEQ ID Nos. 821 and 822; SEQ ID Nos. 841 and 842; SEQ ID Nos. 1611 and 1612; SEQ ID Nos.

[0062] 1631 and 1632; SEQ ID Nos. 1651 and 1652; SEQ ID Nos. 1671 and 1672; SEQ ID Nos. 1691 and 1692; and SEQ ID Nos. 1711 and 1712.

[0063] In some embodiments, the six CDR sequences of the isolated polypeptide include sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 683, 684, 685, 686, 687, and 688; SEQ ID Nos. 703, 704, 705, 706, 707, and 708; SEQ ID Nos. 723, 724, 725, 726, 727, and 728; SEQ ID Nos. 743, 744, 745, 746, 747, and 748; SEQ ID Nos. 763, 764, 765, 766, 767, and 768; SEQ ID Nos. 783, 784, 785, 786, 787, and 788; SEQ ID Nos. 803, 804, 805, 806, 807, and 808; SEQ ID Nos. 823, 824, 825, 826, 827, and 828; SEQ ID Nos. 843, 844, 845, 846, 847, and 848; SEQ ID Nos. 1613, 1614, 1615, 1616, 1617, and 1618; SEQ ID Nos. 1633, 1634, 1635, 1636, 1637, and 1638; SEQ ID Nos. 1653, 1654, 1655, 1656, 1657, and 1658; SEQ ID Nos. 1673, 1674, 1675, 1676, 1677, and 1678; SEQ ID Nos. 1693, 1694, 1695, 1696, 1697, and 1698; and SEQ ID Nos. 1713, 1714, 1715, 1716, 1717, and 1718.

[0064] In some embodiments, the V region sequences of the isolated polypeptide include sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos. 681 and 682; SEQ ID Nos. 701 and 702; SEQ ID Nos. 721 and 722; SEQ ID Nos. 741 and 742; SEQ ID Nos. 761 and 762; SEQ ID Nos. 781 and 782; SEQ ID Nos. 801 and 802; SEQ ID Nos. 821 and 822; SEQ ID Nos. 841 and 842; SEQ ID Nos. 1611 and 1612; SEQ ID Nos. 1631 and 1632; SEQ ID Nos. 1651 and 1652; SEQ ID Nos. 1671 and 1672; SEQ ID Nos. 1691 and 1692; and SEQ ID Nos.

[0065] 1711 and 1712.

[0066] In some embodiments, the six CDR sequences of the isolated polypeptide include sequences substantially identical to six CDR sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 693, 694, 695, 696, 697, and 698; SEQ ID Nos. 713, 714, 715, 716, 717, and 718; SEQ ID Nos. 733, 734, 735, 736, 737, and 738; SEQ ID Nos. 753, 754, 755, 756, 757, and 758; SEQ ID Nos. 773, 774, 775, 776, 777, and 778; SEQ ID Nos. 793, 794, 795, 796, 797, and 798; SEQ ID Nos. 813, 814, 815, 816, 817, and 818; SEQ ID Nos. 833, 834, 835, 836, 837, and 838; SEQ ID Nos. 853, 854, 855, 856, 857, and 858; SEQ ID Nos. 1623, 1624, 1625, 1626, 1627, and 1628; SEQ ID Nos. 1643, 1644, 1645, 1646, 1647, and 1648; SEQ ID Nos. 1663, 1664, 1665, 1666, 1667, and 1668; SEQ ID Nos. 1683, 1684, 1685, 1686, 1687, and 1688; SEQ ID Nos. 1703, 1704, 1705, 1706, 1707, and 1708; and SEQ ID Nos. 1723, 1724, 1725, 1726, 1727, and 1728.

[0067] In some embodiments, the V region sequences of the isolated polypeptide include sequences substantially identical to VH and VL sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 691 and 692; SEQ ID Nos. 711 and 712; SEQ ID Nos. 731 and 732; SEQ ID Nos.

[0068] 751 and 752; SEQ ID Nos. 771 and 772; SEQ ID Nos. 791 and 792; SEQ ID Nos. 811 and 812; SEQ ID Nos. 831 and 832; SEQ ID Nos. 851 and 852; SEQ ID Nos. 1621 and 1622; SEQ ID Nos.

[0069] 1641 and 1642; SEQ ID Nos. 1661 and 1662; SEQ ID Nos. 1681 and 1682; SEQ ID Nos. 1701 and 1702; and SEQ ID Nos. 1721 and 1722.

[0070] In some embodiments, the protein target is a human protein.

[0071] In some embodiments, the isolated polypeptide is selected from an antibody or an antigenbinding fragment thereof, a single-chain variable fragment (scFv), a chimeric or a humanized antibody or antigen-binding fragment thereof, and a chimeric antigen receptor (CAR)-B.

[0072] In some embodiments, the isolated polypeptide is a monoclonal antibody.

[0073] In some embodiments, the isolated polypeptide is conjugated to a functional moiety.

[0074] In some embodiments, the specific binding is characterized by an EC50 of less than about 10, 1, or 0.1 nM.

[0075] In some embodiments, there is provided an isolated nucleic acid molecule including at least one sequence encoding the isolated polypeptide disclosed herein.

[0076] In some embodiments, there is provided a host cell including the isolated polypeptide disclosed herein, or the isolated nucleic acid molecule disclosed herein.

[0077] In some embodiments, the host cell is a hybridoma cell.

[0078] In some embodiments, there is provided a combination including a first isolated polypeptide which is the isolated polypeptide disclosed herein, and an additional polypeptide capable of specifically binding to a protein selected from CRP, BTLA, EGF, FGA, LGALS9, or SAA or to a peptide thereof, wherein the additional polypeptide does not interfere with binding of the isolated polypeptide to the protein. In some embodiments, the additional polypeptide is an isolated polypeptide disclosed herein, different from the first isolated polypeptide. In some embodiments, the additional polypeptide binds to the same protein target as the isolated polypeptide.

[0079] In some embodiments, the isolated polypeptide is capable of specifically binding to CRP and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos.

[0080] 973-978, and the additional polypeptide is capable of specifically binding to CRP and has six CDR sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 1033-1038 and SEQ ID Nos. 1093-1098.

[0081] In some embodiments, the isolated polypeptide is capable of specifically binding to CRP and has V region sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos. 971-972, and the additional polypeptide is capable of specifically binding to CRP and has V region sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos.

[0082] 1031-1032 and SEQ ID Nos. 1091-1092.

[0083] In some embodiments, the isolated polypeptide is capable of specifically binding to CRP and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos.

[0084] 1133-1138, and the additional polypeptide is capable of specifically binding to CRP and has six CDR sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 1033-1038 and SEQ ID Nos. 1093-1098.

[0085] In some embodiments, the isolated polypeptide is capable of specifically binding to CRP and has V region sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos. 1131-1132, and the additional polypeptide is capable of specifically binding to CRP and has V region sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos.

[0086] 1031-1032 and SEQ ID Nos. 1091-1092.

[0087] In some embodiments, the isolated polypeptide is capable of specifically binding to SAA and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos.

[0088] 1653-1658, and the additional polypeptide is capable of specifically binding to SAA and has six CDR sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 1673-1678 and SEQ ID Nos. 1713-1718.

[0089] In some embodiments, the isolated polypeptide is capable of specifically binding to SAA and has V region sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos. 1651-1652, and the additional polypeptide is capable of specifically binding to SAA and has V region sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos.

[0090] 1671-1672 and SEQ ID Nos. 1711-1712.

[0091] In some embodiments, the isolated polypeptide is capable of specifically binding to LGALS9 and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos.

[0092] 1573-1578, and the additional polypeptide is capable of specifically binding to LGALS9 and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos. 1493-1498.

[0093] In some embodiments, the isolated polypeptide is capable of specifically binding to LGALS9 and has V region sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos. 1571-1572, and the additional polypeptide is capable of specifically binding to LGALS9 and has V region sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos.

[0094] 1491-1492.

[0095] In some embodiments, the isolated polypeptide is capable of specifically binding to LGALS9 and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos.

[0096] 1573-1578, and the additional polypeptide is capable of specifically binding to LGALS9 and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos. 1533-1538.

[0097] In some embodiments, the isolated polypeptide is capable of specifically binding to LGALS9 and has V region sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos. 1571-1572, and the additional polypeptide is capable of specifically binding to LGALS9 and has V region sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos.

[0098] 1531-1532.

[0099] In some embodiments, the isolated polypeptide is capable of specifically binding to LGALS9 and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos.

[0100] 1573-1578, and the additional polypeptide is capable of specifically binding to LGALS9 and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos. 1473-1478.

[0101] In some embodiments, the isolated polypeptide is capable of specifically binding to LGALS9 and has V region sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos. 1571-1572, and the additional polypeptide is capable of specifically binding to LGALS9 and has V region sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos.

[0102] 1471-1472. In some embodiments, there is provided a method for predicting in a urine sample of a subject suspected of having an infection, whether the infection is a bacterial infection and / or a viral infection, the method including:

[0103] a. contacting a urine sample of the subject with one or more isolated polypeptides disclosed herein;

[0104] b. detecting binding of the one or more isolated polypeptides to the protein target selected from CRP, BTLA, SAA, LGALS9, EGF, or FGA, or a peptide thereof; and

[0105] c. predicting whether the infection is bacterial and / or viral based on the detecting in step (b).

[0106] In some embodiments, the subject is a human.

[0107] In some embodiments, the infection is an upper respiratory tract infection (URTI).

[0108] In some embodiments, the URTI is selected from streptococcal pharyngitis (strep throat), bacterial tracheitis, sinusitis, epiglottitis, and viral URTIs caused by rhinovirus, coronavirus, adenovirus, influenza virus, and / or human parainfluenza virus.

[0109] In some embodiments, the URTI is caused by a bacterial agent selected from: group A streptococcus, Staphylococcus aureus, Moraxella catarrhalis, Haemophilus influenzae, Streptococcus pneumoniae, and combinations thereof.

[0110] In some embodiments, the URTI is caused by a viral agent selected from: rhinovirus, coronavirus, adenovirus, influenza virus, human parainfluenza virus, and combinations thereof.

[0111] In some embodiments, the detecting the binding is conducted by an assay selected from a lateral flow assay (LFA), a fluorescence activated cell sorting (FACS), enzyme-linked immunosorbent assay (ELISA), a dipstick, a dot-blot, an antibody chip, and magnetic beads.

[0112] In some embodiments, the method further includes a step of treating the subject with an antibiotic treatment when the infection is predicted to be bacterial, and / or treating the subject with an antiviral treatment when the infection is predicted to be viral.

[0113] In some embodiments, there is provided a method for treating a bacterial infection in a subject afflicted with an infection, including:

[0114] a. contacting a urine sample of the subject with one or more isolated polypeptides disclosed herein;

[0115] b. detecting binding of the one or more isolated polypeptides to the protein target or peptide thereof; and

[0116] c. predicting that the infection is bacterial based on the detecting in step (b); and d. treating the subject with antibiotics. In some embodiments, there is provided a method for treating a viral infection in a subject afflicted with an infection, the method including:

[0117] a. contacting a urine sample of the subject with one or more isolated polypeptides disclosed herein;

[0118] b. detecting binding of the one or more isolated polypeptides to the protein target or peptide thereof; and

[0119] c. predicting that the infection is viral based on the detecting in step (b); and d. treating the subject with an antiviral agent.

[0120] In some embodiments, there is provided a method for predicting efficacy of a treatment in a subject afflicted with a bacterial and / or a viral infection, the method including:

[0121] a. administering to the subject a treatment including an antibiotic and / or an antiviral agent;

[0122] b. contacting a urine sample of the subject, taken after administration, with one or more isolated polypeptides disclosed herein;

[0123] c. detecting binding of the one or more isolated polypeptides to the protein target or peptide thereof; and

[0124] d. predicting whether the treatment is effective based on the detecting in step (c), wherein, if binding is detected in step (c) then treatment is not effective.

[0125] In some embodiments, if binding is not detected in step (c) then treatment is effective. In some embodiments, there is provided a kit for predicting in a urine sample whether an infection is a bacterial infection or a viral infection, the kit including:

[0126] a. one or more isolated polypeptides disclosed herein;

[0127] b. at least one reagent for detecting the binding of the one or more isolated polypeptides to the protein target or peptide thereof in a urine sample; and

[0128] c. instructions for use.

[0129] In some embodiments, the kit further includes reagents for use with an assay based on a lateral flow assay (LFA), a fluorescence activated cell sorting (FACS), enzyme-linked immunosorbent assay (ELISA), a dipstick, a dot-blot, an antibody chip, and magnetic beads.

[0130] In some embodiments, the kit further includes a urine collection device selected from a urine cup, a urine bag, a urine diaper, and a urine catheter.

[0131] In addition to the exemplary embodiments described above, further embodiments will become apparent by reference to the figures and by study of the following detailed descriptions. BRIEF DESCRIPTION OF DRAWINGS

[0132] The invention will now be described in relation to certain examples and embodiments with reference to the following illustrative figures.

[0133] Figs. 1A-1K show ELISA binding curves of purified monoclonal antibodies against the indicated peptides: CRP peptides (P01, P02 - Figs. 1A and IB, respectively), BTLA peptides (PO 1, P02 - Figs. 1C and ID, respectively), EGF peptides (P01, P02 - Figs. IE and IF, respectively), FGA peptides (PO 1, P02 - Figs. 1G and 1H, respectively), SAA peptides (PO 1, P02 - Figs. II and 1J, respectively), and LGAL-P01 (Fig. IK). Assays were conducted in a 1: 1 dilution of simulated urine with hybridoma supernatant.

[0134] Figs. 2A-2E show ELISA binding curves of purified monoclonal antibodies against complete proteins in simulated urine. Fig. 2A. SAA; Fig. 2B. LGALS9; Fig. 2C. BTLA; 2D-2E:

[0135] CRP. Figs. 2D-2E show ELISA binding of purified monoclonal antibodies against CRP-His protein in simulated urine.

[0136] Figs. 3A-3E show sandwich ELISA in simulated urine of binding to combinations of antibodies. Fig. 3A. Sandwich ELISA using CRP-PRT-mAbl5 as the capture antibody. Detection was performed with serial dilutions of biotinylated CRP-PRT-mAbO3 or -mAb20. Dose-dependent binding to CRP-His is observed. mlgGl was used as a negative control. Fig. 3B. Sandwich ELISA using CRP-PRT-mAbO3 as the capture antibody. Serial dilutions of biotinylated CRP-PRT-mAbOl, -mAbO4, -mAbO6, -mAbO9, -mAblO, -mAbl5, or -mAbl6 were used for detection, with mlgGl used as a negative control. Dose-dependent binding to CRP-His is observed. Fig. 3C. SAA sandwich ELISA between: SAA-PRT-mAb69 or R-a-SAA as detection antibody and SAA-PRT-mAb71 as capture antibody (upper panel); SAA-PRT-mAb69 R-a-SAA (a commercial polyclonal antibody) as detection antibody and SAA-PRT-mAb73 as capture antibody (lower left panel); and SAA-PRT-mAb71+73 mix as detection antibody and R-a-SAA as capture antibody (lower right panel). SAA concentration (ng / ml, from left to right bars each group): 4000, 2000, 1000, 500, 250, 125, 62.5, and 0. Fig. 3D. LGALS9 sandwich ELISA in simulated urine between the detection antibodies LGAL-PRT-mAb41 (left panel), LGAL-PRT-mAb45 (middle panel), or LGAL-PRT-mAb53 (right panel), and the capture antibodies (left to right bars): LGAL-PRT-mAb41, LGAL-PRT-mAb45, LGAL-PRT-mAb49, LGAL-PRT-mAb53, LGAL-PRT-mAb55, LGAL-PRT-mAb60, and LGAL-PRT-mAb61. Fig. 3E. BTLA sandwich ELISA in simulated urine: capture with BTLA-PRT-mAb25, BTLA-PRT-mAb26, BTLA-PRT-mAb31, BTLA-PRT-mAb32, BTLA-PRT-mAb35, BTLA-PRT-mAb36, BTLA-PRT-mAb37, BTLA-PRT-mAb39, BTLA-PRT-mAb57, and BTLA-PRT-mAb66; upper panel: detection with BTLA-PRT-mAb35; lower panel: detection with BTLA-PRT-mAb31. BTLA concentration for each capture antibody, left to right bars (μg / ml): 1.5, 0.5, 0.17.

[0137] Fig. 4 shows sandwich ELISA results obtained from patient urine for LGALS9. Non-hybrid: both detection and capture are mAbs of the invention; hybrid: a capture mAb of the invention with a commercial polyclonal rabbit anti-LGAL detection antibody (R-a-LGAL). The non-hybrid pair contains LGAL-PRT-mAb60 as capture antibody and LGAL-PRT-mAb45 as detection antibody, while the hybrid pairs included LGAL-PRT-mAb60 as capture antibody and commercial R-a-LGAL as detection. The X axis indicates ID of samples from patients.

[0138] DETAILED DESCRIPTION OF THE INVENTION

[0139] In the following description, various aspects of the disclosure will be described. For the purpose of explanation, specific configurations and details are set forth in order to provide a thorough understanding of the different aspects of the disclosure. However, it will also be apparent to one skilled in the art that the disclosure may be practiced without specific details being presented herein. Furthermore, well-known features may be omitted or simplified in order not to obscure the disclosure.

[0140] In a previous application by the applicant, WO2025 / 115009, the inventors have found that detection of certain biomarkers in urine of a subject having an infection can be used for predicting whether an infection is bacterial or viral.

[0141] Following a statistical analysis described in more detail in WO2025 / 115009, the protein biomarkers (also referred to as protein targets) C-reactive protein (CRP), B- and T-lymphocyte attenuator (BTLA), epidermal growth factor (EGF), fibrinogen alpha chain (FGA), galectin 9 (LGALS9), and serum amyloid A (SAA), as well as peptides therefrom and combinations thereof, were found to be the most successful in distinguishing bacterially-infected subjects from virally-infected subjects by urine testing.

[0142] Accordingly, the present application focuses on reagents, specifically polypeptides (such as antibodies) which specifically bind to the identified protein biomarkers and peptides derived from them, and that are suitable for the detection of these protein biomarkers in urine.

[0143] Isolated polypeptides and antibodies against urinary proteins and / or fragments

[0144] In order to facilitate detection of the protein targets, antibodies were developed against proteins and peptides disclosed herein (see Tables 1 and 4), as detailed in Example 2, and were screened for their ability to bind their respective targets in simulated urine. Some examples for the binding characteristics of the antibodies produced are presented in Tables 6A-6B and Figs. 1A-1K. It is noted that the screening for successful binding was done under conditions which simulate urine conditions (e.g. salts, urea, and pH similar to human urine, e.g., about 6), so that the selected antibodies are capable of specifically binding to their respective antigen in urine. In this respect it should be noted that since the conditions in urine are unique and rather harsh, it cannot be assumed that any antibody capable of specifically binding a specific protein or peptide under any conditions, such as in other bodily fluids (e.g. blood) may be able to bind it under urinary conditions.

[0145] Accordingly, in some embodiments, there is provided an isolated polypeptide capable of specifically binding a protein target selected from CRP, BTLA, EGF, FGA, LGALS9, and SAA, or a peptide thereof.

[0146] In some embodiments, the isolated polypeptide is capable of specifically binding the protein target or peptide thereof in a urine sample. In some embodiments, the isolated polypeptide is capable of specifically binding the protein target or peptide thereof under conditions similar to urine environment, also termed herein “urinary conditions”.

[0147] The term “urinary conditions”, as used herein, means a urine environment, such as urine (e.g. a urine sample), or conditions similar to the urine environment, having a similar pH (such as about 6) and / or some similar components, such as urea, and certain typical salts. Examples for solutions which simulate urinary conditions (also termed herein “simulated urine”) are artificial or synthetic (or simulated) urine products such as Biochemazone artificial urine products. In some embodiments, the term “urinary conditions” includes urine, such as a urine sample.

[0148] In some embodiments, the urinary conditions relate to a urine sample. In some embodiments, the urinary conditions mean a solution having a pH of about 4.6-8, about 5-7, about 5.5-6.5, or about 6. In some embodiments, the urinary conditions mean a solution including at least one of urea, creatinine, uric acid, and ammonia. In some embodiments, urinary conditions further mean a solution including certain salts or proteins.

[0149] Accordingly, in some embodiments, there is provided an isolated polypeptide capable of specifically binding a protein target selected from CRP, BTLA, EGF, FGA, LGALS9, and SAA, or a peptide thereof, in urine, or in a urine sample.

[0150] Accordingly, in some embodiments, there is provided an isolated polypeptide capable of specifically binding a protein target selected from CRP, BTLA, EGF, FGA, LGALS9, and SAA, or a peptide thereof, under urinary conditions.

[0151] The terms “peptide”, as used herein, relates to any peptide or protein fragment having a sequence included in a protein target, that can bind to an isolated protein or antibody disclosed herein.

[0152] It is appreciated that isolated polypeptides identified as capable of specifically binding to a complete protein target were generated in the present invention by immunizing against the complete protein. They may therefore bind a sequence that overlaps with any of the peptides disclosed herein, or they may bind a different sequence of the complete protein. It is also appreciated that peptides of a protein target are not limited to the peptides disclosed herein.

[0153] In some embodiments, the peptide has a length of about 3-500 amino acids. In some embodiments, the peptide fragment has a length of about 5-200, 5-100, 5-90, 5-80, 5-70, 5-60, 5-50, 5-40, 5-30, 5-25, or 7-80 amino acids. In some embodiments, the peptide has a length of at least about 5, 10, or 20 amino acids. In some embodiments, the peptide does not include the complete protein.

[0154] In some embodiments, the protein target is a human protein target.

[0155] Each of the isolated polypeptides includes two different variable regions: a heavy chain variable (VH) region and a light chain variable (VL) region, and six complementarity-determining regions (CDRs), including VH region CDRs: VH-CDR1, VH-CDR2, and VH-CDR3; and VL region CDRs: VL-CDR1, VL-CDR2, and VL-CDR3.

[0156] Several standard methods exist for determining CDRs in a variable region sequence. These methods include the non-limiting examples of Kabat, Chothia, IMGT (International ImMunoGeneTics information system), and AbM.

[0157] Accordingly, in some embodiments, the six CDRs are defined by any standard method known in the art based on sequences of a VH and a VL regions. In some embodiments, the six CDRs are defined by the Kabat method.

[0158] Alternatively, in some embodiments, the six CDRs are defined by their sequence. When defined by sequences, the method of defining the six CDRs may be any method acceptable in the art, including any of the methods mentioned herein (Kabat, Chothia, IMGT, and AbM), for example the Kabat method.

[0159] In some embodiments, the amino acid sequences of the isolated polypeptide or parts thereof (such as the VH, VL, and any of the CDRs) are defined by nucleotide sequences encoding them.

[0160] The above definitions and embodiments apply to all of the isolated polypeptides defined below.

[0161] It is noted that each of the antibodies mentioned by their name in the application is defined by VH, VL, and six CDR sequences presented in Table 2 and Table 9 (and / or encoded by sequences presented in Table 3 and Table 9). Accordingly, the antibody names clearly and unambiguously define the antibodies even without using the SEQ ID Nos. explicitly in each embodiment. Nevertheless, in many cases the sequences are also provided. Anti-CRP antibodies

[0162] In some embodiments, there is provided an isolated polypeptide capable of specifically binding a CRP protein target or a peptide thereof. In some embodiments, there is provided an isolated polypeptide capable of specifically binding a CRP protein target or a peptide thereof in urine, or under urinary conditions.

[0163] In some embodiments, the isolated polypeptide is an anti-CRP antibody. The term “Anti-CRP antibody” as used herein, relates to an antibody capable of specifically binding a CRP protein target or a peptide thereof.

[0164] The term “C-reactive protein (CRP)” is intended to include all forms of the CRP protein, including pentameric and monomeric forms.

[0165] In some embodiments, the CRP peptide includes, or consists of, a sequence selected from SEQ ID Nos: 861-866. In some embodiments, the CRP peptide includes, or consists of, a sequence selected from GYSIFSYATKRQDNEILIFWSK (SEQ ID No: 861, CRP-P01) and RQDNEILIFWSK (SEQ ID No: 862, CRP-P02).

[0166] In some embodiments, there is provided a monoclonal antibody capable of specifically binding to a CRP peptide including, or consisting of, a sequence selected from SEQ ID No: 861 (CRP-P01) and SEQ ID No: 862 (CRP-P02), under urinary conditions.

[0167] In some embodiments, there is provided an isolated polypeptide capable of specifically binding CRP or a CRP peptide, wherein the isolated polypeptide includes a VH region including three CDRs (VH-CDR1, VH-CDR2, VH-CDR3) and a VL region including three CDRs (VL-CDR1, VL-CDR2, and VL-CDR3), and the six CDRs are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences of an antibody selected from the antibodies CRP-P01-mAbl0-15 and CRP-PRT-mAbOl, 03, 04, 06, 07, 09, 10, 11, 15, 16, and 20.

[0168] The VH and VL region amino acid sequences corresponding to the antibodies CRP-P01-mAbl0-15 and CRP-PRT-mAbOl, 03, 04, 06, 07, 09, 10, 11, 15, 16, and 20 are set forth in: SEQ ID Nos. 181 and 182; SEQ ID Nos. 201 and 202; SEQ ID Nos. 221 and 222; SEQ ID Nos. 241 and 242; SEQ ID Nos. 261 and 262; SEQ ID Nos. 281 and 282; SEQ ID Nos. 931 and 932; SEQ ID Nos. 971 and 972; SEQ ID Nos. 991 and 992; SEQ ID Nos. 1031 and 1032; SEQ ID Nos. 1051 and 1052; SEQ ID Nos. 1091 and 1092; SEQ ID Nos. 1111 and 1112; SEQ ID Nos. 1131 and 1132; SEQ ID Nos. 1211 and 1212; SEQ ID Nos. 1231 and 1232; and SEQ ID Nos. 1311 and 1312, respectively.

[0169] The six CDR amino acid sequences of antibodies CRP-P01-mAbl0-15 and CRP-PRT-mAbOl, 03, 04, 06, 07, 09, 10, 11, 15, 16, and 20 are set forth in: SEQ ID Nos. 183, 184, 185, 186, 187, and 188; SEQ ID Nos. 203, 204, 205, 206, 207, and 208; SEQ ID Nos. 223, 224, 225, 226, 227, and 228; SEQ ID Nos. 243, 244, 245, 246, 247, and 248; SEQ ID Nos. 263, 264, 265, 266, 267, and 268; SEQ ID Nos. 283, 284, 285, 286, 287, and 288; SEQ ID Nos. 933, 934, 935, 936, 937, and 938; SEQ ID Nos. 973, 974, 975, 976, 977, and 978; SEQ ID Nos. 993, 994, 995, 996, 997, and 998; SEQ ID Nos. 1033, 1034, 1035, 1036, 1037, and 1038; SEQ ID Nos. 1053, 1054, 1055, 1056, 1057, and 1058; SEQ ID Nos. 1093, 1094, 1095, 1096, 1097, and 1098; SEQ ID Nos.

[0170] 1113, 1114, 1115, 1116, 1117, and 1118; SEQ ID Nos. 1133, 1134, 1135, 1136, 1137, and 1138; SEQ ID Nos. 1213, 1214, 1215, 1216, 1217, and 1218; SEQ ID Nos. 1233, 1234, 1235, 1236, 1237, and 1238; and SEQ ID Nos. 1313, 1314, 1315, 1316, 1317, and 1318, respectively.

[0171] In some embodiments, the six CDR sequences of the isolated polypeptide, include, or consist of, sequences identical or substantially identical to CDR sequences of an antibody selected from the antibodies CRP-P01-mAbl0-15 and CRP-PRT-mAbOl, 03, 04, 06, 07, 09, 10, 11, 15, 16, and 20.

[0172] In some embodiments, the VH and the VL regions of the isolated polypeptide include, or consist of, sequences identical or substantially identical to VH and VL region sequences of an antibody selected from the antibodies CRP-P01-mAbl0-15 and CRP-PRT-mAbOl, 03, 04, 06, 07, 09, 10, 11, 15, 16, and 20.

[0173] The term “substantially identical”, as used herein relates to a sequence identity of at least about 95%, 96% 97%, 98%, or 99%. In some embodiments, when the compared sequences are VH or VL sequence, all differences between the sequences are not in CDR regions.

[0174] The VH and VL regions nucleotide sequences of antibodies CRP-P01-mAbl0-15 and CRP-PRT-mAbOl, 03, 04, 06, 07, 09, 10, 11, 15, 16, and 20 are set forth in: SEQ ID Nos. 191 and 192; SEQ ID Nos. 211 and 212; SEQ ID Nos. 231 and 232; SEQ ID Nos. 251 and 252; SEQ ID Nos.

[0175] 271 and 272; SEQ ID Nos. 291 and 292; SEQ ID Nos. 941 and 942; SEQ ID Nos. 981 and 982; SEQ ID Nos. 1001 and 1002; SEQ ID Nos. 1041 and 1042; SEQ ID Nos. 1061 and 1062; SEQ ID Nos. 1101 and 1102; SEQ ID Nos. 1121 and 1122; SEQ ID Nos. 1141 and 1142; SEQ ID Nos.

[0176] 1221 and 1222; SEQ ID Nos. 1241 and 1242; and SEQ ID Nos. 1321 and 1322, respectively.

[0177] The six CDR nucleotide sequences of antibodies CRP-P01-mAbl0-15 and CRP-PRT-mAbOl, 03, 04, 06, 07, 09, 10, 11, 15, 16, and 20 are set forth in: SEQ ID Nos. 193, 194, 195, 196, 197, and 198; SEQ ID Nos. 213, 214, 215, 216, 217, and 218; SEQ ID Nos. 233, 234, 235, 236, 237, and 238; SEQ ID Nos. 253, 254, 255, 256, 257, and 258; SEQ ID Nos. 273, 274, 275, 276, 277, and 278; SEQ ID Nos. 293, 294, 295, 296, 297, and 298; SEQ ID Nos. 943, 944, 945, 946, 947, and 948; SEQ ID Nos. 983, 984, 985, 986, 987, and 988; SEQ ID Nos. 1003, 1004, 1005, 1006, 1007, and 1008; SEQ ID Nos. 1043, 1044, 1045, 1046, 1047, and 1048; SEQ ID Nos. 1063, 1064, 1065, 1066, 1067, and 1068; SEQ ID Nos. 1103, 1104, 1105, 1106, 1107, and 1108; SEQ ID Nos. 1123, 1124, 1125, 1126, 1127, and 1128; SEQ ID Nos. 1143, 1144, 1145, 1146, 1147, and 1148; SEQ ID Nos. 1223, 1224, 1225, 1226, 1227, and 1228; SEQ ID Nos. 1243, 1244, 1245, 1246, 1247, and 1248; and SEQ ID Nos. 1323, 1324, 1325, 1326, 1327, and 1328, respectively.

[0178] In some embodiments, the six CDR sequences of the isolated polypeptide are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences encoded by nucleotide sequences of an antibody selected from the antibodies CRP-P01-mAbl0-15 and CRP-PRT-mAbOl, 03, 04, 06, 07, 09, 10, 11, 15, 16, and 20.

[0179] In some embodiments, the six CDR sequences of the isolated polypeptide, include, or consist of, sequences identical or substantially identical to CDR sequences encoded by nucleotide sequences of an antibody selected from the antibodies CRP-P01-mAbl0-15 and CRP-PRT-mAbOl, 03, 04, 06, 07, 09, 10, 11, 15, 16, and 20.

[0180] In some embodiments, the VH and the VL regions of the isolated polypeptide include, or consist of, sequences identical or substantially identical to VH and VL region sequences encoded by nucleotide sequences of an antibody selected from the antibodies CRP-P01-mAbl0-15 and CRP-PRT-mAbOl, 03, 04, 06, 07, 09, 10, 11, 15, 16, and 20.

[0181] In some embodiments, the isolated polypeptide is selected from the antibodies (the SEQ ID Nos. of the VH, VL, and six CDRs of each antibody are indicated in parentheses): CRP-PRT-mAbll (SEQ ID Nos: 1131-1138); CRP-PRT-mAb03 (SEQ ID Nos: 971-978); CRP-PRT-mAbO9 (SEQ ID Nos: 1091-1098); CRP-PRT-mAbO4 (SEQ ID Nos: 991-998); CRP-PRT-mAbO7 (SEQ ID Nos: 1051-1058); CRP-PRT-mAbl5 (SEQ ID Nos: 1211-1218); CRP-PRT-mAb20 (SEQ ID Nos: 1311-1318); CRP-PRT-mAbO6 (SEQ ID Nos: 1031-1038); CRP-PRT-mAb10 (SEQ ID Nos: 1111-1118); CRP-PRT-mAbl6 (SEQ ID Nos: 1231-1238); and CRP-PRT-mAbOl (SEQ ID Nos: 931-938).

[0182] In some embodiments, the isolated polypeptide is CRP-PRT-mAbll (SEQ ID Nos: 1131-1138). In some embodiments, the isolated polypeptide is CRP-PRT-mAb03 (SEQ ID Nos: 971-978). In some embodiments, the isolated polypeptide is CRP-PRT-mAbO9 (SEQ ID Nos: 1091-1098). In some embodiments, the isolated polypeptide is CRP-PRT-mAbO4 (SEQ ID Nos: 991-998). In some embodiments, the isolated polypeptide is CRP-PRT-mAbO7 (SEQ ID Nos: 1051-1058). In some embodiments, the isolated polypeptide is CRP-PRT-mAbl5 (SEQ ID Nos: 1211- 1218). In some embodiments, the isolated polypeptide is CRP-PRT-mAb20 (SEQ ID Nos: 1311-1318). In some embodiments, the isolated polypeptide is CRP-PRT-mAb06 (SEQ ID Nos: 1031-1038). In some embodiments, the isolated polypeptide is CRP-PRT-mAb10 (SEQ ID Nos: 1111-1118). In some embodiments, the isolated polypeptide is CRP-PRT-mAbl6 (SEQ ID Nos: 1231- 1238). In some embodiments, the isolated polypeptide is CRP-PRT-mAbOl (SEQ ID Nos: 931-938).

[0183] Anti-BTLA antibodies

[0184] In some embodiments, there is provided an isolated polypeptide capable of specifically binding a BTLA protein target or a peptide thereof. In some embodiments, there is provided an isolated polypeptide capable of specifically binding a BTLA protein target or a peptide thereof under urinary conditions.

[0185] In some embodiments, the isolated polypeptide is an anti-BTLA antibody. The term “Anti-BTLA antibody” as used herein, relates to an antibody capable of specifically binding a BTLA protein target or a peptide thereof.

[0186] In some embodiments, the BTLA peptide includes, or consists of, a sequence selected from SEQ ID Nos.: 867-869. In some embodiments, the BTLA peptide includes, or consists of, a sequence selected from RQSEHSILAGDPFELECPVKYCANRPHVTWCK (SEQ ID No: 867, BTLA-P01) and YCANRPHVTWCK (SEQ ID No: 868, BTLA-P02).

