Anti-MICA / B antibodies and uses thereof

Abstract

The present disclosure relates to anti-MICA (major histocompatibility complex class I chain associated A) and / or anti-MICB (major histocompatibility complex class I chain associated B) antibodies, antigen binding fragments and uses thereof.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 329,221, filed on April 8, 2022. Technical Field

[0002] The present disclosure relates to antibodies that bind to major histocompatibility complex class I chain-associated A (MICA) and antibodies that bind to major histocompatibility complex class I chain-associated B (MICA), collectively referred to as anti-MICA / B antibodies, and uses thereof. Background Art

[0003] Major histocompatibility complex class I chain-related A and B (MICA / B) are highly polymorphic cell surface proteins associated with MHC class I glycoproteins that are ligands for the activation receptor NKG2D expressed on NK cells, CD8+ T cells, and γδ (GD) T cells. Binding of the NKG2D receptor to the MICA / B protein triggers NK cells and co-stimulates T cells, resulting in the elimination of cancer cells or damaged cells by effector cells expressing the NKG2D receptor. (Bauer S et al., NKG2D, the receptor for stress-inducible MICA, activates NK and T cells. Science, 1999 Jul 30;285(5428):727-9; Diefenbach A et al., Ligands for the mouse NKG2D receptor: expression on tumor cells and activation of NK cells and macrophages. Nat Immunol. 2000 Aug;1(2):119-26; and Groh V et al., NKG2D co-stimulates CD8alphabeta T cells by binding to MICs induced on virus-infected cells. Nat Immunol, 2001 Mar;2(3):255-60).

[0004] MICA / B proteins are expressed at low levels on myeloid cells, epithelial cells, endothelial cells, and fibroblasts.

[0005] Stably expressed. MICA / B proteins are upregulated or expressed de novo in response to stimulation, for example, during cancer development, infection, DNA damage response, and various autoimmune diseases. However, as an escape mechanism, in order to prevent NKG2D-mediated responses, tumor cells proteolytically shed MICA / B proteins from the cell surface, resulting in reduced MICA / B surface density and the production of soluble MICA / B (sMICA / B). (Groh V et al., Tumor-derived soluble MIC ligands impair NKG2D expression and T cell activation, Nature, October 17, 2002; 419(6908): 734-8; and Salih HR et al.; Frontiers: Effects of downregulating MICA on human tumors by proteolytic shedding, J Immunol, October 15, 2002; 169(8): 4098-102); MICA / B expression has been reported in a variety of tumor types, with high expression associated with poor patient prognosis. (Spear P et al., NKG2D ligands as therapeutic targets, Cancer Immun, 2013 May 1;13:8; and Ghadially H et al., MHC class I chain-related proteins A and B (MICA and MICB) are predominantly expressed intracellularly in tumors and normal tissues, Br J Cancer, 2017 Apr 25;116(9):1208-1217).

[0006] Genome-wide association studies (GWAS) have shown that MICA / B-related signals are highly correlated with the incidence and poor prognosis of a variety of human cancers. It is believed that specifically blocking the shedding of MICA and MICB proteins in cancer cells can restore or enhance NK and T cells that rely on NKG2D receptor activation in the tumor microenvironment, thereby enhancing the anti-tumor activity of cancer patients. Therefore, it is necessary to produce anti-MICA / B antibodies that bind to and block the shedding of MICA and MICB and enhance NK and T cells. The compositions and methods disclosed herein meet this need. Summary of the invention

[0007] The present disclosure relates to anti-MICA / B antibodies, antigen-binding fragments thereof, and uses thereof.

[0008] In one aspect, the present disclosure relates to an antibody or antigen-binding fragment thereof that binds to MICA (major histocompatibility complex class I chain-related A) and / or MICB (major histocompatibility complex class I chain-related B), comprising: a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, in some embodiments, the VH CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR1 amino acid sequence, the VH CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR2 amino acid sequence, and the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR3 amino acid sequence; and a light chain variable region (VL) comprising CDRs 1, 2, and 3, in some embodiments, the VL CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR1 amino acid sequence, the VL CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR2 amino acid sequence, and the VL CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL The CDR3 amino acid sequence is at least 80% identical to an amino acid sequence. In some embodiments, the selected VH CDRs 1, 2 and 3 amino acid sequences and the selected VL CDRS 1, 2 and 3 amino acid sequences are selected from the VH CDRs 1, 2, 3 and VL CDRS 1, 2, 3 listed in Figures 24A, 24B, 24C, 24D, 24E, 28, 29, 30A, 30B, 30C, 30D and 30E.

[0009] In some embodiments, the selected VH CDRs 1, 2, and 3 amino acid sequences and the selected VL CDRs 1, 2, and 3 amino acid sequences are one of the following:

[0010] (1) The selected amino acid sequences of VH CDRs 1, 2, and 3 are listed in SEQ ID NOs: 3, 4, and 5, respectively, and the selected amino acid sequences of VLCDRS 1, 2, and 3 are listed in SEQ ID NOs: 6, 7, and 8, respectively;

[0011] (2) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 11, 12, and 13, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 14, 15, and 16, respectively;

[0012] (3) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 19, 20, and 21, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 22, 23, and 24, respectively;

[0013] (4) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 27, 28, and 29, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 30, 31, and 32, respectively;

[0014] (5) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 35, 36, and 37, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 38, 39, and 40, respectively;

[0015] (6) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 43, 44, and 45, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 46, 47, and 48, respectively;

[0016] (7) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 51, 52, and 53, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 54, 55, and 56, respectively;

[0017] (8) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 59, 60, and 61, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 62, 63, and 64, respectively;

[0018] (9) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 67, 68, and 69, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 70, 71, and 72, respectively;

[0019] (10) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 75, 76, and 77, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 78, 79, and 80, respectively;

[0020] (11) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 83, 84, and 85, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 86, 87, and 88, respectively;

[0021] (12) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 91, 92, and 93, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 94, 95, and 96, respectively;

[0022] (13) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 99, 100, and 101, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 102, 103, and 104, respectively;

[0023] (14) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 107, 108, and 109, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 110, 111, and 112, respectively;

[0024] (15) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 115, 116, and 117, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 118, 119, and 120, respectively;

[0025] (16) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 123, 124, and 125, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 126, 127, and 128, respectively;

[0026] (17) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 131, 132, and 133, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 134, 135, and 136, respectively;

[0027] (18) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 139, 140, and 141, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 142, 143, and 144, respectively;

[0028] (19) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 147, 148, and 149, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 150, 151, and 152, respectively;

[0029] (20) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 155, 156, and 157, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 158, 159, and 160, respectively;

[0030] (21) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 815, 816, and 817, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 818, 819, and 820, respectively;

[0031] (22) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 821, 822, and 823, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 824, 825, and 826, respectively;

[0032] (23) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 827, 828, and 829, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 830, 831, and 832, respectively;

[0033] (24) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 833, 834, and 835, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 836, 837, and 838, respectively;

[0034] (25) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 839, 840, and 841, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 842, 843, and 844, respectively;

[0035] (26) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 845, 846, and 847, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 848, 849, and 850, respectively;

[0036] (27) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 851, 852, and 853, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 854, 855, and 856, respectively;

[0037] (28) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 857, 858, and 859, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 860, 861, and 862, respectively;

[0038] (29) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 863, 864, and 865, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 866, 867, and 868, respectively;

[0039] (30) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 869, 870, and 871, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 872, 873, and 874, respectively;

[0040] (31) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 875, 876, and 877, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 878, 879, and 880, respectively;

[0041] (32) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 881, 882, and 883, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 884, 885, and 886, respectively;

[0042] (33) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 887, 888, and 889, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 890, 891, and 892, respectively;

[0043] (34) The selected amino acid sequences of VH CDRs 1, 2, and 3 are listed in SEQ ID NOs: 893, 894, and 895, respectively, and the selected amino acid sequences of VL CDRs 1, 2, and 3 are listed in SEQ ID NOs: 896, 897, and 898, respectively;

[0044] (35) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 899, 900, and 901, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 902, 903, and 904, respectively;

[0045] (36) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 905, 906, and 907, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 908, 909, and 910, respectively;

[0046] (37) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 911, 912, and 913, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 914, 915, and 916, respectively;

[0047] (38) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 917, 918, and 919, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 920, 921, and 922, respectively;

[0048] (39) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 923, 924, and 925, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 926, 927, and 928, respectively; and

[0049] (40) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 929, 930, and 931, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 932, 933, and 934, respectively.

[0050] In some embodiments, the CDRs are determined by the IMGT definitions.

[0051] In some embodiments, the selected VH CDRs 1, 2, and 3 amino acid sequences and the selected VL CDRs 1, 2, and 3 amino acid sequences are one of the following:

[0052] (1) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 161, 162, and 163, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 164, 165, and 166, respectively;

[0053] (2) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 167, 168, and 169, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 170, 171, and 172, respectively;

[0054] (3) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 173, 174, and 175, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 176, 177, and 178, respectively;

[0055] (4) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 179, 180, and 181, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 182, 183, and 184, respectively;

[0056] (5) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 185, 186, and 187, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 188, 189, and 190, respectively;

[0057] (6) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 191, 192, and 193, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 194, 195, and 196, respectively;

[0058] (7) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 197, 198, and 199, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 200, 201, and 202, respectively;

[0059] (8) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 203, 204, and 205, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 206, 207, and 208, respectively;

[0060] (9) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 209, 210, and 211, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 212, 213, and 214, respectively;

[0061] (10) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 215, 216, and 217, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 218, 219, and 220, respectively;

[0062] (11) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 221, 222, and 223, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 224, 225, and 226, respectively;

[0063] (12) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 227, 228, and 229, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 230, 231, and 232, respectively;

[0064] (13) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 233, 234, and 235, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 236, 237, and 238, respectively;

[0065] (14) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 239, 240, and 241, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 242, 243, and 244, respectively;

[0066] (15) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 245, 246, and 247, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 248, 249, and 250, respectively;

[0067] (16) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 251, 252, and 253, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 254, 255, and 256, respectively;

[0068] (17) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 257, 258, and 259, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 260, 261, and 262, respectively;

[0069] (18) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 263, 264, and 265, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 266, 267, and 268, respectively;

[0070] (19) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 269, 270, and 271, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 272, 273, and 274, respectively;

[0071] (20) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 275, 276, and 277, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 278, 279, and 280, respectively;

[0072] (21) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 935, 936, and 937, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 938, 939, and 940, respectively;

[0073] (22) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 941, 942, and 943, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 944, 945, and 946, respectively;

[0074] (23) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 947, 948, and 949, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 950, 951, and 952, respectively;

[0075] (24) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 953, 954, and 955, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 956, 957, and 958, respectively;

[0076] (25) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 959, 960, and 961, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 962, 963, and 964, respectively;

[0077] (26) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 965, 966, and 967, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 968, 969, and 970, respectively;

[0078] (27) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 971, 972, and 973, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 974, 975, and 976, respectively;

[0079] (28) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 977, 978, and 979, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 980, 981, and 982, respectively;

[0080] (29) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 983, 984, and 985, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 986, 987, and 988, respectively;

[0081] (30) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 989, 990, and 991, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 992, 993, and 994, respectively;

[0082] (31) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 995, 996, and 997, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 998, 999, and 1000, respectively;

[0083] (32) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1001, 1002, and 1003, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1004, 1005, and 1006, respectively;

[0084] (33) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1007, 1008, and 1009, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1010, 1011, and 1012, respectively;

[0085] (34) The selected amino acid sequences of VH CDRs 1, 2, and 3 are listed in SEQ ID NOs: 1013, 1014, and 1015, respectively, and the selected amino acid sequences of VL CDRs 1, 2, and 3 are listed in SEQ ID NOs: 1016, 1017, and 1018, respectively;

[0086] (35) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1019, 1020, and 1021, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1022, 1023, and 1024, respectively;

[0087] (36) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1025, 1026, and 1027, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1028, 1029, and 1030, respectively;

[0088] (37) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1031, 1032, and 1033, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1034, 1035, and 1036, respectively;

[0089] (38) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1037, 1038, and 1039, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1040, 1041, and 1042, respectively;

[0090] (39) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1043, 1044, and 1045, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1046, 1047, and 1048, respectively; and

[0091] (40) The selected amino acid sequences of VH CDRs 1, 2, and 3 are listed in SEQ ID NOs: 1049, 1050, and 1051, respectively, and the selected amino acid sequences of VL CDRs 1, 2, and 3 are listed in SEQ ID NOs: 1052, 1053, and 1054, respectively.

[0092] In some embodiments, the CDRs are determined by the Kabat definition.

[0093] In some embodiments, the selected VH CDRs 1, 2, and 3 amino acid sequences and the selected VL CDRs 1, 2, and 3 amino acid sequences are one of the following:

[0094] (1) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 281, 282, and 283, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 284, 285, and 286, respectively;

[0095] (2) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 287, 288, and 289, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 290, 291, and 292, respectively;

[0096] (3) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 293, 294, and 295, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 296, 297, and 298, respectively;

[0097] (4) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 299, 300, and 301, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 302, 303, and 304, respectively;

[0098] (5) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 305, 306, and 307, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 308, 309, and 310, respectively;

[0099] (6) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 311, 312, and 313, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 314, 315, and 316, respectively;

[0100] (7) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 317, 318, and 319, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 320, 321, and 322, respectively;

[0101] (8) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 323, 324, and 325, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 326, 327, and 328, respectively;

[0102] (9) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 329, 330, and 331, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 332, 333, and 334, respectively;

[0103] (10) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 335, 336, and 337, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 338, 339, and 340, respectively;

[0104] (11) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 341, 342, and 343, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 344, 345, and 346, respectively;

[0105] (12) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 347, 348, and 349, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 350, 351, and 352, respectively;

[0106] (13) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 353, 354, and 355, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 356, 357, and 358, respectively;

[0107] (14) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 359, 360, and 361, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 362, 363, and 364, respectively;

[0108] (15) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 365, 366, and 367, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 368, 369, and 370, respectively;

[0109] (16) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 371, 372, and 373, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 374, 375, and 376, respectively;

[0110] (17) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 377, 378, and 379, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 380, 381, and 382, ​​respectively;

[0111] (18) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 383, 384, and 385, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 386, 387, and 388, respectively;

[0112] (19) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 389, 390, and 391, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 392, 393, and 394, respectively;

[0113] (20) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 395, 396, and 397, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 398, 399, and 400, respectively;

[0114] (21) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1055, 1056, and 1057, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1058, 1059, and 1060, respectively;

[0115] (22) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1061, 1062, and 1063, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1064, 1065, and 1066, respectively;

[0116] (23) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1067, 1068, and 1069, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1070, 1071, and 1072, respectively;

[0117] (24) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1073, 1074, and 1075, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1076, 1077, and 1078, respectively;

[0118] (25) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1079, 1080, and 1081, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1082, 1083, and 1084, respectively;

[0119] (26) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1085, 1086, and 1087, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1088, 1089, and 1090, respectively;

[0120] (27) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1091, 1092, and 1093, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1094, 1095, and 1096, respectively;

[0121] (28) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1097, 1098, and 1099, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1100, 1101, and 1102, respectively;

[0122] (29) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1103, 1104, and 1105, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1106, 1107, and 1108, respectively;

[0123] (30) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1109, 1110, and 1111, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1112, 1113, and 1114, respectively;

[0124] (31) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1115, 1116, and 1117, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1118, 1119, and 1120, respectively;

[0125] (32) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1121, 1122, and 1123, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1124, 1125, and 1126, respectively;

[0126] (33) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1127, 1128, and 1129, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1130, 1131, and 1132, respectively;

[0127] (34) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1133, 1134, and 1135, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1136, 1137, and 1138, respectively;

[0128] (35) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1139, 1140, and 1141, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1142, 1143, and 1144, respectively;

[0129] (36) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1145, 1146, and 1147, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1148, 1149, and 1150, respectively;

[0130] (37) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1151, 1152, and 1153, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1154, 1155, and 1156, respectively;

[0131] (38) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1157, 1158, and 1159, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1160, 1161, and 1162, respectively;

[0132] (39) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1163, 1164, and 1165, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1166, 1167, and 1168, respectively; and

[0133] (40) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1169, 1170, and 1171, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1172, 1173, and 1174, respectively.