[0187] In some embodiments, there is provided a monoclonal antibody capable of specifically binding to a BTLA peptide including, or consisting of, a sequence selected from SEQ ID No: 867 (BTLA-P01) and SEQ ID No: 868 (BTLA-P02), under urinary conditions.

[0188] In some embodiments, there is provided an isolated polypeptide capable of specifically binding a BTLA or peptide thereof, wherein the isolated polypeptide includes a VH region including three CDRs (VH-CDR1, VH-CDR2, VH-CDR3) and a VL region including three CDRs (VL-CDR1, VL-CDR2, and VL-CDR3), and the six CDRs are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences of an antibody selected from the antibodies BTLA-P01-mAB01-09, and BTLA-PRT-mAb25, 26, 31, 35, 37, 66.

[0189] The VH and VL region sequences corresponding to the antibodies BTLA-P01-mAB01-09, and BTLA-PRT-mAb25, 26, 31, 35, 37, 66 are set forth in: SEQ ID Nos. 01 and 02; SEQ ID Nos.

[0190] 21 and 22; SEQ ID Nos. 41 and 42; SEQ ID Nos. 61 and 62; SEQ ID Nos. 81 and 82; SEQ ID Nos. 101 and 102; SEQ ID Nos. 121 and 122; SEQ ID Nos. 141 and 142; SEQ ID Nos. 161 and 162; SEQ ID Nos. 1351 and 1352; SEQ ID Nos. 1371 and 1372; SEQ ID Nos. 1391 and 1392; SEQ ID Nos. 1411 and 1412; SEQ ID Nos. 1431 and 1432; and SEQ ID Nos. 1451 and 1452, respectively.

[0191] The six CDR sequences of antibodies BTLA-P01-mAB01-09, and BTLA-PRT-mAb25, 26, 31, 35, 37, 66 are set forth in: SEQ ID Nos. 03, 04, 05, 06, 07, and 08; SEQ ID Nos. 23, 24, 25, 26, 27, and 28; SEQ ID Nos. 43, 44, 45, 46, 47, and 48; SEQ ID Nos. 63, 64, 65, 66, 67, and 68; SEQ ID Nos. 83, 84, 85, 86, 87, and 88; SEQ ID Nos. 103, 104, 105, 106, 107, and 108; SEQ ID Nos. 123, 124, 125, 126, 127, and 128; SEQ ID Nos. 143, 144, 145, 146, 147, and 148; SEQ ID Nos. 163, 164, 165, 166, 167, and 168; SEQ ID Nos. 1353, 1354, 1355, 1356, 1357, and 1358; SEQ ID Nos. 1373, 1374, 1375, 1376, 1377, and 1378; SEQ ID Nos. 1393, 1394, 1395, 1396, 1397, and 1398; SEQ ID Nos. 1413, 1414, 1415, 1416, 1417, and 1418; SEQ ID Nos. 1433, 1434, 1435, 1436, 1437, and 1438; and SEQ ID Nos. 1453, 1454, 1455, 1456, 1457, and 1458, respectively.

[0192] In some embodiments, the six CDR sequences of the isolated polypeptide, include, or consist of, sequences identical or substantially identical to CDR sequences of an antibody selected from the antibodies BTLA-P01-mAB01-09, and BTLA-PRT-mAb25, 26, 31, 35, 37, 66.

[0193] In some embodiments, the VH and the VL regions of the isolated polypeptide include, or consist of, sequences identical or substantially identical to VH and VL region sequences of an antibody selected from the antibodies BTLA-P01-mAB01-09, and BTLA-PRT-mAb25, 26, 31, 35, 37, 66.

[0194] The VH and VL regions nucleotide sequences of antibodies BTLA-P01-mAB01-09, and BTLA-PRT-mAb25, 26, 31, 35, 37, 66 are set forth in: SEQ ID Nos. 11 and 12; SEQ ID Nos. 31 and 32; SEQ ID Nos. 51 and 52; SEQ ID Nos. 71 and 72; SEQ ID Nos. 91 and 92; SEQ ID Nos. 111 and 112; SEQ ID Nos. 131 and 132; SEQ ID Nos. 151 and 152; SEQ ID Nos. 171 and 172; SEQ ID Nos. 1361 and 1362; SEQ ID Nos. 1381 and 1382; SEQ ID Nos. 1401 and 1402; SEQ ID Nos. 1421 and 1422; SEQ ID Nos. 1441 and 1442; and SEQ ID Nos. 1461 and 1462, respectively.

[0195] The six CDR nucleotide sequences of antibodies BTLA-P01-mAB01-09, and BTLA-PRT-mAb25, 26, 31, 35, 37, 66 are set forth in: SEQ ID Nos. 13, 14, 15, 16, 17, and 18; SEQ ID Nos.

[0196] 33, 34, 35, 36, 37, and 38; SEQ ID Nos. 53, 54, 55, 56, 57, and 58; SEQ ID Nos. 73, 74, 75, 76, 77, and 78; SEQ ID Nos. 93, 94, 95, 96, 97, and 98; SEQ ID Nos. 113, 114, 115, 116, 117, and 118; SEQ ID Nos. 133, 134, 135, 136, 137, and 138; SEQ ID Nos. 153, 154, 155, 156, 157, and 158; SEQ ID Nos. 173, 174, 175, 176, 177, and 178; SEQ ID Nos. 1363, 1364, 1365, 1366, 1367, and 1368; SEQ ID Nos. 1383, 1384, 1385, 1386, 1387, and 1388; SEQ ID Nos. 1403, 1404, 1405, 1406, 1407, and 1408; SEQ ID Nos. 1423, 1424, 1425, 1426, 1427, and 1428; SEQ ID Nos. 1443, 1444, 1445, 1446, 1447, and 1448; and SEQ ID Nos. 1463, 1464, 1465, 1466, 1467, and 1468, respectively.

[0197] In some embodiments, the six CDR sequences of the isolated polypeptide are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences encoded by nucleotide sequences of an antibody selected from the antibodies BTLA- P01-mAB01-09, and BTLA-PRT-mAb25, 26, 31, 35, 37, 66.

[0198] In some embodiments, the six CDR sequences of the isolated polypeptide, include, or consist of, sequences identical or substantially identical to CDR sequences encoded by nucleotide sequences of an antibody selected from the antibodies BTLA-P01-mAB01-09, and BTLA-PRT-mAb25, 26, 31, 35, 37, 66.

[0199] In some embodiments, the VH and the VL regions of the isolated polypeptide include, or consist of, sequences identical or substantially identical to VH and VL region sequences encoded by nucleotide sequences of an antibody selected from the antibodies BTLA-P01-mAB01-09, and BTLA-PRT-mAb25, 26, 31, 35, 37, 66.

[0200] In some embodiments, the isolated polypeptide is selected from the antibodies (the SEQ ID Nos. of the VH, VL, and six CDRs of each antibody are indicated in parentheses): BTLA-PRT-mAb66 (SEQ ID Nos: 1451-1458); BTLA-PRT-mAb31 (SEQ ID Nos: 1391-1398); BTLA-PRT-mAb35 (SEQ ID Nos: 1411-1418); BTLA-PRT-mAb25 (SEQ ID Nos: 1351-1358); BTLA-PRT-mAb37 (SEQ ID Nos: 1431-1438); BTLA-PRT-mAb26 (SEQ ID Nos: 1371-1378); BTLA-P01-mAbOl (SEQ ID Nos: 1-8); BTLA-P01-mAb02 (SEQ ID Nos: 21-28); BTLA-P01-mAb04 (SEQ ID Nos: 61-68); BTLA-P01-mAb06 (SEQ ID Nos: 101-108); BTLA-P01-mAb07 (SEQ ID Nos: 121-128); and BTLA-P01-mAb08 (SEQ ID Nos: 141-148).

[0201] In some embodiments, the isolated polypeptide is BTLA-PRT-mAb66 (SEQ ID Nos: 1451-1458). In some embodiments, the isolated polypeptide is BTLA-PRT-mAb31 (SEQ ID Nos: 1391-1398). In some embodiments, the isolated polypeptide is BTLA-PRT-mAb35 (SEQ ID Nos: 1411-1418). In some embodiments, the isolated polypeptide is BTLA-PRT-mAb25 (SEQ ID Nos: 1351-1358). In some embodiments, the isolated polypeptide is BTLA-PRT-mAb37 (SEQ ID Nos: 1431-1438). In some embodiments, the isolated polypeptide is BTLA-PRT-mAb26 (SEQ ID Nos: 1371-1378). In some embodiments, the isolated polypeptide is BTLA-P01-mAb01 (SEQ ID Nos: 1-8). In some embodiments, the isolated polypeptide is BTLA-P01-mAb02 (SEQ ID Nos: 21-28). In some embodiments, the isolated polypeptide is BTLA-P01-mAb04 (SEQ ID Nos: 61-68). In some embodiments, the isolated polypeptide is BTLA-P01-mAb06 (SEQ ID Nos: 101-108). In some embodiments, the isolated polypeptide is BTLA-P01-mAb07 (SEQ ID Nos: 121-128). In some embodiments, the isolated polypeptide is BTLA-P01-mAb08 (SEQ ID Nos: 141-148).

[0202] Anti-LGALS9 antibodies

[0203] In some embodiments, there is provided an isolated polypeptide capable of specifically binding an LGALS9 protein target or a peptide thereof. In some embodiments, there is provided an isolated polypeptide capable of specifically binding an LGALS9 protein target or a peptide thereof under urinary conditions.

[0204] In some embodiments, the isolated polypeptide is an anti-LGALS9 antibody. The term “Anti- LGALS9 antibody” as used herein, relates to an antibody capable of specifically binding a LGALS9 protein target or a peptide thereof.

[0205] In some embodiments, the LGALS9 peptide includes, or consists of, a sequence selected from SEQ ID No: 882-888. In some embodiments, the LGALS9 peptide includes, or consists of, a sequence selected from FEDGGYVVCNTRQNGSWGPEER (SEQ ID No: 882, LGAL-P01) and FEDGGYVVCNT (SEQ ID No: 883, LGAL-P02).

[0206] In some embodiments, there is provided a monoclonal antibody capable of specifically binding to an LGALS9 peptide including, or consisting of, a sequence selected from SEQ ID No: 882 (LGAL-P01) and SEQ ID No: 883 (LGAL-P02), under urinary conditions.

[0207] In some embodiments, there is provided an isolated polypeptide capable of specifically binding a LGALS9 peptide, wherein the isolated polypeptide includes a VH region including three CDRs (VH-CDR1, VH-CDR2, VH-CDR3) and a VL region including three CDRs (VL-CDR1, VL-CDR2, and VL-CDR3), and the six CDRs are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences of an antibody selected from antibodies LGAL-P01-mAb34, LGAL-PRT-mAb41, 45, 49, 53, 55, 60, and 61.

[0208] The VH and VL region sequences corresponding to the antibodies LGAL-P01-mAb34, LGAL-PRT-mAb41, 45, 49, 53, 55, 60, and 61 are set forth in: SEQ ID Nos. 661 and 662; SEQ ID Nos. 1471 and 1472; SEQ ID Nos. 1491 and 1492; SEQ ID Nos. 1511 and 1512; SEQ ID Nos.

[0209] 1531 and 1532; SEQ ID Nos. 1551 and 1552; SEQ ID Nos. 1571 and 1572; and SEQ ID Nos.

[0210] 1591 and 1592, respectively.

[0211] The six CDR sequences of antibodies LGAL-P01-mAb34, LGAL-PRT-mAb41, 45, 49, 53, 55, 60, and 61 are set forth in: SEQ ID Nos. 663, 664, 665, 666, 667, and 668; SEQ ID Nos. 1473, 1474, 1475, 1476, 1477, and 1478; SEQ ID Nos. 1493, 1494, 1495, 1496, 1497, and 1498; SEQ ID Nos. 1513, 1514, 1515, 1516, 1517, and 1518; SEQ ID Nos. 1533, 1534, 1535, 1536, 1537, and 1538; SEQ ID Nos. 1553, 1554, 1555, 1556, 1557, and 1558; SEQ ID Nos. 1573, 1574, 1575, 1576, 1577, and 1578; and SEQ ID Nos. 1593, 1594, 1595, 1596, 1597, and 1598, respectively.

[0212] In some embodiments, the six CDR sequences of the isolated polypeptide, include, or consist of, sequences identical or substantially identical to CDR sequences of an antibody selected from the antibodies LGAL-P01-mAb34, LGAL-PRT-mAb41, 45, 49, 53, 55, 60, and 61.

[0213] In some embodiments, the VH and the VL regions of the isolated polypeptide include, or consist of, sequences identical or substantially identical to VH and VL region sequences of an antibody selected from the antibodies LGAL-P01-mAb34, LGAL-PRT-mAb41, 45, 49, 53, 55, 60, and 61.

[0214] The VH and VL regions nucleotide sequences of antibodies LGAL-P01-mAb34, LGAL-PRT-mAb41, 45, 49, 53, 55, 60, and 61 are set forth in: SEQ ID Nos. 671 and 672; SEQ ID Nos.

[0215] 1481 and 1482; SEQ ID Nos. 1501 and 1502; SEQ ID Nos. 1521 and 1522; SEQ ID Nos. 1541 and 1542; SEQ ID Nos. 1561 and 1562; SEQ ID Nos. 1581 and 1582; and SEQ ID Nos. 1601 and 1602, respectively.

[0216] The six CDR nucleotide sequences of antibodies LGAL-P01-mAb34, LGAL-PRT-mAb41, 45, 49, 53, 55, 60, and 61 are set forth in: SEQ ID Nos. 673, 674, 675, 676, 677, and 678; SEQ ID Nos. 1483, 1484, 1485, 1486, 1487, and 1488; SEQ ID Nos. 1503, 1504, 1505, 1506, 1507, and 1508; SEQ ID Nos. 1523, 1524, 1525, 1526, 1527, and 1528; SEQ ID Nos. 1543, 1544, 1545, 1546, 1547, and 1548; SEQ ID Nos. 1563, 1564, 1565, 1566, 1567, and 1568; SEQ ID Nos. 1583, 1584, 1585, 1586, 1587, and 1588; and SEQ ID Nos. 1603, 1604, 1605, 1606, 1607, and 1608, respectively.

[0217] In some embodiments, the six CDR sequences of the isolated polypeptide are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences encoded by nucleotide sequences of an antibody selected from the antibodies LGAL-P01-mAb34, LGAL-PRT-mAb41, 45, 49, 53, 55, 60, and 61.

[0218] In some embodiments, the six CDR sequences of the isolated polypeptide, include, or consist of, sequences identical or substantially identical to CDR sequences encoded by nucleotide sequences of an antibody selected from the antibodies LGAL-P01-mAb34, LGAL-PRT-mAb41, 45, 49, 53, 55, 60, and 61.

[0219] In some embodiments, the VH and the VL regions of the isolated polypeptide include, or consist of, sequences identical or substantially identical to VH and VL region sequences encoded by nucleotide sequences of an antibody selected from the antibodies LGAL-P01-mAb34, LGAL-PRT-mAb41, 45, 49, 53, 55, 60, and 61.

[0220] In some embodiments, the isolated polypeptide is selected from the antibodies (the SEQ ID Nos. of the VH, VL, and six CDRs of each antibody are indicated in parentheses): LGALS9-PRT-mAb45 (SEQ ID Nos: 1491-1498); LGALS9-PRT-mAb60 (SEQ ID Nos: 1571-1578); LGALS9-PRT-mAb49 (SEQ ID Nos: 1511-1518); LGALS9-PRT-mAb41 (SEQ ID Nos: 1471-1478); LGALS9-PRT-mAb61 (SEQ ID Nos: 1591-1598); LGALS9-PRT-mAb55 (SEQ ID Nos: 1551-1558); and LGALS9-PRT-mAb53 (SEQ ID Nos: 1531-1538).

[0221] In some embodiments, the isolated polypeptide is LGALS9-PRT-mAb45 (SEQ ID Nos: 1491-1498). In some embodiments, the isolated polypeptide is LGALS9-PRT-mAb60 (SEQ ID Nos: 1571-1578). In some embodiments, the isolated polypeptide is LGALS9-PRT-mAb49 (SEQ ID Nos: 1511-1518). In some embodiments, the isolated polypeptide is LGALS9-PRT-mAb41 (SEQ ID Nos: 1471-1478). In some embodiments, the isolated polypeptide is LGALS9-PRT-mAb61 (SEQ ID Nos: 1591-1598). In some embodiments, the isolated polypeptide is LGALS9-PRT-mAb55 (SEQ ID Nos: 1551-1558). In some embodiments, the isolated polypeptide is LGALS9-PRT-mAb53 (SEQ ID Nos: 1531-1538).

[0222] Anti-SAA antibodies

[0223] In some embodiments, there is provided an isolated polypeptide capable of specifically binding an SAA protein target or a peptide thereof. In some embodiments, there is provided an isolated polypeptide capable of specifically binding an SAA protein target or a peptide thereof under urinary conditions.

[0224] In some embodiments, the isolated polypeptide is an anti-SAA antibody. The term “Anti-SAA antibody” as used herein, relates to an antibody capable of specifically binding an SAA protein target or a peptide thereof.

[0225] In some embodiments, the SAA peptide includes, or consists of, a sequence selected from SEQ ID NO: 889-898. In some embodiments, the SAA peptide includes, or consists of, a sequence selected from GAEDSLADQAANKWGR (SEQ ID No: 889, SAA-P01), GNYDAAKRGPGGAWAAEVITDAR (SEQ ID No: 890, SAA-P02), GAEDSLADQAANEWGR (SEQ ID No: 891, SAA-P03), and GNYDAAKRGPGGAWAAEVISNAR (SEQ ID No: 892, SAA-P04).

[0226] In some embodiments, there is provided a monoclonal antibody capable of specifically binding to an SAA peptide including, or consisting of, a sequence selected from SEQ ID No: 889 (SAA-P01), SEQ ID No: 890 (SAA-P02), SEQ ID No: 891 (SAA-P03), and SEQ ID No: 892 (SAA-P04), under urinary conditions.

[0227] In some embodiments, there is provided an isolated polypeptide capable of specifically binding a SAA peptide, wherein the isolated polypeptide includes a VH region including three CDRs (VH-CDR1, VH-CDR2, VH-CDR3) and a VL region including three CDRs (VL-CDR1, VL-CDR2, and VL-CDR3), and the six CDRs are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences of an antibody selected from antibodies SAA-P01-mAb35, 36, SAA-P02-mAb37, SAA-P01-mAb38, SAA-P02-mAb39, 40, SAA-P01-mAb41, 42, SAA-P02-mAb43, SAA-PRT-mAb56, 64, 69, and 71-73.

[0228] The VH and VL region sequences corresponding to the antibodies SAA-P01-mAb35, 36, SAA-P02-mAb37, SAA-P01-mAb38, SAA-P02-mAb39, 40, SAA-P01-mAb41, 42, SAA-P02-mAb43, SAA-PRT-mAb56, 64, 69, and 71-73 are set forth in: SEQ ID Nos. 681 and 682; SEQ ID Nos. 701 and 702; SEQ ID Nos. 721 and 722; SEQ ID Nos. 741 and 742; SEQ ID Nos. 761 and 762; SEQ ID Nos. 781 and 782; SEQ ID Nos. 801 and 802; SEQ ID Nos. 821 and 822; SEQ ID Nos. 841 and 842; SEQ ID Nos. 1611 and 1612; SEQ ID Nos. 1631 and 1632; SEQ ID Nos. 1651 and 1652; SEQ ID Nos. 1671 and 1672; SEQ ID Nos. 1691 and 1692; and SEQ ID Nos. 1711 and 1712, respectively.

[0229] The six CDR sequences of antibodies SAA-P01-mAb35, 36, SAA-P02-mAb37, SAA-P01-mAb38, SAA-P02-mAb39, 40, SAA-P01-mAb41, 42, SAA-P02-mAb43, SAA-PRT-mAb56, 64, 69, and 71-73 are set forth in: SEQ ID Nos. 683, 684, 685, 686, 687, and 688; SEQ ID Nos. 703, 704, 705, 706, 707, and 708; SEQ ID Nos. 723, 724, 725, 726, 727, and 728; SEQ ID Nos. 743, 744, 745, 746, 747, and 748; SEQ ID Nos. 763, 764, 765, 766, 767, and 768; SEQ ID Nos. 783, 784, 785, 786, 787, and 788; SEQ ID Nos. 803, 804, 805, 806, 807, and 808; SEQ ID Nos. 823, 824, 825, 826, 827, and 828; SEQ ID Nos. 843, 844, 845, 846, 847, and 848; SEQ ID Nos. 1613, 1614, 1615, 1616, 1617, and 1618; SEQ ID Nos. 1633, 1634, 1635, 1636, 1637, and 1638; SEQ ID Nos. 1653, 1654, 1655, 1656, 1657, and 1658; SEQ ID Nos. 1673, 1674, 1675, 1676, 1677, and 1678; SEQ ID Nos. 1693, 1694, 1695, 1696, 1697, and 1698; and SEQ ID Nos. 1713, 1714, 1715, 1716, 1717, and 1718, respectively.

[0230] In some embodiments, the six CDR sequences of the isolated polypeptide, include, or consist of, sequences identical or substantially identical to CDR sequences of an antibody selected from the antibodies SAA-P01-mAb35, 36, SAA-P02-mAb37, SAA-P01-mAb38, SAA-P02-mAb39, 40, SAA-P01-mAb41, 42, SAA-P02-mAb43, SAA-PRT-mAb56, 64, 69, and 71-73.

[0231] In some embodiments, the VH and the VL regions of the isolated polypeptide include, or consist of, sequences identical or substantially identical to VH and VL region sequences of an antibody selected from the antibodies SAA-P01-mAb35, 36, SAA-P02-mAb37, SAA-P01-mAb38, SAA-P02-mAb39, 40, SAA-P01-mAb41, 42, SAA-P02-mAb43, SAA-PRT-mAb56, 64, 69, and 71-73.

[0232] The VH and VL regions nucleotide sequences of antibodies SAA-P01-mAb35, 36, SAA-P02-mAb37, SAA-P01-mAb38, SAA-P02-mAb39, 40, SAA-P01-mAb41, 42, SAA-P02-mAb43, SAA-PRT-mAb56, 64, 69, and 71-73 are set forth in: SEQ ID Nos. 691 and 692; SEQ ID Nos.

[0233] 711 and 712; SEQ ID Nos. 731 and 732; SEQ ID Nos. 751 and 752; SEQ ID Nos. 771 and 772; SEQ ID Nos. 791 and 792; SEQ ID Nos. 811 and 812; SEQ ID Nos. 831 and 832; SEQ ID Nos.

[0234] 851 and 852; SEQ ID Nos. 1621 and 1622; SEQ ID Nos. 1641 and 1642; SEQ ID Nos. 1661 and 1662; SEQ ID Nos. 1681 and 1682; SEQ ID Nos. 1701 and 1702; and SEQ ID Nos. 1721 and 1722, respectively.

[0235] The six CDR nucleotide sequences of antibodies P01-mAb35, 36, SAA-P02-mAb37, SAA- P01-mAb38, SAA-P02-mAb39, 40, SAA-P01-mAb41, 42, SAA-P02-mAb43, SAA-PRT-mAb56, 64, 69, and 71-73 are set forth in: SEQ ID Nos. 693, 694, 695, 696, 697, and 698; SEQ ID Nos.

[0236] 713, 714, 715, 716, 717, and 718; SEQ ID Nos. 733, 734, 735, 736, 737, and 738; SEQ ID Nos.

[0237] 753, 754, 755, 756, 757, and 758; SEQ ID Nos. 773, 774, 775, 776, 777, and 778; SEQ ID Nos.

[0238] 793, 794, 795, 796, 797, and 798; SEQ ID Nos. 813, 814, 815, 816, 817, and 818; SEQ ID Nos.

[0239] 833, 834, 835, 836, 837, and 838; SEQ ID Nos. 853, 854, 855, 856, 857, and 858; SEQ ID Nos.

[0240] 1623, 1624, 1625, 1626, 1627, and 1628; SEQ ID Nos. 1643, 1644, 1645, 1646, 1647, and 1648; SEQ ID Nos. 1663, 1664, 1665, 1666, 1667, and 1668; SEQ ID Nos. 1683, 1684, 1685, 1686, 1687, and 1688; SEQ ID Nos. 1703, 1704, 1705, 1706, 1707, and 1708; and SEQ ID Nos. 1723, 1724, 1725, 1726, 1727, and 1728, respectively.

[0241] In some embodiments, the six CDR sequences of the isolated polypeptide are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences encoded by nucleotide sequences of an antibody selected from the antibodies P01-mAb35, 36, SAA-P02-mAb37, SAA-P01-mAb38, SAA-P02-mAb39, 40, SAA-P01-mAb41, 42, SAA-P02-mAb43, SAA-PRT-mAb56, 64, 69, and 71-73.

[0242] In some embodiments, the six CDR sequences of the isolated polypeptide, include, or consist of, sequences identical or substantially identical to CDR sequences encoded by nucleotide sequences of an antibody selected from the antibodies P01-mAb35, 36, SAA-P02-mAb37, SAA-P01-mAb38, SAA-P02-mAb39, 40, SAA-P01-mAb41, 42, SAA-P02-mAb43, SAA-PRT-mAb56, 64, 69, and 71-73.

[0243] In some embodiments, the VH and the VL regions of the isolated polypeptide include, or consist of, sequences identical or substantially identical to VH and VL region sequences encoded by nucleotide sequences of an antibody selected from the antibodies P01-mAb35, 36, SAA-P02-mAb37, SAA-P01-mAb38, SAA-P02-mAb39, 40, SAA-P01-mAb41, 42, SAA-P02-mAb43, SAA-PRT-mAb56, 64, 69, and 71-73.

[0244] In some embodiments, the isolated polypeptide is selected from the antibodies (the SEQ ID Nos. of the VH, VL, and six CDRs of each antibody are indicated in parentheses): SAA-PRT-mAb69 (SEQ ID Nos: 1651-1658); SAA-PRT-mAb71 (SEQ ID Nos: 1671-1678); SAA-PRT-mAb72 (SEQ ID Nos: 1691-1698); SAA-PRT-mAb56 (SEQ ID Nos: 1611-1618); SAA-PRT-mAb73 (SEQ ID Nos: 1711-1718); SAA-PRT-mAb64 (SEQ ID Nos: 1631-1638); SAA-P01-mAb35 (SEQ ID Nos: 681-688); SAA-P01-mAb36 (SEQ ID Nos: 701-708); SAA-P01-mAb38 (SEQ ID Nos: 741-748); and SAA-P02-mAb43 (SEQ ID Nos: 841-848).

[0245] In some embodiments, the isolated polypeptide is SAA-PRT-mAb69 (SEQ ID Nos: 1651-1658). In some embodiments, the isolated polypeptide is SAA-PRT-mAb71 (SEQ ID Nos: 1671- 1678). In some embodiments, the isolated polypeptide is SAA-PRT-mAb72 (SEQ ID Nos: 1691-1698). In some embodiments, the isolated polypeptide is SAA-PRT-mAb56 (SEQ ID Nos: 1611-1618). In some embodiments, the isolated polypeptide is SAA-PRT-mAb73 (SEQ ID Nos: 1711-1718). In some embodiments, the isolated polypeptide is SAA-PRT-mAb64 (SEQ ID Nos: 1631- 1638). In some embodiments, the isolated polypeptide is SAA-P01-mAb35 (SEQ ID Nos: 681- 688). In some embodiments, the isolated polypeptide is SAA-P01-mAb36 (SEQ ID Nos: 701- 708). In some embodiments, the isolated polypeptide is SAA-P01-mAb38 (SEQ ID Nos: 741- 748). In some embodiments, the isolated polypeptide is SAA-P02-mAb43 (SEQ ID Nos: 841- 848).

[0246] Anti-EGF antibodies

[0247] In some embodiments, there is provided an isolated polypeptide capable of specifically binding an EGF protein target or a peptide thereof. In some embodiments, there is provided an isolated polypeptide capable of specifically binding an EGF protein target or a peptide thereof under urinary conditions.

[0248] In some embodiments, the isolated polypeptide is an anti-EGF antibody. The term “Anti-EGF antibody” as used herein, relates to an antibody capable of specifically binding an EGF protein target or a peptide thereof.

[0249] In some embodiments, the EGF peptide includes, or consists of, a sequence selected from SEQ ID NO: 870-875. In some embodiments, the EGF peptide includes, or consists of, a sequence selected from RIYWVDLER (SEQ ID No: 870, EGF-P01) and RLFWTDTGINPR (SEQ ID No:

[0250] 871, EGF-P02).

[0251] In some embodiments, there is provided a monoclonal antibody capable of specifically binding to an EGF peptide including, or consisting of, a sequence selected from SEQ ID No: 870 (EGF-P01) and SEQ ID No: 871 (EGF-P02), under urinary conditions.

[0252] In some embodiments, there is provided an isolated polypeptide capable of specifically binding a EGF peptide, wherein the isolated polypeptide includes a VH region including three CDRs (VH-CDR1, VH-CDR2, VH-CDR3) and a VL region including three CDRs (VL-CDR1, VL-CDR2, and VL-CDR3), and the six CDRs are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences of an antibody selected from EGF-P01-mAb16-20, EGF-P02-mAb21, EGF-P01-mAb22, 23, and EGF-P02-mAb24.

[0253] The VH and VL region sequences corresponding to the antibodies EGF-P01-mAb16-20, EGF-P02-mAb21, EGF-P01-mAb22, 23, and EGF-P02-mAb24 are set forth in: SEQ ID Nos. 301 and 302; SEQ ID Nos. 321 and 322; SEQ ID Nos. 341 and 342; SEQ ID Nos. 361 and 362; SEQ ID Nos. 381 and 382; SEQ ID Nos. 401 and 402; SEQ ID Nos. 421 and 422; SEQ ID Nos. 441 and 442; and SEQ ID Nos. 461 and 462, respectively.

[0254] The six CDR sequences of antibodies EGF-P01-mAbl6-20, EGF-P02-mAb21, EGF-P01-mAb22, 23, and EGF-P02-mAb24 are set forth in: SEQ ID Nos. 303, 304, 305, 306, 307, and 308; SEQ ID Nos. 323, 324, 325, 326, 327, and 328; SEQ ID Nos. 343, 344, 345, 346, 347, and 348; SEQ ID Nos. 363, 364, 365, 366, 367, and 368; SEQ ID Nos. 383, 384, 385, 386, 387, and 388; SEQ ID Nos. 403, 404, 405, 406, 407, and 408; SEQ ID Nos. 423, 424, 425, 426, 427, and 428; SEQ ID Nos. 443, 444, 445, 446, 447, and 448; and SEQ ID Nos. 463, 464, 465, 466, 467, and 468, respectively.

[0255] In some embodiments, the six CDR sequences of the isolated polypeptide, include, or consist of, sequences identical or substantially identical to CDR sequences of an antibody selected from the antibodies EGF-P01-mAb16-20, EGF-P02-mAb21, EGF-P01-mAb22, 23, and EGF-P02-mAb24.

[0256] In some embodiments, the VH and the VL regions of the isolated polypeptide include, or consist of, sequences identical or substantially identical to VH and VL region sequences of an antibody selected from the antibodies EGF-P01-mAb16-20, EGF-P02-mAb21, EGF-P01-mAb22, 23, and EGF-P02-mAb24.

[0257] The VH and VL regions nucleotide sequences of antibodies EGF-P01-mAb16-20, EGF-P02-mAb21, EGF-P01-mAb22, 23, and EGF-P02-mAb24 are set forth in: SEQ ID Nos. 311 and 312; SEQ ID Nos. 331 and 332; SEQ ID Nos. 351 and 352; SEQ ID Nos. 371 and 372; SEQ ID Nos.

[0258] 391 and 392; SEQ ID Nos. 411 and 412; SEQ ID Nos. 431 and 432; SEQ ID Nos. 451 and 452; and SEQ ID Nos. 471 and 472.

[0259] The six CDR nucleotide sequences of antibodies EGF-P01-mAb16-20, EGF-P02-mAb21, EGF-P01-mAb22, 23, and EGF-P02-mAb24 are set forth in: SEQ ID Nos. 313, 314, 315, 316, 317, and 318; SEQ ID Nos. 333, 334, 335, 336, 337, and 338; SEQ ID Nos. 353, 354, 355, 356, 357, and 358; SEQ ID Nos. 373, 374, 375, 376, 377, and 378; SEQ ID Nos. 393, 394, 395, 396, 397, and 398; SEQ ID Nos. 413, 414, 415, 416, 417, and 418; SEQ ID Nos. 433, 434, 435, 436, 437, and 438; SEQ ID Nos. 453, 454, 455, 456, 457, and 458; and SEQ ID Nos. 473, 474, 475, 476, 477, and 478, respectively.

[0260] In some embodiments, the six CDR sequences of the isolated polypeptide are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences encoded by nucleotide sequences of an antibody selected from the antibodies EGF-P01-mAb16-20, EGF-P02-mAb21, EGF-P01-mAb22, 23, and EGF-P02-mAb24.

[0261] In some embodiments, the six CDR sequences of the isolated polypeptide, include, or consist of, sequences identical or substantially identical to CDR sequences encoded by nucleotide sequences of an antibody selected from the antibodies EGF-P01-mAb16-20, EGF-P02-mAb21, EGF-P01-mAb22, 23, and EGF-P02-mAb24.

[0262] In some embodiments, the VH and the VL regions of the isolated polypeptide include, or consist of, sequences identical or substantially identical to VH and VL region sequences encoded by nucleotide sequences of an antibody selected from the antibodies EGF-P01-mAb16-20, EGF-P02-mAb21, EGF-P01-mAb22, 23, and EGF-P02-mAb24.

[0263] In some embodiments, the isolated polypeptide is selected from the antibodies (the SEQ ID Nos. of the VH, VL, and six CDRs of each antibody are indicated in parentheses): EGF-P01-mAbl9 (SEQ ID Nos: 361-368); EGF-P01-mAbl8 (SEQ ID Nos: 341-348); EGF-P01-mAb23 (SEQ ID Nos: 441-448); EGF-P02-mAb21 (SEQ ID Nos: 401-408); EGF-P02-mAb24 (SEQ ID Nos: 461-468); EGF-P01-mAbl7 (SEQ ID Nos: 321-328); EGF-P01-mAb22 (SEQ ID Nos: 421-428); EGF-P01-mAb20 (SEQ ID Nos: 381-388); and EGF-P01-mAbl6 (SEQ ID Nos: 301-308).

[0264] In some embodiments, the isolated polypeptide is EGF-POl-mAb 19 (SEQ ID Nos: 361-368). In some embodiments, the isolated polypeptide is EGF-P01-mAbl8 (SEQ ID Nos: 341-348). In some embodiments, the isolated polypeptide is EGF-P01-mAb23 (SEQ ID Nos: 441-448). In some embodiments, the isolated polypeptide is EGF-P02-mAb21 (SEQ ID Nos: 401-408). In some embodiments, the isolated polypeptide is EGF-P02-mAb24 (SEQ ID Nos: 461-468). In some embodiments, the isolated polypeptide is EGF-POl-mAb 17 (SEQ ID Nos: 321-328). In some embodiments, the isolated polypeptide is EGF-P01-mAb22 (SEQ ID Nos: 421-428). In some embodiments, the isolated polypeptide is EGF-P01-mAb20 (SEQ ID Nos: 381-388). In some embodiments, the isolated polypeptide is EGF-P01-mAbl6 (SEQ ID Nos: 301-308).

[0265] Anti-FGA antibodies

[0266] In some embodiments, there is provided an isolated polypeptide capable of specifically binding an FGA protein target or a peptide thereof. In some embodiments, there is provided an isolated polypeptide capable of specifically binding an FGA protein target or a peptide thereof under urinary conditions.

[0267] In some embodiments, the isolated polypeptide is an anti-FGA antibody. The term “Anti-FGA antibody” as used herein, relates to an antibody capable of specifically binding an FGA protein target or a peptide thereof.

[0268] In some embodiments, the FGA peptide includes, or consists of, a sequence selected from SEQ ID NO: 876-881. In some embodiments, the FGA peptide includes, or consists of, a sequence selected from GSESGIFTNTK (SEQ ID No: 876, FGA-P01) and QFTSSTSYNR (SEQ ID No: 877, FGA-P02).

[0269] In some embodiments, there is provided a monoclonal antibody capable of specifically binding to an FGA peptide including, or consisting of, a sequence selected from SEQ ID No: 876 (FGA-P01) and SEQ ID No: 877 (FGA-P02), under urinary conditions.

[0270] In some embodiments, there is provided an isolated polypeptide capable of specifically binding a FGA peptide, wherein the isolated polypeptide includes a VH region including three CDRs (VH-CDR1, VH-CDR2, VH-CDR3) and a VL region including three CDRs (VL-CDR1, VL-CDR2, and VL-CDR3), and the six CDRs are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences of an antibody selected from antibodies FGA-P02-mAb25-29, FGA-P01-mAb30-32, and FGA-P02-mAb33.

[0271] The VH and VL region sequences of antibodies FGA-P02-mAb25-29, FGA-P01-mAb30-32, and FGA-P02-mAb33 are set forth in: SEQ ID Nos. 481 and 482; SEQ ID Nos. 501 and 502; SEQ ID Nos. 521 and 522; SEQ ID Nos. 541 and 542; SEQ ID Nos. 561 and 562; SEQ ID Nos.

[0272] 581 and 582; SEQ ID Nos. 601 and 602; SEQ ID Nos. 621 and 622; and SEQ ID Nos. 641 and 642.

[0273] The VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 regions sequences of antibodies FGA-P02-mAb25-29, FGA-P01-mAb30-32, and FGA-P02-mAb33 are set forth in: SEQ ID Nos. 483, 484, 485, 486, 487, and 488; SEQ ID Nos. 503, 504, 505, 506, 507, and 508; SEQ ID Nos. 523, 524, 525, 526, 527, and 528; SEQ ID Nos. 543, 544, 545, 546, 547, and 548; SEQ ID Nos. 563, 564, 565, 566, 567, and 568; SEQ ID Nos. 583, 584, 585, 586, 587, and 588; SEQ ID Nos. 603, 604, 605, 606, 607, and 608; SEQ ID Nos. 623, 624, 625, 626, 627, and 628; and SEQ ID Nos. 643, 644, 645, 646, 647, and 648, respectively.

[0274] In some embodiments, the six CDR sequences of the isolated polypeptide, include, or consist of, sequences identical or substantially identical to CDR sequences of an antibody selected from the antibodies FGA-P02-mAb25-29, FGA-P01-mAb30-32, and FGA-P02-mAb33.

[0275] In some embodiments, the VH and the VL regions of the isolated polypeptide include, or consist of, sequences identical or substantially identical to VH and VL region sequences of an antibody selected from the antibodies FGA-P02-mAb25-29, FGA-P01-mAb30-32, and FGA-P02-mAb33.

[0276] The VH and VL regions nucleotide sequences of antibodies FGA-P02-mAb25-29, FGA-P01-mAb30-32, and FGA-P02-mAb33 are set forth in: SEQ ID Nos. 491 and 492; SEQ ID Nos.

[0277] 511 and 512; SEQ ID Nos. 531 and 532; SEQ ID Nos. 551 and 552; SEQ ID Nos. 571 and 572; SEQ ID Nos. 591 and 592; SEQ ID Nos. 611 and 612; SEQ ID Nos. 631 and 632; and SEQ ID Nos. 651 and 652. The six CDR nucleotide sequences of antibodies FGA-P02-mAb25-29, FGA-P01-mAb30-32, and FGA-P02-mAb33 are set forth in: SEQ ID Nos. 493, 494, 495, 496,497, and 498; SEQ ID Nos. 513, 514, 515,516, 517, and 518; SEQ ID Nos. 533, 534,535, 536,537, and 538; SEQ ID Nos.

[0278] 553, 554, 555, 556, 557, and 558; SEQ ID Nos. 573, 574, 575, 576, 577, and 578; SEQ ID Nos.

[0279] 593, 594, 595,596, 597, and 598; SEQ ID Nos. 613, 614, 615, 616,617, and 618; SEQ ID Nos.

[0280] 633, 634, 635, 636, 637, and 638; and SEQ ID Nos. 653, 654, 655,656, 657, and 658, respectively.

[0281] In some embodiments, the six CDR sequences of the isolated polypeptide are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences encoded by nucleotide sequences of an antibody selected from the antibodies FGA-P01-mAb30-32, and FGA-P02-mAb33.

[0282] In some embodiments, the six CDR sequences of the isolated polypeptide, include, or consist of, sequences identical or substantially identical to CDR sequences encoded by nucleotide sequences of an antibody selected from the antibodies FGA-P01-mAb30-32, and FGA-P02-mAb33.

[0283] In some embodiments, the VH and the VL regions of the isolated polypeptide include, or consist of, sequences identical or substantially identical to VH and VL region sequences encoded by nucleotide sequences of an antibody selected from the antibodies FGA-P01-mAb30-32, and FGA-P02-mAb33.

[0284] In some embodiments, the isolated polypeptide is selected from the antibodies (the SEQ ID Nos. of the VH, VL, and six CDRs of each antibody are indicated in parentheses): FGA-P02-mAb33 (SEQ ID Nos: 641-648); FGA-P01-mAb32 (SEQ ID Nos: 621-628); FGA-P01-mAb31 (SEQ ID Nos: 601-608); FGA-P02-mAb26 (SEQ ID Nos: 501-508); FGA-P02-mAb25 (SEQ ID Nos: 481-488); and FGA-P01-mAb30 (SEQ ID Nos: 581-588).

[0285] In some embodiments, the isolated polypeptide is FGA-P02-mAb33 (SEQ ID Nos: 641-648). In some embodiments, the isolated polypeptide is FGA-P01-mAb32 (SEQ ID Nos: 621- 628). In some embodiments, the isolated polypeptide is FGA-P01-mAb31 (SEQ ID Nos: 601- 608). In some embodiments, the isolated polypeptide is FGA-P02-mAb26 (SEQ ID Nos: 501- 508). In some embodiments, the isolated polypeptide is FGA-P02-mAb25 (SEQ ID Nos: 481- 488). In some embodiments, the isolated polypeptide is FGA-P01-mAb30 (SEQ ID Nos: 581- 588).

[0286] General features of the isolated polypeptides

[0287] The CDRs define the binding specificity of the antibody and are therefore sufficient to define the antibody. The CDRs may be engrafted in any polypeptide sequence suitable to provide the general 3D structure of the antibody in order to carry out the specific binding. Accordingly, the CDRs do not necessarily have to be linked by any specific antibody sequences, as long as they are connected by sequences which provide the general paratope 3D structure. It is also appreciated that any carrier structure that is capable of assuming or mimicking a structure of an antibody paratope, may be engrafted with the specific CDRs of the invention to provide the isolated polypeptide of the invention with the same specificity, and is intended to be encompassed by the present invention.

[0288] Accordingly, the isolated polypeptide may be in any form suitable for detection of the respective peptide. Non-limiting examples of suitable forms include: an antibody or an antigenbinding fragment thereof, a single-chain variable fragment (scFv), a chimeric or a humanized antibody or antigen-binding fragment thereof, and a chimeric antigen receptor (CAR)-B.

[0289] The term “antibody”, as used herein is an immunoglobulin having two heavy chains and two light chains, each chain having a variable region (as described above) and a constant region, and wherein the variable regions of the heavy and light chains form antigen binding regions. It is noted that while classic antibodies are monospecific, i.e., having a single specificity targeting a single antigen or epitope, an antibody may also be multi-specific, i.e., capable of specifically binding more than one distinct antigen or epitope.

[0290] Antigen-binding fragments of an antibody include an Fv fragment, an Fab fragment, and an F(ab’)2 fragment.

[0291] The term “Fv” (fragment variable), as used herein, relates to an antibody variable domain, including heavy and light chain variable regions.

[0292] The term “Fab” (fragment antigen binding), as used herein, relates to the heavy and light chain variable regions and further includes the CHI region of the heavy and light chains. It may be obtained by a papain digestion above the hinge region, such that the hinge region is not included.

[0293] The term “F(ab’)2”, as used herein relates to two Fab regions linked by a disulfide bond of the hinge region. It may be obtained by a pepsin digestion below the hinge region, such that the hinge region is included and connects the two Fab fragments.

[0294] The term “scFv”, as used herein relates to a fusion protein which includes the variable regions of the heavy and light chains connected by a short linker to make a single polypeptide chain.

[0295] The term “chimeric”, as used herein relates to an antibody or fragment thereof including sequences from more than one species.

[0296] The term “humanized”, as used herein relates to an antibody or fragment thereof which is produced in a non-human species (such as a mouse) but includes human sequences. For example, the framework sequences which separate the CDRs in the variable region may be replaced, or partly replaced, with human sequences.

[0297] The term “CAR-B”, as used herein, relates to a B-cell antigen receptor in which the signaling domains have been fused to an antigen recognition domain specific to a certain antigen, such as from a monoclonal antibody.

[0298] In some embodiments, the isolated polypeptide is selected from an antibody, an Fv fragment, an Fab fragment, an F(ab’)2 fragment, an scFv, a chimeric or a humanized antibody or antibody fragment, and a CAR-B.

[0299] In some embodiments, the isolated polypeptide is an antibody. In some embodiments, the antibody is a monoclonal antibody.

[0300] In some embodiments, the isolated polypeptide is an antibody fragment. In some embodiments, the antibody fragment is selected from an Fv fragment, an Fab fragment, and an F(ab’)2 fragment.

[0301] In some embodiments, the Fv fragment, Fab fragment, F(ab’)2 fragment, scFv, chimeric or humanized antibody or antigen-binding fragment thereof, and / or CAR-B, are derived from a monoclonal antibody, or based on a sequence derived from a monoclonal antibody.

[0302] When the antibody includes a constant (C-) region, it may be derived from any isotype suitable for the desired use, including the common isotypes IgG, IgM, IgD, IgA, or IgE, and a combination thereof. Additionally, the light chain may be kappa or lambda, or a combination thereof. In some embodiments, the heavy chain C-region is derived from an IgG. In some embodiments, the light chain is kappa. In some embodiments, the light chain is lambda. Sequences of constant regions are well known in the art.

[0303] The term “specifically binding”, as used herein, relates to binding that is sufficiently specific so as to specifically detect the respective protein or peptide, without significant background of other proteins or peptides. In some embodiments, specific binding is defined as binding with an EC50 (half maximal effective concentration) of less than about 10, 8, 5, 2, 1, 0.8, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, or 0.04 nM. In some embodiments, specific binding is defined as binding with an EC80 (80% maximal effective concentration) of less than about 10, 8, 5, 2, 1, 0.8, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, or 0.04 nM. In some embodiments, specific binding is defined as binding with an EC50 of less than about 10. In some embodiments, specific binding is defined as binding with an EC50 of less than about 1. In some embodiments, specific binding is defined as binding with an EC50 of less than about 0.5. In some embodiments, specific binding is defined as binding with an association rate constant (Ka) of at least about 10'9, 10'8, or 10'7M’1. It is further appreciated that specifically binding a protein target does not preclude binding to fragments of the protein target.

[0304] In some embodiments, the isolated polypeptide is further conjugated to a functional agent for using in various applications. Nonlimiting examples for functional agents may include fluorophores (fluorescent dyes) such as Fluorescein isothiocyanate (FITC), Phycoerythrin (PE), Allophycocyanin (APC), and Alexa Fluor dyes, for fluorescence detection (such as in flow cytometry); enzymes, e.g. horseradish peroxidase (HRP) or alkaline phosphatase (AP), for assays such as enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, etc.; biotin for binding to avidin during ELISA, western blotting, immunoprecipitation; radioisotopes, e.g., Iodine-CRP-p01125, Iodine-131, Indium-Ill for radio-immunoassays (RIA) and nuclear imaging; chemotherapeutic agents such as monomethyl auristatin E (MMAE), doxorubicin, and calicheamicin in case of therapy; toxins such as Pseudomonas exotoxin, Ricin A-chain, e.g., for cancer therapy; nanoparticles and other particles such as latex beads, gold nanoparticles, iron oxide nanoparticles, quantum dots for drug delivery, imaging, etc.; oligonucleotides for immobilization and nucleic acid-based detection methods; polymers such as polyethylene glycol (PEG), for improving solubility and stability; and small molecules and haptens such as drugs, toxins, for targeted detection and quantification.

[0305] In some embodiments, the isolated polypeptide is conjugated to gold nanoparticles.

[0306] Nucleic acids, vectors, host cells, and hybridomas for generation of antibodies of the invention

[0307] In some embodiments, there is provided at least one nucleic acid molecule including at least one sequence encoding the isolated polypeptide disclosed herein. In some embodiments, the nucleic acid molecule includes a set of VH and VL, and / or six CDR nucleotide sequences encoding a set of VH and VL, and / or six CDR sequences which together define an antibody presented in Table 2. In some embodiments, the nucleic acid molecule includes a set of VH and VL, and / or six CDR sequences which together define an antibody presented in Table 3.

[0308] Since an antibody is composed of several sequences corresponding, e.g., to the light and heavy chains, or to the six CD Rs, it is appreciated that the nucleic acid may be more than a single nucleic acid, and that sequence encoding the isolated polypeptide may include more than one sequence which together encode the isolated polypeptide. For example, the heavy chain and the light chain, or the six CDRs, of an antibody may be encoded on separate nucleic acid molecules, or may be encoded on the same nucleic acid molecules, but separated by a different sequence.

[0309] The nucleic acid molecule may further include sequences encoding additional antibody sequences such as, e.g., heavy / light constant regions or parts thereof, and / or a hinge region. The nucleic acid molecule may further include a promoter, terminator, and further transcription and / or regulation elements, for expression of the polypeptide in a suitable cell, e.g. for producing the isolated polypeptide.

[0310] In some embodiments, there is provided a vector including the nucleic acid molecule disclosed herein. The vector may be any vector suitable for expression of the sequences encoding the isolated polypeptide in a desired cell, i.e., include a suitable promoter and terminator and any additional elements required for expression in the suitable cell.

[0311] In some embodiments, there is provided a host cell including the nucleic acid molecule disclosed herein, the vector disclosed herein, and / or the isolated polypeptide disclosed herein. The host cell may be any cell suitable for expression and / or production (or mass production) of the isolated polypeptides of the invention. In some embodiments, the host cell is an eukaryotic cell. In some embodiments, the host cell is a cell of a cell line. In some embodiments, the host cell is a cell derived from an immune system cell. In some embodiments, the host cell is a human cell. In some embodiments, the host cell is a hybridoma cell.

[0312] In some embodiments, there is provided a hybridoma which is capable of producing the isolated polypeptide disclosed herein. In some embodiments, the hybridoma cell includes the nucleic acid molecule disclosed herein. In some embodiments, the hybridoma cell includes a nucleic acid molecule encoding the isolated polypeptide disclosed herein.

[0313] Definitions and embodiments mentioned above and which may be relevant to the present chapter (nucleic acids, vectors, host cells, hybridoma) also apply here, and vice versa. Some particularly relevant embodiments may be pointed out or explicitly repeated. For terms used herein, unless stated otherwise, their definition and embodiments are intended to be the same as above (mutatis mutandis).

[0314] Combinations including the isolated polypeptide

[0315] For certain applications, a combination of more than one antibody against the same protein is needed. For example, a lateral flow test requires one antibody (capture antibody) which binds to the analyte, such as the protein or peptide target in urine, and is immobilized at the test line (e.g., to a nitrocellulose membrane or substrate), and another antibody (detection antibody) binding to the same analyte and conjugated to a detectable label such as gold nanoparticles, colored latex beads, or fluorescent dyes, for detecting the bound analyte.

[0316] In some embodiments, there is provided a polypeptide combination, including an isolated polypeptide as disclosed herein, and an additional polypeptide which is capable of specifically binding to the same protein target as the isolated polypeptide without interfering with the binding of the isolated polypeptide to the protein target.

[0317] In some embodiments, the isolated polypeptide is used as capture antibody and the additional peptide is used as detection antibody. In some embodiments, the isolated polypeptide is used as detection antibody and the additional peptide is used as capture antibody.

[0318] Definitions and embodiments mentioned above and which may be relevant to the present chapter (combinations) also apply here, and vice versa. Some particularly relevant embodiments may be pointed out or explicitly repeated. For terms used herein, unless stated otherwise, their definition and embodiments are intended to be the same as above (mutatis mutandis).

[0319] In some embodiments, the additional polypeptide is an isolated polypeptide as disclosed herein. In some embodiments, the additional polypeptide is not an isolated polypeptide as disclosed herein, and may be, e.g. an antibody, such as a commercially-available antibody against the protein from which the peptide is derived. Some examples for such antibodies include anti-CRP antibodies such as CRP Antibody (500-P242-100UG, PeproTech), HRP Anti-C Reactive Protein antibody (Abeam, abl9175), and anti-C-Reactive Protein antibody produced in goat (C8284, Sigma-Aldrich); anti BTLA antibodies such as CD272 rabbit pAb (orb767786, Biorbyt), Human BTLA Fc recombinant protein (310-43-1MG, PeproTech), and anti-CD272 / BTLA Antibody (A82744), anti-LGALS9 antibodies such as anti-Galectin-9 Antibody (A34287), anti-LGALS9 antibody produced in rabbit (HPA047218, Sigma- Aldrich), and LGALS9 Antibody (orb675569, Biorbyt); and anti-SAA antibodies such as SAA2 Antibody (orb630935, Biorbyt), polyclonal chicken anti-human SAA1 / SAA / Serum Amyloid A Antibody (LS-C150322, LSBio), and anti-SAAl antibody produced in rabbit (SAB1401349, Sigma- Aldrich).

[0320] In some embodiments, the additional polypeptide binds to the protein fragments or peptides under urinary conditions (e.g., in urine, in a urine sample, or in a urine environment). In some embodiments, the isolated polypeptide binds to the protein fragments or peptides under urinary conditions. In some embodiments, both the isolated polypeptide and the additional polypeptide bind to the protein fragments or peptides under urinary conditions.

[0321] In some embodiments, both the isolated polypeptide and the additional polypeptide are capable of specifically binding to the same peptide.

[0322] In some embodiments, the isolated polypeptide and the additional polypeptide do not compete with each other in a competition assay for binding the protein. The lack of competition indicates that the isolated polypeptide and the additional polypeptide will not interfere with each other in a test, such as a lateral flow test. CRP combinations

[0323] Figs. 3A-3B demonstrate examples for sandwich assays including anti-CRP antibodies. Additionally, Example 5 (Table 8) present an analysis of interaction between different antibody pairs, highlighting combinations of antibodies which may be used together without interfering with each other’s binding.

[0324] In some embodiments, the isolated polypeptide is CRP-PRT-mAbO3 and the additional polypeptide is selected from CRP-PRT-mAbO6 and CRP-PRT-mAbO9.

[0325] In some embodiments, the isolated polypeptide is capable of specifically binding to CRP and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos.

[0326] 973-978, and the additional polypeptide is capable of specifically binding to CRP and has six CDR sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 1033-1038 and SEQ ID Nos. 1093-1098.

[0327] In some embodiments, the isolated polypeptide is capable of specifically binding to CRP and has VH and VL sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos. 971-972, and the additional polypeptide is capable of specifically binding to CRP and has VH and VL sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos. 1031-1032 and SEQ ID Nos. 1091-1092.

[0328] In some embodiments, the isolated polypeptide is CRP-PRT-mAbll and the additional polypeptide is selected from CRP-PRT-mAbO6 and CRP-PRT-mAbO9.

[0329] In some embodiments, the isolated polypeptide is capable of specifically binding to CRP and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos.

[0330] 1133-1138, and the additional polypeptide is capable of specifically binding to CRP and has six CDR sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 1033-1038 and SEQ ID Nos. 1093-1098.

[0331] In some embodiments, the isolated polypeptide is capable of specifically binding to CRP and has VH and VL sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos. 1131-1132, and the additional polypeptide is capable of specifically binding to CRP and has VH and VL sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos. 1031-1032 and SEQ ID Nos. 1091-1092.

[0332] In some embodiments, the isolated polypeptide is CRP-PRT-mAb03 and the additional polypeptide is selected from CRP-PRT-mAbOl, CRP-PRT-mAbO4, CRP-PRT-mAbO6, CRP-PRT-mAbO9, PRT-mAb10, CRP-PRT-mAbI5, and CRP-PRT-mAbI6. In some embodiments, the isolated polypeptide is CRP-PRT-mAbI5 and the additional polypeptide is selected from CRP-PRT-mAb03 and CRP-PRT-mAb20. In some embodiments, the isolated polypeptide is CRP-PRT-mAbl5 and the additional polypeptide is selected from CRP-PRT-mAbO3 and CRP-PRT-mAb20.

[0333] In some embodiments, the isolated polypeptide is CRP-PRT-mAbO 1 and the additional polypeptide is CRP-PRT-mAbO3. In some embodiments, the isolated polypeptide is CRP-PRT-mAbO 1 and the additional polypeptide is CRP-PRT-mAb20.

[0334] In some embodiments, the isolated polypeptide is CRP-PRT-mAbO3 and the additional polypeptide is CRP-PRT-mAbO6. In some embodiments, the isolated polypeptide is CRP-PRT-mAbO3 and the additional polypeptide is CRP-PRT-mAbO9. In some embodiments, the isolated polypeptide is CRP-PRT-mAbO3 and the additional polypeptide is CRP-PRT-mAbl5. In some embodiments, the isolated polypeptide is CRP-PRT-mAbO3 and the additional polypeptide is CRP-PRT-mAb 16.

[0335] In some embodiments, the isolated polypeptide is CRP-PRT-mAbO6 and the additional polypeptide is CRP-PRT-mAb20.

[0336] In some embodiments, the isolated polypeptide is CRP-PRT-mAb 11 and the additional polypeptide is CRP-PRT-mAbO9.

[0337] In some embodiments, the isolated polypeptide is CRP-PRT-mAb 15 and the additional polypeptide is CRP-PRT-mAb20.

[0338] In some embodiments, the isolated polypeptide is CRP-PRT-mAb 16 and the additional polypeptide is CRP-PRT-mAb 15. In some embodiments, the isolated polypeptide is CRP-PRT-mAbl6 and the additional polypeptide is CRP-PRT-mAb20.

[0339] In some embodiments, the isolated polypeptide is CRP-PRT-mAbO3 and the additional polypeptide is a commercial antibody. In some embodiments, the isolated polypeptide is CRP-PRT-mAb20 and the additional polypeptide is a commercial antibody.

[0340] SAA combinations

[0341] Fig. 3C demonstrates some examples for sandwich assays including anti-SAA antibodies. In some embodiments, the isolated polypeptide is SAA-PRT-mAb69 and the additional polypeptide is selected from SAA-PRT-mAb71 and SAA-PRT-mAb73.

[0342] In some embodiments, the isolated polypeptide is capable of specifically binding to SAA and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos.

[0343] 1653-1658, and the additional polypeptide is capable of specifically binding to SAA and has six CDR sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 1673-1678 and SEQ ID Nos. 1713-1718. In some embodiments, the isolated polypeptide is capable of specifically binding to SAA and has VH and VL sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos. 1651-1652, and the additional polypeptide is capable of specifically binding to SAA and has VH and VL sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos. 1671-1672 and SEQ ID Nos. 1711-1712.

[0344] In some embodiments, the isolated polypeptide is SAA-PRT-mAb69 and the additional polypeptide is selected from SAA-PRT-mAb56, SAA-PRT-mAb64, SAA-PRT-mAb71, SAA-PRT-mAb72, and SAA-PRT-mAb73. In some embodiments, the isolated polypeptide is SAA-PRT-mAb73 and the additional polypeptide is selected from SAA-PRT-mAb56 SAA-PRT-mAb64, SAA-PRT-mAb69, SAA-PRT-mAb71, and SAA-PRT-mAb72.

[0345] In some embodiments, the isolated polypeptide is SAA-PRT-mAb69 and the additional polypeptide is SAA-PRT-mAb73. In some embodiments, the isolated polypeptide is SAA-PRT-mAb69 and the additional polypeptide is SAA-PRT-mAb56. In some embodiments, the isolated polypeptide is SAA-PRT-mAb69 and the additional polypeptide is SAA-PRT-mAb71. In some embodiments, the isolated polypeptide is SAA-PRT-mAb71 and the additional polypeptide is SAA-PRT-mAb73.

[0346] LGALS9 combinations

[0347] Figs. 3D and 4B demonstrate some examples for sandwich assays including anti-LGALS9 antibodies.

[0348] In some embodiments, the isolated polypeptide is LGAL-PRT-mAb41 and the additional polypeptide is selected from LGAL-PRT-mAb45, LGAL-PRT-mAb53, and LGAL-PRT-mAb55, and LGAL-PRT-mAb60.

[0349] In some embodiments, the isolated polypeptide is LGAL-PRT-mAb45 and the additional polypeptide is selected from LGAL-PRT-mAb41, LGAL-PRT-mAb49, LGAL-PRT-mAb53, LGAL-PRT-mAb55, LGAL-PRT-mAb60, and LGAL-PRT-mAb61.

[0350] In some embodiments, the isolated polypeptide is LGAL-PRT-mAb53 and the additional polypeptide is selected from LGAL-PRT-mAb41, LGAL-PRT-mAb45, LGAL-PRT-mAb49, LGAL-PRT-mAb55, LGAL-PRT-mAb60, and LGAL-PRT-mAb61.

[0351] In some embodiments, the isolated polypeptide is LGAL-PRT-mAb60 and the additional polypeptide is LGAL-PRT-mAb45. In some embodiments, the isolated polypeptide is LGAL-PRT-mAb60 and the additional polypeptide is LGAL-PRT-mAb53. In some embodiments, the isolated polypeptide is LGAL-PRT-mAb45 and the additional polypeptide is LGAL-PRT-mAb53. In some embodiments, the isolated polypeptide is LGAL-PRT-mAb55 and the additional polypeptide is LGAL-PRT-mAb41.

[0352] BTLA combinations

[0353] Fig. 3E demonstrates some examples for sandwich assays including anti-BTLA antibodies. In some embodiments, the isolated polypeptide is BTLA-PRT-mAb35 and the additional polypeptide is selected from BTLA-PRT-mAb31 and BTLA-PRT-mAb66.

[0354] In some embodiments, the isolated polypeptide is BTLA-PRT-mAb31 and the additional polypeptide is selected from BTLA-PRT-mAb25, BTLA-PRT-mAb26, BTLA-PRT-mAb35, BTLA-PRT-mAb37, BTLA-PRT-mAb39, BTLA-PRT-mAb57, and BTLA-PRT-mAb66.

[0355] Combinations of antibodies against several targets

[0356] The present invention also encompasses combinations of antibodies which together identify more than one target protein, in order to strengthen the diagnostic prediction.

[0357] In some embodiments, there is provided a polypeptide combination, including an isolated polypeptide as disclosed herein, and at least one additional polypeptide capable of specifically binding to a protein target different from that of the isolated polypeptide.

[0358] Definitions and embodiments mentioned above and which may be relevant to the present chapter (combinations) also apply here, and vice versa. Some particularly relevant embodiments may be pointed out or explicitly repeated. For terms used herein, unless stated otherwise, their definition and embodiments are intended to be the same as above (mutatis mutandis).

[0359] As defined above, the additional polypeptide may be an isolated polypeptide of the invention, or a different polypeptide such as an antibody (e.g., a commercially-available antibody), as described above.

[0360] In some embodiments, the additional polypeptide binds to the protein fragments or peptides under urinary conditions (e.g., in urine, in a urine sample, or in a urine environment). In some embodiments, the isolated polypeptide binds to the protein fragments or peptides under urinary conditions. In some embodiments, both the isolated polypeptide and the additional polypeptide bind to the protein fragments or peptides under urinary conditions.

[0361] Example 4 demonstrates a combination of antibodies of the invention which bind to CRP, SAA, and LGALS9, for diagnosing a bacterial vs. viral infection.

[0362] In some embodiments, the combination includes the anti-CRP antibodies CRP-PRT-mAb03 and CRP-PRT-mAb09 and the anti-SAA antibodies SAA-PRT-mAb73 and SAA-PRT-mAb69. In some embodiments, the combination includes the anti-CRP antibodies CRP-PRT-mAb03 and CRP-PRT-mAb09 and the anti-LGALS9 antibodies LGAL-PRT-mAb60 and LGAL-PRT-mAb45.

[0363] In some embodiments, the combination includes the anti-SAA antibodies SAA-PRT-mAb73 and SAA-PRT-mAb69 and the anti-LGALS9 antibodies LGAL-PRT-mAb60 and LGAL-PRT-mAb45.

[0364] In some embodiments, the combination includes the anti-CRP antibodies CRP-PRT-mAb03 and CRP-PRT-mAb09, the anti-SAA antibodies SAA-PRT-mAb73 and SAA-PRT-mAb69, and the anti-LGALS9 antibodies LGAL-PRT-mAb60 and LGAL-PRT-mAb45.

[0365] In some embodiments, the combination of isolated polypeptide and additional polypeptide exhibits a wave shift of at least about 0.2 nanometer in an Octet binding assay with the protein target as antigen.

[0366] Table 1: List of peptide targets with SEQ ID Nos

[0367] Protein Peptide Peptide sequence SEQ ID No.

[0368] CRP CRP-P01 GYSIFSYATKRQDNEILIFWSK 861 CRP CRP-P02 RQDNEILIFWSK 862 CRP GYSIFSYATK 863 CRP APLTKPLK 864 CRP YEVQGEVFTKPQLWP 865 CRP ESDTSYVSLK 866 BTLA BTLA-P01 RQSEHSILAGDPFELECPVKYCANRPHVTWCK 867 BTLA BTLA-P02 YCANRPHVTWCK 868 BTLA RQSEHSILAGDPFELECPVK 869 EGF EGF-P01 RIYWVDLER 870 EGF EGF-P02 RLFWTDTGINPR 871 EGF LCSDIDECEMGVPVCPPASSK 872 EGF LFWIQYNR 873 EGF LYWCDAK 874 EGF CISEGEDATCQCLK 875 FGA FGA-P01 GSESGIFTNTK 876 FGA FGA-P02 QFTSSTSYNR 877 FGA TVIGPDGHK 878 FGA GDSTFESK 879 FGA TVIGPDGHKEVTK 880 FGA VTSGSTTTTR 881 LGALS9 LGAL-P01 FEDGGYVVCNTRQNGSWGPEER 882 LGALS9 LGAL-P02 FEDGGYVVCNT 883 LGALS9 FEDGGYVVCNTR 884 LGALS9 FAVNFQTGFSGNDIAFHFNPR 885 LGALS9 QNGSWGPEER 886

[0369]

[0370] LGALS9 VMVNGILFVQYFHR 887 LGALS9 THMPFQK 888 SAA SAA-P01 GAEDSLADQAANKWGR 889 SAA SAA-P02 GNYDAAKRGPGGAWAAEVITDAR 890 SAA SAA-P03 GAEDSLADQAANEWGR 891 SAA SAA-P04 GNYDAAKRGPGGAWAAEVISNAR 892 SAA EANYIGSDK 893 SAA FFGHGAEDSLADQAANEWGR 894 SAA GPGGVWAAEAISDAR 895 SAA GPGGAWAAEVISNAR 896 SAA RGPGGVWAAEAISDAR 897

[0371]

[0372] SAA DPNHFRPAGLPEK 898

[0373] Diagnostic methods and uses of the isolated polypeptide

[0374] In some embodiments, there is provided a diagnostic method including detecting a protein target or a peptide thereof in a sample from a subject in need of a diagnosis by contacting the sample with the isolated polypeptide disclosed herein or with the combination disclosed herein.

[0375] In some embodiments, there is provided the isolated polypeptide disclosed herein or the combination disclosed herein, for use in a diagnostic method including detecting a protein target or a peptide thereof by using the isolated polypeptide disclosed herein or the combination disclosed herein.

[0376] Definitions and embodiments mentioned above and which may be relevant to the diagnostic methods and use embodiments also apply here, and vice versa. Some particularly relevant embodiments may be pointed out or explicitly repeated. For terms used herein, unless stated otherwise, their definition and embodiments are intended to be the same as above (mutatis mutandis).

[0377] In some embodiments, the diagnostic method is a method for diagnosis of whether an infection is a bacterial or a viral infection. In some embodiments, the diagnostic method is a method for diagnosis or detection of infection, systemic infection, systemic inflammation, cancer, autoimmune condition, kidney disease, infectious disease, urinary tract infection (URTI), cardiovascular disease, cardiac infection, a rheumatic condition, and / or a metabolic disorder.

[0378] In some embodiments, the sample is a urine sample. In some embodiments, the detecting is done by the specific binding of the isolated polypeptide disclosed herein or the combination disclosed herein to the protein target or peptide thereof in the urine sample. In some embodiments, the binding is under urinary conditions.

[0379] In some embodiments, the method includes using more than one different isolated polypeptide. In some embodiments, at least one of the isolated polypeptides is conjugated to a functional molecule. In some embodiments, each of the isolated polypeptides is conjugated to a different functional molecule. Diagnosing bacterial vs. viral infection

[0380] In some embodiments, there is provided a method for predicting in a urine sample of a subject suspected of having an infection, whether the infection is a bacterial infection and / or a viral infection, the method including:

[0381] a. contacting a urine sample of the subject with one or more isolated polypeptides disclosed herein;

[0382] b. detecting binding of the one or more isolated polypeptides to a protein target selected from CRP, BTLA, SAA, LGALS9, EGF, and FGA, or a peptide thereof; and c. predicting whether the infection is bacterial and / or viral based on the detecting in step (b).

[0383] In general, definitions and embodiments mentioned above and which may be relevant to the inflammation prediction embodiments, also apply to the present embodiments, and vice versa. Some particularly relevant embodiments may be pointed out or explicitly repeated. For terms used herein, unless stated otherwise, their definition and embodiments are intended to be the same as above (mutatis mutandis).