[0134] In some embodiments, the CDRs are determined by the Chothia definition.

[0135] In some embodiments, the selected VH CDRs 1, 2, and 3 amino acid sequences and the selected VL CDRs 1, 2, and 3 amino acid sequences are one of the following:

[0136] (1) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 401, 402, and 403, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 404, 405, and 406, respectively;

[0137] (2) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 407, 408, and 409, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 410, 411, and 412, respectively;

[0138] (3) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 413, 414, and 415, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 416, 417, and 418, respectively;

[0139] (4) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 419, 420, and 421, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 422, 423, and 424, respectively;

[0140] (5) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 425, 426, and 427, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 428, 429, and 430, respectively;

[0141] (6) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 431, 432, and 433, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 434, 435, and 436, respectively;

[0142] (7) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 437, 438, and 439, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 440, 441, and 442, respectively;

[0143] (8) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 443, 444, and 445, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 446, 447, and 448, respectively;

[0144] (9) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 449, 450, and 451, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 452, 453, and 454, respectively;

[0145] (10) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 455, 456, and 457, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 458, 459, and 460, respectively;

[0146] (11) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 461, 462, and 463, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 464, 465, and 466, respectively;

[0147] (12) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 467, 468, and 469, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 470, 471, and 472, respectively;

[0148] (13) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 473, 474, and 475, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 476, 477, and 478, respectively;

[0149] (14) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 479, 480, and 481, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 482, 483, and 484, respectively;

[0150] (15) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 485, 486, and 487, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 488, 489, and 490, respectively;

[0151] (16) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 491, 492, and 493, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 494, 495, and 496, respectively;

[0152] (17) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 497, 498, and 499, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 500, 501, and 502, respectively;

[0153] (18) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 503, 504, and 505, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 506, 507, and 508, respectively;

[0154] (19) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 509, 510, and 511, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 512, 513, and 514, respectively;

[0155] (20) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 515, 516, and 517, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 518, 519, and 520, respectively;

[0156] (21) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1175, 1176, and 1177, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1178, 1179, and 1180, respectively;

[0157] (22) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1181, 1182, and 1183, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1184, 1185, and 1186, respectively;

[0158] (23) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1187, 1188, and 1189, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1190, 1191, and 1192, respectively;

[0159] (24) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1193, 1194, and 1195, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1196, 1197, and 1198, respectively;

[0160] (25) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1199, 1200, and 1201, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1202, 1203, and 1204, respectively;

[0161] (26) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1205, 1206, and 1207, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1208, 1209, and 1210, respectively;

[0162] (27) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1211, 1212, and 1213, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1214, 1215, and 1216, respectively;

[0163] (28) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1217, 1218, and 1219, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1220, 1221, and 1222, respectively;

[0164] (29) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1223, 1224, and 1225, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1226, 1227, and 1228, respectively;

[0165] (30) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1229, 1230, and 1231, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1232, 1233, and 1234, respectively;

[0166] (31) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1235, 1236, and 1237, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1238, 1239, and 1240, respectively;

[0167] (32) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1241, 1242, and 1243, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1244, 1245, and 1246, respectively;

[0168] (33) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1247, 1248, and 1249, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1250, 1251, and 1252, respectively;

[0169] (34) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1253, 1254, and 1255, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1256, 1257, and 1258, respectively;

[0170] (35) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1259, 1260, and 1261, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1262, 1263, and 1264, respectively;

[0171] (36) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1265, 1266, and 1267, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1268, 1269, and 1270, respectively;

[0172] (37) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1271, 1272, and 1273, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1274, 1275, and 1276, respectively;

[0173] (38) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1277, 1278, and 1279, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1280, 1281, and 1282, respectively;

[0174] (39) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1283, 1284, and 1285, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1286, 1287, and 1288, respectively; and

[0175] (40) The selected amino acid sequences of VH CDRs 1, 2, and 3 are listed in SEQ ID NOs: 1289, 1290, and 1291, respectively, and the selected amino acid sequences of VL CDRs 1, 2, and 3 are listed in SEQ ID NOs: 1292, 1293, and 1294, respectively.

[0176] In some embodiments, the CDRs are determined by the Aho definition.

[0177] In some embodiments, the selected VH CDRs 1, 2, and 3 amino acid sequences and the selected VL CDRs 1, 2, and 3 amino acid sequences are one of the following:

[0178] (1) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 521, 522, and 523, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 524, 525, and 526, respectively;

[0179] (2) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 527, 528, and 529, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 530, 531, and 532, respectively;

[0180] (3) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 533, 534, and 535, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 536, 537, and 538, respectively;

[0181] (4) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 539, 540, and 541, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 542, 543, and 544, respectively;

[0182] (5) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 545, 546, and 547, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 548, 549, and 550, respectively;

[0183] (6) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 551, 552, and 553, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 554, 555, and 556, respectively;

[0184] (7) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 557, 558, and 559, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 560, 561, and 562, respectively;

[0185] (8) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 563, 564, and 565, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 566, 567, and 568, respectively;

[0186] (9) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 569, 570, and 571, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 572, 573, and 574, respectively;

[0187] (10) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 575, 576, and 577, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 578, 579, and 580, respectively;

[0188] (11) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 581, 582, and 583, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 584, 585, and 586, respectively;

[0189] (12) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 587, 588, and 589, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 590, 591, and 592, respectively;

[0190] (13) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 593, 594, and 595, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 596, 597, and 598, respectively;

[0191] (14) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 599, 600, and 601, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 602, 603, and 604, respectively;

[0192] (15) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 605, 606, and 607, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 608, 609, and 610, respectively;

[0193] (16) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 611, 612, and 613, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 614, 615, and 616, respectively;

[0194] (17) The selected amino acid sequences of VH CDRs 1, 2, and 3 are listed in SEQ ID NOs: 617, 618, and 619, respectively, and the selected amino acid sequences of VL CDRs 1, 2, and 3 are listed in SEQ ID NOs: 620, 621, and 622, respectively;

[0195] (18) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 623, 624, and 625, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 626, 627, and 628, respectively;

[0196] (19) The selected amino acid sequences of VH CDRs 1, 2, and 3 are listed in SEQ ID NOs: 629, 630, and 631, respectively, and the selected amino acid sequences of VL CDRs 1, 2, and 3 are listed in SEQ ID NOs: 632, 633, and 634, respectively;

[0197] (20) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 635, 636, and 637, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 638, 639, and 640, respectively;

[0198] (21) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1295, 1296, and 1297, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1298, 1299, and 1300, respectively;

[0199] (22) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1301, 1302, and 1303, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1304, 1305, and 1306, respectively;

[0200] (23) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1307, 1308, and 1309, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1310, 1311, and 1312, respectively;

[0201] (24) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1313, 1314, and 1315, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1316, 1317, and 1318, respectively;

[0202] (25) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1319, 1320, and 1321, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1322, 1323, and 1324, respectively;

[0203] (26) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1325, 1326, and 1327, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1328, 1329, and 1330, respectively;

[0204] (27) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1331, 1332, and 1333, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1334, 1335, and 1336, respectively;

[0205] (28) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1337, 1338, and 1339, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1340, 1341, and 1342, respectively;

[0206] (29) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1343, 1344, and 1345, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1346, 1347, and 1348, respectively;

[0207] (30) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1349, 1350, and 1351, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1352, 1353, and 1354, respectively;

[0208] (31) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1355, 1356, and 1357, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1358, 1359, and 1360, respectively;

[0209] (32) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1361, 1362, and 1363, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1364, 1365, and 1366, respectively;

[0210] (33) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1367, 1368, and 1369, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1370, 1371, and 1372, respectively;

[0211] (34) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1373, 1374, and 1375, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1376, 1377, and 1378, respectively;

[0212] (35) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1379, 1380, and 1381, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1382, 1383, and 1384, respectively;

[0213] (36) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1385, 1386, and 1387, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1388, 1389, and 1390, respectively;

[0214] (37) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1391, 1392, and 1393, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1394, 1395, and 1396, respectively;

[0215] (38) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1397, 1398, and 1399, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1400, 1401, and 1402, respectively;

[0216] (39) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1403, 1404, and 1405, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1406, 1407, and 1408, respectively; and

[0217] (40) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1409, 1410, and 1411, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1412, 1413, and 1414, respectively.

[0218] In some embodiments, the CDRs are determined by the Northern definition.

[0219] In some embodiments, the selected VH CDRs 1, 2, and 3 amino acid sequences and the selected VL CDRs 1, 2, and 3 amino acid sequences are one of the following:

[0220] (1) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 708, 709, and 710, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 711, 712, and 713, respectively;

[0221] (2) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 714, 715, and 716, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 717, 718, and 719, respectively;

[0222] (3) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 720, 721, and 722, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 723, 724, and 725, respectively;

[0223] (4) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 726, 727, and 728, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 729, 730, and 731, respectively;

[0224] (5) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 732, 733, and 734, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 735, 736, and 737, respectively;

[0225] (6) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 738, 739, and 740, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 741, 742, and 743, respectively;

[0226] (7) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 744, 745, and 746, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 747, 748, and 749, respectively;

[0227] (8) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 750, 751, and 752, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 753, 754, and 755, respectively;

[0228] (9) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 756, 757, and 758, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 759, 760, and 761, respectively;

[0229] (10) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 762, 763, and 764, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 765, 766, and 767, respectively;

[0230] (11) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 768, 769, and 770, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 771, 772, and 773, respectively;

[0231] (12) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 774, 775, and 776, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 777, 778, and 779, respectively;

[0232] (13) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 780, 781, and 782, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 783, 784, and 785, respectively;

[0233] (14) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 786, 787, and 788, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 789, 790, and 791, respectively;

[0234] (15) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 792, 793, and 794, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 795, 796, and 797, respectively;

[0235] (16) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 798, 799, and 800, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 801, 802, and 803, respectively;

[0236] (17) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 804, 805, and 806, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 807, 808, and 809, respectively; and

[0237] (18) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 810, 811, and 812, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 813, 814, and 815, respectively.

[0238] In some embodiments, the antibody or its antigen binding fragment specifically binds to human MICA and / or human MICB. In some embodiments, the antibody or its antigen binding fragment specifically binds to monkey MICA and / or monkey MICB. In some embodiments, the antibody or its antigen binding fragment can block MICA and / or MICB from falling off the surface of cancer cells. In some embodiments, the antibody or its antigen binding fragment is a humanized antibody or its antigen binding fragment. In some embodiments, the antibody or its antigen binding fragment is a single chain variable fragment (scFV) or a multispecific antibody (e.g., a bispecific antibody).

[0239] In one aspect, the present disclosure relates to an antibody or antigen-binding fragment thereof that binds to MICA and / or MICB, comprising a heavy chain variable region (VH), comprising a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90% identical to a selected VH sequence, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90% identical to a selected VL sequence, and in some embodiments, the selected VH sequence and the selected VL sequence are selected from Fig.23 , 25, 26, 27, 28 or 29.

[0240] In some embodiments, the selected VH sequence and the selected VL sequence are one of the following:

[0241] (1) The selected VH sequence is SEQ ID NO: 1, and the selected VL sequence is SEQ ID NO: 2;

[0242] (2) the selected VH sequence is SEQ ID NO: 9, and the selected VL sequence is SEQ ID NO: 10;

[0243] (3) The VH sequence was selected as SEQ ID NO: 17, and the VL sequence was selected as SEQ ID NO: 18;

[0244] (4) the selected VH sequence is SEQ ID NO: 25, and the selected VL sequence is SEQ ID NO: 26;

[0245] (5) The VH sequence was selected as SEQ ID NO: 33, and the VL sequence was selected as SEQ ID NO: 34;

[0246] (6) the selected VH sequence is SEQ ID NO: 41, and the selected VL sequence is SEQ ID NO: 42;

[0247] (7) the selected VH sequence is SEQ ID NO: 49, and the selected VL sequence is SEQ ID NO: 50;

[0248] (8) the selected VH sequence is SEQ ID NO: 57, and the selected VL sequence is SEQ ID NO: 58;

[0249] (9) the selected VH sequence is SEQ ID NO: 65, and the selected VL sequence is SEQ ID NO: 66;

[0250] (10) the selected VH sequence is SEQ ID NO: 73, and the selected VL sequence is SEQ ID NO: 74;

[0251] (11) the selected VH sequence is SEQ ID NO: 81, and the selected VL sequence is SEQ ID NO: 82;

[0252] (12) The VH sequence was selected as SEQ ID NO: 89, and the VL sequence was selected as SEQ ID NO: 90;

[0253] (13) the selected VH sequence is SEQ ID NO: 97, and the selected VL sequence is SEQ ID NO: 98;

[0254] (14) the selected VH sequence is SEQ ID NO: 105, and the selected VL sequence is SEQ ID NO: 106;

[0255] (15) The VH sequence was selected as SEQ ID NO: 113, and the VL sequence was selected as SEQ ID NO: 114;

[0256] (16) the selected VH sequence is SEQ ID NO: 121, and the selected VL sequence is SEQ ID NO: 122;

[0257] (17) The VH sequence was selected as SEQ ID NO: 129, and the VL sequence was selected as SEQ ID NO: 130;

[0258] (18) the selected VH sequence is SEQ ID NO: 137, and the selected VL sequence is SEQ ID NO: 138;

[0259] (19) the selected VH sequence is SEQ ID NO: 145, the selected VL sequence is SEQ ID NO: 146; and

[0260] (20) The selected VH sequence is SEQ ID NO: 153, and the selected VL sequence is SEQ ID NO: 154.

[0261] In some embodiments, the selected VH sequence is SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706, and the selected VL sequence is SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. In some embodiments, the selected VH sequence is SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, or 652, and the selected VL sequence is SEQ ID NOs: 653, 654, 655, 656, 657, or 658. In some embodiments, the selected VH sequence is SEQ ID NO: 659, and the selected VL sequence is SEQ ID NO: 660. In some embodiments, the selected VH sequence is SEQ ID NOs: 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679 or 680, and the selected VL sequence is SEQ ID NOs: 681, 682, 683, 684, 685, 686, 687, 688 or 689. In some embodiments, the VH comprises the sequence of SEQ ID NO: 668 and the VL comprises the sequence of SEQ ID NO: 681. In some embodiments, the VH comprises the sequence of SEQ ID NO: 669 and the VL comprises the sequence of SEQ ID NO: 681. In some embodiments, the VH comprises the sequence of SEQ ID NO: 671 and the VL comprises the sequence of SEQ ID NO: 681. In some embodiments, the VH comprises the sequence of SEQ ID NO: 665 and the VL comprises the sequence of SEQ ID NO: 681. In some embodiments, the VH comprises the sequence of SEQ ID NO: 666 and the VL comprises the sequence of SEQ ID NO: 681. In some embodiments, the VH comprises the sequence of SEQ ID NO: 670 and the VL comprises the sequence of SEQ ID NO: 681. In some embodiments, the VH comprises the sequence of SEQ ID NO: 674 and the VL comprises the sequence of SEQ ID NO: 682. In some embodiments, the VH comprises the sequence of SEQ ID NO: 675 and the VL comprises the sequence of SEQ ID NO: 683. In some embodiments, the VH comprises the sequence of SEQ ID NO: 676 and the VL comprises the sequence of SEQ ID NO: 682.In some embodiments, the VH comprises the sequence of SEQ ID NO: 678 and the VL comprises the sequence of SEQ ID NO: 682. In some embodiments, the VH comprises the sequence of SEQ ID NO: 677 and the VL comprises the sequence of SEQ ID NO: 684. In some embodiments, the VH comprises the sequence of SEQ ID NO: 672 and the VL comprises the sequence of SEQ ID NO: 681. In some embodiments, the VH comprises the sequence of SEQ ID NO: 673 and the VL comprises the sequence of SEQ ID NO: 681. In some embodiments, the VH comprises the sequence of SEQ ID NO: 667 and the VL comprises the sequence of SEQ ID NO: 681. In some embodiments, the VH comprises the sequence of SEQ ID NO: 659 and the VL comprises the sequence of SEQ ID NO: 660. In some embodiments, the VH comprises the sequence of SEQ ID NO: 680 and the VL comprises the sequence of SEQ ID NO: 687. In some embodiments, the VH comprises the sequence of SEQ ID NO: 661 and the VL comprises the sequence of SEQ ID NO: 685. In some embodiments, the VH comprises the sequence of SEQ ID NO: 662 and the VL comprises the sequence of SEQ ID NO: 685. In some embodiments, the VH comprises the sequence of SEQ ID NO: 663 and the VL comprises the sequence of SEQ ID NO: 685. In some embodiments, the VH comprises the sequence of SEQ ID NO: 664 and the VL comprises the sequence of SEQ ID NO: 685. In some embodiments, the VH comprises the sequence of SEQ ID NO: 665 and the VL comprises the sequence of SEQ ID NO: 685. In some embodiments, the VH comprises the sequence of SEQ ID NO: 665 and the VL comprises the sequence of SEQ ID NO: 688. In some embodiments, the VH comprises the sequence of SEQ ID NO: 665 and the VL comprises the sequence of SEQ ID NO: 689. In some embodiments, the VH comprises the sequence of SEQ ID NO: 665 and the VL comprises the sequence of SEQ ID NO: 686. In some embodiments, the VH comprises the sequence of SEQ ID NO: 679 and the VL comprises the sequence of SEQ ID NO: 686. In some embodiments, VH comprises the sequence of SEQ ID NO: 641 and VL comprises the sequence of SEQ ID NO: 653. In some embodiments, VH comprises the sequence of SEQ ID NO: 642 and VL comprises the sequence of SEQ ID NO: 653. In some embodiments, VH comprises the sequence of SEQ ID NO: 643 and VL comprises the sequence of SEQ ID NO: 653.In some embodiments, the VH comprises the sequence of SEQ ID NO: 644 and the VL comprises the sequence of SEQ ID NO: 653. In some embodiments, the VH comprises the sequence of SEQ ID NO: 647 and the VL comprises the sequence of SEQ ID NO: 654. In some embodiments, the VH comprises the sequence of SEQ ID NO: 648 and the VL comprises the sequence of SEQ ID NO: 654. In some embodiments, the VH comprises the sequence of SEQ ID NO: 649 and the VL comprises the sequence of SEQ ID NO: 654. In some embodiments, the VH comprises the sequence of SEQ ID NO: 650 and the VL comprises the sequence of SEQ ID NO: 654. In some embodiments, the VH comprises the sequence of SEQ ID NO: 645 and the VL comprises the sequence of SEQ ID NO: 653. In some embodiments, the VH comprises the sequence of SEQ ID NO: 646 and the VL comprises the sequence of SEQ ID NO: 653. In some embodiments, the VH comprises the sequence of SEQ ID NO: 651 and the VL comprises the sequence of SEQ ID NO: 654. In some embodiments, the VH comprises the sequence of SEQ ID NO: 650 and the VL comprises the sequence of SEQ ID NO: 655. In some embodiments, the VH comprises the sequence of SEQ ID NO: 650 and the VL comprises the sequence of SEQ ID NO: 656. In some embodiments, the VH comprises the sequence of SEQ ID NO: 650 and the VL comprises the sequence of SEQ ID NO: 657. In some embodiments, the VH comprises the sequence of SEQ ID NO: 647 and the VL comprises the sequence of SEQ ID NO: 655. In some embodiments, the VH comprises the sequence of SEQ ID NO: 647 and the VL comprises the sequence of SEQ ID NO: 657. In some embodiments, the VH comprises the sequence of SEQ ID NO: 651 and the VL comprises the sequence of SEQ ID NO: 656. In some embodiments, the VH comprises the sequence of SEQ ID NO: 651 and the VL comprises the sequence of SEQ ID NO: 657. In some embodiments, the VH comprises the sequence of SEQ ID NO: 652 and the VL comprises the sequence of SEQ ID NO: 656. In some embodiments, VH comprises the sequence of SEQ ID NO: 652 and VL comprises the sequence of SEQ ID NO: 657. In some embodiments, VH comprises the sequence of SEQ ID NO: 651 and VL comprises the sequence of SEQ ID NO: 658. In some embodiments, VH comprises the sequence of SEQ ID NO: 652 and VL comprises the sequence of SEQ ID NO: 658.In some embodiments, the VH comprises the sequence of SEQ ID NO: 647 and the VL comprises the sequence of SEQ ID NO: 658. In some embodiments, the VH comprises the sequence of SEQ ID NO: 690 and the VL comprises the sequence of SEQ ID NO: 691. In some embodiments, the VH comprises the sequence of SEQ ID NO: 692 and the VL comprises the sequence of SEQ ID NO: 693. In some embodiments, the VH comprises the sequence of SEQ ID NO: 694 and the VL comprises the sequence of SEQ ID NO: 695. In some embodiments, the VH comprises the sequence of SEQ ID NO: 696 and the VL comprises the sequence of SEQ ID NO: 697. In some embodiments, the VH comprises the sequence of SEQ ID NO: 698 and the VL comprises the sequence of SEQ ID NO: 699. In some embodiments, the VH comprises the sequence of SEQ ID NO: 700 and the VL comprises the sequence of SEQ ID NO: 701. In some embodiments, the VH comprises the sequence of SEQ ID NO: 702 and the VL comprises the sequence of SEQ ID NO: 703. In some embodiments, VH comprises the sequence of SEQ ID NO: 704 and VL comprises the sequence of SEQ ID NO: 705. In some embodiments, VH comprises the sequence of SEQ ID NO: 706 and VL comprises the sequence of SEQ ID NO: 707.

[0262] In some embodiments, the antibody or antigen binding fragment specifically binds to human MICA and / or MICB. In some embodiments, the antibody or antigen binding fragment is a humanized antibody or antigen binding fragment thereof. In some embodiments, the antibody or antigen binding fragment is a single chain variable fragment (scFV) or a multispecific antibody (e.g., a bispecific antibody).

[0263] In one aspect, the disclosure relates to antibodies or antigen-binding fragments thereof that cross-compete with an antibody or antigen-binding fragment thereof as described herein.

[0264] In one aspect, the disclosure relates to an antibody or antigen-binding fragment thereof, comprising a heavy chain variable region (VH) comprising VH CDR1, VH CDR2, and VH CDR3, and a light chain variable region (VL) comprising VL CDR1, VL CDR2, and VL CDR3, in some embodiments, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 are identical to the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 of an antibody or antigen-binding fragment thereof described herein.

[0265] In one aspect, the present disclosure relates to an antibody-drug conjugate covalently bound to an antibody or antigen-binding fragment thereof as described herein and a therapeutic agent. In some embodiments, the therapeutic agent is a cytotoxic or cytostatic agent.

[0266] In one aspect, the disclosure relates to a method of treating a subject with cancer, the method comprising administering to the subject an effective dose of a composition comprising an antibody or antigen-binding fragment thereof or an antibody-drug conjugate described herein. In some embodiments, the subject has a solid tumor or a blood cancer. In some embodiments, the cancer is melanoma, neuroblastoma, prostate cancer, kidney cancer, multiple myeloma, or chronic lymphocytic leukemia.

[0267] In one aspect, the disclosure relates to a method of reducing the growth rate of a tumor, the method comprising contacting a tumor cell with an effective amount of a composition comprising an antibody or antigen-binding fragment thereof, or an antibody-drug conjugate as described herein.

[0268] In one aspect, the present disclosure relates to a method of killing a tumor cell, comprising contacting the tumor cell with an effective dose of a composition comprising an antibody or antigen-binding fragment thereof, or an antibody-drug conjugate as described herein.

[0269] In one aspect, the present disclosure relates to a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof, or an antibody-drug conjugate as described herein and a pharmaceutically acceptable carrier.

[0270] In one aspect, the disclosure relates to a nucleic acid comprising a polynucleotide encoding a polypeptide comprising: (1) an immunoglobulin heavy chain or fragment thereof, comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, wherein the VH CDRs 1, 2, 3 are shown in Figures 24A, 24B, 24C, 24D, 24E, 28, 29, 30A, 30B, 30C, 30D, or 30E, and in certain embodiments, the VH binds to MICA and / or MICB when paired with a corresponding light chain variable region (VL); or (2) an immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, wherein the VL comprises a VL shown in Figures 24A, 24B, 24C, 24D, 24E, 28, 29, 30A, 30B, 30C, 30C, or 30E, and when paired with a corresponding VH, is capable of binding to MICA and / or MICB.

[0271] In some embodiments, one of the following:

[0272] (1) an immunoglobulin heavy chain or a fragment thereof, comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2 and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 3, 4 and 5, respectively, and in some embodiments, when the VH is paired with a light chain variable region (VL), the light chain variable region (VL) comprises the amino acid sequence set forth in SEQ ID NO: 2, and binds to MICA and / or MICB;

[0273] (2) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 11, 12, and 13, respectively, wherein in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 10;

[0274] (3) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 19, 20, and 21, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 18;

[0275] (4) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 27, 28, and 29, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 26;

[0276] (5) an immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, wherein the VH comprises the amino acid sequences set forth in SEQ ID NOs: 35, 36, and 37, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 34;

[0277] (6) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 43, 44, and 45, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 42;

[0278] (7) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 51, 52, and 53, respectively, wherein in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 50;

[0279] (8) an immunoglobulin immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 59, 60, and 61, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 58;

[0280] (9) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 67, 68, and 69, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 66;

[0281] (10) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 75, 76, and 77, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 74;

[0282] (11) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 83, 84, and 85, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 82;

[0283] (12) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 91, 92, and 93, respectively, wherein in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 90;

[0284] (13) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 99, 100, and 101, respectively, wherein in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 98;

[0285] (14) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 107, 108, and 109, respectively, wherein in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 106;

[0286] (15) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 115, 116, and 117, respectively, wherein in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 114;

[0287] (16) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 123, 124, and 125, respectively, wherein in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 122;

[0288] (17) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 131, 132, and 133, respectively, wherein in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 130;

[0289] (18) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 139, 140, and 141, respectively, wherein in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 138;

[0290] (19) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 147, 148, and 149, respectively, wherein in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 146;

[0291] (20) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 155, 156, and 157, respectively, wherein in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 154;

[0292] (21) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 6, 7, and 8, respectively, wherein in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 1;

[0293] (22) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 14, 15, and 16, respectively, wherein in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 9;

[0294] (23) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 22, 23, and 24, respectively, wherein in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 17;

[0295] (24) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, wherein the VL comprises the amino acid sequences set forth in SEQ ID NOs: 30, 31 and 32, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 25;

[0296] (25) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, wherein the VL comprises the amino acid sequences set forth in SEQ ID NOs: 38, 39 and 40, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 33;

[0297] (26) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 46, 47, and 48, respectively, wherein in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 41;

[0298] (27) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 54, 55, and 56, respectively, wherein in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 49;

[0299] (28) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, wherein the VL comprises the amino acid sequences set forth in SEQ ID NOs: 62, 63 and 64, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 57;

[0300] (29) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 70, 71, and 72, respectively, wherein in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 65;

[0301] (30) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 78, 79, and 80, respectively, wherein in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 73;

[0302] (31) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, which respectively comprise the amino acid sequences set forth in SEQ ID NOs: 86, 87, and 88, wherein in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 81;

[0303] (32) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, wherein the VL comprises the amino acid sequences set forth in SEQ ID NOs: 94, 95, and 96, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 89;

[0304] (33) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 102, 103, and 104, respectively, wherein in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 97;

[0305] (34) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, wherein the CDRs comprise the amino acid sequences set forth in SEQ ID NOs: 110, 111 and 112, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 105;

[0306] (35) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 118, 119, and 120, respectively, wherein in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 113;

[0307] (36) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, wherein the CDRs comprise the amino acid sequences set forth in SEQ ID NOs: 126, 127, and 128, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 121;

[0308] (37) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 134, 135, and 136, respectively, wherein in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 129;

[0309] (38) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 142, 143, and 144, respectively, wherein in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 137;

[0310] (39) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, wherein the CDRs comprise the amino acid sequences set forth in SEQ ID NOs: 150, 151, and 152, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 145;

[0311] (40) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 158, 159, and 160, respectively, wherein in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 153;

[0312] (41) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 815, 816, and 817, respectively, wherein in some embodiments, when the VH is paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707 binds to MICA and / or MICB;

[0313] (42) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 821, 822, and 823, respectively, wherein in some embodiments, when the VH is paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707 binds to MICA and / or MICB;

[0314] (43) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 827, 828, and 829, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0315] (44) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 833, 834, and 835, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0316] (45) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 839, 840, and 841, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0317] (46) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 845, 846, and 847, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0318] (47) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 851, 852, and 853, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0319] (48) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 857, 858, and 859, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0320] (49) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising CDRs 1, 2, and 3 of the amino acid sequences set forth in SEQ ID NOs: 863, 864, and 865, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0321] (50) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 869, 870, and 871, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0322] (51) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 875, 876, and 877, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0323] (52) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 881, 882, and 883, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0324] (53) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 887, 888, and 889, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0325] (54) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 893, 894, and 895, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0326] (55) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 899, 900, and 901, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0327] (56) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 905, 906, and 907, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0328] (57) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 911, 912, and 913, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0329] (58) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, comprising the amino acid sequences set forth in SEQ ID NOs: 917, 918, and 919, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0330] (59) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3, wherein the VH comprises the amino acid sequences set forth in SEQ ID NOs: 923, 924, and 925, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0331] (60) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 929, 930, and 931, respectively, and in some embodiments, the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707;

[0332] (61) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 818, 819, and 820, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0333] (62) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 824, 825, and 826, respectively, which, in some embodiments, binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0334] (63) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 830, 831, and 832, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0335] (64) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 836, 837, and 838, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0336] (65) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 842, 843, and 844, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0337] (66) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 848, 849, and 850, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0338] (67) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, the VL comprising CDRs 1, 2, and 3 of the amino acid sequences set forth in SEQ ID NOs: 854, 855, and 856, respectively, which, in some embodiments, binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0339] (68) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 860, 861, and 862, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0340] (69) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 866, 867, and 868, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0341] (70) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 872, 873, and 874, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0342] (71) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 878, 879, and 880, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0343] (72) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 884, 885, and 886, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0344] (73) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 890, 891, and 892, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0345] (74) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 896, 897, and 898, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0346] (75) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, wherein the CDRs comprise the amino acid sequences set forth in SEQ ID NOs: 902, 903, and 904, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0347] (76) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 908, 909, and 910, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0348] (77) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3, the VL comprising CDRs 1, 2, and 3 of the amino acid sequences set forth in SEQ ID NOs: 914, 915, and 916, respectively, which, in some embodiments, binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0349] (78) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 920, 921, and 922, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706;

[0350] (79) an immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 926, 927, and 928, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706; or

[0351] (80) An immunoglobulin heavy chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences listed in SEQ ID NOs: 932, 933 and 934, respectively, and in some embodiments, the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence listed in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706.