[0384] It is appreciated that the protein target detected in step (b) is the protein target to which the isolated polypeptide is capable of specifically binding. Accordingly, in some embodiments, the isolated polypeptide in step (a) is capable of specifically binding to CRP and the protein target in step (b) is CRP. In some embodiments, the isolated polypeptide in step (a) is capable of specifically binding to BTLA and the protein target in step (b) is BTLA. In some embodiments, the isolated polypeptide in step (a) is capable of specifically binding to SAA and the protein target in step (b) is SAA. In some embodiments, the isolated polypeptide in step (a) is capable of specifically binding to LGALS9 and the protein target in step (b) is LGALS9. In some embodiments, the isolated polypeptide in step (a) is capable of specifically binding to EGF and the protein target in step (b) is EGF. In some embodiments, the isolated polypeptide in step (a) is capable of specifically binding to FGA and the protein target in step (b) is FGA.

[0385] In some embodiments, when binding of at least one protein target selected from CRP, FGA, and SAA or to a peptide thereof is detected in step (b), the infection is predicted to be a bacterial infection.

[0386] In some embodiments, when binding of at least one protein target selected from BTLA, EGF, LGALS9 or to a peptide thereof is detected in step (b), the infection is predicted to be a viral infection.

[0387] The term “suspected of having an infection” with reference to a subject, means that the subject presents with symptoms typical of an infection in general, such as fever, pain, feeling weak and / or tired, signs of inflammation, etc. In some embodiments, the subject presents symptoms which are typical to a bacterial or to a viral infection. In some embodiments, the subject presents symptoms which are typical to a specific infection.

[0388] The term “urine sample” may refer to any form of urine that may be tested, including, for example, a urine sample provided in a container such as a urine cup; urine used directly during urination, such as urinating on a device, such as on a stick, which is capable of detecting the presence of peptides in the urine; and urine taken from a urine output device such as a device already containing urine (e.g. a stick after urination), a urine bag, a diaper, or a catheter. In some embodiments, the urine sample has previously been obtained from the subject.

[0389] Contacting the urine sample in step (a) is generally done under suitable conditions (such as pH, salt concentrations), which facilitate binding of isolated polypeptides to the protein target or peptide thereof. Such conditions may be empirically determined for each antibody.

[0390] In some embodiments, the peptide includes at least one sequence selected from sequences having at least 90%, 95%, 98%, or 99% identity to sequences presented in Table 1.

[0391] Detecting the isolated polypeptides binding to the proteins or peptides in step (b) may be conducted by any suitable method, such as fluorescent assays, colorimetric assays, radioactive assays, magnetic beads assays, methods based on binding partners (such as biotin and avidin), etc. More specific examples for suitable assays include fluorescence activated cell sorting (FACS), enzyme-linked immunosorbent assay (ELISA), a dot blot assay, a dipstick, an antibody chip, a multiplex bead immunoassay, and a lateral flow test. Accordingly, the isolated polypeptides may be labelled, such as fluorescently-labelled, radioactively labelled, or by any other label that may be later detected.

[0392] It is appreciated that the sensitivity of detection depends on the method used, e.g. on an antibody concentration and binding constant and / or on the concentrations and sensitivities of detection agents used in the method, as well as on additional parameters. Accordingly, the sensitivity of detection may be calibrated such that detection of binding corresponds to a desired result.

[0393] The predicting in step (c) may be conducted by methods known in the art, such as by visual detection of a color reaction which directly indicates a positive result, by imaging, by computer processing, etc.

[0394] In some embodiments, “predicting” means predicting a desired parameter with a high probability. This is meant to reflect the fact that the predicting in step (c) most likely does not indicate a 100% certainty. However, the prediction is expected to provide a reasonable basis for determining the desired parameter, and treating the subject with a suitable agent, if needed. The desired parameter may be, e.g., bacterial or viral infection. In some embodiments, “predicting” means increasing a probability of predicting a desired parameter. In some embodiments, the high probability is a probability of at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

[0395] In some embodiments, predicting that the infection is bacterial means that the infection has a high probability of being a bacterial infection. In some embodiments, predicting that the infection is viral means that that the infection has a high probability of being a viral infection.

[0396] The term “increasing a probability of predicting”, reflects the fact that the prediction according to the methods of the invention may be done in addition to other parameters such as physical features of the subject, e.g., that are typical to a bacterial or to a viral infection (e.g., fever, presence of additional symptoms such as rash, puss, immune system activity parameters such as types of cells involved in the immune response, etc.). Accordingly, the methods of the invention may be used as an additional test, which increases the probability of a correct prediction. However, in some embodiments, the methods of the invention are used without additional parameters. In some embodiments, the methods of the invention are suitable for use by the subject without a need for a health care professional. In some embodiments, the methods of the invention are suitable for use in the home of the subject. The advantage is that it allows the subject to know, for example, whether or not there is a need to reach a physician in order to receive antibiotics.

[0397] In some embodiments, the high probability is higher than a reference probability, where the methods of the invention are not used. In some embodiments, the high probability is higher than a reference probability by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. In some embodiments, the increasing the probability is by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%, compared to a reference where the methods of the invention are not used.

[0398] In some embodiments, the predicting in step (c) requires further processing, computation, or calculation. In some embodiments, the predicting is conducted by a processor, In some embodiments, the detection in step (b) is performed by a processor, as noted above, and the detection is further processed in step (c). In some embodiments, the detection in step (b) may be based on images, such as by a camera, a cell phone, or another appropriate imaging device, and the image may be viewed or analyzed by a processor.

[0399] In some embodiments, the predicting in step (c) includes processing by a computer analysis, e.g., by using machine learning algorithms such as learning and pattern recognition algorithms, clustering algorithms, supervised classification algorithms including, but not limited to, gradient boosted trees, random forest, regularized regression, multiple linear regression (MLR), principal component regression (PCR), partial least squares (PLS), discriminant function analysis (DFA) including linear discriminant analysis (LDA), nearest neighbor, artificial neural networks, multilayer perceptrons (MLP), generalized regression neural network (GRNN), and combinations thereof, or non-supervised clustering algorithms, including, but not limited to, K-means, spectral clustering, hierarchical clustering, gaussian mixture models, and combinations thereof. In a particular embodiment, the algorithm is selected from the group consisting of gradient boosted trees, random forest, regularized regression, and combinations thereof.

[0400] The subject may be any subject, including a mammal such as a human or an animal subject. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human subject. It is noted that the present invention is suitable for veterinary applications.

[0401] In some embodiments, the subject is a child. In some embodiments, the subject is an adult. In some embodiments, the subject is an elderly adult.

[0402] In some embodiments, the infection is chronic. In some embodiments, the infection is acute. In some embodiments, the infection is systemic. In some embodiments, the infection is local.

[0403] In some embodiments, the infection is selected from: abscess, bacteremia, bronchitis, cellulitis, cholangitis, cholecystitis, colitis, cytomegalovirus (CMV) infection, dengue infection, dental infection, diverticulitis, empyema, endocarditis, Epstein-Barr virus (EBV) infection, folliculitis, herpes zoster infection, influenza, lower respiratory tract infection, measles, meningitis, mononucleosis, myositis, osteomyelitis, parainfluenza bronchitis, parotitis, peritonitis, pharyngitis, pneumonia, rickettsia infection, stemitis, upper respiratory tract infection (URTI), varicella-zoster virus (VZV) infection, and combinations thereof.

[0404] In some embodiments, the infection is a URTI.

[0405] In some embodiments, the URTI is selected from: bacterial tracheitis, bronchitis, cytomegalovirus (CMV) infection, epiglottitis, measles, meningitis, mumps, pneumonia, sinusitis, streptococcal pharyngitis (strep throat), and viral URTIs, such as those caused by adenovirus, coronavirus, influenza, parainfluenza virus respiratory syncytial virus (RSV), rhinovirus, and / or varicella zoster virus.

[0406] In some embodiments, the URTI is caused by gram positive bacteria. In some embodiments, the URTI is caused by gram negative bacteria. In some embodiments, the URTI is caused by a bacterial agent selected from: Bordetella pertussis, Burkholderia pseudomallei, Chlamydophila pneumoniae, Corynebacterium diphtheriae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Staphylococcus aureus, Streptococcus pyogenes (Group A Streptococcus), Streptococcus pneumoniae (Pneumococcus), and combinations thereof.

[0407] In some embodiments, the URTI is caused by a viral agent selected from: adenoviruses, CMV, coronaviruses (e.g. SARS-CoV-2; COVID-19), human metapneumovirus, influenza virus (including influenza virus type A, B, and / or C), measles virus, mumps virus, parainfluenza virus, respiratory syncytial virus, rhinoviruses, RSV, varicella zoster virus, and combinations thereof.

[0408] In some embodiments, the method further includes a treatment step. In some embodiments, the treatment step includes treating the subject with an antibiotic or with an antiviral treatment.

[0409] The antibiotic or antiviral treatment may be adapted to the specific case, based on additional symptoms.

[0410] In some embodiments, suitable antibiotics include broad-spectrum gram-positive antibiotics, such as vancomycin and linezolid; broad-spectrum gram-negative antibiotics, such as penicillin (e.g., piperacillin and tazobactam), cephalosporin (e.g., cefoperazone, cefotaxime, cefepime and cefpirome); imipenem (e.g., imipenem monohydrate); and aminoglycosides (e.g., gentamicin, tobramycin, amikacin, plazomicin, streptomycin, neomycin, and paromomycin); and combinations thereof.

[0411] Suitable antiviral treatments may include broad spectrum anti-viral drugs, or drugs specific to certain viruses, based on symptoms or on further analysis.

[0412] Administration regimens and doses are generally known in the art and may be calculated based on specific features relevant to a specific case.

[0413] Methods of treatment by using the isolated polypeptide for diagnosis

[0414] In some embodiments, there is provided a method of treating a subject in need thereof, including a step of detecting a protein target or peptide thereof in a sample from the subject by contacting the sample with the isolated polypeptide disclosed herein or with the combination disclosed herein; and a step of treating the subject based on the results of the diagnostic step.

[0415] In some embodiments, there is provided a method for treating a bacterial infection in a subject in need thereof, including:

[0416] a. contacting a urine sample of the subject with one or more isolated polypeptides disclosed herein;

[0417] b. detecting binding of the one or more isolated polypeptides to a protein target selected from CRP, BTLA, SAA, LGALS9, EGF, and FGA, or a peptide thereof; c. predicting that the infection is a bacterial infection based on the detection of binding of the one or more isolated polypeptides to the protein target or peptide thereof; and d. treating the subject with an antibiotics.

[0418] In some embodiments, the one or more isolated polypeptides is capable of specifically binding CRP, FGA, and / or SAA and the protein target is CRP, FGA, and / or SAA. In some embodiments, there is provided a method for treating a viral infection in a subject in need thereof, including:

[0419] a. contacting a urine sample of the subject with one or more isolated polypeptides disclosed herein;

[0420] b. detecting binding of the one or more isolated polypeptides to a protein target selected from CRP, BTLA, SAA, LGALS9, EGF, and FGA, or a peptide thereof; c. predicting that the infection is a viral infection or based on the detection of binding of the one or more isolated polypeptides to the protein target or peptide thereof; and d. treating the subject with an antiviral treatment.

[0421] In some embodiments, the one or more isolated polypeptides is capable of specifically binding BTLA, EGF, and / or LGALS9 and the protein target is BTLA, EGF, and / or LGALS9.

[0422] It is appreciated that the protein target detected in step (b) is the protein target to which the isolated polypeptide is capable of specifically binding.

[0423] Definitions and embodiments mentioned above and which may be relevant to the treatment methods embodiments, also apply here, and vice versa. Some particularly relevant embodiments may be pointed out or explicitly repeated. For terms used herein, unless stated otherwise, their definition and embodiments are intended to be the same as above (mutatis mutandis).

[0424] The term “treating” or “treatment”, as used herein, refers to means of obtaining a desired physiological effect. The effect may be therapeutic in terms of partially or completely curing a disease and / or symptoms attributed to the disease. The term includes inhibiting the disease, i.e. arresting its development; or ameliorating the disease, i.e. causing regression of the disease, e.g., by eliminating or ameliorating its symptoms.

[0425] Methods of administration include, but are not limited to, parenteral, e.g., intravenous, intraperitoneal, intramuscular, subcutaneous; mucosal (e.g., oral, sublingual, intranasal, buccal, vaginal, rectal, intraocular), intrathecal, topical, and intradermal routes. Administration can be systemic or local.

[0426] Methods for predicting efficacy of treatment

[0427] In some embodiments, there is provided a method for predicting efficacy of a treatment in a subject suffering from a bacterial or a viral infection, the method including:

[0428] a. administering to the subject a treatment including an antibiotics or antiviral treatment; b. contacting a urine sample of the subject, taken after administration, with one or more isolated polypeptides disclosed herein; c. detecting binding of the one or more isolated polypeptides to a protein target selected from CRP, BTLA, SAA, LGALS9, EGF, and FGA, or a peptide thereof; and d. predicting whether the treatment is effective based on the detecting in step (c).

[0429] In some embodiments, if binding is detected in step (c) then treatment is not effective. In some embodiments, if binding is not detected in step (c) then treatment is effective.

[0430] It is appreciated that the protein target detected in step (b) is the protein target to which the isolated polypeptide is capable of specifically binding.

[0431] In general, definitions and embodiments mentioned above and which may be relevant to the kit embodiments also apply here, and vice versa. Some particularly relevant embodiments may be pointed out or explicitly repeated. For terms used herein, unless stated otherwise, their definition and embodiments are intended to be the same as above (mutatis mutandis).

[0432] Kits and devices for using the isolated polypeptide

[0433] In some embodiments, there is provided a diagnostic kit including the isolated polypeptide disclosed herein or the combinations disclosed herein, and instructions for use.

[0434] In some embodiments, there is provided a kit for predicting in a urine sample of a subject suspected of having an infection, whether the infection is a bacterial infection and / or a viral infection, the kit including:

[0435] a. one or more one or more isolated polypeptides disclosed herein;

[0436] b. at least one reagent for detecting the binding of the one or more isolated polypeptides to a protein target selected from CRP, BTLA, SAA, LGALS9, EGF, and FGA or a peptide thereof, in a urine sample; and

[0437] c. instructions for use.

[0438] Definitions and embodiments mentioned above and which may be relevant to the kits embodiments, also apply here, and vice versa. Some particularly relevant embodiments may be pointed out or explicitly repeated. For terms used herein, unless stated otherwise, their definition and embodiments are intended to be the same as above (mutatis mutandis).

[0439] In some embodiments, the reagent is suitable for use with an assay based on a fluorescent assay, a colorimetric assays, a radioactive assays, a magnetic beads assays, etc. In some embodiments, the reagent is suitable for use with lateral flow (LFA), ELISA, dipstick, antibody chip, western blot, immunohistochemistry (IHC), flow cytometry, chemiluminescent immunoassay (CLIA), radioimmunoassay (RIA), magnetic bead-based immunoassay, ELISPOT (enzyme-linked immunoSpot), immunoprecipitation, dot blot, and biotin-streptavidin immunoassay. In some embodiments, the kit further includes reagents and / or a device for performing a lateral flow assay.

[0440] Lateral flow assays are known in the art, and generally include a series of pads including capillary beds, along which a tested urine (fluid) sample moves. Some of the pads include one or more immobilized binding agents (such as antibodies) and necessary reagents, such that when a peptide in the urine sample binds to an immobilized binding agent, a color reaction is produces, by principles similar to the affinity chromatography principles on which an ELISA test is based. This color reaction provides a positive detection of the bound peptide.

[0441] In some embodiments, the kit further includes an additional polypeptide, as described above. In some embodiments, the isolated polypeptide and / or the additional polypeptide is an antibody. In some embodiments, the isolated polypeptide and / or the additional polypeptide is conjugated to a functional agent, such as described hereinabove.

[0442] In some embodiments, the diagnostic kit includes the combination disclosed herein, wherein the isolated polypeptide is conjugated to a functional agent, and the additional polypeptide is conjugated to a different functional agent. The functional agent may be any agent suitable for the method of detection the kit is used for. In some embodiments, the isolated or the additional polypeptide, whichever functions as a detection antibody in a test such as a lateral flow assay, is conjugated to gold nanoparticles, for use in a colloidal gold (colorimetric) detection method. In some embodiments, the functional agent is a fluorescent label or nanoparticle.

[0443] In some embodiments, the kit further includes a detection device, such as a lateral flow device and / or an immunoassay device-based reader designed to rapidly and accurately measure specific protein levels in patient samples. It may utilize technologies like fluorescence, chemiluminescence, or electrochemical detection for precise measurement.

[0444] In some embodiments, there is provided an article of manufacture including the isolated polypeptide disclosed herein. In some embodiments, the article of manufacture is a lateral flow device.

[0445] Table 2: Protein SEQ ID Nos. for antibodies

[0446] SEQ ID No.

[0447] VH VH VH VL VL VL

[0448] Antibody name VH VLCDR1 CDR2 CDR3 CDR1 CDR2 CDR3BTLA-P01-mAb01 1 2 3 4 5 6 7 8 BTLA-P01-mAb02 21 22 23 24 25 26 27 28 BTLA-P01-mAb03 41 42 43 44 45 46 47 48 BTLA-P01-mAb04 61 62 63 64 65 66 67 68

[0449]

[0450] BTLA-P01-mAb05 81 82 83 84 85 86 87 88 BTLA-P01-mAb06 101 102 103 104 105 106 107 108 BTLA-P01-mAb07 121 122 123 124 125 126 127 128 BTLA-P01-mAb08 141 142 143 144 145 146 147 148 BTLA-P01-mAb09 161 162 163 164 165 166 167 168 BTLA-PRT-mAb25 1351 1352 1353 1354 1355 1356 1357 1358 BTLA-PRT-mAb26 1371 1372 1373 1374 1375 1376 1377 1378 BTLA-PRT-mAb31 1391 1392 1393 1394 1395 1396 1397 1398 BTLA-PRT-mAb35 1411 1412 1413 1414 1415 1416 1417 1418 BTLA-PRT-mAb37 1431 1432 1433 1434 1435 1436 1437 1438 BTLA-PRT-mAb66 1451 1452 1453 1454 1455 1456 1457 1458 CRP-POl-mAblO 181 182 183 184 185 186 187 188 CRP-POl-mAbll 201 202 203 204 205 206 207 208 CRP-P01-mAbl2 221 222 223 224 225 226 227 228 CRP-POl-mAbl3 241 242 243 244 245 246 247 248 CRP-P01-mAbl4 261 262 263 264 265 266 267 268 CRP-POl-mAbl5 281 282 283 284 285 286 287 288 CRP-PRT-mAbOl 931 932 933 934 935 936 937 938 CRP-PRT-mAbO3 971 972 973 974 975 976 977 978 CRP-PRT-mAbO4 991 992 993 994 995 996 997 998 CRP-PRT-mAbO6 1031 1032 1033 1034 1035 1036 1037 1038 CRP-PRT-mAbO7 1051 1052 1053 1054 1055 1056 1057 1058 CRP-PRT-mAbO9 1091 1092 1093 1094 1095 1096 1097 1098 CRP-PRT-mAb10 1111 1112 1113 1114 1115 1116 1117 1118 CRP-PRT-mAbll 1131 1132 1133 1134 1135 1136 1137 1138 CRP-PRT-mA l5 1211 1212 1213 1214 1215 1216 1217 1218 CRP-PRT-mAbl6 1231 1232 1233 1234 1235 1236 1237 1238 CRP-PRT-mAb20 1311 1312 1313 1314 1315 1316 1317 1318 EGF-P01-mAbl6 301 302 303 304 305 306 307 308 EGF-P01-mAbl7 321 322 323 324 325 326 327 328 EGF-POl-mAbl8 341 342 343 344 345 346 347 348 EGF-P01-mAbl9 361 362 363 364 365 366 367 368 EGF-P01-mAb20 381 382 383 384 385 386 387 388 EGF-P02-mAb21 401 402 403 404 405 406 407 408 EGF-P01-mAb22 421 422 423 424 425 426 427 428 EGF-P01-mAb23 441 442 443 444 445 446 447 448 EGF-P02-mAb24 461 462 463 464 465 466 467 468 FGA-P02-mAb25 481 482 483 484 485 486 487 488 FGA-P02-mAb26 501 502 503 504 505 506 507 508 FGA-P02-mAb27 521 522 523 524 525 526 527 528 FGA-P02-mAb28 541 542 543 544 545 546 547 548 FGA-P02-mAb29 561 562 563 564 565 566 567 568 FGA-P01-mAb30 581 582 583 584 585 586 587 588 FGA-POl-mAb31 601 602 603 604 605 606 607 608 FGA-P01-mAb32 621 622 623 624 625 626 627 628 FGA-P02-mAb33 641 642 643 644 645 646 647 648 LGAL-P01-mAb34 661 662 663 664 665 666 667 668 LGAL-PRT-mAb41 1471 1472 1473 1474 1475 1476 1477 1478 LGAL-PRT-mAb45 1491 1492 1493 1494 1495 1496 1497 1498 LGAL-PRT-mAb49 1511 1512 1513 1514 1515 1516 1517 1518 LGAL-PRT-mAb53 1531 1532 1533 1534 1535 1536 1537 1538 LGAL-PRT-mAb55 1551 1552 1553 1554 1555 1556 1557 1558 LGAL-PRT-mAb60 1571 1572 1573 1574 1575 1576 1577 1578 LGAL-PRT-mAb61 1591 1592 1593 1594 1595 1596 1597 1598 SAA-P01-mAb35 681 682 683 684 685 686 687 688 SAA-P01-mAb36 701 702 703 704 705 706 707 708 SAA-P02-mAb37 721 722 723 724 725 726 727 728 SAA-P01-mAb38 741 742 743 744 745 746 747 748 SAA-P02-mAb39 761 762 763 764 765 766 767 768 SAA-P02-mAb40 781 782 783 784 785 786 787 788 SAA-P01-mAb41 801 802 803 804 805 806 807 808 SAA-P01-mAb42 821 822 823 824 825 826 827 828 SAA-P02-mAb43 841 842 843 844 845 846 847 848 SAA-PRT-mAb56 1611 1612 1613 1614 1615 1616 1617 1618 SAA-PRT-mAb64 1631 1632 1633 1634 1635 1636 1637 1638 SAA-PRT-mAb69 1651 1652 1653 1654 1655 1656 1657 1658 SAA-PRT-mAb71 1671 1672 1673 1674 1675 1676 1677 1678 SAA-PRT-mAb72 1691 1692 1693 1694 1695 1696 1697 1698 SAA-PRT-mAb73 1711 1712 1713 1714 1715 1716 1717 1718

[0451] Table 3: Nucleic acid SEQ ID Nos. for antibodies

[0452] SEQ ID No.

[0453] VH VH VH VL VL VL

[0454] Ab name VH VLCDR1 CDR2 CDR3 CDR1 CDR2 CDR3BTLA-P01-mAb01 11 12 13 14 15 16 17 18 BTLA-P01-mAb02 31 32 33 34 35 36 37 38 BTLA-P01-mAb03 51 52 53 54 55 56 57 58 BTLA-P01-mAb04 71 72 73 74 75 76 77 78 BTLA-P01-mAb05 91 92 93 94 95 96 97 98 BTLA-P01-mAb06 111 112 113 114 115 116 117 118 BTLA-P01-mAb07 131 132 133 134 135 136 137 138 BTLA-P01-mAb08 151 152 153 154 155 156 157 158 BTLA-P01-mAb09 171 172 173 174 175 176 177 178 BTLA-PRT-mAb25 1361 1362 1363 1364 1365 1366 1367 1368 BTLA-PRT-mAb26 1381 1382 1383 1384 1385 1386 1387 1388 BTLA-PRT-mAb31 1401 1402 1403 1404 1405 1406 1407 1408 BTLA-PRT-mAb35 1421 1422 1423 1424 1425 1426 1427 1428 BTLA-PRT-mAb37 1441 1442 1443 1444 1445 1446 1447 1448 BTLA-PRT-mAb66 1461 1462 1463 1464 1465 1466 1467 1468 CRP-POl-mAblO 191 192 193 194 195 196 197 198 CRP-POl-mAbll 211 212 213 214 215 216 217 218 CRP-P01-mAbl2 231 232 233 234 235 236 237 238 CRP-P01-mAbl3 251 252 253 254 255 256 257 258 CRP-P01-mAbl4 271 272 273 274 275 276 277 278 CRP-P01-mAbl5 291 292 293 294 295 296 297 298 CRP-PRT-mAbOl 941 942 943 944 945 946 947 948 CRP-PRT-mAbO3 981 982 983 984 985 986 987 988 CRP-PRT-mAbO4 1001 1002 1003 1004 1005 1006 1007 1008 CRP-PRT-mAbO6 1041 1042 1043 1044 1045 1046 1047 1048 CRP-PRT-mAbO7 1061 1062 1063 1064 1065 1066 1067 1068 CRP-PRT-mAbO9 1101 1102 1103 1104 1105 1106 1107 1108 CRP-PRT-mAb10 1121 1122 1123 1124 1125 1126 1127 1128 CRP-PRT-mAbl 1 1141 1142 1143 1144 1145 1146 1147 1148 CRP-PRT-mAbl 5 1221 1222 1223 1224 1225 1226 1227 1228 CRP-PRT-mAbl 6 1241 1242 1243 1244 1245 1246 1247 1248 CRP-PRT-mAb20 1321 1322 1323 1324 1325 1326 1327 1328 EGF-P01-mAb16 311 312 313 314 315 316 317 318 EGF-P01-mAbl7 331 332 333 334 335 336 337 338 EGF-POl-mAbl8 351 352 353 354 355 356 357 358 EGF-P01-mAbl9 371 372 373 374 375 376 377 378 EGF-P01-mAb20 391 392 393 394 395 396 397 398 EGF-P02-mAb21 411 412 413 414 415 416 417 418 EGF-P01-mAb22 431 432 433 434 435 436 437 438 EGF-P01-mAb23 451 452 453 454 455 456 457 458 EGF-P02-mAb24 471 472 473 474 475 476 477 478 FGA-P02-mAb25 491 492 493 494 495 496 497 498 FGA-P02-mAb26 511 512 513 514 515 516 517 518 FGA-P02-mAb27 531 532 533 534 535 536 537 538 FGA-P02-mAb28 551 552 553 554 555 556 557 558 FGA-P02-mAb29 571 572 573 574 575 576 577 578 FGA-POl-mAb3O 591 592 593 594 595 596 597 598 FGA-POl-mAb31 611 612 613 614 615 616 617 618 FGA-P01-mAb32 631 632 633 634 635 636 637 638 FGA-P02-mAb33 651 652 653 654 655 656 657 658 LGAL-P01-mAb34 671 672 673 674 675 676 677 678 LGAL-PRT-mAb41 1481 1482 1483 1484 1485 1486 1487 1488 LGAL-PRT-mAb45 1501 1502 1503 1504 1505 1506 1507 1508 LGAL-PRT-mAb49 1521 1522 1523 1524 1525 1526 1527 1528 LGAL-PRT-mAb53 1541 1542 1543 1544 1545 1546 1547 1548 LGAL-PRT-mAb55 1561 1562 1563 1564 1565 1566 1567 1568 LGAL-PRT-mAb60 1581 1582 1583 1584 1585 1586 1587 1588 LGAL-PRT-mAb61 1601 1602 1603 1604 1605 1606 1607 1608 SAA-POl-mAb35 691 692 693 694 695 696 697 698 SAA-P01-mAb36 711 712 713 714 715 716 717 718 SAA-P02-mAb37 731 732 733 734 735 736 737 738 SAA-POl-mAb38 751 752 753 754 755 756 757 758 SAA-P02-mAb39 771 772 773 774 775 776 777 778 SAA-P02-mAb40 791 792 793 794 795 796 797 798 SAA-P01-mAb41 811 812 813 814 815 816 817 818 SAA-P01-mAb42 831 832 833 834 835 836 837 838 SAA-P02-mAb43 851 852 853 854 855 856 857 858 SAA-PRT-mAb56 1621 1622 1623 1624 1625 1626 1627 1628 SAA-PRT-mAb64 1641 1642 1643 1644 1645 1646 1647 1648 SAA-PRT-mAb69 1661 1662 1663 1664 1665 1666 1667 1668 SAA-PRT-mAb71 1681 1682 1683 1684 1685 1686 1687 1688 SAA-PRT-mAb72 1701 1702 1703 1704 1705 1706 1707 1708 SAA-PRT-mAb73 1721 1722 1723 1724 1725 1726 1727 1728

[0455] The antibody name includes the protein target (e.g., BTLA), the target it was raised against (PRT - a complete protein, P01 / P02 - a specific peptide), and a serial antibody number. It is noted that many BTLA, CRP, and LGALS9 antibodies bind both PO 1 and P02 of the same protein (these peptides overlap in sequence, as seen from Table 4), however at different affinities, as can be seen from Fig. 1. Additionally, SAA antibodies binding P01 also bind to SAA-P03, and SAA antibodies binding P02 also bind to SAA-P04. Finally, as may be seen from Fig. 1, some antibodies also bind to some extent two peptides from the same protein, although the peptides do not overlap in sequence.

[0456] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains.

[0457] The term "a" and "an" refers to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0458] The term "about", when referring to a measurable value such as an amount, a ratio, and the like, is meant to encompass variations of ±10% of the indicated value, as such variations are also suitable to perform the disclosed invention. Any numerical values appearing in the application are intended to be construed as if preceded by “about”, unless indicated otherwise.

[0459] The term “nucleic acid molecule” is a molecule including at least one nucleotide sequence. A nucleic acid molecule may be linear, circular, or branched, and the nucleotides may be modified or unmodified. In some embodiments, a nucleic acid molecule is a nucleic acid vector (usually a DNA vector) which includes elements such as genes, promoters, linkers, etc.

[0460] The term “bp”, as used herein, means base pair, or base pairs.

[0461] The term “aa”, as used herein, means amino acid or amino acids.

[0462] While certain embodiments of the invention have been illustrated and described, it will be clear that the invention is not limited to the embodiments described herein. Numerous modifications, changes, variations, substitutions, and equivalents will be apparent to those skilled in the art without departing from the spirit and scope of the present invention as described by the claims, which follow.

[0463] The following examples are presented in order to more fully illustrate some embodiments of the invention. They should in no way be construed, however, as limiting the broad scope of the invention. One skilled in the art can readily devise many variations and modifications of the principles disclosed herein without departing from the scope of the invention.

[0464] EXAMPLES

[0465] Methods

[0466] Table 4: Target human proteins and peptides

[0467] „,. UniProt Peptide „

[0468] Protein..rPeptide sequence

[0469] Accession name

[0470] CRP-P01 GYSIFSYATKRQDNEILIFWSK

[0471] CRP P02741

[0472] CRP-P02 RQDNEILIFWSK

[0473] BTLA-P01 RQSEHSILAGDPFELECPVKYCANRPH BTLA Q7Z6A9 VTWCK

[0474] BTLA-P02 YCANRPHVTWCK

[0475] LGAL-P01 FEDGGYVVCNTRQNGSWGPEER LGALS9 000182

[0476] LGAL-P02 FEDGGYVVCNT

[0477] SAA-P01 GAEDSLADQAANKWGR

[0478] P0DJI8, SAA-P02 GNYDAAKRGPGGAWAAEVITDAR

[0479] SAA

[0480] P0DJI9 SAA-P03 GAEDSLADQAANEWGR

[0481] SAA-P04 GNYDAAKRGPGGAWAAEVISNAR

[0482] EGF-P01 RIYWVDLER

[0483] EGF P01133

[0484] EGF-P02 RLFWTDTGINPR

[0485] FGA-P01 GSESGIFTNTK

[0486] FGA P02671

[0487] FGA-P02 QFTSSTSYNR

[0488]

[0489] SEQ ID Numbers for all peptide sequences are provided in Table 1 above.

[0490] Animal immunization

[0491] For immunization, targets (complete proteins or peptides) presented in Table 4 were conjugated at the N-terminus to keyhole limpet hemocyanin (KLH).

[0492] 6-8 weeks old SJL mice and Balb / c mice (Shanghai SLAC Laboratory Animal Center) were immunized with peptides mixture. Mice were housed under Specific Pathogen Free (SPF) conditions. For primary immunization, total 40 pg of peptides with Titermax® adjuvants were intraperitoneally injected into each mouse as planned. After 3 days, total 40 pg of peptides with CpG plus Alum adjuvants were intraperitoneally injected into each mouse in order to enhance the immune response, and subsequent boosts were administered 3-4 days apart. Blood samples from each mouse were collected 3 days after boost 4. The antibody titers in sera (test bleed (TB) sera) were subjected to analysis by enzyme-linked immunosorbent assay (ELISA). Mice with a strong immune response as determined by serum titer were selected and used for hybridoma generation. All the treatment of the animals were strictly followed the ethical committee guidelines.

[0493] Test blood (TB) test by ELISA

[0494] Peptides were conjugated to bovine serum albumin (BSA) and diluted to proper final concentrations into lx phosphate-buffered saline (PBS), coated 100 pL / well on ELISA plate (cat: 9018, Coming). Following overnight incubation at 4°C, plates were blocked with 250 pL assay buffer (1% BSA and 0.05% Tween-20 in PBS) for 1 hr at 37°C. Following 4 washes with PBST (1%BSA and 0.05% Tween®-20 in PBS) using Biotek (Elx 405), Primary bleed (PB) and Test Bleed (TB) sera were diluted by 1:100 and were 10-fold serially diluted (6 points, including 0 point) by assay buffer or urine buffer (1%BSA and 0.05% Tween-20 in simulated urine solution such as Artificial Urine Solution (BIOCHEMAZONE, Cat:#BZ186) respectively. 100 pL / well of the diluted serum solution were added to the plate, incubated for 1 hr at 37°C and wash 4 times with PBST. 100 pL / well secondary antibody (anti-mouse-Fc-HRP (Sigma, A0168, 1:5000) were added and incubated for 0.5 hr at 37°C. Following 4 washes with PBST, 100 pL / well of TMB substrate was added and incubated at room temperature for 5 min. 100 pL / well of IN HC1 were then added to terminate reaction. Plates were read using ELISA plate reader at 450nm wavelength (instrument SpectraMax M5e). Data Analysis was performed using Graphpad prism 6 software.

[0495] Spleen lymphocyte / splenocyte harvest and culture

[0496] Mice selected for fusion were given a final intraperitoneal boost with total 40pg peptide mixture for each target without adjuvant. Three days later the mice were euthanized by carbon dioxide asphyxiation following an approved Institutional Animal Care and Use Committee (IACUC) protocol, and a blood sample, lymphocytes and splenocytes were collected. Serum was generated and used as a positive control (designated as final bleed (FB)) at the hybridoma screening stage. Lymphocytes / splenocytes were centrifuged at 400 g (or 1000 rpm) for 5 min and the supernatant was discarded. Lymphocyte / splenocytes were re-suspended in 5 mL red cell lysis buffer, incubated for 5 min at 4°C, the reaction was stopped by the addition of Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) to 50 mL. Lymphocyte / splenocytes were then centrifuged at 400 g for 5 min, and re-suspended in DMEM.

[0497] SP2 / 0 mouse spleen cells were collected and centrifuged at 400 g for 5 min at room temperature. Culture medium was aspirated and the cells were re-suspended in 20 mL fusion media. Typically, 2.5 x 107SP2 / 0 cells were re-suspended in 20 mL fusion medium.

[0498] Electrofusion

[0499] 5xl07SP2 / 0 cells were added to IxlO8lymphocyte / splenocytes (7:3) to give a final ratio of lymphocytes / splenocytes: SP2 / 0 of 2: 1. The cells were centrifuged at 400 g for 5 minutes, and the medium was discarded. The cell pellet was washed twice with 25ml electrofusion (EF) solution (QIWEN BITECH Cat#CEB005) by centrifuging for 5 minutes at 1500 rpm. and re-suspended in EF solution. The mixture of cells was placed in a fusion slot of a BTX ECM2001 electrofusion system and the fusion was effectuated by a cell fusion generator using an optimized program. After electrofusion, the fused cells were placed in the slot for an additional 10 min. Cells were resuspended in DMEM with 20% FBS + hypoxanthine and thymidine (HT, Coming-cellgro, 25-047-C1), adjusted to 0.5xl06cells / mL, and seeded 100 pL / well in a 96-well plate. Plates were transferred carefully to a 37°C, 5 % CO2 incubator. 100 pL DMEM, 20%FBS, 2xHAT (medium containing hypoxanthine, aminopterin, and thymidine, Sigma, H0262) was then added 24 hrs post-electro-fusion. Cell growth condition and potential contamination were monitored daily. When cell colonies reached 1-2 mm in diameter (usually 10- 14 days post fusion), hybridoma supernatant was collected for screening.

[0500] Hybridoma supernatant screening

[0501] For screening, the peptides were conjugated to biotin at both the N and the C termini. Fusion plates were monitored for growth and fed weekly. Wells with cell growth were screened by primary screening assays in 10-14 days with ELISA assay. After 3 days, secondary screening by confirmatory ELISA was performed.

[0502] Hybridoma clones that exhibited binding to target peptides by ELISA were expanded into 24-well plates. Hybridoma supernatant was collected from 24-well cultures and tested confirmatory ELISA binding assay. Clones that specifically bound target peptides in assay buffer and in urine solution (e.g. Artificial Urine Solution (BIOCHEMAZONE, Cat:#BZ186)) were selected for subcloning.

[0503] Subcloning was performed by limiting dilution for the desired positive parental clones. 96-well plates containing subcloned cells were incubated in a CO2 incubator and the cells were expanded for 7 days. ELISA with target peptides was performed for the subcloning plates. Based on results for each subcloning cell line, subcloned wells (single clones) with a strong and specific positive signal were expanded into a 24-well plate, and the resultant hybridoma supernatants were evaluated by confirmatory ELISA binding assay. Subclones with the specific binding to target peptides in assay buffer and in urine solution were expanded to T-75 cm2flasks. Hybridoma cells were then frozen down.

[0504] For the hybridoma ELISA screening, typically, BSA conjugated peptide were diluted to proper final concentrations into 1 *PBS, coated 100 pL / well on ELISA plate (cat: 9018, Coming). Following overnight incubation at 4°C, plates were blocked with 250 pL assay buffer (1%BSA and 0.05% Tween-20 in PBS) for 1 hr at 37°C. Following 4 washes with PBST using Biotek (Elx 405), hybridoma supernatant (or 1:1 diluted by simulated urine solution) were added to the plate, incubated for 1 hr at 37°C and wash 4 times with PBST. 100 pL / well secondary antibody (anti-mouse-Fc-HRP (Sigma, A0168, 1:5000) were added and incubated for 0.5 hr at 37°C. Following 4 washes with PBST, 100 pL / well of TMB substrate was added and incubated at room temperature for 5 min. 100 pL / well of IN HC1 were then added to terminate reaction. Plates were read using ELISA plate reader at 450nm wavelength (instrument SpectraMax M5e).

[0505] Example 1. Identifying peptides indicative of bacterial vs. viral upper respiratory tract infections (URTI)

[0506] A previous application by the applicant, WO 2025 / 115009 (published after the filing of the present application), focused on identifying biomarkers in urine for distinguishing bacterial from viral infections, based on analyzing urine samples from patients diagnosed with infections including bacterial pneumonia, CMV, Influenza, parainfluenza, meningitis aseptic, Varicella zoster virus (VZV), bronchitis, respiratory syncytial virus (RSV), pneumonia, and measles. The results are briefly summarized here, and additional details can be found in WO 2025 / 115009.

[0507] 80 peptides out of >50,000 peptides were initially identified in urine samples of patients by liquid chromatography-mass spectrometry (LC-MS) and data-independent acquisition (DIA)-NN (APTILA) analysis as being most distinctive in distinguishing bacterial from viral infections. Following validation, the top 20 peptides were selected by having the highest mean entropy gain. Cross validation of the type Leave One Out (LOO) was further used to reduce bias. Briefly, one patient is removed at each iteration, and entropy calculations are repeated each time to find the highest entropy threshold and to train a logistic regression model. The patient removed is used as the test for the model. Following establishing predictions for all patients, accuracy, precision, and additional parameters are calculated for the bacterial infection-related as the positive assumption. The best six peptides were finally selected based on a manual review of histograms showing correlation with bacterial and viral infections (not shown here). Accuracy of predictions by the six best peptides are presented in Table 5. B and V represent average log intensities for the bacterial and viral subgroups. Various combinations of the six peptides (including 2-6 peptides per combination) were also tested for the same parameters, generally exhibiting good prediction values, many combinations exhibiting accuracy (proportion of correct classifications across all samples) above 0.8 and specificity (proportion of bacterial cases correctly identified) of over 0.9 (not shown here). Table 5: Top 20 peptides after LOO, sorted by the mean entropy gain Peptide Gene Accuracy Accuracy B V Classifier Validation YCANRPHVTWCK BTLA 0.729730 0.631579 5.78E+04 2.29E+05 RLFWTDTGINPR EGF 0.716216 0.701754 1.03E+07 2.29E+07 RQDNEILIFWSK CRP 0.770270 0.631579 2.00E+06 5.51E+05 FEDGGYVVCNTR LGALS9 0.716216 0.736842 2.25E+06 5.74E+06 EANYIGSDK SAA 0.729730 0.701754 7.03E+06 2.57E+05

[0508]

[0509] GSESGIFTNTK FGA 0.797297 0.649123 2.69E+07 2.50E+06 SEQ ID Nos for all sequences are provided in Table 1 above.

[0510] Example 2: Monoclonal antibodies (mAbs) against diagnostic proteins and peptides in urine Hybridomas were screened for antibodies capable of binding to proteins or peptides presented in Table 4 by dilution of 1:1 in simulated urine (Artificial Urine Solution (BIOCHEMAZONE, Cat:#BZ186)). Amino acid sequences of the most specific antibodies are presented in Table 9 below. Figs. 1A-1K show ELISA binding of mAbs to the corresponding peptides (Figs. 1A-1B: with CRP P01 and P02, respectively; Figs. 1C-1D: with BTLA P01 and P02, respectively; Figs. 1E-1F: with EGF P01 and P02, respectively; Figs. 1G-1H: with FGA P01 and P02, respectively; Figs. 1I-1J: with SAA P01 and P02, respectively; Fig. IK: with LGALS9 P01). EC50 values forthe same antibodies are presented in Tables 6A and 6B. Figs. 2A-2E show binding of antibodies to complete proteins: SAA (Fig. 2A), LGALS9 (Fig. 2B), BTLA (Fig. 2C), and CRP (Figs.2D-2E). Finally, Figs.3A-3E show binding of specific combinations of antibodies against CRP (Figs. 3A and 3B), SAA (Fig. 3C), LGALS9 (Fig. 3D), and BTLA (Fig. 3E).

[0511] Table 6A: EC50 values of anti-peptide mAbs

[0512] Ab Name EC50 P01 EC50 P02

[0513] BTLA-P01-mAb01 0.05318 /

[0514] BTLA-P01-mAb02 0.04417 /

[0515] BTLA-P01-mAb03 0.1529 /

[0516] BTLA-P01-mAb04 0.0372 0.2875

[0517] BTLA-P01-mAb05 0.1524 /

[0518] BTLA-P01-mAb06 0.04887 /

[0519] BTLA-P01-mAb07 0.03994 /

[0520] BTLA-P01-mAb08 0.04204 /

[0521] BTLA-P01-mAb09 0.05175 /

[0522] CRP-POl-mAblO 0.1622 0.03585

[0523] CRP-POl-mAbll 0.0675 0.04601

[0524] CRP-P01-mAb12 0.2676 0.1235

[0525] CRP-P01-mAbl3 0.1091 0.07181 CRP-P01-mAbl4 0.6598 0.04516

[0526] CRP-P01-mAbl5 0.3944 0.1516

[0527] EGF-P01-mAbl6 0.6569 /

[0528] EGF-P01-mAb17 0.06224 /

[0529] EGF-P01-mAbl8 0.03841 /

[0530] EGF-P01-mAbl9 0.03682 /

[0531] EGF-P01-mAb20 0.1124 /

[0532] EGF-P02-mAb21 / 0.0553

[0533] EGF-P01-mAb22 0.1781 /

[0534] EGF-P01-mAb23 0.05255 0.2908

[0535] EGF-P02-mAb24 / 0.06185

[0536] FGA-P02-mAb25 / 0.06095

[0537] FGA-P02-mAb26 / 0.05278

[0538] FGA-P02-mAb27 / 1.757

[0539] FGA-P02-mAb28 / /

[0540] FGA-P02-mAb29 / /

[0541] FGA-P01-mAb30 0.06719 /

[0542] FGA-P01-mAb31 0.03911 /

[0543] FGA-P01-mAb32 0.03697 /

[0544] FGA-P02-mAb33 / 0.03038 l.(jAl.-I’()l-inAb34 7 7

[0545] SAA-P01-mAb35 0.03512 /

[0546] SAA-P01-mAb36 0.03802 /

[0547] SAA-P02-mAb37 8.632 0.05115

[0548] SAA-P01-mAb38 0.04635 /

[0549] SAA-P02-mAb39 / 0.05972

[0550] SAA-P02-mAb40 / 0.2774

[0551] SAA-P01-mAb41 0.07365 /

[0552] SAA-P01-mAb42 0.06478 /

[0553] SAA-P02-mAb43 7.45 0.03684

[0554] EC50 could not be determined (the graph did not reach a plateau)

[0555] Table 6B: EC50 values of anti-complete protein mAbsB | 1Ab Name EC50

[0556] BTLA-PRT-mAb25 0.1665

[0557] BTLA-PRT-mAb26 0.0386

[0558] BTLA-PRT-mAb31 0.1771

[0559] BTLA-PRT-mAb35 0.021

[0560] BTLA-PRT-mAb37 0.1597

[0561] BTLA-PRT-mAb66 0.0397

[0562] CRP-PRT-mAbOl 0.099

[0563] CRP-PRT-mAbO3 0.0957

[0564] CRP-PRT-mAb04 0.057

[0565] CRP-PRT-mAbO6 0.117

[0566] CRP-PRT-mAbO7 0.0629 CRP-PRT-mAb10 0.128

[0567] CRP-PRT-mAbll 0.1088

[0568] CRP-PRT-mAbl5 0.0895

[0569] CRP-PRT-mAbl6 0.1105

[0570] CRP-PRT-mAb20 0.131

[0571] LGALS9-PRT-mAb41 0.1147

[0572] LGALS9-PRT-mAb45 0.09922 LGALS9-PRT-mAb49 0.0775

[0573] LGALS9-PRT-mAb53 0.09727

[0574] LGALS9-PRT-mAb55 0.1224

[0575] LGALS9-PRT-mAb60 0.1155

[0576] LGALS9-PRT-mAb61 0.09776

[0577] SAA-PRT-mAb56 1.889

[0578] SAA-PRT-mAb64 0.4294

[0579] SAA-PRT-mAb69 0.307

[0580] SAA-PRT-mAb71 0.4204

[0581] SAA-PRT-mAb72 0.6507

[0582]

[0583] SAA-PRT-mAb73 0.4192

[0584] Example 3: Sandwich assays for detection of LGALS9 in urine

[0585] Urine samples from patients were analyzed for the presence of LGALS9 by sandwich ELISA. The capture antibody was LGALS9-PRT-mAb60, and detection was performed either with LGALS9-PRT-mAb45 (non-hybrid, monoclonal-monoclonal pair of the invention) or with a commercial polyclonal anti-LGALS9-HRP (R-a-LGAL linked to horseradish peroxidase, hybrid, monoclonal-polyclonal pair). The hybrid format with the commercial antibody failed to generate signal across samples, while the non-hybrid LGALS9-PRT-mAb60 + LGALS9-PRT-mAb45 pair produced distinct positive results in several urine samples, indicating specific and effective detection of urinary LGALS9.

[0586] The results presented in Fig. 4 clearly demonstrate that in patient urine, the pair of LGAL-PRT-mAb60 as capture and LGAL-PRT-mAb45 as detection (non-hybrid mAb-mAb pair) provides reliable quantification of LGALS9, consistently yielding much higher signals across all samples (darker bars). In contrast, the hybrid format produced almost undetectable signals, indicating poor detection capability in this matrix likely since the commercial antibody does not bind the target under urinary conditions (lighter bars).

[0587] Example 4: Diagnosing bacterial vs. viral infections by sandwich ELISA with antibodies of the invention

[0588] ELISA assays in simulated urine were set for detecting CRP, SAA, and LGALS9 by the antibodies indicated in Table 7A. Table 7A: sets of specific antibodies:

[0589] Target Protein Capture Detection

[0590] CRP CRP-PRT-mAb03 CRP-PRT-mAbO9

[0591] SAA SAA-PRT-mAb73 SAA-PRT-mAb69

[0592] LGALS9 LGAL-PRT-mAb60 LGAL-PRT-mAb45

[0593]

[0594] Clinical validation of the developed sandwich ELISA assays was performed using frozen urine samples from 33 patients with acute respiratory infections (20 bacterial, 13 viral infections) within the original 269-patient cohort. A rule-based classification algorithm was developed employing optimized thresholds for three biomarkers: calibrated CRP, SAA, and LGLSA9. Optimal discrimination thresholds were determined through exhaustive grid search methodology, systematically evaluating all unique measured sample values as potential threshold candidates across all three biomarkers, testing over 31,000 possible threshold combinations to identify cutoffs that maximize classification accuracy. The classification rule employs a two-stage Boolean logic framework: samples are classified as bacterial infection if (CRP > 5.80 OR SAA > 29.0 ngr / ml) AND LG < 62 ngr / ml). This structure incorporates an OR-gate for inflammatory markers (CRP, SAA) to provide diagnostic redundancy and robustness against individual marker variability, recognizing that patients may exhibit differential inflammatory responses, while the AND-gate with the viral-associated marker LG ensures specificity by requiring concordant suppression of viral signatures. The multi-biomarker approach achieved 85% sensitivity (95% CI: 62.1-96.8%) for bacterial detection and 69% specificity (95% CI: 38.6-90.9%) for viral detection, with 81% positive predictive value and 75% negative predictive value, successfully demonstrating translation from proteomic discovery to targeted diagnostic implementation (Table 7B). The 85% bacterial sensitivity prioritizes clinical safety by minimizing missed bacterial infections requiring antibiotic treatment, while the interpretable rule-based structure (rather than black-box machine learning models) supports regulatory approval and implementation in point-of-care devices suitable for home testing applications.

[0595] Table 7B. Clinical Validation Performance of Integrated Biomarker Panel Performance Metric Value 95% CI Clinical Interpretation Sensitivity 85.0% (62.1%-96.8%) Bacterial detection rate (17 / 20) Specificity 69.2% (38.6%-90.9%) Viral detection rate (9 / 13)

[0596]

[0597] Positive Predictive Value 81.0% (58.1%-94.6%) Bacterial prediction accuracy Negative Predictive Value 75.0% (43.8%-93.5%) Viral prediction accuracy Overall Accuracy 78.8% (61. l%-91.0%) Correct classification (26 / 33)

[0598] Classification Results

[0599] True Positive 17 - Correctly identified bacterial True Negative 9 - Correctly identified viral

[0600] False Positive 4 - Viral misclassified as bacterial False Negative 3 - Bacterial misclassified as viral

[0601]

[0602] Example 5: Epitope binning and sandwich ELISA validation of CRP monoclonal antibody pairs.

[0603] The assays were designed to identify compatible antibody pairs that recognize distinct, noncompeting epitopes on a CRP protein. Table 8A presents an epitope binning matrix determined by biolayer interferometry (Octet® RED384 (Sartorius, Cat. No. 18-5156)). Values represent binding response levels between antibody pairs. Bold highlights indicates non-competing antibodies (binding response > 0.2 nm) capable of simultaneous binding to CRP. Table 8B presents results of a sandwich ELISA validation confirming functional antibody pairing. Values represent optical density at 450 nm for each capture-detection combination. Bold highlights indicate high-performing sandwich pairs (OD > 0.8), with optimal combinations achieving 1.3-2.3 OD units. Control antibody (mlgG) and incompatible pairs showed baseline signals < 0.1 OD units. All data represent mean values of duplicate assays. As can be seen, most results overlap between the two methods.

[0604] Table 8A. Epitope binning matrix (Octet)

[0605] AB# mAbOl mAb03 mAbO6 mAbl5 mAbl6 mAb20 Control mAbOl 0.038 0.481 0.046 0.068 0.061 0.538 -0.017 mAbO3 0.266 0.068 0.279 0.218 0.293 0.059 -0.012 mAbO6 0.037 0.446 0.051 0.068 0.058 0.474 -0.013 mAbO9 0.065 0.357 0.102 0.109 0.141 0.337 -0.010 mAbl5 0.052 0.484 0.072 0.047 0.305 0.563 -0.027 mAbl6 0.048 0.254 0.068 0.03 0.028 0.282 -0.044 mAb20 0.228 0.045 0.229 0.194 0.276 0.069 -0.024 Control 0.058 0.099 0.085 0.092 0.076 0.088 -0.002

[0606] Table 8B. Epitope binning matrix (ELISA) AB# mAbOl mAb03 mAbO6 mAbl5 mAbl6 mAb20 Control mAbOl 0.063 1.317 0.066 0.059 0.052 1.463 0.051 mAbO3 2.297 0.059 2.265 2.106 1.853 0.061 0.052 mAbO6 0.066 1.483 0.066 0.064 0.053 1.488 0.053 mAbl5 0.071 1.715 0.205 0.099 0.132 1.799 0.053 mAbl6 0.077 0.59 0.216 0.11 0.053 0.815 0.053 mAb20 1.698 0.343 1.767 1.706 1.455 0.06 0.054 Control 0.052 0.052 0.083 0.061 0.05 0.054 0.054

[0607] Example 6: Detection of biomarkers in urine

[0608] The monoclonal antibodies described above are used in a lateral flow assay for detecting the target proteins or peptides thereof in urine. For that purpose, a first monoclonal antibody targeting CRP, BTLA, LGALS9, SAA, EGF, or FGA or a peptide thereof is immobilized on a substrate, such as a nitrocellulose membrane, of a lateral flow device. A second monoclonal antibody, which targets the same protein as the first monoclonal antibody (or a peptide thereof), is conjugated to a suitable agent for detection, such as gold nanoparticles, for use in a colorimetric detection method, and added to the lateral flow device, or to a kit for using with the lateral flow device. At least the first or the second antibody is selected from the monoclonal antibodies described herein, while the other antibody may either also be selected from antibodies described herein, or obtained from a different source (such a commercial antibody capable of recognizing its target in urine conditions). When the lateral flow device is contacted with urine which contains the target protein, a colored line will appear.

[0609] Table 9: Amino acid sequences for mAbs

[0610] Prot. SID Ab name Ab part Protein Sequence DNA SID EVLLQQSGPELVKPGASVKIPCKASGYT FTDYNMAWVKQSHEKSLEWIGDINPNN

[0611] 1 BTLA-P01 -mAbOl VH GGTIYNLKFKGKATLTVDKSSSTAYME 11

[0612] LRSLTSEDTAVYYCTRDGFDYWGQGTT LTVSS DIKMTQSPSSMYASLGERVTITCKASQD

[0613] 2 BTLA-P01-mAb01 VL DIKMTQSPSSMYASLGERVTITCKASQD INSYLSWFQQKPGKSPKTLIYRANRLVD GVPSRFSGSGSGQDYSLTISSLEYEDMGI YYCLQYDEFPLTFGAGTKLELK

[0614] 3 BTLA-P01 -mAbOl VH CDR1 DYNMA 13 4 BTLA-P01 -mAbOl VH CDR2 DINPNNGGTIYNLKFKG 14 5 BTLA-P01 -mAbOl VH CDR3 DGFDY 15 6 BTLA-P01 -mAbOl VL CDR1 KASQDINSYLS 16 7 BTLA-P01 -mAbOl VL CDR2 RANRLVD 17

[0615]

[0616] 8 BTLA-P01 -mAbOl VL CDR3 LQYDEFPLT 18 DVKVVESGGGLVKPGGSLKLSCAASGF IFSRYTMSWVRQTPEKRLEWVAHSSGG BTLA-P01-mAb02 VH SYIYYPDSVKGRFAISRDNAKNTLYLQ 31

[0617] MTSLKSEDTAMYYCTRDSMDGYDPSY AMDYWGQGTSVTVS S DIVMTQAAFSNPVTLGTSASISCRSSKSL BTLA-P01-mAb02 VL LDSNGITYLYWYLQKPGQSPQLLIYQM mADuz vi. SNLASGVPDRFSSSGSGTDFTLRISRVEA EDVGVYYCAQNLELPRTFGGGTKLEIK BTLA-P01-mAb02 VH CDR1 RYTMS 33 BTLA-P01-mAb02 VH CDR2 TISSGGSYIYYPDSVKG 34 BTLA-P01-mAb02 VH CDR3 DSMDGYDPSYAMDY 35 BTLA-P01-mAb02 VL CDR1 RSSKSLLDSNGITYLY 36 BTLA-P01-mAb02 VL CDR2 QMSNLAS 37 BTLA-P01-mAb02 VL CDR3 AQNLELPRT 38

[0618] QVQLQQSGADLVRPGASVKLSCKALGD TSTDYEMHWVKQTPVHGLEWIGEIHPG BTLA-P01-mAb03 VH SGDTAYNQKFKGKATLTADKSSTTAY 51

[0619] MELSGLTSEDSAVYYCTTGPMEYWGQ GTSVTVSS DIKMTQSPSSMHASLGERVTITCKASQD DTI A Dm AkM V! INRYLSWFQQKPGKSPKTLIYRAKRLVD _ BTLA-P01-mAb03 VL GVPSRFSGSGSGQDYSLTISSLEYEDMGI52

[0620] YYCLQYDEFPFTFGSGTKLEIK BTLA-P01-mAb03 VH CDR1 DYEMH 53 BTLA-P01-mAb03 VH CDR2 EIHPGSGDTAYNQKFKG 54 BTLA-P01-mAb03 VH CDR3 GPMEY 55 BTLA-P01-mAb03 VL CDR1 KASQDINRYLS 56 BTLA-P01-mAb03 VL CDR2 RAKRLVD 57 BTLA-P01-mAb03 VL CDR3 LQYDEFPFT 58

[0621] QVQLKQSGPGLVQPSQSLSITCTVSGFS LTTYGVHWVRQSPGKGLEWLGVMWR BTLA-P01-mAb04 VH GGGTDYDAAFMSRLSITKDNSKSQVFF 71

[0622] KMNSLQLDDTAIYYCAKNKDYGRIRDY Y AMDYWGQGTSVTVS S DIQMNQSPSSLSASLGDTITITCHASQNI 62 BTLA-P01-mAb04 VL DIQMNQSPSSLSASLGDTITITCHASQNI NVWLSWYQQKPGNIPKLLIYKSSNLHT GVPSRFSGSGSGTGFTFTISGLQPEDIAT YYCQQGQDYPLTFGGGTKLDMK BTLA-P01-mAb04 VH CDR1 TYGVH 73 BTLA-P01-mAb04 VH CDR2 VMWRGGGTDYDAAFMS 74 BTLA-P01-mAb04 VH CDR3 NKDYGRIRDYYAMDY 75 BTLA-P01-mAb04 VL CDR1 HASQNINVWLS 76 BTLA-P01-mAb04 VL CDR2 KSSNLHT 77 BTLA-P01-mAb04 VL CDR3 QQGQDYPLT 78

[0623] EVQVQQSGPELVKPGASVKISCKASGY BTLA-P01-mAb05 VH MFTDYYMNWMKQSHGKSLDWIGDINL 91

[0624]

[0625] SNDTTAYNQKFKGKATLTVDKSSSTAY MELRSLTSEDSAVYYCAIWGPMDYWG QGTSVTVSS DIKMTQSPSSMYASLGERVTITCKASQD

[0626] 82 BTLA-P01-mAb05 VL DIKMTQSPSSMYASLGERVTITCKASQD INSYLTWFQQKPGKSPKTLIYRANRLVD GVPSRFSGSGSGQDYSLTISSLEYEDLGI

[0627] YYCLQYDEFPLTFGAGTKLELK

[0628] 3 BTLA-P01-mAb05 VH CDR1 DYYMN 93 4 BTLA-P01-mAb05 VH CDR2 DINLSNDTTAYNQKFKG 94 5 BTLA-P01-mAb05 VH CDR3 WGPMDY 95 6 BTLA-P01-mAb05 VL CDR1 KASQDINSYLT 96 7 BTLA-P01-mAb05 VL CDR2 RANRLVD 97 8 BTLA-P01-mAb05 VL CDR3 LQYDEFPLT 98

[0629] QIHLVQSGPELKKPGETVKISCKASGYT FTAFGMSWVKQAPGKGLKWMGWINT

[0630] 01 BTLA-P01-mAb06 VH YSGVPTYTDDFKGRFAFSLETSASTAYL 111

[0631] QINNLKSEDTASYFCTRQGRMDYWGQ GTSVTVSS DVVMTQTPLTLSVTIGQPASISCKSSQSL LDSDGKTYLNWLLQRPGQSPKRLIYLM

[0632] 02 BTLA-P01-mAb06 VL SKLDSGVPDRFTGSGSGTDFTLKISRVE 112

[0633] AEDLGVYYCWQGTHFPFTFGSGTKLEI

[0634] K

[0635] 03 BTLA-P01-mAb06 VH CDR1 AFGMS 113 04 BTLA-P01-mAb06 VH CDR2 WINTYSGVPTYTDDFKG 114 05 BTLA-P01-mAb06 VH CDR3 QGRMDY 115 06 BTLA-P01-mAb06 VL CDR1 KSSQSLLDSDGKTYLN 116 07 BTLA-P01-mAb06 VL CDR2 LMSKLDS 117 08 BTLA-P01-mAb06 VL CDR3 WQGTHFPFT 118

[0636] QVTLKESGPGILQPSQTLSLTCSFSGFSL TTFGMGVGWIRQPSGKGLEWLAHIWW

[0637] 21 BTLA-P01-mAb07 VH DDDKYYNSVLKSRLTISKDTSKSQVFLK 131

[0638] IANVDAADTATYYCARVAGIFFAYWGQ GTLVTVSA EIVLTQSPTTMAASPGEKITITCSASSSIS

[0639] 122 BTLA-P01-mAb07 VL EIVLTQSPTTMAASPGEKITITCSASSSIS SNYLHWYQQKPGFSPKLLIYRTSNLASG VPARFSGSGSGTSYSLSIGTMEAEDVAT

[0640] YYCQQGGSLPLTFGVGTKLELK

[0641] 23 BTLA-P01-mAb07 VH CDR1 TFGMGVG 133 24 BTLA-P01-mAb07 VH CDR2 HIWWDDDKYYNSVLKS 134 25 BTLA-P01-mAb07 VH CDR3 VAGIFFAY 135 26 BTLA-P01-mAb07 VL CDR1 SASSSISSNYLH 136 27 BTLA-P01-mAb07 VL CDR2 RTSNLAS 137 28 BTLA-P01-mAb07 VL CDR3 QQGGSLPLT 138

[0642] QIQLVQSGPELKKPGETVKISCKASGYT FTDYSVHWVKQTPGKGLKWIGWINTET

[0643] 41 BTLA-P01-mAb08 VH GEPTYADDFKGRFAFSLETSASTAYLQI 151

[0644] NNLKNEDTATYFCTSTADVWGAGTTV

[0645]

[0646] TVSS DVVMTQTPLSLPVSLGDQASISCRSSQS 142 BTLA-P01-mAb08 VL DVVMTQTPLSLPVSLGDQASISCRSSQS LVHSNGNTYLHWYLQKPGQSPKLLIYK VSNRFSGVPDRFSGSGSGTDFTLKISRVE AEDLGVYFCSQSTHIPWTFGGGTKLEIE

[0647] 143 BTLA-P01-mAb08 VH CDR1 DYSVH 153 144 BTLA-P01-mAb08 VH CDR2 WINTETGEPTYADDFKG 154 145 BTLA-P01-mAb08 VH CDR3 TADV 155 146 BTLA-P01-mAb08 VL CDR1 RSSQSLVHSNGNTYLH 156 147 BTLA-P01-mAb08 VL CDR2 KVSNRFS 157 148 BTLA-P01-mAb08 VL CDR3 SQSTHIPWT 158

[0648] ELKLEESGGGLVQPGGSMKLSCVASGF NFSNYWMNWVRQSPEKGLEWVAQIRL

[0649] 161 BTLA-P01-mAb09 VH KSDNYATHYAESVKGRFTISRDDSKNS 171

[0650] VYLQMNNLRAEDTGIYYCTSIYFLFDY WGQGTTLTVSS DVVMTQTPLSLPVSLGDQASISCRSSQS

[0651] 162 BTLA-P01-mAb09 VL DVVMTQTPLSLPVSLGDQASISCRSSQS LLHSNGNTYLHWYLQKPGQSPKLLIYK VSNRFSGVPDRFSGSGSGTDFTLEISRVE 172

[0652] AEDLGVYFCSQSTHVYTFGGGTKLEIK

[0653] 163 BTLA-P01-mAb09 VH CDR1 NYWMN 173 164 BTLA-P01-mAb09 VH CDR2 QIRLKSDNYATHYAESVKG 174 165 BTLA-P01-mAb09 VH CDR3 IYFLFDY 175 166 BTLA-P01-mAb09 VL CDR1 RSSQSLLHSNGNTYLH 176 167 BTLA-P01-mAb09 VL CDR2 KVSNRFS 177 168 BTLA-P01-mAb09 VL CDR3 SQSTHVYT 178

[0654] EVQLQQSGAELVKPGASVKLSCTASGF NIKDTYIHWVKQRPEQGLEWIGRIDPAN

[0655] 1351 BTLA-PRT-mAb25 VH ANSQYDPKFQGKATITADTSSNTAYLH 1361

[0656] LS SLTSEDTAVYYCVRYNYDGAMDYW GQGTSVIVSS SIVMTQTPKFLLVSAGDRVTITCKASQS 1352 BTLA-PRT-mAb25 VL SIVMTQTPKFLLVSAGDRVTITCKASQS VSNDVAWYQQKPGQSPKLLISYASNHY TGVPDRFTGSGYGTDFTFTISTVQAEDL AFYFCQQDYYSPLTFGGGTKLELK

[0657] 1353 BTLA-PRT-mAb25 VH CDR1 DTYIH 1363 1354 BTLA-PRT-mAb25 VH CDR2 RIDPANANSQYDPKFQG 1364 1355 BTLA-PRT-mAb25 VH CDR3 YNYDGAMDY 1365 1356 BTLA-PRT-mAb25 VL CDR1 KASQSVSNDVA 1366 1357 BTLA-PRT-mAb25 VL CDR2 YASNHYT 1367 1358 BTLA-PRT-mAb25 VL CDR3 QQDYYSPLT 1368

[0658] EVQLQQSGPELVKPGASVKMSCKASGY TFTDYYMKWVKQ SHGKSLEWIGDINPN

[0659] 1371 BTLA-PRT-mAb26 VH NTYTFYNQNFKGKATLTVDKSSSTAYL 1381

[0660] QLNSLTSEDSAVYYCARSIYDVDYVYF GYWGQGTLVTVSA DVLMTQTPLSLPVSLGDQASISCRSSQTI 1372 BTLA-PRT-mAb26 VL DVLMTQTPLSLPVSLGDQASISCRSSQTI VHNNGNTYLEWYLQKPGQSPKLLIYKV SNRFSGVPDRFSGSGSGTDFTLKISRVEA 1382

[0661]

[0662] EDLGVYYCFQGSHVPRTFGGGTKLEIK 1373 BTLA-PRT-mAb26 VH CDR1 DYYMK 1383 1374 BTLA-PRT-mAb26 VH CDR2 DINPNNTYTFYNQNFKG 1384 1375 BTLA-PRT-mAb26 VH CDR3 SIYDVDYVYFGY 1385 1376 BTLA-PRT-mAb26 VL CDR1 RSSQTIVHNNGNTYLE 1386 1377 BTLA-PRT-mAb26 VL CDR2 KVSNRFS 1387 1378 BTLA-PRT-mAb26 VL CDR3 FQGSHVPRT 1388

[0663] EVQLQQSGPELVKTGASVKISCKASGYS FTGYYIHWVKQAHGKSLEWFGFINCYN

[0664] 1391 BTLA-PRT-mAb31 VH GATSYNQKFKGKATFTVDTSSSTAYMQ 1401

[0665] FNSLTSEDSAVYYCARGDHDYWGQGT TLTVSS DAVMTQTPLYLPVSLGDQASISCRSSQS LEHSNGDTYLNWYLQKPGQSPQLLIYRI

[0666] 1392 BTLA-PRT-mAb31 VL SNRFSGVLDRFSGSGSGTDFTLKISRVE 1402

[0667] AEDLGVYFCLQLTHVPPTFGAGTKLDL

[0668] K

[0669] 1393 BTLA-PRT-mAb31 VH CDR1 GYYIH 1403 1394 BTLA-PRT-mAb31 VH CDR2 FINCYNGATSYNQKFKG 1404 1395 BTLA-PRT-mAb31 VH CDR3 GDHDY 1405 1396 BTLA-PRT-mAb31 VL CDR1 RSSQSLEHSNGDTYLN 1406 1397 BTLA-PRT-mAb31 VL CDR2 RISNRFS 1407 1398 BTLA-PRT-mAb31 VL CDR3 LQLTHVPPT 1408

[0670] QVQLQQSGAELVKPGASVRLSCKPSGY TFTSYYMFWLKQRPGQGLEWIGEINPR

[0671] 1411 BTLA-PRT-mAb35 VH NGETNFNEKFKSKATLTVDKSSSTAYL 1421

[0672] QLNSLTSEDSAVYYCTRGSYWGQGTLV TVSA DVVMTQTPLTLSVTIGQPASISCKSSQSL LDSDGKTYLNWLLQRPGQSPKRLIYLV

[0673] 1412 BTLA-PRT-mAb35 VL SKLDSGVPDRFTGSGSGTDFTLKISRVE 1422

[0674] AEDLGVYYCWQGTHYPLTFGAGTKLE LK

[0675] 1413 BTLA-PRT-mAb35 VH CDR1 SYYMF 1423 1414 BTLA-PRT-mAb35 VH CDR2 EINPRNGETNFNEKFKS 1424 1415 BTLA-PRT-mAb35 VH CDR3 GSY 1425 1416 BTLA-PRT-mAb35 VL CDR1 KSSQSLLDSDGKTYLN 1426 1417 BTLA-PRT-mAb35 VL CDR2 LVSKLDS 1427 1418 BTLA-PRT-mAb35 VL CDR3 WQGTHYPLT 1428