[0352] In some embodiments, when VH is paired with VL, it specifically binds to human MICA and / or MICB; or when VL is paired with VH, it specifically binds to human MICA and / or MICB. In some embodiments, the immunoglobulin heavy chain or its fragment is a humanized immunoglobulin heavy chain or its fragment, and the immunoglobulin light chain or its fragment is a humanized immunoglobulin light chain or its fragment. In some embodiments, the nucleic acid encodes a single-chain variable fragment (scFv) or a multispecific antibody (e.g., a bispecific antibody). In some embodiments, the nucleic acid is a cDNA.

[0353] In one aspect, the disclosure relates to a vector comprising one or more nucleic acids described herein. In one aspect, the disclosure relates to a vector comprising two nucleic acids described herein, in some embodiments, the vector encodes a VL region and a VH region that bind to MICA and / or MICB together. In one aspect, the disclosure relates to a pair of vectors, in some embodiments, each vector comprises one of the nucleic acids as described herein, in some embodiments, the pair of vectors together encodes a VL region and a VH region that bind to MICA and / or MICB.

[0354] In one aspect, the disclosure is related to a cell comprising a vector or vector pair as described herein. In some embodiments, the cell is a CHO cell. In one aspect, the disclosure is related to a cell comprising one or more nucleic acids described herein. In one aspect, the disclosure is related to a cell comprising two nucleic acids described herein. In some embodiments, the two nucleic acids together encode a VL region and a VH region that bind to MICA and / or MICB together.

[0355] In one aspect, the present disclosure relates to a method for producing an antibody or an antigen-binding fragment thereof, the method comprising (a) culturing a cell as described herein under conditions sufficient for the cell to produce the antibody or antigen-binding fragment; and (b) collecting the antibody or antigen-binding fragment produced by the cell.

[0356] The term "cancer" as used herein refers to cells with autonomous growth capacity. Examples of such cells include cells with abnormal states or conditions characterized by rapid cell proliferation. The term includes cancerous growths, such as tumors; oncogenic processes, metastatic tissues, and malignantly transformed cells, tissues, or organs, regardless of the histopathological type or invasive stage. Malignant tumors of various organ systems, such as the respiratory system, cardiovascular system, renal system, reproductive system, blood system, nervous system, liver system, gastrointestinal system, and endocrine system are also included; as well as adenocarcinomas, including malignant tumors such as most colon cancers, renal cell carcinomas, prostate cancers, and / or testicular tumors, non-small cell lung cancers, and small intestine cancers. "Naturally occurring" cancers include any cancer that is not induced by experimental implantation of cancer cells into a subject, for example, including spontaneously occurring cancers, cancers caused by exposure of patients to carcinogens, cancers caused by insertion of transgenic oncogenes or knockout of tumor suppressor genes, and cancers caused by infection, for example, viral infection. The term "cancer" is recognized in the art and refers to malignant tumors of epithelial or endocrine tissues. The term also includes carcinosarcoma, which includes malignant tumors composed of cancerous tissue and sarcoma tissue. "Adenocarcinoma" refers to a cancer that originates from glandular tissue or a cancer in which the tumor cells form a recognizable glandular structure. The term "sarcoma" is recognized and refers to a malignant tumor of mesenchymal derivation. The term "hematopoietic neoplastic disease" includes diseases involving hyperplastic / neoplastic cells of hematopoietic origin. Hematopoietic neoplastic diseases may arise from cells of the myeloid, lymphoid, or erythroid lineages or their precursors.

[0357] The term "antibody" as used herein refers to any antigen binding molecule comprising at least one (e.g., one, two, three, four, five or six) complementary determining regions (CDRs) (e.g., any one of the three CDRs from an immunoglobulin light chain or any one of the three CDRs from an immunoglobulin heavy chain) and capable of specifically binding to an epitope. Non-limiting examples of antibodies include: monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), single-chain antibodies, chimeric antibodies, human antibodies, and humanized antibodies. In some embodiments, the antibody may include the Fc region of a human antibody. The term antibody also includes derivatives such as bispecific antibodies, single-chain antibodies, double antibodies, linear antibodies, and multispecific antibodies formed by antibody fragments.

[0358] As used herein, the term "antigen binding fragment" refers to a portion of a full-length antibody, wherein the portion of the antibody is capable of specifically binding to an antigen. In some embodiments, the antigen binding fragment comprises at least one variable domain (e.g., a variable domain of a heavy chain or a variable domain of a light chain). Non-limiting examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments.

[0359] The term "human antibody" as used herein refers to an antibody encoded by an endogenous nucleic acid present in the human body (e.g., a rearranged human immunoglobulin heavy chain or light chain locus). In some embodiments, human antibodies are collected from the human body or produced in human cell cultures (e.g., human hybridoma cells). In some embodiments, human antibodies are produced in non-human cells (e.g., mouse or hamster cell lines). In some embodiments, human antibodies are produced in bacteria or yeast cells. In some embodiments, human antibodies are produced in non-human transgenic animals (e.g., cattle) containing unrearranged or rearranged human immunoglobulin loci (e.g., heavy chain or light chain human immunoglobulin loci).

[0360] The term "chimeric antibody" as used herein refers to an antibody comprising sequences present in at least two different antibodies (e.g., antibodies from two different mammalian species, such as human antibodies and mouse antibodies). A non-limiting example of a chimeric antibody is an antibody comprising a variable domain sequence (e.g., all or part of a light chain and / or heavy chain variable domain sequence) of a non-human (e.g., mouse) antibody and a constant domain of a human antibody. Other embodiments of chimeric antibodies are described herein and are known in the art.

[0361] The term "humanized antibody" used herein refers to a non-human antibody comprising a sequence derived from a non-human (e.g., mouse) immunoglobulin (Ig) sequence and a sequence derived from a human immunoglobulin (HIG) comprising a minimized sequence. In a non-limiting example, a humanized antibody is a human antibody (receptor antibody), wherein the hypervariable (e.g., CDR) region residues of the receptor antibody are replaced by the hypervariable (e.g., CDR) region residues from a non-human antibody (e.g., donor antibody), such as a mouse, rat, or rabbit antibody, with the required specificity, affinity, and capacity. In some embodiments, the Fv framework residues of a human immunoglobulin (HIG) are replaced by corresponding non-human (e.g., mouse) immunoglobulin (Ig) residues. In some embodiments, a humanized antibody may be included in residues not found in a receptor antibody or a donor antibody. These modifications may be made to further improve antibody performance. In some embodiments, a humanized antibody substantially comprises at least one and generally all of two variable domains, wherein all or substantially all of the hypervariable loops (CDR) correspond to the hypervariable loops of a non-human (e.g., mouse) immunoglobulin, and all or substantially all of the framework regions are the framework regions of a human immunoglobulin (HIG). Humanized antibodies can also include at least a portion of an immunoglobulin constant region (Fc), typically a constant region of a human immunoglobulin. Humanized antibodies can be produced using molecular biology methods known in the art. Non-limiting examples of methods for producing humanized antibodies are described herein.

[0362] The term "single-chain antibody" as used herein refers to a single polypeptide comprising at least two immunoglobulin variable domains (eg, variable domains of mammalian immunoglobulin heavy or light chains) capable of specific binding to an antigen. Non-limiting examples of single-chain antibodies are described herein.

[0363] The term "multimeric antibody" as used herein refers to an antibody comprising 4 or more (e.g., 6, 8, or 10) immunoglobulin variable domains. In some embodiments, the multimeric antibody is capable of cross-linking a target molecule (e.g., MICA or MICB) with at least one second target molecule (e.g., MICA or MICB) on the surface of a mammalian cell (e.g., a human T cell).

[0364] As used herein, the terms "subject" and "patient" are used interchangeably throughout the patent specification and generally refer to animals, humans or non-humans, that are treated according to the methods of the present invention. Veterinary and non-veterinary applications are contemplated by the present invention. Human patients can be adults or adolescents (e.g., humans under the age of 18). In addition to humans, patients include, but are not limited to, mice, rats, hamsters, guinea pigs, rabbits, ferrets, cats, dogs, and primates. For example, non-human primates (e.g., monkeys, chimpanzees, gorillas, etc.), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, rabbits), lagomorphs, pigs (e.g., pigs, miniature pigs), horses, dogs, cats, cattle, and other livestock, farm and zoo animals are included.

[0365] As used herein, when referring to antibodies, the phrases "specific binding" and "specifically binds" refer to the interaction of an antibody with its target molecule (e.g., MICA and / or MICB) over other molecules because the interaction depends on the presence of a specific structure (i.e., antigenic determinant or epitope) on the target molecule; in other words, it recognizes and binds to molecules containing a specific structure, rather than all molecules in general. An antibody that specifically binds to a target molecule may be referred to as a target-specific antibody. For example, an antibody that specifically binds to a MICA and / or MICB molecule may be referred to as a MICA and / or MICB-specific antibody or an anti-MICA / B antibody.

[0366] As used herein, the terms "polypeptide," "peptide," and "protein" are used interchangeably to refer to amino acid polymers of any length of at least two amino acids.

[0367] As used herein, the terms "polynucleotide," "nucleic acid molecule," and "nucleic acid sequence" are used interchangeably herein to refer to a polymer of nucleotides of any length of at least two nucleotides, including but not limited to DNA, RNA, DNA / RNA hybrids, and modifications thereof.

[0368] Unless otherwise defined, 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 belongs. Methods and materials for use in the present invention are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are not intended to limit the present invention. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In the event of a conflict, the present patent specification, including definitions, shall prevail.

[0369] Other features and advantages of the invention will appear from the following detailed description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0370] Figure 1A Shown through Binding affinity of chimeric anti-MICA / B antibodies to MICB005, MICA002, MICA004, and MICA008 polypeptides measured by a high-throughput antibody analysis platform. Anti-MICA / B antibodies 1D5, 3F9, 13A9, 6E1.1.12, and B10G5 were reference antibodies used for comparative evaluation purposes;

[0371] Figure 1B Shown by Binding affinity of humanized anti-MICA / B antibodies to MICB005, MICA002, MICA004, and MICA008 polypeptides measured by a high-throughput antibody analysis platform; anti-MICA / B antibodies 1D5, 3F9, and 13A9 were reference antibodies;

[0372] Figure 1C Wrap-up by GatorPrime TM Binding affinities of humanized and optimized anti-MICA / B antibodies to MICB005, MICA002, MICA004, MICA008, MICA009, and cynoMICA polypeptides measured by the biolayer interferometry platform; anti-MICA / B antibodies 1D5, 3F9, 13A9, 6E1.1.12, and B10G5-2 were reference antibodies for comparative evaluation purposes;

[0373] Figure 2AThe binding of chimeric anti-MICA / B antibodies to MICA / B polypeptides in CHO-MICA002 cells is shown; CHO-MICA002 cells were incubated with serially diluted anti-MICA / B antibodies and APC-labeled anti-human Fc antibodies; anti-MICA / B antibodies 1D5, 3F9, 13A9, and 6E1.1.12 were reference antibodies; IgG1 was an isotype control (IgG); APC signals (gMFI) of antibody binding to MICA / B were measured by flow cytometry;

[0374] Figure 2B The binding of chimeric anti-MICA / B antibodies to MICA / B polypeptides in CHO-MICA004 cells is shown; CHO-MICA004 cells were incubated with serial dilutions of anti-MICA / B antibodies and then incubated with APC-labeled anti-human Fc antibodies; anti-MICA / B antibodies 1D5, 3F9, 13A9, and 6E1.1.12 are reference antibodies; IgG1 is an isotype control (IgG); APC signals (gMFI) of antibody binding to MICA / B were measured by flow cytometry;

[0375] Figure 2C The binding of chimeric anti-MICA / B antibodies to MICA / B polypeptides in CHO-MICA008 cells is shown; CHO-MICA008 cells were incubated with serially diluted anti-MICA / B antibodies and APC-labeled anti-human Fc antibodies; anti-MICA / B antibodies 1D5, 3F9, 13A9, and 6E1.1.12 were reference antibodies; IgG1 was an isotype control (IgG); APC signals (gMFI) of antibody binding to MICA / B were measured by flow cytometry;

[0376] Figure 2D The binding of chimeric anti-MICA / B antibodies to MICA / B polypeptides in CHO-MICB005 cells is shown; CHO-MICB005 cells were incubated with serially diluted anti-MICA / B antibodies and APC-labeled anti-human Fc antibodies; anti-MICA / B antibodies 1D5, 3F9, 13A9, and 6E1.1.12 were reference antibodies; IgG1 was an isotype control (IgG); APC signals (gMFI) of antibody binding to MICA / B were measured by flow cytometry;

[0377] Figure 2EThe binding of chimeric anti-MICA / B antibodies to MICA / B polypeptides in HeLa cells expressing MICA008 is shown; HeLa cells were incubated with serially diluted anti-MICA / B antibodies and APC-labeled anti-human Fc antibodies; anti-MICA / B antibodies 1D5, 3F9, 13A9, and 6E1.1.12 were reference antibodies; IgG1 was an isotype control (IgG); APC signals (gMFI) of antibody binding to MICA / B were measured by flow cytometry;