[0676] EVQLQQSGTVLARPGASVKMSCKASGY S STN Y W M H W V KQ R PGQG LE W IG A I Y P

[0677] 1431 BTLA-PRT-mAb37 VH GNSDADYNQKFKGKAKLTAVTSASTA 1441

[0678] YMELSSLTDDDSAVYYCTRLGYGYWG QGTTLTVSS DVVMTQTPLTLSVTIGQPASISCKSSQSL LDSDGKTYLNWLLQRPGQSPKRLIYLV

[0679] 1432 BTLA-PRT-mAb37 VL SKLDSGVPDRFTGSGSGTDFTLKISRVE 1442

[0680] AEDLGVYYCWQGTHFPQTFGGGTKLEI

[0681] K

[0682]

[0683] 1433 BTLA-PRT-mAb37 VH CDR1 NYWMH 1443 1434 BTLA-PRT-mAb37 VH CDR2 AIYPGNSDADYNQKFKG 1444 1435 BTLA-PRT-mAb37 VH CDR3 LGYGY 1445 1436 BTLA-PRT-mAb37 VL CDR1 KSSQSLLDSDGKTYLN 1446 1437 BTLA-PRT-mAb37 VL CDR2 LVSKLDS 1447 1438 BTLA-PRT-mAb37 VL CDR3 WQGTHFPQT 1448

[0684] EVQLQESGPSLVKPSQTLSLTCSVTGDSI TSGFWNWIRKFPGNKLEYMGSISYSGN

[0685] 1451 BTLA-PRT-mAb66 VH TYYNPSLKSRISITRDTSKNQYYLQLSSV 1461

[0686] TTEDTATFYCARLPPLYPYYAMDYWG QGTSVTVSS DIVLTQSPASLAVSLGQRATIFCRASQSV

[0687] 1452 BTLA-PRT-mAb66 VL DYKGISYMHWFQQKPGQPPKLLIYGAS mADOO VL NLKSGIPARFSGSGSGTDFTLNIHPVEEE DAATYYCQQGLEDPFTFGSGTKLEIK

[0688] 1453 BTLA-PRT-mAb66 VH CDR1 SGFWN 1463 1454 BTLA-PRT-mAb66 VH CDR2 SISYSGNTYYNPSLKS 1464 1455 BTLA-PRT-mAb66 VH CDR3 LPPLYPYYAMDY 1465 1456 BTLA-PRT-mAb66 VL CDR1 RASQSVDYKGISYMH 1466 1457 BTLA-PRT-mAb66 VL CDR2 GASNLKS 1467 1458 BTLA-PRT-mAb66 VL CDR3 QQGLEDPFT 1468

[0689] QVQLQQSGAELARPGASVKLSCKASGY TFPKYWMQWVKQRPRQGLEWIGAIYP

[0690] 181 CRP-POl-mAblO VH EDDDSRYAQKFRDKATLTADKSSSTAY 191

[0691] MQLTSLTSEDSAVYYCARFRYDSSPYTL DYWGQGTSVTVSS DVVMTQTPLSLPVSLGDQASISCRSSQS LVYSNGNTYLHWYLQKPGQSPKLLIYK

[0692] 182 CRP-POl-mAblO VL VSNRFSGVPDRFSGSGSGTDFIFKISRVE 192

[0693] AEDLGVYFCSQSTHVPLTFGAGTKLEL

[0694] K

[0695] 183 CRP-POl-mAblO VH CDR1 KYWMQ 193 184 CRP-POl-mAblO VH CDR2 AIYPEDDDSRYAQKFRD 194 185 CRP-POl-mAblO VH CDR3 FRYDSSPYTLDY 195 186 CRP-POl-mAblO VL CDR1 RSSQSLVYSNGNTYLH 196 187 CRP-POl-mAblO VL CDR2 KVSNRFS 197 188 CRP-POl-mAblO VL CDR3 SQSTHVPLT 198

[0696] QVQLQQSGAELVRPGTSVKISCKASGY TFTNYWLGCIRQRPGHGLEWIGNIHPGG

[0697] 201 CRP-P01-mAb11 VH GYTNYNE1< FI< GI< ATLTADTSSSTAYMQ 211

[0698] LSSLTSDDSAVYFCASGNSGNPFAYWG QGTLVTVSA DIRMTQSPSSLSASLGERVSLTCRASQEI CPP POl Ahl 1 VT SAFLTWLQQKPDGTIKRLIYAASTLDYG LKf-rui-mADii VL VPKRFSGSRSGSGYSLTISSLESEDFADY

[0699] YCLQYASYPFTFGSRTKLEMR

[0700] 203 CRP-P01-mAb11 VH CDR1 NYWLG 213 204 CRP-P01-mAb11 VH CDR2 NIHPGGGYTNYNEKFKG 214

[0701]

[0702] 205 CRP-P01-mAb11 VH CDR3 GNSGNPFAY 215 206 CRP-POl-mAbl 1 VL CDR1 RASQEISAFLT 216 207 CRP-POl-mAbll VL CDR2 AASTLDY 217 208 CRP-POl-mAbll VL CDR3 LQYASYPFT 218

[0703] QVQLQQSGTELVRPGTSVKISCKASGYT FTHYWLGWIKQRPGHGLEWIGNISPGGI

[0704] 221 CRP-P01-mAbl2 VH YTNYNENFKGKATLTADTSSSFAYMQL 231

[0705] SSLTSEDSAVYFCANGDYGNPFAYWGQ GTLVTVSA DIQMTQSPSSLSASLGERVSLTCRTSQEI

[0706] 222 CRP-P01-mAb12 VL SGYLSWLQQKPDGTIKRLIYAASTLDSS VPKRFSGSRSGSDYSLTISSLESEDFADY YCLQYASYPFTFGSGTKLEIR

[0707] 223 CRP-POl-mAbl 2 VH CDR1 HYWLG 233 224 CRP-P01-mAbl2 VH CDR2 NISPGGIYTNYNENFKG 234 225 CRP-POl-mAbl 2 VH CDR3 GDYGNPFAY 235 226 CRP-POl-mAbl 2 VL CDR1 RTSQEISGYLS 236 227 CRP-P01-mAbl2 VL CDR2 AASTLDS 237

[0708]

[0709] 228 CRP-P01-mAbl2 VL CDR3 LQYASYPFT 238

[0710] EVKLDETGGGLVQPGGPMKLSCVASGF TFSDYWMNWVRQSPEKGLEWVAQIRN

[0711] 241 CRP-P01-mAbl3 VH KFYNYETYYSDSVRGRFTISRDDSKSSV 251

[0712] YLQMNNLGTEDMGIYSCTSYRYGFAY WGQGTLVTVSA _ QAVVTQESALTTSPGETVTLTCRSSTGA

[0713] 242 CRP-P01-mAb13 VL VTASNYVSWVQEKPDHLFVQEKPDHLFTSLIGSTNN __ 242 CRP-POl-mAbl 3 VL RRPGVPARFSGSLIGDKAALTITGAQTE252

[0714] DEAIYFCALRYSNYFVFGGGTKLTVL

[0715] 243 CRP-POl-mAbl 3 VH CDR1 DYWMN 253 244 CRP-POl-mAbl 3 VH CDR2 QIRNKFYNYETYYSDSVRG 254 245 CRP-POl-mAbl 3 VH CDR3 SYRYGFAY 255 246 CRP-P01-mAbl3 VL CDR1 RSSTGAVTASNYVS 256 247 CRP-POl-mAbl 3 VL CDR2 STNNRRP 257

[0716]

[0717] 248 CRP-POl-mAbl 3 VL CDR3 ALRYSNYFV 258

[0718] DVQLQESGPGLVKPSQSLSLTCSVTGYS ITSGYYWNWIRQFPGNKLEWMGYIRYD

[0719] 261 CRP-POl-mAbl 4 VH GSNKYTPSLKNRISITRDTSKNQFFLKLN 271

[0720] SVTTEDTGTYFCAGVFTTVEIMDWYSD VWGTGTTVTVSS DIVMTQAAFSNPVILGTSASISCRSSKSL

[0721] 262 CRP-P01-mAb14 VL LYSNGITYLYWYLQRPGQSPQLLIYQMS NLASGVPDRFSSSGSGTDFTLRISRVEAE DVGVYFCAQNLELWTFGGGTKLEIK

[0722] 263 CRP-POl-mAbl 4 VH CDR1 SGYYWN 273 264 CRP-POl-mAbl 4 VH CDR2 YIRYDGSNKYTPSLKN 274 265 CRP-POl-mAbl 4 VH CDR3 FTTVEIMDWYSDV 275 266 CRP-P01-mAbl4 VL CDR1 RSSKSLLYSNGITYLY 276 267 CRP-POl-mAbl 4 VL CDR2 QMSNLAS 277

[0723]

[0724] 268 CRP-P01-mAbl4 VL CDR3 AQNLELWT 278 QVQLQQSGTELVRPGTSVKMSCKASGY TFTNQWIGWTKQRPGHDLEWIGNIYPG CRP-P01-mAbl5 VH GDYTNYNEI< FI< GI< ATLTADRSSSTAYM 291

[0725] QFSSLTSEDSAIYYCARGYYGDPFASWG QGTLVTVSA DIQMTQSPSSLSASLGERVSLTCRASQDI 282 CRP-P01-mAb15 VL GSSLNWLQQGPDGTIKRLIYATSSVDSG VPKRFSGSRSGSDYSLTISSLESEDFVDY YCLQYASFPFTFGSGTKLEKK CRP-P01-mAbl5 VH CDR1 NQWIG 293 CRP-P01-mAbl5 VH CDR2 NIYPGGDYTNYNEKFKG 294 CRP-P01-mAbl5 VH CDR3 GYYGDPFAS 295 CRP-P01-mAbl5 VL CDR1 RASQDIGSSLN 296 CRP-P01-mAbl5 VL CDR2 ATSSVDS 297 CRP-P01-mAbl5 VL CDR3 LQYASFPFT 298

[0726] QVQLQQTGTELVRPGTSVKVSCKASGY GIINYLIEWVKQRPGQGLEWIGVINPGS CRP-PRT-mAbOl VH GVTNNNEKFKGKATLTADKSSNTAYM 941

[0727] QLSSLTSEDSAVYFCARSPLYDYDRDW YFDVWGTGTTVTVSS DIKMTQSPSSMYAFLGERVTITCKASQD CRP-PRT-mAbOl VL INSYLSWFQQKPGKSPKTLIYRANRLVD GVPSRFSGSGSGQDYSLTISSLEYEDMGI YYCLQYDEFPVTFGAGTKLELQ CRP-PRT-mAbOl VH CDR1 NYLIE 943 CRP-PRT-mAbOl VH CDR2 VINPGSGVTNNNEKFKG 944 CRP-PRT-mAbOl VH CDR3 RSPLY 945 CRP-PRT-mAbOl VL CDR1 KASQDINSYLS 946 CRP-PRT-mAbOl VL CDR2 RANRLVD 947 CRP-PRT-mAbOl VL CDR3 LQYDEFPVT 948

[0728] EVQLQQSGPELVKPGSSVKMSCMASGY TFTDYNMHWVKQ SHGKALEWIGYIHP CRP-PRT-mAbO3 VH NNGGTTYNQKFKGKATLTVNKSSSTAY 981

[0729] MELRSLTSEDSAVYYCAMDDRWGQGT LVTVSA DIVMTQSPSSLAVSVGQKVSMSCKSSQT LLSSSNQKNYLAWYQQKPGQSPKLLVY CRP-PRT-mAbO3 VL LASTRESGVPDRFIGSGSGTDFTLTISSV 982

[0730] QAEDLADYFCQQHFSIPVTFGAGTKLEL K CRP-PRT-mAbO3 VH CDR1 DYNMH 983 CRP-PRT-mAbO3 VH CDR2 YIHPNNGGTTYNQKFKG 984 CRP-PRT-mAbO3 VH CDR3 DDR 985 CRP-PRT-mAbO3 VL CDR1 KSSQTLLSSSNQKNYLA 986 CRP-PRT-mAbO3 VL CDR2 LASTRES 987

[0731]

[0732] CRP-PRT-mAbO3 VL CDR3 QQHFSIPVT 988 EVQLQQSGPDLVKPGASVKISCKASGY TFTDLYMNWVKESHGKSLEWIGEINPT

[0733] 991 CRP-PRT-mAbO4 VH NGGTTYNQKFKGKATLTVDKSSSTAY 1001

[0734] MELRSLTSEDSAVYYCARGFYVLFDYW GQGTTLTVSS DVLMTQTPLSLPVSLGDQASISCRSSQSI

[0735] 992 CRP-PRT-mAbO4 VL VHSNGNTYLEWYLQKPGQSPKLLIYKV Vzivr rivi UPWW vv SNRFSGVPDRFSGSGSGTDFTLKISRVEA EDLGVYYCFQGSHVPPTFGGGTKLEIK

[0736] 993 CRP-PRT-mAbO4 VH CDR1 DLYMN 1003 994 CRP-PRT-mAbO4 VH CDR2 EINPTNGGTTYNQKFKG 1004 995 CRP-PRT-mAbO4 VH CDR3 GFYVLFDY 1005 996 CRP-PRT-mAbO4 VL CDR1 RSSQSIVHSNGNTYLE 1006 997 CRP-PRT-mAbO4 VL CDR2 KVSNRFS 1007 998 CRP-PRT-mAbO4 VL CDR3 FQGSHVPPT 1008

[0737] QVQLQQTGTELVRPGTSVKVSCKASGY AFTNYLIEWVKQRPGQGLEWIGVINPGS

[0738] 1031 CRP-PRT-mAbO6 VH GVTNNNE1< FI< GI< ATLTTDRSSNTAYM 1041

[0739] QLSSLTSEDSAVYFCARSPLFDYDRDW YFDVWGTGTTVTVSS DIKMTQSPSSMYAFLGERVTITCKASQD

[0740] 1032 CRP-PRT-mAb06 VL INSYLSWFQQKPGKSPKTLIYRANRLVD GVPSRVSGSGSGQDYSLTISSLEYEDVGI1042

[0741] YYCLQYDKFPVTFGAGTKLELK

[0742] 1033 CRP-PRT-mAbO6 VH CDR1 NYLIE 1043 1034 CRP-PRT-mAbO6 VH CDR2 VINPGSGVTNNNEKFKG 1044 1035 CRP-PRT-mAbO6 VH CDR3 RSPLF 1045 1036 CRP-PRT-mAbO6 VL CDR1 KASQDINSYLS 1046 1037 CRP-PRT-mAbO6 VL CDR2 RANRLVD 1047 1038 CRP-PRT-mAbO6 VL CDR3 LQYDKFPVT 1048

[0743] EVQLQQSGPELVKPGASVKISCKASGYT FTDYYLNWVKQSHGKSLEWIGDMNSK

[0744] 1051 CRP-PRT-mAbO7 VH NGGPTYNQKFKGKATLIIDKSSNTAYM 1061

[0745] ELRSLTSEDSAVYYCARYHSYGSYYEA YWGQGTLVTVSA DIQMTQTTSSLSASLGDRVTITCRASQDI

[0746] 1052 CRP-PRT-mAb07 VL SNYLNWYQQKPDGTVKLLIYYTSRLHS GVPSRFSGSGSGTDYSLTISNLEQEDLAT1062

[0747] YFCQQGNTLPLTFGGGTKLELK

[0748] 1053 CRP-PRT-mAbO7 VH CDR1 DYYLN 1063 1054 CRP-PRT-mAbO7 VH CDR2 DMNSKNGGPTYNQKFKG 1064 1055 CRP-PRT-mAbO7 VH CDR3 YHSYGSYYEAY 1065 1056 CRP-PRT-mAbO7 VL CDR1 RASQDISNYLN 1066 1057 CRP-PRT-mAbO7 VL CDR2 YTSRLHS 1067 1058 CRP-PRT-mAbO7 VL CDR3 QQGNTLPLT 1068

[0749] EVQLQQSGPVLVKPGASVKMSCKASGY

[0750] 1091 CRP-PRT-mAbO9 VH TFTDYYTNWVKQSHGKSLEWIGVINPY 1101

[0751]

[0752] NGRTSYNQNFKGKATLTFDKSSSTAFM ELNSLTSEESAVYYCAREGYNSIYGASF DYWGQGTTLTVSS QIVLTQSPAIMSASPGEKVTISCSASSSV

[0753] 1092 CRP-PRT-mAb09 VL SNMYWYQQKPGSSPKPWIYRTSNLASG VPGRFSGSGSGTIYSLTISSMEAEDAATY1102

[0754] YCQQYNSYPPTFGGGTKLEIK

[0755] 1093 CRP-PRT-mAbO9 VH CDR1 DYYTN 1103 1094 CRP-PRT-mAbO9 VH CDR2 VINPYNGRTSYNQNFKG 1104 1095 CRP-PRT-mAbO9 VH CDR3 EGYNSIYGASFDY 1105 1096 CRP-PRT-mAbO9 VL CDR1 SASSSVSNMY 1106 1097 CRP-PRT-mAbO9 VL CDR2 RTSNLAS 1107 1098 CRP-PRT-mAbO9 VL CDR3 QQYNSYPPT 1108

[0756] QVQLQQTGTELVRPGTSVKVSCKASGY GIINYLIEWVKQRPGQGLEWIGVINPGS

[0757] 1111 CRP-PRT-mAb10 VH GVSNNNEKFKGKATLTADKSSNTAYM 1121

[0758] QLSSLTSEDSAVYFCARSPLYDYDRDW YFDVWGTGTTVTVSS DIKMTQSPSSMYAFLGERVTITCKASQD

[0759] m o rpn uPT Aki n VT INNYLSWFQQKPGKSPKTLIYRANRLVD 1112 CRP-PRT-mAb10 VL GVPSRFSGSGSGQDYSLTISSLDYEDMG1122

[0760] IYYCLQYDKFPVTFGAGTKLELK

[0761] 1113 CRP-PRT-mAb10 VH CDR1 NYLIE 1123 1114 CRP-PRT-mAb10 VH CDR2 VINPGSGVSNNNEKFKG 1124 1115 CRP-PRT-mAb10 VH CDR3 SPLYDYDRDWYFDV 1125 1116 CRP-PRT-mAb10 VL CDR1 KASQDINNYLS 1126 1117 CRP-PRT-mAb10 VL CDR2 RANRLVD 1127 1118 CRP-PRT-mAb10 VL CDR3 LQYDKFPVT 1128

[0762] EVQLQQSGPELVKPGSSVKMSCMASGY TFTDYNMHWVKQ SHGKALEWIGYIHP

[0763] 1131 CRP-PRT-mAbll VH NNGGTTYNQKFKGKATLTVNKSSSTAY 1141

[0764] MELRSLTSEDSAVYYCAMDDRWGQGT LVTVSA DIVMTQSPSSLAVSVGQKVSMSCKSSQS LLSSSNQKNYLAWYQQKPGQSPKLLVY

[0765] 1132 CRP-PRT-mAbll VL LASTRESGVPDRFIGSGSGTDFTLTISSV 1142

[0766] QAEDLADYFCQQHFSIPVTFGTGTKLEL

[0767] K

[0768] 1133 CRP-PRT-mAbll VH CDR1 DYNMH 1143 1134 CRP-PRT-mAbll VH CDR2 YIHPNNGGTTYNQKFKG 1144 1135 CRP-PRT-mAbll VH CDR3 WGQGTLVTVSA 1145 1136 CRP-PRT-mAbll VL CDR1 KSSQSLLSSSNQKNYLA 1146 1137 CRP-PRT-mAbll VL CDR2 LASTRES 1147 1138 CRP-PRT-mAbll VL CDR3 QQHFSIPVT 1148

[0769] EAQLQQSGAELVRSGASVKLSCTASGF

[0770] 1211 CRP-PRT-mAbl5 VH NIKDYYMHWVKQRPEQGLEWIGWIDP 1221

[0771]

[0772] ENGDTDYAPKFQGKATMTTDTS SNTAY LQLSSLTSEDTAVYYCNAHGNVVDWG QGTLVTVSA DVLMTQTPLSLPVSLGDQASISCRSSQS LVHSNGNTYLQWYLQKPGQSPKLLIYK

[0773] 1212 CRP-PRT-mAbl5 VL VSDRFSGVPDRFSGSGSGTDFTLKISRVE 1222

[0774] AEDLGVYYCFQGSHVPWTFGGGTKLEI

[0775] K

[0776] 1213 CRP-PRT-mAbl5 VH CDR1 DYYMH 1223 1214 CRP-PRT-mAbl5 VH CDR2 WIDPENGDTDYAPKFQG 1224 1215 CRP-PRT-mAbl5 VH CDR3 HGNW 1225 1216 CRP-PRT-mAbl5 VL CDR1 RSSQSLVHSNGNTYLQWYLQ 1226 1217 CRP-PRT-mAbl5 VL CDR2 KVSDRFS 1227 1218 CRP-PRT-mAbl5 VL CDR3 FQGSHVPWT 1228

[0777] EVQLVESGGGLVQPKGSLKLSCAASGF TYNTYAMNWVRQAPGKGLEWVARIRN

[0778] 1231 CRP-PRT-mAbl6 VH KSKNYATDYADSVKDRFTLSRDDSQSM 1241

[0779] VYLQMNNLKTEDTAIYYCVKGLLLYW GQGTLVTVSA DVVLTQTPLYVPVNIGAQASISCKCSKS

[0780] 1232 CRP-PRT-mAb16 VL LLNSDGFIYLEWYLQKPGQSPQLQIYLV CNRFSGVPDRFSGSGSGTDFTLNISRVEE EDLGVYSWNQSNYLPYTFGGGTKLEIK

[0781] 1233 CRP-PRT-mAbl6 VH CDR1 TYAMN 1243 1234 CRP-PRT-mAbl6 VH CDR2 RIRNKSKNYATDYADSVKD 1244 1235 CRP-PRT-mAbl6 VH CDR3 GLLLY 1245 1236 CRP-PRT-mAbl6 VL CDR1 KCSKSLLNSDGFIYLE 1246 1237 CRP-PRT-mAbl6 VL CDR2 LVCNRFS 1247 1238 CRP-PRT-mAbl6 VL CDR3 NQSNYLPYT 1248

[0782] EVQLQQSGPELVKPGSSVKMSCMASGY TFTDYNMHWVKQ SHGKALEWIGYIHP

[0783] 1311 CRP-PRT-mAb20 VH NNGGTTYNQKFKGKATLTVNKSSSTAY 1321

[0784] MELRSLTSEDSAVYYCAMDDRWGQGT LVSVSA DIVMTQSPSSLAVSVGQKVSMSCKSSQ RLLSSSNQKNYLAWYQQKPGQSPKLLV

[0785] 1312 CRP-PRT-mAb20 VL YLASTRESGVPDRFIGSGSGTDFTLTISS 1322

[0786] VQAEDLADYFCQQHFSIPVTFGAGTKLE LK

[0787] 1313 CRP-PRT-mAb20 VH CDR1 DYNMH 1323 1314 CRP-PRT-mAb20 VH CDR2 YIHPNNGGTTYNQKFKG 1324 1315 CRP-PRT-mAb20 VH CDR3 DDR 1325 1316 CRP-PRT-mAb20 VL CDR1 KSSQRLLSSSNQKNYLA 1326 1317 CRP-PRT-mAb20 VL CDR2 LASTRES 1327 1318 CRP-PRT-mAb20 VL CDR3 QQHFSIPVT 1328

[0788] EVQVVESGGDLVKPGGSLKLSCAASGF

[0789] 301 EGF-P01-mAbl6 VH TFSSYGMSWVRQTPDKRLEWVATIDSS 311

[0790]

[0791] GFYTYYPDSVKGRFIISRDNAKNTLYLQ MSSLKSEDTAMYYCTRDGRGGFAYWG QGTLVTVSA DIVMTQTPLTLSVTIGQPASISCKSSQSL LHSDGMTYLNWLLQRPGQSPKRLLFLV EGF-P01-mAbl6 VL SKLDSGVPDRFTGSGSGTDFTLKISRVE 312

[0792] AEDLGIYYCWQGTHFPFTFGAGTKLEL K EGF-P01-mAbl6 VH CDR1 SYGMS 313 EGF-P01-mAbl6 VH CDR2 TIDSSGFYTYYPDSVKG 314 EGF-P01-mAbl6 VH CDR3 DGRGGFAY 315 EGF-P01-mAbl6 VL CDR1 KSSQSLLHSDGMTYLN 316 EGF-P01-mAbl6 VL CDR2 LVSKLDS 317 EGF-P01-mAbl6 VL CDR3 WQGTHFPFT 318

[0793] QVQLQQSGAELVRPGASVKLSCKASVY TFTGQWIEWVKQRPGHGLEWIAEILPGS EGF-P01-mAbl7 VH GDTHYNEKFKGKATFTADTSSYTAYM 331

[0794] QLSSLTTEDSAIYYCVRHYGEHYWGQG TTLTVSS DVLLTQTPLSLPVSLGDQVSISCRSSQTI VHSNGNTYLEWFLQKPGQSPKLLIYKV EGF-P01-mAbl7 VL SNRFSGVPARFRGSGSGTDFTLKISRVE 332

[0795] AEDLGVYYCFQGSHVPYTFGGGTKLEI K EGF-P01-mAbl7 VH CDR1 GQWIE 333 EGF-P01-mAbl7 VH CDR2 EILPGSGDTHYNEKFKG 334 EGF-P01-mAbl7 VH CDR3 HYGEHY 335 EGF-P01-mAbl7 VL CDR1 RSSQTIVHSNGNTYLE 336 EGF-P01-mAbl7 VL CDR2 KVSNRFS 337 EGF-P01-mAbl7 VL CDR3 FQGSHVPYT 338

[0796] EVKLVESGGGLVQPGGSLKLSCAASGF TFSDYGMAWVRQAPRKGPEWVAFISNL EGF-P01-mAbl8 VH AYSIYYADTVTGRFTISRDNAKNTLYLE 351

[0797] MSSLRSEDTAMYYCARHENFGNSFDY WGQGTTLTVSS DIVMTQTPLTLSVTIGQPASISCKSSQSL LDSDGKTYLNWLLQRPGQSPKRLIYLV

[0798] 342 EGF-P01-mAb18 VL SKLDSGVPDRFTGSGSGTDFTLKISRVE AEDLGVYYCWQGTHFPTFGGGTKLEIK EGF-P01-mAbl8 VH CDR1 DYGMA 353 EGF-P01-mAbl8 VH CDR2 FISNLAYSIYYADTVTG 354 EGF-P01-mAbl8 VH CDR3 HENFGNSFDY 355 EGF-P01-mAbl8 VL CDR1 KSSQSLLDSDGKTYLN 356 EGF-P01-mAbl8 VL CDR2 LVSKLDS 357 EGF-P01-mAbl8 VL CDR3 WQGTHFPT 358

[0799] EVQLVESGGDLVKPGGSLKLSCAASGF EGF-P01-mAbl9 VH TFSSYGMSWVRQTPDKRLEWVASISTS 371

[0800]

[0801] GTYTYYPD SVKGRFTISRDNAKNTLYL QMNSLKSEDTAMYYCARNYGYDEAWF AYWGQGTLVTVSA DILLTQSPAILSVSPGERVSFSCRASQSIG 362 EGF-P01-mAb19 VL TSIHWYQQRTNGSPRLLIKYASESISGIP SRFSGSGSGTDFTLSINSVESEDIADYYC HQSNSWPLTFGAGTKLELK EGF-P01-mAbl9 VH CDR1 SYGMS 373 EGF-P01-mAbl9 VH CDR2 SISTSGTYTYYPDSVKG 374 EGF-P01-mAbl9 VH CDR3 NYGYDEAWFAY 375 EGF-P01-mAbl9 VL CDR1 RASQSIGTSIH 376 EGF-P01-mAbl9 VL CDR2 YASESIS 377 EGF-P01-mAbl9 VL CDR3 HQSNSWPLT 378

[0802] QIQLVQSGPELKKPGETIKISCKASGYTF TDYSMHWVKQAPGKGLKWMGWINPE EGF-P01-mAb20 VH TAEPTYADDFQGRFAFSLETSASTAFLQI 391

[0803] NNLKNEDTATYFCTRGGNYDYWGQGT TLTVSS DVVLTQTPLTLSVTIGQPASVSCTSSQSL LHSNGKTYLNWLLHRPGQSPKRLIYLV EGF-P01-mAb20 VL SKLDSGVPDRFTGSGSGTDFTLKISRVE 392

[0804] AEDLGVYYCVQGTHFPQTFGGGSKLEI K EGF-P01-mAb20 VH CDR1 DYSMH 393 EGF-P01-mAb20 VH CDR2 PETAEPTYADDFQG 394 EGF-P01-mAb20 VH CDR3 GGNYDY 395 EGF-P01-mAb20 VL CDR1 TSSQSLLHSNGKTYLN 396 EGF-P01-mAb20 VL CDR2 LVSKLDS 397 EGF-P01-mAb20 VL CDR3 VQGTHFPQT 398

[0805] QVQLQQSGPELVRPGVSVKISCKGSGY RFTEYAMHWVKQSPAKSLEWIGIISSYS EGF-P02-mAb21 VH GNAKYNQKFKGKATMTVDKSSGTAYM 411

[0806] ELARLTSEDSAIYYCARERPYGDYWYF DVWGAGTTVTVSS DIQMTQTTSSLSASLGDRVTISCSASQDI EGF-P02-mAb21 VL SNYLNWYQQTPDGTVKLLIYYTSGLHS Vl. GVPSRFSGGGSGTDYSLTISNLEPEDFAT YYCQQYSKLPLTFGAGTKLELK EGF-P02-mAb21 VH CDR1 EYAMH 413 EGF-P02-mAb21 VH CDR2 IISSYSGNAKYNQKFKG 414 EGF-P02-mAb21 VH CDR3 ERPYGDYWYFDV 415 EGF-P02-mAb21 VL CDR1 SASQDISNYLN 416 EGF-P02-mAb21 VL CDR2 YTSGLHS 417 EGF-P02-mAb21 VL CDR3 QQYSKLPLT 418

[0807] QVQLQQSGPDLVRPGVSVKISCKGSGY EGF-P01-mAb22 VH TFTDFAMHWVKQSHAKSLEWIGVISTY 431

[0808]

[0809] SGYTNSHQKFKGKATMTVDKSSSTAYL ELARLTSEDSAIYYCTRANWEGLPYWG QGTLVTVSA QAVVTQESALTTSPGETVTLTCRSSTGA

[0810] 422 EGF-P01-mAb22 VL VTPSNYANWVQEKPDHLFTGLISGTNN RAPGVPARFSGSLIGDKAALTITGAQTE432

[0811] DEAIYFCALWYSNHWVFGGGTKLTVL

[0812] 23 EGF-P01-mAb22 VH CDR1 DFAMH 433 24 EGF-P01-mAb22 VH CDR2 VISTYSGYTNSHQKFKG 434 25 EGF-P01-mAb22 VH CDR3 ANWEGLPY 435 26 EGF-P01-mAb22 VL CDR1 RSSTGAVTPSNYAN 436 27 EGF-P01-mAb22 VL CDR2 GTNNRAP 437 28 EGF-P01-mAb22 VL CDR3 ALWYSNHWV 438

[0813] EFQLQQSGPELVKPGASVKISCKASGFS FTDYNMNWMKQSNGKSLEWIGLINPK

[0814] 41 EGF-P01-mAb23 VH YGTTTYNQKFKGKATLTVDQSSSIAYM 451

[0815] QLNSLTSEDSAVYYCLYDGYYDYWGQ GTTLTVSS DILMTQSPSSMSVSLGDTVSITCHASQVI

[0816] 42 EGF-P01-mAb23 VL SNNIGWLQQKPGKSFKGLIYLGTNLED GVPSRFSGSGSGADYSLTISSLESEDFAD YYCVQYAQFPYTFGGGTKLEIK

[0817] 43 EGF-P01-mAb23 VH CDR1 DYNMN 453 44 EGF-P01-mAb23 VH CDR2 LINPKYGTTTYNQKFKG 454 45 EGF-P01-mAb23 VH CDR3 DGYYDY 455 46 EGF-P01-mAb23 VL CDR1 HASQVISNNIG 456 47 EGF-P01-mAb23 VL CDR2 LGTNLED 457 48 EGF-P01-mAb23 VL CDR3 VQYAQFPYT 458

[0818] QVQLQQSGTELARPGASVKLSCKASGY TFTSSGITWVKQRTGQGLEWIGEIYPRS

[0819] 61 EGF-P02-mAb24 VH DNTYYNEKFKGKATLTADKSSSTAYME 471

[0820] LRSLTSED SAVYFCAYDADHWGQGTTL TVSS DVLMTQTPLSLPVSLGDQASISCRSSQNI

[0821] 62 EGF-P02-mAb24 VL VHSNGNTYLEWYLQKPGQSPKLLIYKV SNRFSGVPDRFSGSGSGTDFTLKISRVEA

[0822] EDLGIYYCFQGSHVPYTFGGGTKLEIK

[0823] 63 EGF-P02-mAb24 VH CDR1 SSGIT 473 64 EGF-P02-mAb24 VH CDR2 EIYPRSDNTYYNEK 474 65 EGF-P02-mAb24 VH CDR3 DADH 475 66 EGF-P02-mAb24 VL CDR1 RSSQNIVHSNGNTYLE 476 67 EGF-P02-mAb24 VL CDR2 KVSNRFS 477 68 EGF-P02-mAb24 VL CDR3 FQGSHVPYT 478

[0824] EVQLQQSGAELVRSGASVKLSCTASGF NIKVYYMHWVKQKPDQGLEWIGWIDP

[0825] 81 FGA-P02-mAb25 VH ENGDTEYVPNLQGKATMTADISSNTAY 491

[0826] LQLSSLTSEDTAVYYCNAYGNYGHLLD

[0827]

[0828] YWGQGTSVTVSS DVVMTQTPLTLSVTIGQPASISCKSGQS LLDSDGKTYLNWLLQRPGQSPKRLIYL FGA-P02-mAb25 VL VSKLDSGVPDRFTGSGSGTDFTLKISRV 492

[0829] EAEDLGVYYCWQGTHFPWTFGGGTKL EIK FGA-P02-mAb25 VH CDR1 VYYMH 493 FGA-P02-mAb25 VH CDR2 WIDPENGDTEYVPNLQG 494 FGA-P02-mAb25 VH CDR3 YGNYGHLLDY 495 FGA-P02-mAb25 VL CDR1 KSGQSLLDSDGKTYLN 496 FGA-P02-mAb25 VL CDR2 LVSKLDS 497 FGA-P02-mAb25 VL CDR3 WQGTHFPWT 498

[0830] EVQLQQSGAELVRSGASVKLSCTASGF NIKVYYLHWVKQKPDQGLEWIGWIDPE FGA-P02-mAb26 VH NGDTEYVPNLQGKATMTADISSNTAYL 511

[0831] QLS SLTSEDTAVYYCNVYGNYDHLMD YWGQGTSVTVSS DVVMTQTPLTLSVTIGQPASISCKSGQS LLDSDGKTYLNWLLQRPGQSPKRLIYL FGA-P02-mAb26 VL VSKLDSGVPDRFTGSGSGTDFTLKISRV 512

[0832] EAEDLGVYYCWQGTHFPWTFGGGTKL EIK FGA-P02-mAb26 VH CDR1 VYYLH 513 FGA-P02-mAb26 VH CDR2 WIDPENGDTEYVPNLQG 514 FGA-P02-mAb26 VH CDR3 YGNYDHLMDY 515 FGA-P02-mAb26 VL CDR1 KSGQSLLDSDGKTYLN 516 FGA-P02-mAb26 VL CDR2 LVSKLDS 517 FGA-P02-mAb26 VL CDR3 WQGTHFPWT 518

[0833] QVQLQQPGAELVRPGASVKLSCKASGY TFTSYWINWVKQRPGQGLEWIGNIYPS FGA-P02-mAb27 VH DSYTNYNQKFKDKATLTVDKSSSTAYM 531

[0834] QLSSPTSEDSAVYYCMTLYDGVWGAG TTVTVSS DVVMTQTPFTLSVTLGQPASISCKSSQS LLDSDGKTYLNWLLQRPGQSPKRLIYL FGA-P02-mAb27 VL VSKLDSGVPDRFTGSGSGTDFTLKISRV 532

[0835] EAEDLGVYYCWQGTHFPFTFGSGTKLEI K FGA-P02-mAb27 VH CDR1 SYWIN 533 FGA-P02-mAb27 VH CDR2 NIYPSDSYTNYNQKFKD 534 FGA-P02-mAb27 VH CDR3 LYDGV 535 FGA-P02-mAb27 VL CDR1 KSSQSLLDSDGKTYLN 536 FGA-P02-mAb27 VL CDR2 LVSKLDS 537 FGA-P02-mAb27 VL CDR3 WQGTHFPFT 538

[0836] EVQLVESGGGLVKPGGSLKLSCAASGF TLSDYGMHWVRQAPEKGLECVAYISSD

[0837]

[0838] FGA-P02-mAb28 VH SSTIYYADTVKGRFTISRDNAKNTLFLQ 551

[0839] MTSLRSEDTAIYYCARLYEGHYWGQGT TLTVSS DVVMTQTPLTLSVTIGQPASISCKSSQSL

[0840] LYSNGKTYLNWLLQRPGQSPKRLIYLV

[0841] 2 FGA-P02-mAb28 VL SKLDSGVPDRFTGSGSGTDFTLKIRRVE 552

[0842] AEDLGVYYCMQGTHFPLTFGAGTKLEL

[0843] K

[0844] 3 FGA-P02-mAb28 VH CDR1 DYGMH 553 4 FGA-P02-mAb28 VH CDR2 YISSDSSTIYYADTVKG 554 5 FGA-P02-mAb28 VH CDR3 LYEGHYW 555 6 FGA-P02-mAb28 VL CDR1 KSSQSLLYSNGKTYLN 556 7 FGA-P02-mAb28 VL CDR2 LVSKLDS 557 8 FGA-P02-mAb28 VL CDR3 MQGTHFPLT 558

[0845] EVQLQQSGPELVKPGTSVKISCEASGYT FNDYYMNWLKQSHGKSLEWIGDFNPK

[0846] 1 FGA-P02-mAb29 VH NGGTTYNQKFKGKATLTVDKSSSTAY 571

[0847] MELRSLTSEDSAVYYCAIFTDFDYWGQ GTTLTVSS DVVMTQTPLTLSVTIGQPASISCKSSQSL

[0848] m Dm Akoo vi LDSDGKTYLNWLLQRPGQSPKRLICLVS 2 FGA-P02-mAb29 VL KLDSGVPDRFTGSGSGTDFTLKISRVEA572

[0849] EDLGVYYCWQGTHFPYTFGGGTKLEIK

[0850] 3 FGA-P02-mAb29 VH CDR1 DYYMN 573 4 FGA-P02-mAb29 VH CDR2 DFNPKNGGTTYNQKFKG 574 5 FGA-P02-mAb29 VH CDR3 FTDFDY 575 6 FGA-P02-mAb29 VL CDR1 KSSQSLLDSDGKTYLN 576 7 FGA-P02-mAb29 VL CDR2 LVSKLDS 577 8 FGA-P02-mAb29 VL CDR3 WQGTHFPYT 578

[0851] DVQLQESGPGLVKPSQSLSLTCSVTGYS ITSGYFWNWIRQFPGNKLEWMGYISYD

[0852] 1 FGA-P01-mAb30 VH SSNNYNPSLKNRISITRDTSKNQFFLKLN 591

[0853] SVTTEDTATYYCARDRNWGSWYFDVW GTGTTVTVSS DVLMTQTPLSLPVSLGDQASISCRSSQSI

[0854] ? FCA P01 AhVi VT VHSNGNTYLEWYLQKPGQSPKLLIYKV ruA-HJi-niADju VL SNRFSGVPDRFSGSGSGTDFTLKISRVEA

[0855] EDLGVYYCFQGSYFPPTFGGGTKLEIK

[0856] 3 FGA-P01-mAb30 VH CDR1 SGYFWN 593 4 FGA-P01-mAb30 VH CDR2 YISYDSSNNYNPSLKN 594 5 FGA-P01-mAb30 VH CDR3 DRNWGSWYFDV 595 6 FGA-P01-mAb30 VL CDR1 RSSQSIVHSNGNTYLE 596 7 FGA-P01-mAb30 VL CDR2 KVSNRFS 597 8 FGA-P01-mAb30 VL CDR3 FQGSYFPPT 598

[0857] QVQLQQPGAELVKPGASVRLSCKPSGYI FTYYWIHWVKQRPGRGLEWIGRIDPHS

[0858]

[0859] 1 FGA-P01-mAb31 VH GGTRYNEKFKSKATLTVDKPSSTAYMH 611

[0860] LSSLTSEDSAVYYCSRDRSDYGFAYWG QGTLVTVSA DIQMTQTTSSLSASLGDRVTISCRASQDIFr A P01 AMI VT SNYLNWYQQKPDGTVKLLIYYTSRLHS ruA-Hii-niADJi VL GVPSRFSGSGSGTDYSLTISNLEQEDIAT

[0861] YFCQQGNMLPFTFGSGTKLEIK

[0862] 03 FGA-P01-mAb31 VH CDR1 YYWIH 613 04 FGA-P01-mAb31 VH CDR2 RIDPHSGGTRYNEKFKS 614 05 FGA-P01-mAb31 VH CDR3 DRSDYGFAY 615 06 FGA-P01-mAb31 VL CDR1 RASQDISNYLN 616 07 FGA-P01-mAb31 VL CDR2 YTSRLHS 617 08 FGA-P01-mAb31 VL CDR3 QQGNMLPFT 618

[0863] QVQLQQPGAELVKPGASVKLSCKGAG YTFTFYWMHWVKQRPGRGLEWIGRIDP

[0864] 21 FGA-P01-mAb32 VH HSGGIRYNENFKNRATLTVDKPSSTAY 631

[0865] MQLSSLTSEDSAVYYCARDRSDYGFAY WGQGTLVTVSA DVQMTQTTSSLSASLGDRVTISCRASQD

[0866] ?? FC A POl Ab?? VT INNYLNWYQQKPDGTVKVLIYHTSRLH ruA-Hii-niADV VL SGVPSRFSGSGSGTDYSLTISNLEQEDIA

[0867] TYFCQQGKTLPFTFGSGTKLEIK

[0868] 23 FGA-P01-mAb32 VH CDR1 FYWMH 633 24 FGA-P01-mAb32 VH CDR2 RIDPHSGGIRYNENFKN 634 25 FGA-P01-mAb32 VH CDR3 DRSDYGFAY 635 26 FGA-P01-mAb32 VL CDR1 RASQDINNYLN 636 27 FGA-P01-mAb32 VL CDR2 HTSRLHS 637 28 FGA-P01-mAb32 VL CDR3 QQGKTLPFT 638

[0869] EVQLQQSGPELVKPGASVKISCKASGYT FTDYYMNWMKQSHGRSLEWIGDINPN

[0870] 41 FGA-P02-mAb33 VH NGVTTYNQKFKGKATLTVDKSSSTAY 651

[0871] MELRSLTSEDSAVYYCARTYDGSFWGQ GTTLTVSS DVAMTQTPLTLSVTIGQPASISCKSSQSL LDSDGKTYLNWLLQRPGQSPKRLIYLV

[0872] 42 FGA-P02-mAb33 VL SKLDSGVPDRFTGSGSGTDFTLKISRVE 652

[0873] AEDLGVYYCWQGIHFPYTFGGGTKLEI

[0874] K

[0875] 43 FGA-P02-mAb33 VH CDR1 DYYMN 653 44 FGA-P02-mAb33 VH CDR2 DINPNNGVTTYNQKFKG 654 45 FGA-P02-mAb33 VH CDR3 TYDGSF 655 46 FGA-P02-mAb33 VL CDR1 KSSQSLLDSDGKTYLN 656 47 FGA-P02-mAb33 VL CDR2 LVSKLDS 657 48 FGA-P02-mAb33 VL CDR3 WQGIHFPYT 658

[0876] QVQLKESGPGLVAPSQSLSITCTVSGFSL TSYGVHWVRQPPGKGLEWLGLIWAGG

[0877] 61 LGAL-P01-mAb34 VH STNYNSALMSRLSISI< DNSI< SQVFL1< M 671

[0878] NSLQTDDTAIYYCARGGPIFAFWGQGT LVTVSA

[0879] l f. A I nniDIVMTQAAFSNPVTLGTSASISCRSSKSL 62 LGAL-P01-mAb34 VL LHSNGITYLYWYLQKPGQSPQLLIYQM

[0880]

[0881] 672 SNLASGVPDRFSSSGSGTDFTLRISRVEA EDVGVYYCAQNLELPPTFGGGTKLEIK

[0882] 663 LGAL-P01-mAb34 VH CDR1 SYGVH 673 664 LGAL-P01-mAb34 VH CDR2 LIWAGGSTNYN SALMS 674 665 LGAL-P01-mAb34 VH CDR3 GGPIFAF 675 666 LGAL-P01-mAb34 VL CDR1 RSSKSLLHSNGITYLY 676 667 LGAL-P01-mAb34 VL CDR2 QMSNLAS 677

[0883]

[0884] 668 LGAL-P01-mAb34 VL CDR3 AQNLELPPT 678

[0885] QVQLQQPGAEVVKSGASVKLSCKASGY TFTGYWMYWVKQRPGQGLEWIGMIHP

[0886] 1471 LGAL-PRT-mAb41 VH NSGSNKDNEKFKNKATLTVDKSSSTAY 1481

[0887] MQLSSLTSEDSAVYYCAREGDYVGLAY WGQGTLVTVSA _ DIVMTQSQKFMSTSVGNRVSVTCKASQ

[0888] 1472 LGAL-PRT-mAb41 VL NVGSNVAWYQQKPGQSPKALIYSASYR niAu^i vi. YSGVPDRFTGSGSGPVFTLTISNVQSED LSEYFCQQYNDYPWTFGGGTKLEIK

[0889] 1473 LGAL-PRT-mAb41 VH CDR1 GYWMY 1483 1474 LGAL-PRT-mAb41 VH CDR2 MIHPNSGSNKDNEKFKN 1484 1475 LGAL-PRT-mAb41 VH CDR3 EGDYVGLAY 1485 1476 LGAL-PRT-mAb41 VL CDR1 KASQNVGSNVA 1486 1477 LGAL-PRT-mAb41 VL CDR2 SASYRYS 1487

[0890]

[0891] 1478 LGAL-PRT-mAb41 VL CDR3 QQYNDYPWT 1488

[0892] EVQLVESGGDLVKPGGSLKLSCAASGF TLSDYGMHWVRQAPEKGLEWVAYITG

[0893] 1491 LGAL-PRT-mAb45 VH GSSAIYYVDTMKGRFTISRDKAKNTLFL 1501

[0894] QITSLRSEDTAMYYCVRDDYDRAWFA YWGQGTLVTVSA _ DIVMTQSHKFMSTSVGDRVSITCKASQ

[0895] 1492 LGAL-PRT-mAb45 VL DVSPAVAWYQQKPGQSPKLLIYWASTR HTGVPDRFTGSGSGTDYTLTISSVQAED LALYYCQQHFSTPFTFGSGTKLEIK

[0896] 1493 LGAL-PRT-mAb45 VH CDR1 DYGMH 1503 1494 LGAL-PRT-mAb45 VH CDR2 YITGGSSAIYYVDTMKG 1504 1495 LGAL-PRT-mAb45 VH CDR3 DDYDRAWFAY 1505 1496 LGAL-PRT-mAb45 VL CDR1 KASQDVSPAVA 1506 1497 LGAL-PRT-mAb45 VL CDR2 WASTRHT 1507 1498 LGAL-PRT-mAb45 VL CDR3 QQHFSTPFT 1508

[0897] EVQLQQSGPELVKPGASVKMSCKASGY TFTDYNIHWVKQSHGKSLEWIGYINPNS

[0898] 1511 LGAL-PRT-mAb49 VH GDNPYNQRFRGKATLTVNRSSSTAYME 1521

[0899] LRSLTAEDSAVYYCSRSYSMDYWGQG TSVTVSS QIVLTQSPAIMSASPGEKVTMTCSASSS

[0900] r r u DDT Ak / io VT VNYMYWYQQKPGSSPRLLIYDTSNLAS 1512 LGAL-PRT-mAb49 VL GVPVRFSGGGSGTSHSLTISRMEAEDAA1522

[0901] TYYCQQWISYPPTWTFGGGTKLEIK

[0902] 1513 LGAL-PRT-mAb49 VH CDR1 DYNIH 1523

[0903]

[0904] 1514 LGAL-PRT-mAb49 VH CDR2 YINPNSGDNPYNQRFRG 1524 1515 LGAL-PRT-mAb49 VH CDR3 SYSMDY 1525 1516 LGAL-PRT-mAb49 VL CDR1 SASSSVNYMY 1526 1517 LGAL-PRT-mAb49 VL CDR2 DTSNLAS 1527 1518 LGAL-PRT-mAb49 VL CDR3 QQWISYPPTWT 1528

[0905] EVQLQQSGPELVKPGASVKMSCKASGY TFTDYNIHWVKQSHGKSLEWIGYINPNS

[0906] 1531 LGAL-PRT-mAb53 VH GDNPYNQRFRGKATLTVNRSSSTAYME 1541

[0907] LRSLTAEDSAVYYCSRSYSMDYWGQG TSVTVSS DIQMTQTTSSLSASLGDRVTISCSASQGI

[0908] 157? T CAT PRT Ah5? VT SNYLNWYQQKPDGTVKLLISYTSSLHS LUAL-rai-niAO?j VL GVPSRFSGSGSGTDYSLTISNLEPEDIAT YYCQHYSNLPWTFGGGTKLEIK

[0909] 1533 LGAL-PRT-mAb53 VH CDR1 GYYMN 1543 1534 LGAL-PRT-mAb53 VH CDR2 EINPSTGGTTYNQKFKA 1544 1535 LGAL-PRT-mAb53 VH CDR3 WGRSPYAMDY 1545 1536 LGAL-PRT-mAb53 VL CDR1 SASQGISNYLN 1546 1537 LGAL-PRT-mAb53 VL CDR2 YTSSLHS 1547

[0910]

[0911] 1538 LGAL-PRT-mAb53 VL CDR3 QHYSNLPWT 1548

[0912] EVQLVESGGDLVKPGGSLTLSCAASGFT FSSYGMSWIRQTPDKRLESVATISSGGS

[0913] 1551 LGAL-PRT-mAb55 VH YFSYPDSVKGRFTISRDNAKNTLYLRMT 1561

[0914] SLKSEDTAMYYCARLAYDYEYFEYWG QGTTLTVSS _ DIQMTQSPSSLSASLGGKVTITCKASQDI

[0915] 155? T CAT PRT Ah55 VT YKYLAWYQHKPGKGPRLLILNTSTLQP LUAL-I K i -m ADJJ VL GIPSRFSGSGSGREYSFTIGNLEPEDLAT YYCLQYNNLRTFGGGTKLEIR

[0916] 1553 LGAL-PRT-mAb55 VH CDR1 SYGMS 1563 1554 LGAL-PRT-mAb55 VH CDR2 TISSGGSYFSYPDSVKG 1564 1555 LGAL-PRT-mAb55 VH CDR3 LAYDYEYFEY 1565 1556 LGAL-PRT-mAb55 VL CDR1 KASQDIYKYLA 1566 1557 LGAL-PRT-mAb55 VL CDR2 NTSTLQP 1567

[0917]

[0918] 1558 LGAL-PRT-mAb55 VL CDR3 LQYNNLRT 1568

[0919] QVQLQQPGAEVVKSGASVKLSCKASGY TFTGYWMYWVKQRPGQGLEWIGMIHP

[0920] 1571 LGAL-PRT-mAb60 VH NSGSNKDNEKFKNKATLTVDKSSSTAY 1581

[0921] MQLSSLTSEDSAVYYCAREGDYVGLAY WGQGTLVTVSA _ DIVMTQSQKFMSTSVGNRVSVTCKASQ

[0922] r r-Ai DDT AUD VT NVGSNVAWYQQKPGQSPKALIYSASYR 1572 LGAL-PRT-mAb60 VL YSGVPDRFTGSGSGPVFTLTISNVQSED1582

[0923] LSEYFCQQYNDYPWTFGGGTKLEIK

[0924] 1573 LGAL-PRT-mAb60 VH CDR1 GYWMY 1583 1574 LGAL-PRT-mAb60 VH CDR2 MIHPNSGSNKDNEKFKN 1584 1575 LGAL-PRT-mAb60 VH CDR3 EGDYVGLAY 1585 1576 LGAL-PRT-mAb60 VL CDR1 KASQNVGSNVA 1586

[0925]

[0926] 1577 LGAL-PRT-mAb60 VL CDR2 SASYRYS 1587 1578 LGAL-PRT-mAb60 VL CDR3 QQYNDYPWT _ 1588

[0927] EVQLQQSGPELVKPGASVKMSCKASGY TFTDYNIHWVKQSHGKSLEWIGYINPNS

[0928] 1591 LGAL-PRT-mAb61 VH GDNPYNQRFKGKATLTVNRSSSTAYME 1601

[0929] LRSLTAEDSAVYYCSRSYSMDYWGQG

[0930]

[0931] TSVTVSS QIVLTQSPAIMSASPGEKVTMTCSASSS

[0932] 1^09. T AI DDT AU1 VT VSYMYWYQQKPGSSPRLLIYDTSNLAS 1592 LGAL-PRT-mAb61 VL GVPVRFSGSGSGTSYSLTISRMEAEDAA1602

[0933] TYYCQQWISYPPTWTFGGGTKLEIK

[0934] 1593 LGAL-PRT-mAb61 VH CDR1 DYNIH 1603 1594 LGAL-PRT-mAb61 VH CDR2 YINPNSGDNPYNQRFKG 1604 1595 LGAL-PRT-mAb61 VH CDR3 SYSMDY 1605 1596 LGAL-PRT-mAb61 VL CDR1 SASSSVSYMY 1606 1597 LGAL-PRT-mAb61 VL CDR2 DTSNLAS 1607

[0935]

[0936] 1598 LGAL-PRT-mAb61 VL CDR3 QQWISYPPTWT 1608

[0937] QVTLKESGPGILQPSQTLSLTCSFSGFSL STSGMGVSWIRQPSGKGLEWLSHIYWD

[0938] 681 SAA-P01-mAb35 VH DDKRSNPSLKSRLTISKDTSRNQVFLKIT 691

[0939] SVDTADTATYYCVRRGLRLRDYVMDY

[0940] _ WGQGTSVTVSS _

[0941] DIVMTQSPSSLTVTAGEKVTMSCKSSQS LFNSRSQKNYLTWFQRKPGQPPKLLIY

[0942] 682 SAA-P01-mAb35 VL WASTRDSGVPDRFTGSGSGTDFTLTINS 692

[0943] VQAEDLAVYYCQNDYSYPWTFGRGTK LEIK

[0944] 683 SAA-P01-mAb35 VH CDR1 TSGMGVS 693 684 SAA-P01-mAb35 VH CDR2 HIYWDDDKRSNPSLKS 694 685 SAA-P01-mAb35 VH CDR3 RGLRLRDYVMDY 695 686 SAA-P01-mAb35 VL CDR1 KSSQSLFNSRSQKNYLT 696 687 SAA-P01-mAb35 VL CDR2 WASTRDS 697

[0945]

[0946] 688 SAA-P01-mAb35 VL CDR3 QNDYSYPWT 698

[0947] QVQLQQPGAELVKPGASVKLSCKASGY TFINYWIHWVSQTPGRGLEWIGWIDPIS

[0948] 701 SAA-P01-mAb36 VH GGTKYNEKFKTKATLTVDKSSSTAYMQ 711

[0949] LSSLTSEDSADYYCIRDYHDSSFSFFYW GQGTLVTVSA _ QIVLTQSPAIMSASPGEKVTMTCSASSS

[0950] 70? SA A POl AMO VT VRYMHWFQQKPGTSPKLLIYRTSNLAS »AA-rui-mAwo VL GVPTRFSGSGSGTSYSLTISRMEAEDAA TYFCQQRTSYPFTFGSGTKLKIK

[0951] 703 SAA-P01-mAb36 VH CDR1 NYWIH 713 704 SAA-P01-mAb36 VH CDR2 WIDPISGGTKYNEKFKT 714 705 SAA-P01-mAb36 VH CDR3 DYHDSSFSFFY 715 706 SAA-P01-mAb36 VL CDR1 SASSSVRYMH 716 707 SAA-P01-mAb36 VL CDR2 RTSNLAS 717

[0952]

[0953] 708 SAA-P01-mAb36 VL CDR3 QQRTSYPFT 718 QVQLQQPGAELVRPGASVKMSCKASG YTFTSYNVHWIKQTPGQGLEWIGAIYPG SAA-P02-mAb37 VH NGDTSYNQKFILKATLTADKSSSTVYM 731

[0954] QLSSLTSEDSAVYYCTRGGYYGNSGYW GQGTTLTVSS TVLMTQTPLSLPVSLGDQASISCRSSQNI SAA-P02-mAb37 VL VLSNGYTYLEWYLQKPGQSPKLLIYKV jAA ruz mAOj / VI. SNRFSGVPDRFSGSGSGTEFTLKISRVEA EDLGVYYCFQGSHAPYTFGGGTKLEIK SAA-P02-mAb37 VH CDR1 SYNVH 733 SAA-P02-mAb37 VH CDR2 AIYPGNGDTSYNQKFIL 734 SAA-P02-mAb37 VH CDR3 GGYYGNSGY 735 SAA-P02-mAb37 VL CDR1 RSSQNIVLSNGYTYLE 736 SAA-P02-mAb37 VL CDR2 KVSNRFS 737 SAA-P02-mAb37 VL CDR3 FQGSHAPYT 738

[0955] QVQLHQSGTELMKPGASVKISCKATGY KFSSYWIEWIKVRPGHGLEWIGEILPRN SAA-P01-mAb38 VH GSAYYIEKFKGKATFTADTSSNTAYMQ 751

[0956] LS SLTSDD SAVYYCARFGQNYFDYWGQ GTTLTVSS DVLMTQTPLSLPVSLGDQASISCRSSQSI SAA-P01-mAb38 VL VHSNGNTYLEWYLQKPGQSPKLLIYKV SNRFSGVPDRFSGSGSGTDFTLKISRVEA EDLGVYYCFQGSHVPYTFGGGTKLEIK SAA-P01-mAb38 VH CDR1 SYWIE 753 SAA-P01-mAb38 VH CDR2 EILPRNGSAYYIEKFKG 754 SAA-P01-mAb38 VH CDR3 FGQNYFDY 755 SAA-P01-mAb38 VL CDR1 RSSQSIVHSNGNTYLE 756 SAA-P01-mAb38 VL CDR2 KVSNRFS 757 SAA-P01-mAb38 VL CDR3 FQGSHVPYT 758

[0957] QVQLQQSGPELMKPGASVTISCKATGY TFSTNWIDWVKQTPGHGLEWIGDIFPG SAA-P02-mAb39 VH NGTTNYNEQFKGKATFSADTSSNTAYM 771

[0958] QLSSLTSEDSAVYYCSSYPEYWGQGITL TVSS DVVMTQTPLTLSVTTGQPASISCKSSQS LLDSDGKTYLNWLLQRPGQSPKRLIYL SAA-P02-mAb39 VL VSKLESGVPDRFTGRGSGTDFTLKISRV 772

[0959] EAEDLGVYYCWQGTHFPQTFGGGTKV EIK SAA-P02-mAb39 VH CDR1 TNWID 773 SAA-P02-mAb39 VH CDR2 DIFPGNGTTNYNEQFKG 774 SAA-P02-mAb39 VH CDR3 YPEY 775 SAA-P02-mAb39 VL CDR1 KSSQSLLDSDGKTYLN 776 SAA-P02-mAb39 VL CDR2 LVSKLES 777

[0960]

[0961] SAA-P02-mAb39 VL CDR3 WQGTHFPQT 778 QVQLQQSGAELAKPGASVKLSCKASGY TFTSCWMHWVKQRPGQGLEWIGYINPS SAA-P02-mAb40 VH NGYTKYNQKFKDKATLTADKSSSTAY 791

[0962] MQLNSLTYEDSAVYCCVLEDFDYWGQ GTTLTVSS DVLMTQTPLSLPVSLGDQASISCRSSQNI SAA-P02-mAb40 VL VHNNGNTYLQWYLQKPGQSPKLLIYKV aAA ruz niAuw V L SNRFSGVPDRFSGSGSGTDFTLKISRVEA EDLGVYYCFQGSHVPLTFGAGTKLELK SAA-P02-mAb40 VH CDR1 SCWMH 793 SAA-P02-mAb40 VH CDR2 YINPSNGYTKYNQKFKD 794 SAA-P02-mAb40 VH CDR3 EDFDY 795 SAA-P02-mAb40 VL CDR1 RSSQNIVHNNGNTYLQ 796 SAA-P02-mAb40 VL CDR2 KVSNRFS 797 SAA-P02-mAb40 VL CDR3 FQGSHVPLT 798

[0963] EVQLQQSGPELVKPGASVKISCKASGYT FTDYYINWVKQSHGKSLEWIGDINPNN SAA-P01-mAb41 VH GDTSHNQKFKGKATLTVDKSSSTAYME 811

[0964] VRSLTSEDSAIYYCATGDWYFDVWGTG TTVTVSS DVVMTQTPLTLSVTTGQPASISCKSSQS LLDSDGKTYLNWLLQRPGQSPKRLIYR SAA-P01-mAb41 VL VSKLDSGVPDRFTGSGSGTDFTLKISRV 812

[0965] EAEDLGVYYCWQATHFPRTFGGGTKLE IK SAA-P01-mAb41 VH CDR1 DYYIN 813 SAA-P01-mAb41 VH CDR2 DINPNNGDTSHNQKFKG 814 SAA-P01-mAb41 VH CDR3 GDWYFDV 815 SAA-P01-mAb41 VL CDR1 KSSQSLLDSDGKTYLN 816 SAA-P01-mAb41 VL CDR2 RVSKLDS 817 SAA-P01-mAb41 VL CDR3 WQATHFPRT 818

[0966] QVQLQQPGAELVKPGASVKLSCKASGY TFTSYWMHWVSQTPGRGLEWIGWIDPI SAA-P01-mAb42 VH SGGTKYNERFKTKATLTVDKSSSTAYM 831

[0967] QLSSLTSEDSAVYYCIRDYYDSSFSFFY WGQGTLVTVSA QIVLTQSPAIMSASPGEKVTMTCSASSS SAA-P01-mAb42 VL VRYMHWFQQKPGTSPKLLIYRTSNLAS mAD4z VL GVPARFSGSGSGTSYSLTISRMEAEDAA TYFCQQRTSYPFTFGSGTKLKIK SAA-P01-mAb42 VH CDR1 SYWMH 833 SAA-P01-mAb42 VH CDR2 WIDPISGGTKYNERFKT 834 SAA-P01-mAb42 VH CDR3 DYYDSSFSFFY 835 SAA-P01-mAb42 VL CDR1 SASSSVRYMH 836 SAA-P01-mAb42 VL CDR2 RTSNLAS 837

[0968]

[0969] SAA-P01-mAb42 VL CDR3 QQRTSYPFT 838 EVQLQQSGAELVKPGASVKLSCTASGF NIKDHNVHWVKQRTEQGLEWIGRIDPE

[0970] 841 SAA-P02-mAb43 VH ADESKYDPKFQGRATIKVEISSNTAYLQ 851

[0971] LS SLTPEDTAVYYCVRRGLGVFWGQGT LVTVSA DVLMTQTPLSLPVSLGDQASISCRSSQSI

[0972] 842 SAA-P02-mAb43 VL IHSNGNTYLEWYLQKPGQSPKLLIYKVS V L NRFSGVPDRFSGSGSGTDFTLKISRVEA EDLGVYYCFQGSHVPLTFGAGTKLELK

[0973] 843 SAA-P02-mAb43 VH CDR1 DHNVH 853 844 SAA-P02-mAb43 VH CDR2 RIDPEADESKYDPKFQG 854 845 SAA-P02-mAb43 VH CDR3 RGLGVF 855 846 SAA-P02-mAb43 VL CDR1 RSSQSIIHSNGNTYLE 856 847 SAA-P02-mAb43 VL CDR2 KVSNRFS 857 848 SAA-P02-mAb43 VL CDR3 FQGSHVPLT 858

[0974] EVRLVESGGGLVQPKGSLKLSCVASGFS YKTYAMNWVRQAPGKGMKWVARIRN

[0975] 1611 SAA-PRT-mAb56 VH KSSYYATYYADSVKDRFTISRDDSESML 1621

[0976] YLQMNNLKTEDTAIYYCVSNSMDYWG QGTSVTVSS DVVMTQTPLTLSVTIGQPASISCKSSQSL LDSDGKTYLNWLLQRPGQSPKRLIYLV

[0977] 1612 SAA-PRT-mAb56 VL SKLDSGVPDRFTGSGSGTDFTLKISRVE 1622

[0978] AEDLGLYYCWQGTHFPQTFGGGTKVEI

[0979] K

[0980] 1613 SAA-PRT-mAb56 VH CDR1 TYAMN 1623 1614 SAA-PRT-mAb56 VH CDR2 RIRNKSSYYATYYADSVKD 1624 1615 SAA-PRT-mAb56 VH CDR3 NSMDY 1625 1616 SAA-PRT-mAb56 VL CDR1 KSSQSLLDSDGKTYLN 1626 1617 SAA-PRT-mAb56 VL CDR2 LVSKLDS 1627 1618 SAA-PRT-mAb56 VL CDR3 WQGTHFPQT 1628

[0981] EVQLVESGGGLVQPKGSLKLSCAASGF SFNTYAMNWVRQAPGKGLEWVARIRN

[0982] 1631 SAA-PRT-mAb64 VH KSTNYARYYADSVKDRFTISRDDSESIL 1641

[0983] YLQMNNLKIEDTAMYYCVSNSLDYWG QGTSVTVSS DVVMTQTPLTLSVTIGQPASISCKSSQSL LDSDGKTYLNWLLQRPGQSPKRLIYLV

[0984] 1632 SAA-PRT-mAb64 VL SRLDSGVPDRFTGSGSGTDFTLKISRVE 1642

[0985] AEDLGLYYCWQGTHFPQTFGGGTKLEI

[0986] K

[0987] 1633 SAA-PRT-mAb64 VH CDR1 TYAMN 1643 1634 SAA-PRT-mAb64 VH CDR2 RIRNKSTNYARYYADSVKD 1644 1635 SAA-PRT-mAb64 VH CDR3 NSLDY 1645 1636 SAA-PRT-mAb64 VL CDR1 KSSQSLLDSDGKTYLN 1646 1637 SAA-PRT-mAb64 VL CDR2 LVSRLDS 1647 1638 SAA-PRT-mAb64 VL CDR3 WQGTHFPQT 1648 1651 SAA-PRT-mAb69 VH EVQLQQSGPELVKPGASVKMSCKASGY

[0988]

[0989] vn TFTDYNIHWVKQSHGKSLEWIGYINPD NGASTYNQNFKGKATLTVNKSSSTAYM DLRSLTSEDSAVYYCRIAYFDYWGQGT TLTVSS DVVMTQTPLTLSVTIGQPASISCKSSQSL C A A DDT AUO VT LDSDGKTYLNWFLQRPGQSPKRLIYLVS

[0990] 1652 SAA-PRT-mAb69 VL ELDSGVPDRFTGSGSGTDFTLKISRVEA1662

[0991] EDLGVYYCWQGTHFPQTFGGGTKLEIK

[0992] 1653 SAA-PRT-mAb69 VH CDR1 DYNIH 1663 1654 SAA-PRT-mAb69 VH CDR2 YINPDNGASTYNQNFKG 1664 1655 SAA-PRT-mAb69 VH CDR3 AYFDY 1665 1656 SAA-PRT-mAb69 VL CDR1 KSSQSLLDSDGKTYLN 1666 1657 SAA-PRT-mAb69 VL CDR2 LVSELDS 1667 1658 SAA-PRT-mAb69 VL CDR3 WQGTHFPQT 1668

[0993] QVTLKESGPGILQPSQTLSLTCSFSGFSL STFGMGVGWIRQPSGKGLEWLAHIWW

[0994] 1671 SAA-PRT-mAb71 VH DDDKYYNPALKSRLTISRDASKTQVFL 1681

[0995] KIANVDTEDTATYYCARIVRGS AYFDY WGQGTPLTVSS DVVMTQTPLSLPVSLGDQASISCRSSQS LVHSNGNTYLDWYLQKPGQSPKLLIYK

[0996] 1672 SAA-PRT-mAb71 VL VSNRFSGVPDRFSGSGSGTDFTLKISRVE 1682

[0997] AEDLGVYFCCQSTHVPPWTFGGGTKLE IK

[0998] 1673 SAA-PRT-mAb71 VH CDR1 TFGMGVG 1683 1674 SAA-PRT-mAb71 VH CDR2 HIWWDDDKYYNPALKS 1684 1675 SAA-PRT-mAb71 VH CDR3 IVRGSAYFDY 1685 1676 SAA-PRT-mAb71 VL CDR1 RSSQSLVHSNGNTYLD 1686 1677 SAA-PRT-mAb71 VL CDR2 KVSNRFS 1687 1678 SAA-PRT-mAb71 VL CDR3 CQSTHVPPWT 1688

[0999] QVTLKESGPGILQPSQTLSLTCSFSGFSL STFGMGVGWIRQPSGKGLEWLAHIWW

[1000] 1691 SAA-PRT-mAb72 VH DDDKYYNPVLKSRLTISRDASKTQVFFK 1701

[1001] IANVDTEDTATYYCARIVRGSAYFDYW GQGTPLTVSS DVVMTQTPLSLPVSLGDQASISCRSSQS LVHSNGNTYLDWYLQKPGQSPKLLIYK

[1002] 1692 SAA-PRT-mAb72 VL VSNRFSGVPDRFSGSGSGTDFTLKISRVE 1702

[1003] AEDLGVYFCCQSTHVPPWTFGGGTKLE IK

[1004] 1693 SAA-PRT-mAb72 VH CDR1 TFGMGVG 1703 1694 SAA-PRT-mAb72 VH CDR2 HIWWDDDKYYNPVLKS 1704 1695 SAA-PRT-mAb72 VH CDR3 IVRGSAYFDY 1705 1696 SAA-PRT-mAb72 VL CDR1 RSSQSLVHSNGNTYLD 1706 1697 SAA-PRT-mAb72 VL CDR2 KVSNRFS 1707 1698 SAA-PRT-mAb72 VL CDR3 CQSTHVPPWT 1708

[1005] EVKVEESGRDLVQPGGSMKLSCVASGF

[1006] 1711 SAA-PRT-mAb73 VH TFSNYYMNWVRQSPEKGLEWVAQIRL 1721

[1007]

[1008] KSDNYATHYAESVKRRFTISRDDSKSSV YLQMNNLRAEDTGIYYCTGFYDHDGFD YWGQGTTLTVSS DIVMSQSPSSLAVSAGEKVTMSCKSSQS LLNSRTRKNYLAWYQQKPGQSPKLLIY

[1009] 1712 SAA-PRT-mAb73 VL WASTRESGVPDRFTGSGSGTDFTLTISS 1722

[1010] VQAEDLAVYYCKQSFNLFTFGSGTKLEI

[1011] K

[1012] 1713 SAA-PRT-mAb73 VH CDR1 NYYMN 1723 1714 SAA-PRT-mAb73 VH CDR2 QIRLKSDNYATHYAESVKR 1724 1715 SAA-PRT-mAb73 VH CDR3 FYDHDGFDY 1725 1716 SAA-PRT-mAb73 VL CDR1 KSSQSLLNSRTRKNYLA 1726 1717 SAA-PRT-mAb73 VL CDR2 WASTRES 1727

[1013]

[1014] 1718 SAA-PRT-mAb73 VL CDR3 KQSFNLFT 1728 Ab name: Protein-Peptide / PRT-antibody number; SID: SEQ ID No.