[0378] Figure 2F is a table showing the maximum MFI and calculated EC50 of chimeric anti-MICA / B antibodies binding to MICA / B polypeptides;

[0379] Figure 3A The binding of humanized anti-MICA / B antibodies to MICA / B polypeptides in CHO-MICA002 cells is shown; the cells were incubated with serial dilutions of anti-MICA / B antibodies and then with APC-labeled anti-human Fc antibodies; anti-MICA / B antibody 1D5 is a reference antibody; IgG1 is an isotype control (IgG); APC signals (gMFI) of antibody binding to MICA / B were measured by flow cytometry;

[0380] Figure 3B Humanized anti-MICA / B antibodies bind to MICA / B polypeptides in CHO-MICA004 cells; these cells were incubated with serial dilutions of anti-MICA / B antibodies and then incubated with APC-labeled anti-human Fc antibodies; anti-MICA / B antibody 1D5 is a reference antibody; IgG1 is an isotype control (IgG); APC signals (gMFI) of antibody binding to MICA / B were measured by flow cytometry;

[0381] Figure 3C The binding of humanized anti-MICA / B antibodies to MICA / B polypeptides in CHO-MICA008 cells is shown; the cells were incubated with serial dilutions of anti-MICA / B antibodies and then with APC-labeled anti-human Fc antibodies; anti-MICA / B antibody 1D5 is a reference antibody; IgG1 is an isotype control (IgG); APC signals (gMFI) of antibody binding to MICA / B were measured by flow cytometry;

[0382] Figure 3DFigure 2 shows the binding of humanized anti-MICA / B antibodies to MICA / B polypeptides in CHO-MICA005 cells; these cells were incubated with serial dilutions of anti-MICA / B antibodies and then with APC-labeled anti-human Fc antibodies; anti-MICA / B antibody 1D5 is a reference antibody; IgG1 is an isotype control (IgG); APC signals (gMFI) of antibody binding to MICA / B were measured by flow cytometry;

[0383] Figure 3E The binding of humanized anti-MICA / B antibodies to MICA / B polypeptides in CHO-MICA002 cells is shown; the cells were incubated with serial dilutions of anti-MICA / B antibodies and then with APC-labeled anti-human Fc antibodies; anti-MICA / B antibodies 1D5 and 3F9 are reference antibodies; IgG1 is an isotype control (IgG); APC signals (gMFI) of antibody binding to MICA / B were measured by flow cytometry;

[0384] Figure 3F The binding of humanized anti-MICA / B antibodies to MICA / B polypeptides in CHO-MICB004 cells is shown; the cells were incubated with serial dilutions of anti-MICA / B antibodies and then with APC-labeled anti-human Fc antibodies; anti-MICA / B antibodies 1D5 and 3F9 are reference antibodies; IgG1 is an isotype control (IgG); APC signals (gMFI) of antibody binding to MICA / B were measured by flow cytometry;

[0385] Figure 3G The binding of humanized anti-MICA / B antibodies to MICA / B polypeptides in CHO-MICA008 cells is shown; the cells were incubated with serial dilutions of anti-MICA / B antibodies and then with APC-labeled anti-human Fc antibodies; anti-MICA / B antibodies 1D5 and 3F9 are reference antibodies; IgG1 is an isotype control (IgG); APC signals (gMFI) of antibody binding to MICA / B were measured by flow cytometry;

[0386] Figure 3H The binding of humanized anti-MICA / B antibodies to MICA / B polypeptides in CHO-MICB005 cells is shown; these cells were incubated with serial dilutions of anti-MICA / B antibodies and then with APC-labeled anti-human Fc antibodies; anti-MICA / B antibodies 1D5 and 3F9 are reference antibodies; IgG1 is an isotype control (IgG); APC signals (gMFI) of antibody binding to MICA / B were measured by flow cytometry;

[0387] Fig. 3IThe optimized h36B3 variants are shown to bind to MICA / B polypeptides in CHO-MICA002 cells; these cells were incubated with serial dilutions of anti-MICA / B antibodies and then with APC-labeled anti-human Fc antibodies; IgG1 is an isotype control (IgG); APC signals (gMFI) of antibody binding to MICA / B were measured by flow cytometry;

[0388] Figure 3J The binding of the optimized h36B3 variant to the MICA / B polypeptide in CHO-MICA004 cells is shown; the cells were incubated with serial dilutions of anti-MICA / B antibodies and then with APC-labeled anti-human Fc antibodies; IgG1 is an isotype control (IgG); the APC signal (gMFI) of antibody binding to MICA / B was measured by flow cytometry;

[0389] Figure 3K The optimized h36B3 variants are shown to bind to MICA / B polypeptides in CHO-MICA008 cells; these cells were incubated with serial dilutions of anti-MICA / B antibodies and then with APC-labeled anti-human Fc antibodies; IgG1 is an isotype control (IgG); APC signals (gMFI) of antibody binding to MICA / B were measured by flow cytometry;

[0390] Figure 3L The optimized h36B3 variants are shown to bind to MICA / B polypeptides in CHO-MICB005 cells; these cells were incubated with serial dilutions of anti-MICA / B antibodies and APC-labeled anti-human Fc antibodies; IgG1 is an isotype control (IgG); the APC signal (gMFI) of antibody binding to MICA / B was measured by flow cytometry;

[0391] Figure 3M The binding of humanized anti-MICA / B antibodies to MICA / B polypeptides in HeLa cells is shown; the antibodies were incubated with serial dilutions of anti-MICA / B antibodies and then with APC-labeled anti-human Fc antibodies; anti-MICA / B antibodies 1D5 and 3F9 are reference antibodies; IgG1 is an isotype control (IgG); APC signal (gMFI) of antibody binding to MICA / B was measured by flow cytometry;

[0392] Figure 3N The optimized h36B3 variants bind to the MICA / B polypeptide in HeLa cells; these cells were incubated with serially diluted anti-MICA / B antibodies and APC-labeled anti-human Fc antibodies; the APC signal (gMFI) of antibody binding to MICA / B was measured by flow cytometry;

[0393] Fig.3O The optimized h36B3 variants are shown to bind to MICA / B polypeptides in CHO-MICA002 cells; these cells were incubated with serial dilutions of anti-MICA / B antibodies and then with APC-labeled anti-human Fc antibodies; IgG1 is an isotype control (IgG); APC signals (gMFI) of antibody binding to MICA / B were measured by flow cytometry;

[0394] Figure 3P The binding of the optimized h36B3 variant to the MICA / B polypeptide in CHO-MICA004 cells is shown; these cells were incubated with serial dilutions of anti-MICA / B antibodies and APC-labeled anti-human Fc antibodies; IgG1 is an isotype control (IgG); the APC signal (gMFI) of antibody binding to MICA / B was measured by flow cytometry;

[0395] Figure 3Q The optimized h36B3 variants are shown to bind to MICA / B polypeptides in CHO-MICA008 cells; these cells were incubated with serial dilutions of anti-MICA / B antibodies and then with APC-labeled anti-human Fc antibodies; IgG1 is an isotype control (IgG); APC signals (gMFI) of antibody binding to MICA / B were measured by flow cytometry;

[0396] Figure 3R The optimized h36B3 variants are shown to bind to MICA / B polypeptides in CHO-MICB005 cells; these cells were incubated with serial dilutions of anti-MICA / B antibodies and APC-labeled anti-human Fc antibodies; IgG1 is an isotype control (IgG); the APC signal (gMFI) of antibody binding to MICA / B was measured by flow cytometry;

[0397] Figure 3S is a table showing the maximum MFI and calculated EC50 of humanized anti-MICA / B antibodies binding to MICA / B polypeptide expressed in CHO cells;

[0398] Figure 3T is a table showing the maximum MFI and calculated EC50 of humanized anti-MICA / B antibodies binding to MICA / B polypeptide expressed in CHO cells or HeLa cells;

[0399] Figure 3U is a table showing the maximum MFI and calculated EC50 of the optimized h36B3 variants binding to MICA / B polypeptide expressed in CHO cells;

[0400] Figure 4Ais a graph showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptides in CHO-MICA002 cells; the shedding of MICA / B polypeptides in the cell culture medium was quantified by sandwich ELISA;

[0401] Figure 4B is a graph showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptides in C1R-MICA004 cells; the shedding of MICA / B polypeptides in the cell culture medium was quantified by sandwich ELISA;

[0402] Figure 4C is a graph showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptides in C1R-MICA008 cells; the shedding of MICA / B polypeptides in the cell culture medium was quantified by sandwich ELISA;

[0403] Figure 4D is a graph showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptides in C1R-MICB005 cells; the shedding of MICA / B polypeptides in the cell culture medium was quantified by sandwich ELISA;

[0404] Figure 4E is a graph showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptides in HeLa cells expressing MICA008 polypeptides; the shedding of MICA / B polypeptides in the cell culture medium was quantified by sandwich ELISA;

[0405] Figure 4F is a table showing the maximum shedding inhibition of MICA / B polypeptide by chimeric anti-MICA / B antibodies and the calculated IC50;

[0406] Figure 5A is a graph showing surface MICA / B expression in C1R-MICA002 cells treated with chimeric anti-MICA / B antibodies; MICA / B signals were quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4, which does not compete with our anti-MICA / B;

[0407] Figure 5B is a graph showing surface MICA / B expression in C1R-MICA004 cells treated with chimeric anti-MICA / B antibodies; MICA / B signals were quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4, which does not compete with our anti-MICA / B;

[0408] Figure 5Cis a graph showing surface MICA / B expression in C1R-MICA008 cells treated with chimeric anti-MICA / B antibodies; MICA / B signals were quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4, which does not compete with our anti-MICA / B;

[0409] Figure 5D is a graph showing surface MICA / B expression in C1R-MICA005 cells treated with chimeric anti-MICA / B antibodies; MICA / B signals were quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4, which does not compete with our anti-MICA / B;

[0410] Figure 5E is a graph showing surface MICA / B expression in HeLa cells treated with chimeric anti-MICA / B antibodies; MICA / B signals were quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4, which does not compete with our anti-MICA / B;

[0411] Fig. 5F is a table showing the increase in MICA / B expression and the calculated EC50 of chimeric anti-MICA / B antibodies against MICA / B polypeptides;

[0412] Fig. 6A is a graph showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptides in C1R-MICA002 cells; the shedding of MICA / B polypeptides in the cell culture medium was quantified by sandwich ELISA;

[0413] Figure 6B is a graph showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptides in C1R-MICA004 cells; the shedding of MICA / B polypeptides in the cell culture medium was quantified by sandwich ELISA;

[0414] Figure 6C is a graph showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptides in C1R-MICA008 cells; the shedding of MICA / B polypeptides in the cell culture medium was quantified by sandwich ELISA;

[0415] Fig.6D is a graph showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptides in C1R-MICB005 cells; the shedding of MICA / B polypeptides in the cell culture medium was quantified by sandwich ELISA;

[0416] Fig. 6Eis a graph showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptides in C1R-MICA002 cells; the shedding of MICA / B polypeptides in the cell culture medium was quantified by sandwich ELISA;

[0417] Fig. 6F is a graph showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptides in C1R-MICA004 cells; the shedding of MICA / B polypeptides in the cell culture medium was quantified by sandwich ELISA;

[0418] Figure 6G is a graph showing that anti-MICA / B antibodies can inhibit MICA / B polypeptide shedding in C1R-MICA008 cells; MICA / B polypeptide shedding in cell culture medium was quantified by sandwich ELISA;

[0419] Figure 6H is a graph showing that anti-MICA / B antibodies can inhibit MICA / B polypeptide shedding in C1R-MICB005 cells; MICA / B polypeptide shedding in cell culture medium was quantified by sandwich ELISA;

[0420] Fig.6I is a graph showing that the optimized h36B3 variant can inhibit the shedding of MICA / B polypeptides in C1R-MICA002 cells; the MICA / B polypeptides shedding in the cell culture medium were quantified by sandwich ELISA;

[0421] Figure 6J is a graph showing that the optimized h36B3 variant can inhibit the shedding of MICA / B polypeptides in C1R-MICA004 cells; the shedding of MICA / B polypeptides in the cell culture medium was quantified by sandwich ELISA;

[0422] Figure 6K is a graph showing that the optimized h36B3 variant can inhibit the shedding of MICA / B polypeptides in C1R-MICA008 cells; the MICA / B polypeptides shedding in the cell culture medium were quantified by sandwich ELISA;

[0423] Figure 6L is a graph showing that the optimized h36B3 variant can inhibit the shedding of MICA / B polypeptides in C1R-MICB005 cells; the MICA / B polypeptides shedding in the cell culture medium were quantified by sandwich ELISA;

[0424] Figure 6M is a graph showing that the optimized h36B3 variant can inhibit the shedding of MICA / B polypeptides in C1R-MICA002 cells; the MICA / B polypeptides shedding in the cell culture medium were quantified by sandwich ELISA;

[0425] Figure 6N is a graph showing that the optimized h36B3 variant can inhibit the shedding of MICA / B polypeptides in C1R-MICA004 cells; the shedding of MICA / B polypeptides in the cell culture medium was quantified by sandwich ELISA;

[0426] Fig.6O is a graph showing that the optimized h36B3 variant can inhibit the shedding of MICA / B polypeptides in C1R-MICA008 cells; the MICA / B polypeptides shedding in the cell culture medium were quantified by sandwich ELISA;

[0427] Figure 6P is a graph showing that the optimized h36B3 variant can inhibit the shedding of MICA / B polypeptides in C1R-MICB005 cells; the MICA / B polypeptides shedding in the cell culture medium were quantified by sandwich ELISA;

[0428] Figure 6Q is a table showing the maximum shedding inhibition and calculated IC50 of several MICA / B polypeptides by humanized anti-MICA / B antibodies;

[0429] Figure 6R is a table showing the maximum shedding inhibition and calculated IC50 of several MICA / B polypeptides by humanized anti-MICA / B antibodies;

[0430] Figure 6S is a table showing the maximum shedding inhibition and calculated IC50 of the optimized h36B3 variants against several MICA / B polypeptides;

[0431] Figure 6T is a table showing the maximum shedding inhibition and calculated IC50 of the optimized h36B3 variants against several MICA / B polypeptides;

[0432] Figure 6U is a graph comparing the ability of D2M001-209 and an anti-MICA / B reference antibody to inhibit MICA / B polypeptide shedding in C1R-MICB005 cells; MICA / B polypeptide shedding in cell culture fluid was quantified by sandwich ELISA; maximum shedding inhibition and calculated IC50 are shown below the graph;

[0433] Figure 6V is a graph comparing the ability of D2M001-209 and an anti-MICA / B reference antibody to inhibit MICA / B polypeptide shedding in C1R-MICA002 cells; MICA / B polypeptide shedding in cell culture fluid was quantified by sandwich ELISA; maximum shedding inhibition and calculated IC50 are shown below the graph;

[0434] Figure 6Wis a graph comparing the ability of D2M001-209 and an anti-MICA / B reference antibody to inhibit MICA / B polypeptide shedding in C1R-MICA004 cells; MICA / B polypeptide shedding in cell culture fluid was quantified by sandwich ELISA; maximum shedding inhibition and calculated IC50 are shown below the graph;

[0435] Figure 6X is a graph comparing the ability of D2M001-209 and an anti-MICA / B reference antibody to inhibit MICA / B polypeptide shedding by C1R-MICA008 cells; MICA / B polypeptide shedding in cell culture fluid was quantified by sandwich ELISA; maximum shedding inhibition and calculated IC50 are shown below the graph;

[0436] Fig. 7A is a graph showing surface MICA / B expression in C1R-MICA002 cells treated with humanized anti-MICA / B antibody; MICA / B signal was quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4;

[0437] Figure 7B is a graph showing surface MICA / B expression in C1R-MICA004 cells treated with humanized anti-MICA / B antibody; MICA / B signal was quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4;

[0438] Figure 7C is a graph showing surface MICA / B expression in C1R-MICA008 cells treated with humanized anti-MICA / B antibody; MICA / B signal was quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4;

[0439] Fig.7D is a graph showing surface MICA / B expression in C1R-MICB005 cells treated with humanized anti-MICA / B antibody; MICA / B signal was quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4;

[0440] Fig. 7E is a graph showing surface MICA / B expression in C1R-MICA002 cells treated with humanized anti-MICA / B antibody; MICA / B signal was quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4;

[0441] Figure 7F is a graph showing surface MICA / B expression in C1R-MICA004 cells treated with humanized anti-MICA / B antibody; MICA / B signal was quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4;

[0442] Figure 7Gis a graph showing surface MICA / B expression in C1R-MICA008 cells treated with humanized anti-MICA / B antibody; MICA / B signal was quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4;

[0443] Figure 7H is a graph showing surface MICA / B expression in C1R-MICB005 cells treated with humanized anti-MICA / B antibody; MICA / B signal was quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4;

[0444] Fig.7I is a graph showing surface MICA / B expression in C1R-MICA002 cells treated with optimized h36B3 variants; MICA / B signal was quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4;

[0445] Figure 7J is a graph showing surface MICA / B expression in C1R-MICA004 cells treated with optimized h36B3 variants; MICA / B signal was quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4;

[0446] Figure 7K is a graph showing surface MICA / B expression in C1R-MICA008 cells treated with optimized h36B3 variants; MICA / B signal was quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4;

[0447] Figure 7L is a graph showing surface MICA / B expression in C1R-MICB005 cells treated with optimized h36B3 variants; MICA / B signal was quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4;

[0448] Figure 7M is a graph showing surface MICA / B expression in C1R-MICA002 cells treated with optimized h36B3 variants; MICA / B signal was quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4;

[0449] Figure 7N is a graph showing surface MICA / B expression in C1R-MICA004 cells treated with optimized h36B3 variants; MICA / B signal was quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4;

[0450] Fig.7Ois a graph showing surface MICA / B expression in C1R-MICA008 cells treated with optimized h36B3 variants; MICA / B signal was quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4;

[0451] Figure 7P is a graph showing surface MICA / B expression in C1R-MICB005 cells treated with optimized h36B3 variants; MICA / B signal was quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4;

[0452] Figure 7Q is a table showing the maximum increased expression levels and calculated EC50s of humanized anti-MICA / B antibodies against several MICA / B polypeptides;

[0453] Figure 7R is a table showing the maximum increased expression levels and calculated EC50s of humanized anti-MICA / B antibodies against several MICA / B polypeptides;

[0454] Figure 7S is a table showing the maximum increased expression and calculated EC50 of h36B3 variants for several MICA / B polypeptides;

[0455] Figure 7T is a table showing the maximum increased expression and calculated EC50 of h36B3 variants for several MICA / B polypeptides;

[0456] Figure 7U is a graph comparing the ability of D2M001-209 and anti-MICA / B reference antibodies to stabilize MICA / B polypeptides on the surface of C1R-MICB005 cells; MICA / B signals were quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4; calculated EC50, TopMFI, and surface MICB005 increase (%) are shown below the graph;

[0457] Figure 7V is a graph comparing the ability of D2M001-209 and anti-MICA / B reference antibodies to stabilize MICA / B polypeptides on the surface of C1R-MICA002 cells; MICA / B signals were quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4; calculated EC50, TopMFI, and surface MICA002 increase (%) are shown below the graph;

[0458] Figure 7Wis a graph comparing the ability of D2M001-209 and anti-MICA / B reference antibodies to stabilize MICA / B polypeptides on the surface of C1R-MICA004 cells; MICA / B signals were quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4; calculated EC50, TopMFI, and surface MICA004 increase (%) are shown below the graph;

[0459] Figure 7X is a graph comparing the ability of D2M001-209 and anti-MICA / B reference antibodies to stabilize MICA / B polypeptides on the surface of C1R-MICA008 cells; MICA / B signals were quantified by flow cytometry using PE-conjugated anti-MICA / B 6D4; calculated EC50, TopMFI, and surface MICA008 increase (%) are shown below the graph;

[0460] Fig. 8A is a diagram showing that chimeric anti-MICA / B antibodies can capture MICA002 polypeptides shed from cells; the shed / bound MICA / B polypeptides are from the growth medium of cultured CHO-MICA002 cells;

[0461] Figure 8B is a diagram showing that chimeric anti-MICA / B antibodies can capture MICA004 polypeptides shed from cells; the shed / bound MICA / B polypeptides are from the growth medium of cultured CHO-MICA004 cells;

[0462] Figure 8C is a diagram showing that chimeric anti-MICA / B antibodies can capture MICA008 polypeptides shed from cells; the shed / bound MICA / B polypeptides are from the growth medium of cultured CHO-MICA008 cells;

[0463] Fig.8D is a diagram showing that chimeric anti-MICA / B antibodies can capture MICB005 polypeptides shed from cells; the shed / bound MICA / B polypeptides are from the growth medium of cultured CHO-MICB005 cells;

[0464] Fig. 8E is a table showing the maximum OD 450 and calculated EC50 of chimeric anti-MICA / B antibody binding to various shed MICA / B polypeptides;

[0465] Fig.9A is a diagram showing that humanized anti-MICA / B antibody (#39 variant) can capture MICA002 polypeptide shed from cells; the shed / bound MICA / B polypeptide is from the growth medium of CHO-MICA002 cells cultured;

[0466] Fig. 9Bis a diagram showing that humanized anti-MICA / B antibody (#39 variant) can capture MICA004 polypeptide shed from cells; the shed / bound MICA / B polypeptide is from the growth medium of CHO-MICA004 cells cultured;

[0467] Fig. 9C is a graph showing that humanized anti-MICA / B antibody (#39 variant) can capture MICA008 polypeptide shed from cells; shed / bound MICA / B polypeptide is from conditioned growth medium of CHO-MICA008 cells;

[0468] Fig.9D is a diagram showing that humanized anti-MICA / B antibody (#39 variant) can capture MICB005 polypeptide shed from cells; the shed / bound MICA / B polypeptide is from the growth medium of CHO-MICB005 cells cultured;

[0469] Fig.9E is a diagram showing that humanized anti-MICA / B antibodies can capture soluble MICA002 polypeptides shed by cells; the shed / bound MICA / B polypeptides are from the growth medium of CHO-MICA002 cells cultured;

[0470] Fig.9F is a diagram showing that humanized anti-MICA / B antibodies can capture soluble MICA004 polypeptides shed by cells; the shed / bound MICA / B polypeptides are from the growth medium of CHO-MICA004 cells;

[0471] Figure 9G is a diagram showing that humanized anti-MICA / B antibodies can capture soluble MICA008 polypeptides shed by cells; the shed / bound MICA / B polypeptides are from the growth medium of CHO-MICA008 cells;

[0472] Figure 9H is a diagram showing that humanized anti-MICA / B antibodies can capture soluble MICB005 polypeptides shed by cells; the shed / bound MICA / B polypeptides are from the growth medium of CHO-MICB005 cells;

[0473] Fig.9I is a table showing the maximum OD 450 and calculated EC50 of humanized anti-MICA / B antibody (#39 variant) binding to several shed MICA / B polypeptides;

[0474] Figure 9J is a table showing the maximum OD 450 and calculated EC50 of humanized anti-MICA / B antibody binding to several shed MICA / B polypeptides;

[0475] Figure 9K is a graph showing that humanized anti-MICA / B antibodies (optimized h36B3 variants) can capture soluble MICA002 polypeptides shed from cells; shed / bound MICA / B polypeptides are from the growth medium of CHO-MICA008 cells;

[0476] Figure 9L is a graph showing that humanized anti-MICA / B antibody (optimized h36B3 variant) can capture soluble MICA004 polypeptide shed from cells; shed / bound MICA / B polypeptide is from the growth medium of CHO-MICB005 cells;

[0477] Figure 9M is a graph showing that humanized anti-MICA / B antibodies (optimized h36B3 variants) can capture soluble MICA008 polypeptides shed from cells; shed / bound MICA / B polypeptides are from the growth medium of CHO-MICA008 cells;

[0478] Figure 9N is a graph showing that humanized anti-MICA / B antibodies (optimized h36B3 variants) can capture soluble MICB005 polypeptides shed from cells; shed / bound MICA / B polypeptides are from the growth medium of CHO-MICB005 cells;

[0479] Fig.9O is a table showing the maximum OD 450 and calculated EC50 of humanized anti-MICA / B antibodies (optimized h36B3 variants) binding to several shed MICA / B polypeptides;

[0480] Fig. 10A is a graph showing the interaction of NKG2D with synthetic MICA / B polypeptides measured by ELISA;

[0481] Fig. 10B is a graph showing the interaction of NKG2D and humanized anti-MICA / B antibody (#39 variant) with immune complexes of shed MICA002 polypeptide measured by ELISA;

[0482] Fig. 10C is a graph showing the interaction of NKG2D and humanized anti-MICA / B antibody (#39 variant) with immune complexes of shed MICA004 polypeptide measured by ELISA;

[0483] Fig. 10D is a table showing the maximum OD 450 and calculated EC50 of humanized anti-MICA / B antibodies (#39 variant) against MICA002 and MICA004 polypeptides;

[0484] Fig.10E is a graph showing the effect of treatment with an immune complex of a chimeric anti-MICA / B antibody and shed MICA002 polypeptide on IL2 secretion by Hut-78 T cells in the presence of anti-CD3 stimulation;

[0485] Fig.10F is a graph showing the effect of treatment with an immune complex of a chimeric anti-MICA / B antibody and shed MICB005 polypeptide on IL2 secretion by Hut-78 T cells in the presence of anti-CD3 stimulation;

[0486] Figure 10G is a graph showing the effect of treatment with immune complexes of humanized MICA / B antibody and shed MICA002 polypeptide on IL2 secretion by Hut-78 T cells in the presence of anti-CD3 stimulation;

[0487] Fig. 10H is a graph showing the effect of treatment with immune complexes of humanized MICA / B antibody and shed MICA004 polypeptide on IL2 secretion by Hut-78 T cells in the presence of anti-CD3 stimulation;

[0488] Fig.10I is a graph showing the effect of treatment with immune complexes of humanized MICA / B antibody and shed MICA008 polypeptide on IL2 secretion by Hut-78 T cells in the presence of anti-CD3 stimulation;

[0489] Fig.10J is a graph showing the effect of treatment with immune complexes of humanized MICA / B antibody and shed MICB005 polypeptide on IL2 secretion by Hut-78 T cells in the presence of anti-CD3 stimulation;

[0490] Figure 10K is a graph showing the effect of treatment with immune complexes of humanized MICA / B antibody (h36B3 variant) and shed MICA002 polypeptide on IL2 secretion by Hut-78 T cells in the presence of anti-CD3 stimulation;

[0491] Fig.10L is a graph showing the effect of treatment with immune complexes of humanized MICA / B antibody (h36B3 variant) and shed MICA004 polypeptide on IL2 secretion by Hut-78 T cells in the presence of anti-CD3 stimulation;

[0492] Figure 10M is a graph showing the effect of treatment with immune complexes of humanized MICA / B antibody (h36B3 variant) and shed MICA008 polypeptide on IL2 secretion by Hut-78 T cells in the presence of anti-CD3 stimulation;

[0493] Fig.10N is a graph showing the effect of treatment with immune complexes of humanized MICA / B antibody (h36B3 variant) and shed MICB005 polypeptide on IL2 secretion by Hut-78 T cells in the presence of anti-CD3 stimulation;

[0494] Fig.11A is a graph showing the effect of treatment with immune complexes of humanized anti-MICA / B antibodies and shed soluble MICA002 polypeptides on IFN-γ secretion by human primary NK cells from multiple donors; each data point represents NK cells from one donor;

[0495] Fig. 11B is a graph showing the effect of treatment with immune complexes of humanized anti-MICA / B antibodies and shed soluble MICA004 polypeptides on IFN-γ secretion by human primary NK cells from multiple donors; each data point represents NK cells from one donor;

[0496] Fig. 11C is a graph showing the effect of treatment with immune complexes of humanized anti-MICA / B antibodies and shed soluble MICA008 polypeptides on IFN-γ secretion by human primary NK cells from multiple donors; each data point represents NK cells from one donor;

[0497] Fig.11D is a graph showing the effect of treatment with immune complexes of humanized anti-MICA / B antibodies and shed soluble MICB005 polypeptides on IFN-γ secretion by human primary NK cells from multiple donors; each data point represents NK cells from one donor;

[0498] Fig.11E is a graph showing the effect of treatment with immune complexes of humanized anti-MICA / B antibody (h36B3 variant) and shed soluble MICA002 polypeptide on IFN-γ secretion by human primary NK cells from multiple donors; each data point represents NK cells from one donor;

[0499] Fig.11F is a graph showing the effect of treatment with immune complexes of humanized anti-MICA / B antibody (h36B3 variant) and shed soluble MICA004 polypeptide on IFN-γ secretion by human primary NK cells from multiple donors; each data point represents NK cells from one donor;

[0500] Fig.11Gis a graph showing the effect of treatment with immune complexes of humanized anti-MICA / B antibody (h36B3 variant) and shed soluble MICA008 polypeptide on IFN-γ secretion by human primary NK cells from multiple donors; each data point represents NK cells from one donor;

[0501] Fig.11H is a graph showing the effect of treatment with immune complexes of humanized anti-MICA / B antibody (h36B3 variant) and shed soluble MICB005 polypeptide on IFN-γ secretion by human primary NK cells from multiple donors; each data point represents NK cells from one donor;

[0502] Fig. 12A is a graph showing the expression level of IFN-γ in NK cells co-cultured with C1R tumor cells expressing the MICA004 polypeptide in the presence of a chimeric anti-MICA / B antibody;

[0503] Fig. 12B is a graph showing the expression level of IFN-γ in NK cells co-cultured with C1R tumor cells expressing the MICA008 polypeptide in the presence of chimeric anti-MICA / B antibody;

[0504] Fig. 12C is a graph showing the expression level of IFN-γ in NK cells co-cultured with C1R tumor cells expressing MICB005 polypeptide in the presence of chimeric anti-MICA / B antibody;