Claims

CLAIMS1. An isolated polypeptide capable of specifically binding a galectin 9 (LGALS9) protein target or a peptide thereof under urinary conditions.

2. The isolated polypeptide of claim 1, wherein the LGALS9 peptide comprises a sequence selected from sequences set forth in SEQ ID Nos. 882-888.

3. The isolated polypeptide of claim 1 or 2, comprising a heavy chain variable (VH) region including three complementarity determining region (CDR) sequences and a light chain variable (VL) region including three CDR sequences, and the six CDR sequences are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences selected from: SEQ ID Nos. 1571 and 1572; SEQ ID Nos. 661 and 662; SEQ ID Nos. 1471 and 1472; SEQ ID Nos. 1491 and 1492; SEQ ID Nos. 1511 and 1512; SEQ ID Nos. 1531 and 1532; SEQ ID Nos. 1551 and 1552; and SEQ ID Nos. 1591 and 1592.

4. The isolated polypeptide of claim 3, wherein the six CDR sequences comprise sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 1573, 1574, 1575, 1576, 1577, and 1578; SEQ ID Nos. 663, 664, 665, 666, 667, and 668; SEQ ID Nos. 1473, 1474, 1475, 1476, 1477, and 1478; SEQ ID Nos. 1493, 1494, 1495, 1496, 1497, and 1498; SEQ ID Nos. 1513, 1514, 1515, 1516, 1517, and 1518; SEQ ID Nos. 1533, 1534, 1535, 1536, 1537, and 1538; SEQ ID Nos. 1553, 1554, 1555, 1556, 1557, and 1558; and SEQ ID Nos.1593, 1594, 1595, 1596, 1597, and 1598.

5. The isolated polypeptide of claim 3 or 4, wherein the VH and VL region sequences comprise sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos. 1571 and 1572; SEQ ID Nos. 661 and 662; SEQ ID Nos. 1471 and 1472; SEQ ID Nos. 1491 and 1492; SEQ ID Nos. 1511 and 1512; SEQ ID Nos. 1531 and 1532; SEQ ID Nos. 1551 and 1552; and SEQ ID Nos. 1591 and 1592.

6. The isolated polypeptide of any one of claims 3-5, wherein the six CDR sequences comprise sequences substantially identical to six CDR sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 1583, 1584, 1585, 1586, 1587, and 1588; SEQ ID Nos. 673, 674, 675, 676, 677, and 678; SEQ ID Nos. 1483, 1484, 1485, 1486, 1487, and 1488; SEQ ID Nos.1503, 1504, 1505, 1506, 1507, and 1508; SEQ ID Nos. 1523, 1524, 1525, 1526, 1527, and 1528; SEQ ID Nos. 1543, 1544, 1545, 1546, 1547, and 1548; SEQ ID Nos. 1563, 1564, 1565, 1566, 1567, and 1568; and SEQ ID Nos. 1603, 1604, 1605, 1606, 1607, and 1608.

7. The isolated polypeptide of any one of claims 3-6, wherein the VH and VL region sequences comprise sequences substantially identical to VH and VL sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 1581 and 1582; SEQ ID Nos. 671 and 672; SEQ ID Nos. 1481 and 1482; SEQ ID Nos. 1501 and 1502; SEQ ID Nos. 1521 and 1522; SEQ ID Nos.1541 and 1542; SEQ ID Nos. 1561 and 1562; and SEQ ID Nos. 1601 and 1602.

8. An isolated polypeptide capable of specifically binding a C-reactive protein (CRP) target or a peptide thereof under urinary conditions.

9. The isolated polypeptide of claim 8, wherein the CRP peptide comprises a sequence selected from sequences set forth in SEQ ID Nos. 861-866.

10. The isolated polypeptide of claim 8 or 9, comprising a heavy chain variable (VH) region including three complementarity determining region (CDR) sequences and a light chain variable (VL) region including three CDR sequences, and the six CDR sequences are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences selected from: SEQ ID Nos. 181 and 182; SEQ ID Nos. 201 and 202; SEQ ID Nos. 221 and 222; SEQ ID Nos. 241 and 242; SEQ ID Nos. 261 and 262; SEQ ID Nos. 281 and 282; SEQ ID Nos. 931 and 932; SEQ ID Nos. 971 and 972; SEQ ID Nos. 991 and 992; SEQ ID Nos. 1031 and 1032; SEQ ID Nos. 1051 and 1052; SEQ ID Nos. 1091 and 1092; SEQ ID Nos. 1111 and 1112; SEQ ID Nos. 1131 and 1132; SEQ ID Nos. 1211 and 1212; SEQ ID Nos. 1231 and 1232; and SEQ ID Nos. 1311 and 1312.

11. The isolated polypeptide of claim 10, wherein the six CDR sequences comprise sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 183, 184, 185, 186, 187, and 188; SEQ ID Nos. 203, 204, 205, 206, 207, and 208; SEQ ID Nos. 223, 224, 225, 226, 227, and 228; SEQ ID Nos. 243, 244, 245, 246, 247, and 248; SEQ ID Nos. 263, 264, 265, 266, 267, and 268; SEQ ID Nos. 283, 284, 285, 286, 287, and 288; SEQ ID Nos. 933, 934, 935, 936, 937, and 938; SEQ ID Nos. 973, 974, 975, 976, 977, and 978; SEQ ID Nos.993, 994, 995, 996, 997, and 998; SEQ ID Nos. 1033, 1034, 1035, 1036, 1037, and 1038; SEQ ID Nos. 1053, 1054, 1055, 1056, 1057, and 1058; SEQ ID Nos. 1093, 1094, 1095, 1096, 1097, and 1098; SEQ ID Nos. 1113, 1114, 1115, 1116, 1117, and 1118; SEQ ID Nos. 1133, 1134, 1135, 1136, 1137, and 1138; SEQ ID Nos. 1213, 1214, 1215, 1216, 1217, and 1218; SEQ ID Nos. 1233, 1234, 1235, 1236, 1237, and 1238; and SEQ ID Nos. 1313, 1314, 1315, 1316, 1317, and 1318.

12. The isolated polypeptide of claim 10 or 11, wherein the VH and VL region sequences comprise sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos. 181 and 182; SEQ ID Nos. 201 and 202; SEQ ID Nos. 221 and 222; SEQ ID Nos. 241 and 242; SEQ ID Nos. 261 and 262; SEQ ID Nos. 281 and 282; SEQ ID Nos. 931 and 932; SEQ ID Nos. 971 and 972; SEQ ID Nos. 991 and 992; SEQ ID Nos. 1031 and 1032; SEQ ID Nos. 1051 and 1052; SEQ ID Nos. 1091 and 1092; SEQ ID Nos. 1111 and 1112; SEQ ID Nos. 1131 and 1132; SEQ ID Nos. 1211 and 1212; SEQ ID Nos. 1231 and 1232; and SEQ ID Nos. 1311 and 1312.

13. The isolated polypeptide of any one of claims 10-12, wherein the six CDR sequences comprise sequences substantially identical to six CDR sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 193, 194, 195, 196, 197, and 198; SEQ ID Nos. 213, 214, 215, 216, 217, and 218; SEQ ID Nos. 233, 234, 235, 236, 237, and 238; SEQ ID Nos. 253, 254, 255, 256, 257, and 258; SEQ ID Nos. 273, 274, 275, 276, 277, and 278; SEQ ID Nos. 293, 294, 295, 296, 297, and 298; SEQ ID Nos. 943, 944, 945, 946, 947, and 948; SEQ ID Nos.983, 984, 985, 986, 987, and 988; SEQ ID Nos. 1003, 1004, 1005, 1006, 1007, and 1008; SEQ ID Nos. 1043, 1044, 1045, 1046, 1047, and 1048; SEQ ID Nos. 1063, 1064, 1065, 1066, 1067, and 1068; SEQ ID Nos. 1103, 1104, 1105, 1106, 1107, and 1108; SEQ ID Nos. 1123, 1124, 1125, 1126, 1127, and 1128; SEQ ID Nos. 1143, 1144, 1145, 1146, 1147, and 1148; SEQ ID Nos. 1223, 1224, 1225, 1226, 1227, and 1228; SEQ ID Nos. 1243, 1244, 1245, 1246, 1247, and 1248; and SEQ ID Nos. 1323, 1324, 1325, 1326, 1327, and 1328.

14. The isolated polypeptide of any one of claims 10-13, wherein the VH and VL region sequences comprise sequences substantially identical to VH and VL sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 191 and 192; SEQ ID Nos. 211 and 212; SEQ ID Nos.231 and 232; SEQ ID Nos. 251 and 252; SEQ ID Nos. 271 and 272; SEQ ID Nos. 291 and 292; SEQ ID Nos. 941 and 942; SEQ ID Nos. 981 and 982; SEQ ID Nos. 1001 and 1002; SEQ ID Nos. 1041 and 1042; SEQ ID Nos. 1061 and 1062; SEQ ID Nos. 1101 and 1102; SEQ ID Nos. 1121 and 1122; SEQ ID Nos. 1141 and 1142; SEQ ID Nos. 1221 and 1222; SEQ ID Nos.1241 and 1242; and SEQ ID Nos. 1321 and 1322.

15. An isolated polypeptide capable of specifically binding a B- and T-lymphocyte attenuator (BTLA) protein target or a peptide thereof under urinary conditions.

16. The isolated polypeptide of claim 15, wherein the BTLA peptide comprises a sequence selected from sequences set forth in SEQ ID Nos. 867-869.

17. The isolated polypeptide of claim 15 or 16, comprising a heavy chain variable (VH) region including three complementarity determining region (CDR) sequences and a light chain variable (VL) region including three CDR sequences, and the six CDR sequences are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences selected from: SEQ ID Nos. 01 and 02; SEQ ID Nos. 21 and 22; SEQ ID Nos. 41 and 42; SEQ ID Nos. 61 and 62; SEQ ID Nos. 81 and 82; SEQ ID Nos. 101 and 102; SEQ ID Nos. 121 and 122; SEQ ID Nos. 141 and 142; SEQ ID Nos. 161 and 162; SEQ ID Nos. 1351 and 1352; SEQ ID Nos. 1371 and 1372; SEQ ID Nos. 1391 and 1392; SEQ ID Nos.1411 and 1412; SEQ ID Nos. 1431 and 1432; and SEQ ID Nos. 1451 and 1452.

18. The isolated polypeptide of claim 17, wherein the six CDR sequences comprise sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 03, 04, 05, 06, 07, and 08; SEQ ID Nos. 23, 24, 25, 26, 27, and 28; SEQ ID Nos. 43, 44, 45, 46, 47, and 48; SEQ ID Nos. 63, 64, 65, 66, 67, and 68; SEQ ID Nos. 83, 84, 85, 86, 87, and 88; SEQ ID Nos. 103, 104, 105, 106, 107, and 108; SEQ ID Nos. 123, 124, 125, 126, 127, and 128; SEQ ID Nos.143, 144, 145, 146, 147, and 148; SEQ ID Nos. 163, 164, 165, 166, 167, and 168; SEQ ID Nos. 1353, 1354, 1355, 1356, 1357, and 1358; SEQ ID Nos. 1373, 1374, 1375, 1376, 1377, and 1378; SEQ ID Nos. 1393, 1394, 1395, 1396, 1397, and 1398; SEQ ID Nos. 1413, 1414, 1415, 1416, 1417, and 1418; SEQ ID Nos. 1433, 1434, 1435, 1436, 1437, and 1438; and SEQ ID Nos. 1453, 1454, 1455, 1456, 1457, and 1458.

19. The isolated polypeptide of claim 17 or 18, wherein the VH and VL region sequences comprise sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos. 01 and 02; SEQ ID Nos. 21 and 22; SEQ ID Nos. 41 and 42; SEQ ID Nos. 61 and 62; SEQ ID Nos.81 and 82; SEQ ID Nos. 101 and 102; SEQ ID Nos. 121 and 122; SEQ ID Nos. 141 and 142; SEQ ID Nos. 161 and 162; SEQ ID Nos. 1351 and 1352; SEQ ID Nos. 1371 and 1372; SEQ ID Nos. 1391 and 1392; SEQ ID Nos. 1411 and 1412; SEQ ID Nos. 1431 and 1432; and SEQ ID Nos. 1451 and 1452.

20. The isolated polypeptide of any one of claims 17-19, wherein the six CDR sequences comprise sequences substantially identical to six CDR sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 13, 14, 15, 16, 17, and 18; SEQ ID Nos. 33, 34, 35, 36, 37, and 38; SEQ ID Nos. 53, 54, 55, 56, 57, and 58; SEQ ID Nos. 73, 74, 75, 76, 77, and 78; SEQ ID Nos. 93, 94, 95, 96, 97, and 98; SEQ ID Nos. 113, 114, 115, 116, 117, and 118; SEQ ID Nos.133, 134, 135, 136, 137, and 138; SEQ ID Nos. 153, 154, 155, 156, 157, and 158; SEQ ID Nos. 173, 174, 175, 176, 177, and 178; SEQ ID Nos. 1363, 1364, 1365, 1366, 1367, and 1368;SEQ ID Nos. 1383, 1384, 1385, 1386, 1387, and 1388; SEQ ID Nos. 1403, 1404, 1405, 1406, 1407, and 1408; SEQ ID Nos. 1423, 1424, 1425, 1426, 1427, and 1428; SEQ ID Nos. 1443, 1444, 1445, 1446, 1447, and 1448; and SEQ ID Nos. 1463, 1464, 1465, 1466, 1467, and 1468.

21. The isolated polypeptide of any one of claims 17-20, wherein the VH and VL region sequences comprise sequences substantially identical to VH and VL sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 11 and 12; SEQ ID Nos. 31 and 32; SEQ ID Nos. 51 and 52; SEQ ID Nos. 71 and 72; SEQ ID Nos. 91 and 92; SEQ ID Nos. 111 and 112; SEQ ID Nos. 131 and 132; SEQ ID Nos. 151 and 152; SEQ ID Nos. 171 and 172; SEQ ID Nos. 1361 and 1362; SEQ ID Nos. 1381 and 1382; SEQ ID Nos. 1401 and 1402; SEQ ID Nos. 1421 and 1422; SEQ ID Nos. 1441 and 1442; and SEQ ID Nos. 1461 and 1462.

22. An isolated polypeptide capable of specifically binding an epidermal growth factor (EGF) protein target or a peptide thereof under urinary conditions.

23. The isolated polypeptide of claim 22, wherein the EGF peptide comprises a sequence selected from sequences set forth in SEQ ID Nos. 870-875.

24. The isolated polypeptide of claim 22 or 23, comprising a heavy chain variable (VH) region including three complementarity determining region (CDR) sequences and a light chain variable (VL) region including three CDR sequences, and the six CDR sequences are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences selected from: SEQ ID Nos. 301 and 302; SEQ ID Nos. 321 and 322; SEQ ID Nos. 341 and 342; SEQ ID Nos. 361 and 362; SEQ ID Nos. 381 and 382; SEQ ID Nos. 401 and 402; SEQ ID Nos. 421 and 422; SEQ ID Nos. 441 and 442; and SEQ ID Nos. 461 and 462.

25. The isolated polypeptide of claim 24, wherein the six CDR sequences comprise sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 303, 304, 305, 306, 307, and 308; SEQ ID Nos. 323, 324, 325, 326, 327, and 328; SEQ ID Nos. 343, 344, 345, 346, 347, and 348; SEQ ID Nos. 363, 364, 365, 366, 367, and 368; SEQ ID Nos. 383, 384, 385, 386, 387, and 388; SEQ ID Nos. 403, 404, 405, 406, 407, and 408; SEQ ID Nos. 423, 424, 425, 426, 427, and 428; SEQ ID Nos. 443, 444, 445, 446, 447, and 448; and SEQ ID Nos.463, 464, 465, 466, 467, and 468.

26. The isolated polypeptide of claim 24 or 25, wherein the VH and VL region sequences comprise sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos. 301and 302; SEQ ID Nos. 321 and 322; SEQ ID Nos. 341 and 342; SEQ ID Nos. 361 and 362; SEQ ID Nos. 381 and 382; SEQ ID Nos. 401 and 402; SEQ ID Nos. 421 and 422; SEQ ID Nos. 441 and 442; and SEQ ID Nos. 461 and 462.

27. The isolated polypeptide of any one of claims 24-26, wherein the six CDR sequences comprise sequences substantially identical to six CDR sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 313, 314, 315, 316, 317, and 318; SEQ ID Nos. 333, 334, 335, 336, 337, and 338; SEQ ID Nos. 353, 354, 355, 356, 357, and 358; SEQ ID Nos. 373, 374, 375, 376, 377, and 378; SEQ ID Nos. 393, 394, 395, 396, 397, and 398; SEQ ID Nos. 413, 414, 415, 416, 417, and 418; SEQ ID Nos. 433, 434, 435, 436, 437, and 438; SEQ ID Nos.453, 454, 455, 456, 457, and 458; and SEQ ID Nos. 473, 474, 475, 476, 477, and 478.

28. The isolated polypeptide of any one of claims 24-27, wherein the VH and VL region sequences comprise sequences substantially identical to VH and VL sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 311 and 312; SEQ ID Nos. 331 and 332; SEQ ID Nos.351 and 352; SEQ ID Nos. 371 and 372; SEQ ID Nos. 391 and 392; SEQ ID Nos. 411 and 412; SEQ ID Nos. 431 and 432; SEQ ID Nos. 451 and 452; and SEQ ID Nos. 471 and 472.

29. An isolated polypeptide capable of specifically binding a fibrinogen alpha chain (FGA) protein target or a peptide thereof under urinary conditions.

30. The isolated polypeptide of claim 29, wherein the FGA peptide comprises a sequence selected from sequences set forth in SEQ ID Nos. 876-881.

31. The isolated polypeptide of claim 29 or 30, comprising a heavy chain variable (VH) region including three complementarity determining region (CDR) sequences and a light chain variable (VL) region including three CDR sequences, and the six CDR sequences are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences selected from: SEQ ID Nos. 481 and 482; SEQ ID Nos. 501 and 502; SEQ ID Nos. 521 and 522; SEQ ID Nos. 541 and 542; SEQ ID Nos. 561 and 562; SEQ ID Nos. 581 and 582; SEQ ID Nos. 601 and 602; SEQ ID Nos. 621 and 622; and SEQ ID Nos. 641 and 642.

32. The isolated polypeptide of claim 31, wherein the six CDR sequences comprise sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 483, 484, 485, 486, 487, and 488; SEQ ID Nos. 503, 504, 505, 506, 507, and 508; SEQ ID Nos. 523, 524, 525, 526, 527, and 528; SEQ ID Nos. 543, 544, 545, 546, 547, and 548; SEQ ID Nos. 563, 564,565, 566, 567, and 568; SEQ ID Nos. 583, 584, 585, 586, 587, and 588; SEQ ID Nos. 603, 604, 605, 606, 607, and 608; SEQ ID Nos. 623, 624, 625, 626, 627, and 628; and SEQ ID Nos.643, 644, 645, 646, 647, and 648.

33. The isolated polypeptide of claim 31 or 32, wherein the VH and VL region sequences comprise sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos. 481 and 482; SEQ ID Nos. 501 and 502; SEQ ID Nos. 521 and 522; SEQ ID Nos. 541 and 542; SEQ ID Nos. 561 and 562; SEQ ID Nos. 581 and 582; SEQ ID Nos. 601 and 602; SEQ ID Nos. 621 and 622; and SEQ ID Nos. 641 and 642.

34. The isolated polypeptide of any one of claims 31-33, wherein the six CDR sequences comprise sequences substantially identical to six CDR sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 493, 494, 495, 496,497, and 498; SEQ ID Nos. 513, 514, 515,516, 517, and 518; SEQ ID Nos. 533, 534,535, 536,537, and 538; SEQ ID Nos. 553, 554, 555, 556, 557, and 558; SEQ ID Nos. 573, 574, 575, 576, 577, and 578; SEQ ID Nos. 593, 594, 595,596, 597, and 598; SEQ ID Nos. 613, 614, 615, 616,617, and 618; SEQ ID Nos. 633, 634, 635, 636, 637, and 638; and SEQ ID Nos. 653, 654, 655,656, 657, and 658.

35. The isolated polypeptide of any one of claims 31-34, wherein the VH and VL region sequences comprise sequences substantially identical to VH and VL sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 491 and 492; SEQ ID Nos. 511 and 512; SEQ ID Nos.531 and 532; SEQ ID Nos. 551 and 552; SEQ ID Nos. 571 and 572; SEQ ID Nos. 591 and 592; SEQ ID Nos. 611 and 612; SEQ ID Nos. 631 and 632; and SEQ ID Nos. 651 and 652.

36. An isolated polypeptide capable of specifically binding a serum amyloid A (SAA) protein target or a peptide thereof under urinary conditions.

37. The isolated polypeptide of claim 36, wherein the SAA peptide comprises a sequence selected from sequences set forth in SEQ ID Nos. 889-898.

38. The isolated polypeptide of claim 36 or 37, comprising a heavy chain variable (VH) region including three complementarity determining region (CDR) sequences and a light chain variable (VL) region including three CDR sequences, and the six CDR sequences are defined by a standard method selected from Kabat, Chothia, IMGT, and AbM, based on VH and VL regions sequences selected from: SEQ ID Nos. 681 and 682; SEQ ID Nos. 701 and 702; SEQ ID Nos. 721 and 722; SEQ ID Nos. 741 and 742; SEQ ID Nos. 761 and 762; SEQ ID Nos. 781 and 782; SEQ ID Nos. 801 and 802; SEQ ID Nos. 821 and 822; SEQ ID Nos. 841 and 842;SEQ ID Nos. 1611 and 1612; SEQ ID Nos. 1631 and 1632; SEQ ID Nos. 1651 and 1652; SEQ ID Nos. 1671 and 1672; SEQ ID Nos. 1691 and 1692; and SEQ ID Nos. 1711 and 1712.

39. The isolated polypeptide of claim 38, wherein the six CDR sequences comprise sequences substantially identical to six CDR sequences selected from: SEQ ID Nos. 683, 684, 685, 686, 687, and 688; SEQ ID Nos. 703, 704, 705, 706, 707, and 708; SEQ ID Nos. 723, 724, 725, 726, 727, and 728; SEQ ID Nos. 743, 744, 745, 746, 747, and 748; SEQ ID Nos. 763, 764, 765, 766, 767, and 768; SEQ ID Nos. 783, 784, 785, 786, 787, and 788; SEQ ID Nos. 803, 804, 805, 806, 807, and 808; SEQ ID Nos. 823, 824, 825, 826, 827, and 828; SEQ ID Nos.843, 844, 845, 846, 847, and 848; SEQ ID Nos. 1613, 1614, 1615, 1616, 1617, and 1618; SEQ ID Nos. 1633, 1634, 1635, 1636, 1637, and 1638; SEQ ID Nos. 1653, 1654, 1655, 1656, 1657, and 1658; SEQ ID Nos. 1673, 1674, 1675, 1676, 1677, and 1678; SEQ ID Nos. 1693, 1694, 1695, 1696, 1697, and 1698; and SEQ ID Nos. 1713, 1714, 1715, 1716, 1717, and 1718.

40. The isolated polypeptide of claim 38 or 39, wherein the VH and VL region sequences comprise sequences substantially identical to VH and VL sequences selected from: SEQ ID Nos. 681 and 682; SEQ ID Nos. 701 and 702; SEQ ID Nos. 721 and 722; SEQ ID Nos. 741 and 742; SEQ ID Nos. 761 and 762; SEQ ID Nos. 781 and 782; SEQ ID Nos. 801 and 802; SEQ ID Nos. 821 and 822; SEQ ID Nos. 841 and 842; SEQ ID Nos. 1611 and 1612; SEQ ID Nos. 1631 and 1632; SEQ ID Nos. 1651 and 1652; SEQ ID Nos. 1671 and 1672; SEQ ID Nos. 1691 and 1692; and SEQ ID Nos. 1711 and 1712.

41. The isolated polypeptide of any one of claims 38-40, wherein the six CDR sequences comprise sequences substantially identical to six CDR sequences encoded by nucleic acid sequences selected from: SEQ ID Nos. 693, 694, 695, 696, 697, and 698; SEQ ID Nos. 713, 714, 715, 716, 717, and 718; SEQ ID Nos. 733, 734, 735, 736, 737, and 738; SEQ ID Nos. 753, 754, 755, 756, 757, and 758; SEQ ID Nos. 773, 774, 775, 776, 777, and 778; SEQ ID Nos. 793, 794, 795, 796, 797, and 798; SEQ ID Nos. 813, 814, 815, 816, 817, and 818; SEQ ID Nos.833, 834, 835, 836, 837, and 838; SEQ ID Nos. 853, 854, 855, 856, 857, and 858; SEQ ID Nos. 1623, 1624, 1625, 1626, 1627, and 1628; SEQ ID Nos. 1643, 1644, 1645, 1646, 1647, and 1648; SEQ ID Nos. 1663, 1664, 1665, 1666, 1667, and 1668; SEQ ID Nos. 1683, 1684, 1685, 1686, 1687, and 1688; SEQ ID Nos. 1703, 1704, 1705, 1706, 1707, and 1708; and SEQ ID Nos. 1723, 1724, 1725, 1726, 1727, and 1728.

42. The isolated polypeptide of any one of claims 38-41, wherein the VH and VL region sequences comprise sequences substantially identical to VH and VL sequences encoded by nucleic acidsequences selected from: SEQ ID Nos. 691 and 692; SEQ ID Nos. 711 and 712; SEQ ID Nos.731 and 732; SEQ ID Nos. 751 and 752; SEQ ID Nos. 771 and 772; SEQ ID Nos. 791 and 792; SEQ ID Nos. 811 and 812; SEQ ID Nos. 831 and 832; SEQ ID Nos. 851 and 852; SEQ ID Nos. 1621 and 1622; SEQ ID Nos. 1641 and 1642; SEQ ID Nos. 1661 and 1662; SEQ ID Nos. 1681 and 1682; SEQ ID Nos. 1701 and 1702; and SEQ ID Nos. 1721 and 1722.

43. The isolated polypeptide of any one of the preceding claims, wherein the protein target is a human protein.

44. The isolated polypeptide of any one of the preceding claims, wherein the isolated polypeptide is selected from an antibody or an antigen-binding fragment thereof, a single-chain variable fragment (scFv), a chimeric or a humanized antibody or antigen-binding fragment thereof, and a chimeric antigen receptor (CAR)-B.

45. The isolated polypeptide of any one of the preceding claims, wherein the isolated polypeptide is a monoclonal antibody.

46. The isolated polypeptide of any one of the preceding claims, wherein the isolated polypeptide is conjugated to a functional moiety.

47. The isolated polypeptide of any one of claims 1-46, wherein the specific binding is characterized by an EC50 of less than about 10, 1, or 0.1 nM.

48. An isolated nucleic acid molecule comprising at least one sequence encoding the isolated polypeptide of any one of claims 1-47.

49. A host cell comprising the isolated polypeptide of any one of claims 1-47, or the isolated nucleic acid molecule of claim 48.

50. The host cell of claim 49, wherein the host cell is a hybridoma cell.

51. A combination comprising the isolated polypeptide of any one of claims 1-47, and an additional polypeptide capable of specifically binding to a protein selected from CRP, BTLA, EGF, FGA, LGALS9, or SAA or to a peptide thereof, wherein the additional polypeptide does not interfere with binding of the isolated polypeptide to the protein target.

52. The combination of claim 51, wherein the additional polypeptide is an isolated polypeptide of any one of claims 1-47, different from the isolated polypeptide of claim 51.

53. The combination of claim 52, wherein the isolated polypeptide is capable of specifically binding to LGALS9 and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos. 1573-1578, and the additional polypeptide is capable of specifically binding to LGALS9 and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos. 1493-1498.

54. The combination of claim 52, wherein the isolated polypeptide is capable of specifically binding to LGALS9 and has VH and VL sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos. 1571-1572, and the additional polypeptide is capable of specifically binding to LGALS9 and has VH and VL sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos. 1491-1492.

55. The combination of claim 52, wherein the isolated polypeptide is capable of specifically binding to LGALS9 and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos. 1573-1578, and the additional polypeptide is capable of specifically binding to LGALS9 and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos. 1533-1538.

56. The combination of claim 52, wherein the isolated polypeptide is capable of specifically binding to LGALS9 and has VH and VL sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos. 1571-1572, and the additional polypeptide is capable of specifically binding to LGALS9 and has VH and VL sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos. 1531-1532.

57. The combination of claim 52, wherein the isolated polypeptide is capable of specifically binding to LGALS9 and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos. 1573-1578, and the additional polypeptide is capable of specifically binding to LGALS9 and has six CDR sequences substantially identical to six CDR sequences set forth in SEQ ID Nos. 1473-1478.

58. The combination of claim 52, wherein the isolated polypeptide is capable of specifically binding to LGALS9 and has VH and VL sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos. 1571-1572, and the additional polypeptide is capable of specifically binding to LGALS9 and has VH and VL sequences substantially identical to VH and VL sequences set forth in SEQ ID Nos. 1471-1472.

59. A method for predicting in a urine sample of a subject suspected of having an infection, whether the infection is a bacterial infection and / or a viral infection, the method comprising:a. contacting a urine sample of the subject with one or more isolated polypeptides of any one of claims 1-47;b. detecting binding of the one or more isolated polypeptides to the protein target selected from CRP, BTLA, SAA, LGALS9, EGF, or FGA, or a peptide thereof; and c. predicting whether the infection is bacterial and / or viral based on the detecting in step (b).

60. The method of claim 59, wherein the subject is a human.

61. The method of claim 59 or 60, wherein the infection is an upper respiratory tract infection (URTI).

62. The method of claim 61, wherein the URTI is selected from streptococcal pharyngitis (strep throat), bacterial tracheitis, sinusitis, epiglottitis, and viral URTIs caused by rhinovirus, coronavirus, adenovirus, influenza virus, and / or human parainfluenza virus.

63. The method of claim 61 or 62, wherein the URTI is caused by a bacterial agent selected from:group A streptococcus, Staphylococcus aureus, Moraxella catarrhalis, Haemophilus influenzae, Streptococcus pneumoniae, and combinations thereof.

64. The method of claim 61 or 62, wherein the URTI is caused by a viral agent selected from:rhinovirus, coronavirus, adenovirus, influenza virus, human parainfluenza virus, and combinations thereof.

65. The method of any one of claims 59-64, wherein the detecting the binding is conducted by an assay selected from a lateral flow assay (LFA), a fluorescence activated cell sorting (FACS), enzyme-linked immunosorbent assay (ELISA), a dipstick, a dot-blot, an antibody chip, and magnetic beads.

66. The method of any one of claims 59-65, further comprising a step of treating the subject with an antibiotic treatment when the infection is predicted to be bacterial, and / or treating the subject with an antiviral treatment when the infection is predicted to be viral.

67. A method for treating a bacterial infection in a subject afflicted with an infection, comprising:a. contacting a urine sample of the subject with one or more isolated polypeptides of any one of claims 1-47;b. detecting binding of the one or more isolated polypeptides to the protein target or peptide thereof; andc. predicting that the infection is bacterial based on the detecting in step (b); and d. treating the subject with antibiotics.

68. A method for treating a viral infection in a subject afflicted with an infection, the method comprising:a. contacting a urine sample of the subject with one or more isolated polypeptides of any one of claims 1-47;b. detecting binding of the one or more isolated polypeptides to the protein target or peptide thereof; andc. predicting that the infection is viral based on the detecting in step (b); and d. treating the subject with an antiviral agent.

69. A method for predicting efficacy of a treatment in a subject afflicted with a bacterial and / or a viral infection, the method comprising:a. administering to the subject a treatment comprising an antibiotic and / or an antiviral agent;b. contacting a urine sample of the subject, taken after administration, with one or more isolated polypeptides of any one of claims 1-47;c. detecting binding of the one or more isolated polypeptides to the protein target or peptide thereof; andd. predicting whether the treatment is effective based on the detecting in step (c), wherein, if binding is detected in step (c) then treatment is not effective. In some embodiments, if binding is not detected in step (c) then treatment is effective.

70. A kit for predicting in a urine sample whether an infection is a bacterial infection or a viral infection, the kit comprising:a. one or more isolated polypeptides of any one of claims 1-47;b. at least one reagent for detecting the binding of the one or more isolated polypeptides to the protein target or peptide thereof in a urine sample; andc. instructions for use.

71. The kit of claim 70, wherein the kit further comprises reagents for use with an assay based on a lateral flow assay (LFA), a fluorescence activated cell sorting (FACS), enzyme-linked immunosorbent assay (ELISA), a dipstick, a dot-blot, an antibody chip, and magnetic beads.

72. The kit of claim 70 or 71, wherein the kit further comprises a urine collection device selected from a urine cup, a urine bag, a urine diaper, and a urine catheter.

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