[0505] Fig.12D is the expression level of CD107a in NK cells co-cultured with C1R tumor cells expressing MICA004 polypeptide in the presence of chimeric anti-MICA / B antibody;

[0506] Fig.12E is a graph of the expression level of CD107a in NK cells co-cultured with C1R tumor cells expressing MICA008 polypeptide in the presence of chimeric anti-MICA / B antibody;

[0507] Fig.12F is a graph showing the expression level of CD107a in NK cells co-cultured with C1R tumor cells expressing MICB005 polypeptide in the presence of chimeric anti-MICA / B antibody;

[0508] Figure 12G is a graph showing the expression level of IFN-γ in NK cells co-cultured with C1R tumor cells expressing MICA002 polypeptide in the presence of humanized anti-MICA / B antibody;

[0509] Fig.12His a graph showing the expression level of IFN-γ in NK cells co-cultured with C1R tumor cells expressing the MICA004 polypeptide in the presence of humanized anti-MICA / B antibody;

[0510] Fig.12I is a graph showing the expression level of IFN-γ in NK cells co-cultured with C1R tumor cells expressing the MICA008 polypeptide in the presence of humanized anti-MICA / B antibody;

[0511] Fig.12J is a graph showing the expression level of IFN-γ in NK cells co-cultured with C1R tumor cells expressing MICB005 polypeptide in the presence of humanized anti-MICA / B antibody;

[0512] Figure 12K is a graph showing the expression level of CD107a in NK cells co-cultured with C1R tumor cells expressing MICA002 polypeptide in the presence of humanized anti-MICA / B antibody;

[0513] Figure 12L is a graph showing the expression level of CD107a in NK cells co-cultured with C1R tumor cells expressing MICA004 polypeptide in the presence of humanized anti-MICA / B antibody;

[0514] Figure 12M is a graph showing the expression level of CD107a in NK cells co-cultured with C1R tumor cells expressing the MICA008 polypeptide in the presence of humanized anti-MICA / B antibody;

[0515] Fig.12N is a graph showing the expression level of CD107a in NK cells co-cultured with C1R tumor cells expressing MICB005 polypeptide in the presence of humanized anti-MICA / B antibody;

[0516] Fig.12O is a graph showing the expression level of IFN-γ in NK cells from two independent donors co-cultured with C1R tumor cells expressing MICA002 polypeptide in the presence of humanized anti-MICA / B antibody (h36B3 variant);

[0517] Figure 12P is a graph showing the expression level of IFN-γ in NK cells from two independent donors co-cultured with C1R tumor cells expressing MICA004 polypeptide in the presence of humanized anti-MICA / B antibody (h36B3 variant);

[0518] Figure 12Qis a graph showing the expression level of IFN-γ in NK cells from two independent donors co-cultured with C1R tumor cells expressing MICA008 polypeptide in the presence of humanized anti-MICA / B antibody (h36B3 variant);

[0519] Figure 12R is a graph showing the expression level of IFN-γ in NK cells from two independent donors co-cultured with C1R tumor cells expressing MICB005 polypeptide in the presence of humanized anti-MICA / B antibody (h36B3 variant);

[0520] Figure 12S is a graph showing the expression level of CD107a in NK cells from two independent donors co-cultured with C1R tumor cells expressing MICA002 polypeptide in the presence of humanized anti-MICA / B antibody (h36B3 variant);

[0521] Figure 12T is a graph showing the expression level of CD107a in NK cells from two independent donors co-cultured with C1R tumor cells expressing MICA004 polypeptide in the presence of humanized anti-MICA / B antibody (h36B3 variant);

[0522] Figure 12U is a graph showing the expression level of CD107a in NK cells from two independent donors co-cultured with C1R tumor cells expressing MICA008 polypeptide in the presence of humanized anti-MICA / B antibody (h36B3 variant);

[0523] Figure 12V is a graph showing the expression level of CD107a in NK cells from two independent donors co-cultured with C1R tumor cells expressing MICB005 polypeptide in the presence of humanized anti-MICA / B antibody (h36B3 variant);

[0524] Fig.13A is a graph showing the percentage of C1R tumor cells expressing MICA004 polypeptide in the presence of chimeric anti-MICA / B antibody;

[0525] Fig. 13B is a graph showing the percentage of C1R tumor cells expressing MICA008 polypeptide in the presence of chimeric anti-MICA / B antibody;

[0526] Fig. 13C is a graph showing the percentage of C1R tumor cells expressing MICB005 polypeptide in the presence of chimeric anti-MICA / B antibody;

[0527] Fig.13Dis a graph showing the percentage of C1R tumor cells expressing MICA002 polypeptide in the presence of humanized anti-MICA / B antibody;

[0528] Fig.13E is a graph showing the percentage of C1R tumor cells expressing MICA004 polypeptide in the presence of humanized anti-MICA / B antibody;

[0529] Fig.13F is a graph showing the percentage of C1R tumor cells expressing MICA008 polypeptide in the presence of humanized anti-MICA / B antibody;

[0530] Figure 13G is a graph showing the percentage of C1R tumor cells expressing MICB005 polypeptide in the presence of humanized anti-MICA / B antibodies;

[0531] Fig.13H is a graph showing the percentage of C1R tumor cells expressing MICA002 polypeptide in the presence of humanized anti-MICA / B antibody (h36B3 variant);

[0532] Fig.13I is a graph showing the percentage of C1R tumor cells expressing MICA004 polypeptide in the presence of humanized anti-MICA / B antibody (h36B3 variant);

[0533] Fig.13J is a graph showing the percentage of C1R tumor cells expressing MICA008 polypeptide in the presence of humanized anti-MICA / B antibody (h36B3 variant);

[0534] Figure 13K is a graph showing the percentage of C1R tumor cells expressing MICB005 polypeptide in the presence of humanized anti-MICA / B antibody (h36B3 variant);

[0535] Fig.14A is a graph showing the thermal stability of humanized anti-MICA / B antibody full IgG; melting curve measured by protein thermal shift dye kit using qPCR thermal cycler; the fluorescence intensity was subtracted from the lowest intensity before the peak (bottom) and normalized to the peak-to-trough amplitude;

[0536] Fig. 14B is a graph showing the thermal stability of the F(ab')2 fragment of the humanized anti-MICA / B antibody; the melting curve was measured by a protein thermal shift dye kit using a qPCR thermal cycler; the fluorescence intensity was subtracted from the minimum intensity before the peak (bottom) and normalized to the peak-to-trough amplitude;

[0537] Fig. 14Cis a graph showing the thermal stability of humanized anti-MICA / B antibody full IgG; melting curves were measured using a qPCR thermal cycler with a protein thermal shift dye kit; the fluorescence intensity was subtracted from the lowest intensity before the peak (bottom) and normalized to the peak-to-trough amplitude;

[0538] Fig.14D Graph showing thermal stability of the F(ab')2 fragment of humanized anti-MICA / B antibody; melting curves were measured using a qPCR thermal cycler with a protein thermal shift dye kit; the fluorescence intensity was subtracted from the minimum intensity before the peak (bottom) and normalized to the peak-to-trough amplitude;

[0539] Fig.14E The Tm values ​​of intact IgG and F(ab')2 fragments of humanized anti-MICA / B antibodies, reference antibodies, and isotype control IgG are summarized based on Figures 14A-14D The graphs shown in the figure are from the bottom to the temperature of 50% of the peak amplitude; the mean and + / - standard deviation are calculated from two experiments, each with two replicates;

[0540] Fig.15 The table shows the binding affinity of humanized anti-MICA / B antibodies to various MICA / B peptides after stress in low pH and high pH buffers; the antibodies were stressed at 40°C for two weeks in pH 5.5 or pH 8.5 buffers; TM Biofilm interferometry measures binding kinetics;

[0541] Fig.16 Is shown through GatorPrime TM Table of clone-by-clone interactions (CSI) of humanized and optimized anti-MICA / B antibodies measured by biofilm interferometry;

[0542] Fig.17A is a graph showing nonspecific binding of humanized and optimized anti-MICA / B antibodies to whole cell lysates produced by CHO cells, which were tested by sandwich ELISA at a concentration of 15 μg / mL;

[0543] Fig. 17B is a graph showing nonspecific binding of humanized and optimized anti-MICA / B antibodies to whole cell lysates produced by CHO cells, which were tested by sandwich ELISA at a concentration of 1.5 μg / mL;

[0544] Fig. 17C is a graph showing nonspecific binding of humanized and optimized anti-MICA / B antibodies to whole cell lysates generated from C1R cancer cells, where the antibodies were tested at a concentration of 15 μg / mL by sandwich ELISA;

[0545] Fig.17D is a graph showing nonspecific binding of humanized and optimized anti-MICA / B antibodies to whole cell lysates generated from C1R cancer cells, which was tested by sandwich ELISA at a concentration of 1.5 μg / mL of antibody;

[0546] Fig.18A is a curve showing the binding affinity of humanized and optimized anti-MICA / B antibodies to CHO-MICB005 after treatment in human serum at 37°C for 1 week;

[0547] Fig.18B is a curve showing the binding affinity of humanized and optimized anti-MICA / B antibodies to CHO-MICB005 after treatment in human serum at 37°C for 2 weeks;

[0548] Fig.18C It is shown Figures 18A-18B Table showing calculated EC50s for humanized and optimized anti-MICA / B antibodies drawn in;

[0549] Fig.18D is a curve showing the binding affinity of D2M001-209 in CHO-MICA002 treated in human plasma or PBS at 37°C for 2 weeks;

[0550] Fig.18E is a curve showing the binding affinity of D2M001-209 in CHO-MICA004 treated in human plasma or PBS at 37°C for 2 weeks;

[0551] Fig.18F is a curve showing the binding affinity of D2M001-209 in CHO-MICA008 treated in human plasma or PBS at 37°C for 2 weeks;

[0552] Figure 18G is a curve showing the binding affinity of D2M001-209 in CHO-MICB005 treated in human plasma or PBS at 37°C for 2 weeks;

[0553] Fig.19A is a graph showing the abundance of humanized anti-MICB antibody (D2M001-010) in mice over time during a 10-day in vivo experiment; the antibody was quantified by sandwich ELISA using MICB recombinant protein or anti-human Fab as capture reagent and anti-human FC as detection reagent;

[0554] Fig.19Bis a graph showing the abundance of humanized anti-MICB antibody (D2M001-h39F53GS) in mice over time during a 10-day in vivo experiment; the antibody was quantified by sandwich ELISA using MICB recombinant protein or anti-human Fab as capture reagent and anti-human FC as detection reagent;

[0555] Fig.19C is a graph showing the abundance of humanized anti-MICB antibody (D2M001-h36B3) in mice over time during a 10-day in vivo experiment; the antibody was quantified by sandwich ELISA using MICB recombinant protein or anti-human Fab as capture reagent and anti-human FC as detection reagent;

[0556] Fig.19D is a graph showing the abundance of humanized anti-MICB antibody (D2M001-h36B3GS) in mice over time during a 10-day in vivo experiment; the antibody was quantified by sandwich ELISA using MICB recombinant protein or anti-human Fab as capture reagent and anti-human FC as detection reagent;

[0557] Fig.19E Figure 1 is a plot of the kinetic abundance of D2M001-209 in B16F10-MICAB tumor-bearing mice; blood samples were collected over time for a 9-day experiment at doses of 10 mg / kg or 30 mg / kg; the antibody was quantified by sandwich ELISA using anti-human F(ab')2 as capture reagent and anti-human FC as detection reagent;

[0558] Fig.19F Figure 2 is a curve showing the kinetic abundance of plasma soluble MICB in tumor-bearing mice treated with D2M001-209 and normalized to that of mice treated with PBS (untreated); B16F10-MICAB tumor-bearing mice were treated with PBS or a single dose of 10 mg / kg or 30 mg / kg; blood samples were collected over time for a 9-day experiment, as shown in Figure 2. Fig.19E The same time points as described in; MICB in plasma was quantified by sandwich ELISA;

[0559] Fig. 20A is a graph showing that transgenic mouse tumor cells are able to shed MICA in vitro, and that humanized and optimized anti-MICA / B antibodies inhibit MICA polypeptide shedding by transgenic mouse tumor cells in vitro;

[0560] Fig. 20B is a graph showing that transgenic mouse tumor cells are able to shed MICB in vitro, and that MICB polypeptide shedding by transgenic mouse tumor cells is inhibited in vitro by humanized and optimized anti-MICA / B antibodies;

[0561] Fig. 20Cis a graph showing the reduction of soluble MICA polypeptide shedding measured in vivo from transgenic mouse tumor cells by humanized and optimized anti-MICA / B antibody h36B3;

[0562] Fig.20D is a graph showing the reduction of soluble MICA polypeptide shedding measured in vivo from transgenic mouse tumor cells by humanized and optimized anti-MICA / B antibody h36B3;

[0563] Fig.21A is the tumor area (mm 2 ) Response to humanized and optimized anti-MICA / B antibody D2M001-010, control IgG alone, anti-PD1 antibody alone, or combination treatment with anti-MICA / B antibody D2M001-010 and anti-PD1 antibody; Statistical analysis was performed using t-test; P values ​​were calculated by t-test; *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, ns not significant;

[0564] Fig.21B A graph showing that humanized and optimized anti-MICA / B antibodies inhibit the shedding of soluble MICB polypeptides in transgenic mouse tumor cells in vivo; t-test was used for statistical analysis; P values ​​were calculated by t-test; *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, ns not significant;

[0565] Fig. 21C Is the tumor area (mm 2 ) Response to humanized and optimized anti-MICA / B antibody h36B3, control IgG alone, anti-PD1 antibody alone, or combination treatment with anti-MICA / B antibody h36B3 and anti-PD1 antibody; Statistical analysis was performed using t-test; P values ​​were calculated by t-test; *P<0.05, **P<0.01, ns not significant;

[0566] Fig.21D A graph showing the inhibition of soluble MICB polypeptide shedding by transgenic mouse tumor cells by humanized and optimized anti-MICA / B antibodies in vivo;

[0567] Fig.21E Is the tumor area (mm 2 ) Response to Fc function-invalid anti-MICA / B antibody h36B3 (h36B3-LALAPA), control IgG alone, anti-PD1 antibody alone, or combination treatment with h36B3-LALAPA and anti-PD1 antibody; Statistical analysis was performed using t-test; P values ​​were calculated by t-test; *P<0.05, **P<0.01, ns not significant;

[0568] Fig.21F A graph showing that humanized and optimized anti-MICA / B antibodies inhibit the shedding of soluble MICB polypeptides in transgenic mouse tumor cells in vivo; t-test was used for statistical analysis; P values ​​were calculated by t-test; *P<0.05, **P<0.01, ns not significant;

[0569] Figure 21G is the tumor volume (mm 3 ) Response curve graph of single dose 30 mg / kg D2M001-209, reference antibody 3F9 or control PBS treatment; statistical analysis was performed using Two-way ANOVA, Tukey comparison test;

[0570] Fig.21H is the tumor volume (mm 3 ) Response curves of humanized and optimized anti-MICA / B antibody D2M001-209, PBS alone, anti-PD1 antibody alone, or combination treatment of D2M001-209 and anti-PD1 antibody; P values ​​were calculated by two-way ANOVA; *P<0.05, ****P<0.0001, ns not significant;

[0571] Fig.21I D2M001-209 was shown to increase the surface expression of MICA on tumor cells in vivo; residual tumor cells were harvested from tumor-bearing animals treated with anti-MICA / B D2M001-209 antibody and PBS control, as Fig.21H As shown; P values ​​were calculated by t-test; *P<0.05, ***P<0.001;

[0572] Fig.21J D2M001-209 was shown to increase the surface expression of MICB on tumor cells in vivo; residual cells were harvested from tumor-bearing animals treated with anti-MICA / B D2M001-209 antibody and PBS control, as Fig.21H As shown; P values ​​were calculated by t-test; *P<0.05, ***P<0.001;

[0573] Figure 21K Display D2M001-209 reduces Fig.21H Concentration of soluble MICA peptide in the plasma of animals treated with anti-MICA / B D2M001-209 antibody or the combination of D2M001-209 and anti-PD1 antibody; P values ​​were calculated by t-test; *P<0.05, **P<0.01, ***P<0.001;

[0574] Figure 21L Display D2M001-209 reduces Fig.21HConcentration of soluble MICB peptide in the plasma of animals treated with anti-MICA / B D2M001-209 antibody or the combination of D2M001-209 and anti-PD1 antibody; P values ​​were calculated by t-test; *P<0.05, **P<0.01, ***P<0.001;

[0575] Fig.22A A series of lung images collected from B6 mice bearing metastatic B16F10-MICA / B tumor cells; animals in the treatment group were treated with anti-MICA / B D2M001-010 antibody or h36B3, and animals in the control group were treated with IgG isotype control; animals were sacrificed and images were taken 14 days after treatment;

[0576] Fig. 22B Lung tumor nodule counts of animals treated with anti-MICA / B D2M001-010 antibody, animals treated with anti-MICA / Bh36B3 antibody, and control group animals treated with IgG isotype control are shown; P values ​​were calculated by t-test; ****P<0.0001;

[0577] Fig. 22C Plasma concentrations of soluble MICA peptides are shown for animals treated with anti-MICA / B D2M001-010 antibody and control animals treated with IgG isotype control; P values ​​were calculated by t-test; *P<0.05, **P<0.01, P<0.0001;

[0578] Fig.22D Plasma concentrations of soluble MICB peptides are shown for animals treated with anti-MICA / B D2M001-010 antibody and control animals treated with IgG isotype control; P values ​​were calculated by t-test; *P<0.05, **P<0.01, ****P<0.0001;

[0579] Fig.22E Lung tumor nodule counts of B6 mice bearing metastatic B16F10-MICA / B tumor cells are shown; animals in the treatment group were treated with anti-MICA / B h36B3 antibody, Fc function null h36B3 antibody (h36B3-LALAPA), and IgG1 isotype control; P values ​​were calculated by t-test; *P<0.05, ****P<0.0001;

[0580] Fig.22F Plasma concentrations of soluble MICA peptides in animals treated with anti-MICA / B h36B3 antibody, Fc-invalid h36B3 antibody (h36B3-LALAPA), and IgG1 isotype control are shown; P values ​​were calculated by t-test; **P<0.01, ***P<0.001, ****P<0.0001.

[0581] Figure 22G Plasma concentrations of soluble MICB peptides in animals treated with anti-MICA / B h36B3 antibody, Fc-null h36B3 antibody (h36B3-LALAPA), and IgG1 isotype control are shown; P values ​​were calculated by t-test; *P<0.05, ****P<0.0001;

[0582] Fig.22H is a graph showing the response of A375 tumor-bearing SCID mice to treatment with humanized and optimized anti-MICA / B antibody D2M001-209 and IgG1 isotype control; t-test was used for statistical analysis; P values ​​were calculated by t-test; **P<0.01, ***P<0.001, ****P<0.0001, ns not significant;

[0583] Fig.22I Lung tumor nodule counts of SCID mice bearing metastatic A375 tumor cells are shown; animals in the treatment group were treated with anti-MICA / B D2M001-209 antibody and IgG1 isotype control; P values ​​were calculated by t-test; **P<0.01;

[0584] Fig.23 The VH and VL sequences of several antibodies are shown;

[0585] Figures 24A-24E provide CDR sequences of several antibodies;

[0586] Figure 25 shows the humanized VH and VL sequences;

[0587] Figure 26 shows the humanized VH and VL sequences of candidate IDs #38 and #39;

[0588] Figure 27 shows the humanized VH and VL sequences of candidate ID #36;

[0589] Figure 28 shows the humanized CDR sequences of candidate ID#36;

[0590] Figure 29 shows the humanized CDR sequences of candidate IDs #38 and #39;

[0591] Figures 30A-30E provide CDR sequences of several humanized antibodies;

[0592] Fig.31 The protein sequence of the reference antibody is provided;

[0593] Fig.32 Provides the protein sequence of the full-length MICA / B stably expressed in transgenic cell lines

[0594] Fig.33The protein sequence expressed by the DNA immunogen used in immunization is provided;

[0595] Fig.34 The protein immunogen sequences used in immunization are provided;

[0596] Fig.35 Sequences of recombinant ECD proteins used for affinity measurements are provided. DETAILED DESCRIPTION

[0597] The present disclosure provides examples of antibodies, antigen-binding fragments that bind to MICA (major histocompatibility complex class I chain-associated A) and / or MICB (major histocompatibility complex class I chain-associated B). In some embodiments, the antibody or its antigen-binding fragment binds to MICA. In some embodiments, the antibody or its antigen-binding fragment binds to MICB. In some embodiments, the antibody or its antigen-binding fragment binds to MICA and MICB.

[0598] MICA and MICB

[0599] Major histocompatibility complex (MHC) class I peptides related to A and B (MICA / B) are highly polymorphic cell surface proteins related to MHC class I glycoproteins and are ligands for the activating receptor NKG2D expressed on natural killer (NK) cells, CD8+ T cells, and γδ T cells. Binding of NKG2D to MICA / B triggers NK cells and co-stimulates T cells, leading to the elimination of cancerous or damaged cells by effector cells expressing the NKG2D receptor.

[0600] MICA / B proteins are constitutively expressed at low levels on myeloid cells, epithelial cells, endothelial cells, and fibroblasts. MICA / B proteins are upregulated or expressed de novo under stress, for example, during carcinogenesis, infection, DNA damage response, and in various autoimmune diseases. Expression of MICA / B can mark cells for killing by cytotoxic lymphocytes through activation of the NKG2D receptor. However, as an escape mechanism to prevent NKG2D-mediated responses, tumor cells can shed MICA / B proteins from cell surface proteolysis, resulting in a decrease in MICA / B surface density and the generation of soluble MICA / B (sMICA / B). High serum concentrations of shed MICA polypeptides are associated with disease progression in many human cancers, including melanoma, neuroblastoma, prostate cancer, renal cancer, multiple myeloma, and chronic lymphocytic leukemia. Expression of MICA / B has also been reported in a variety of tumor types, with high expression associated with poor patient prognosis.

[0601] It is believed that specifically blocking the shedding of MICA and MICB proteins in cancer cells can restore or enhance the NKG2D-dependent activation of NKG and T cells in the tumor microenvironment, and thus may enhance the anti-tumor activity in cancer patients. In the MICA / B polypeptide, the extracellular domain of MICA / B consists of three C-type Ig-like domains, called α-1, α-2 and α-3 domains. The α-1 and α-2 domains are far away from the cell membrane, while the α-3 domain is close to the cell membrane. It is reported that the 6 amino acid motifs in the α-3 domain are proteolytic cleavage sites, and proteolysis causes the MICA / B polypeptide to fall off the surface of cancer cells. A detailed description can be found in, for example, Wang, X. et al., "The six amino acid motif in the MICA α3 domain is a cancer therapy target that inhibits shedding", Research Communications (Biochemistry and Biophysics Research Communications) 387.3 (2009): 476-481, the literature, which is fully incorporated herein by reference.

[0602] The functions of MICA / B and their relationship to various diseases are described in the following literature. For example: Groh V,etal.Tumour-derived soluble MIC ligands impair expression ofNKG2D and T-cellactivation.Nature.2002Oct 17;419(6908):734-8.; Salih HR,etal.Cutting edge:down-regulation of MICA on human tumors by proteolytic shedding.JImmunol.2002Oct 15; 169(8):4098-102; Spear P, et al. NKG2D ligands as therapeutic targets. Cancer Immun. 2013 May 1; 13:8.; Ghadially H, et al. MHC class I chain-related protein A and B (MICA and MICB) are predominantly expressed intracellularly in tumor and normal tissue. Br J Cancer. 2017Apr 25;116(9):1208-1217; Xing S, Ferrari de Andrade L. NKG2D and MICA / B shedding: a'tag game'between NK cells and malignant cells. Clin Transl Immunology. 2020Dec 22;9(12):e1230; each of which is incorporated herein by reference in its entirety.

[0603] Antibodies that recognize MICA / B polypeptides on the surface of cancer cells, especially the specific epitope required for initiating proteolytic shedding, namely the α-3 domain, may prevent MICA / B polypeptides from shedding from the surface of cancer cells and reduce the abundance of soluble MICA / B polypeptides released by cancer cells. This article discloses several anti-MICA / B antibodies, antigen-binding fragments thereof, and methods of using these antibodies and antigen-binding fragments to inhibit MICA / B polypeptide shedding from cancer cells, inhibit tumor growth, and treat cancer.

[0604] Anti-MICA / B antibodies and antigen-binding fragments

[0605] The present disclosure provides antibodies and antigen-binding fragments thereof that specifically bind to MICA and / or MICB. The antibodies and antigen-binding fragments described herein are capable of binding to MICA and / or MICB polypeptides, and can bind to and block MICA / B polypeptides from being shed from the surface of cancer cells and enhance NK and T cells.The present disclosure provides, for example, anti-MICA / B antibodies PL114D01 ("#21"), PL111H05 ("#22"), PL114C07 ("#23"), PL114C04 ("#24"), PL116C11 ("#25"), PL115E08 ("#26"), PL116H02 ("#27"), PL114F03 ("#28"), PL115B06 ("#29"), PL111C04 ("#30"), PL116D11 ("#31"), PL116E04 ("#32"), PL111B08 ("#33")) , PL111H04("#34"), PL111B05("#35"), PL116H11("#36"), PL115C05("#37"), PL114H02("#38"), PL114G03("#39"), PL113C03("#40"), D2M001-001, D2M001-002, D2M001-003, D2M001-004, D2M001-005, D2M001-006, D2M001-007, D2M001-008, D2M001-009, D2M001-010, D2M0 01-011, D2M001-201, D2M001-202, D2M001-203, D2M001-204, D2M001-205, D2M001-206, D2M001-207, D2M001-208, D2M001-209, D2M001- 210, D2M001-211, D2M001-212, D2M001-213, h36, h36B3, h36B3, h36B3GS, h36B3(DE), h36B3(GA), hh36B3(GA), h236D26, h36D28, h39F53 , h39F53GS, h39-max-E3S-P3-P2#1, h39-max-E3S-P3-P2#4, h39-010F3S-P2-P2#7, h39-010F3F53E1, h39-010F3F53E2(GS), h39-010F3S-P2-P2#4, h39-010F3F53E2, D2M001-101, D2M001-102, D2M001-103, D2M001-104, D2M001-105, D2M001-106, D2M001-107, chimeric antibodies thereof, and humanized antibodies thereof. The CDR sequences, VH and VL of these antibodies or antibodies derived therefrom are as follows. Fig.23 -30.

[0606] For example, the CDR sequences of "#21" and "#21" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 3, 4, 5, and CDRs of the light chain variable domain, SEQ ID NOs: 6, 7, 8, e.g., as defined by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0607] For example, the CDR sequences of "#22" and "#22" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 11, 12, 13 and CDRs of the light chain variable domain, SEQ ID NOs: 14, 15, 16, e.g., as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0608] For example, the CDR sequences of "#23" and "#23" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 19, 20, 21, and CDRs of the light chain variable domain, SEQ ID NOs: 22, 23, 24, e.g., as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0609] For example, the CDR sequences of "#24" and "#24" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 27, 28, 29, and CDRs of the light chain variable domain, SEQ ID NOs: 30, 31, 32, e.g., as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0610] For example, the CDR sequences of "#25" and "#25" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 35, 36, 37, and CDRs of the light chain variable domain, SEQ ID NOs: 38, 39, 40, e.g., as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0611] For example, the CDR sequences of "#26" and "#26" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 43, 44, 45, and CDRs of the light chain variable domain, SEQ ID NOs: 46, 47, 48, e.g., as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0612] For example, the CDR sequences of "#27" and "#27" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 51, 52, 53, and CDRs of the light chain variable domain, SEQ ID NOs: 54, 55, 56, e.g., as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0613] For example, the CDR sequences of "#28" and "#28" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 59, 60, 61, and CDRs of the light chain variable domain, SEQ ID NOs: 62, 63, 64, e.g., as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0614] For example, the CDR sequences of "#29" and "#29" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 67, 68, 69, and CDRs of the light chain variable domain, SEQ ID NOs: 70, 71, 72, e.g., as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0615] For example, the CDR sequences of "#30" and "#30" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 75, 76, 77, and CDRs of the light chain variable domain, SEQ ID NOs: 78, 79, 80, e.g., as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0616] For example, the CDR sequences of "#31" and "#31" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 83, 84, 85, and CDRs of the light chain variable domain, SEQ ID NOs: 86, 87, 88, e.g., as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0617] For example, the CDR sequences of "#32" and "#32" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 91, 92, 93, and CDRs of the light chain variable domain, SEQ ID NOs: 94, 95, 96, e.g., as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0618] For example, the CDR sequences of "#33" and "#33" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 99, 100, 101 and CDRs of the light chain variable domain, SEQ ID NOs: 102, 103, 104, e.g., defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0619] For example, the CDR sequences of "#34" and "#34" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 107, 108, 109 and CDRs of the light chain variable domain, SEQ ID NOs: 110, 111, 112, e.g., as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0620] For example, the CDR sequences of "#35" and "#35" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 115, 116, 117 and CDRs of the light chain variable domain, SEQ ID NOs: 118, 119, 120, e.g., as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0621] For example, the CDR sequences of "#36" and "#36" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID numbers: 123, 124, 125 and CDRs of the light chain variable domain, SEQ ID numbers: 126, 127, 128, e.g., defined by IMGT numbers. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0622] For example, the CDR sequences of "#37" and "#37" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 131, 132, 133 and CDRs of the light chain variable domain, SEQ ID NOs: 134, 135, 136, e.g., as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0623] For example, the CDR sequences of "#38" and "#38" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 139, 140, 141 and CDRs of the light chain variable domain, SEQ ID NOs: 142, 143, 144, e.g., defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0624] For example, the CDR sequences of "#39" and "#39" derived antibodies (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain, SEQ ID NOs: 147, 148, 149 and the CDRs of the light chain variable domain, SEQ ID NOs: 150, 151, 152, e.g., as defined by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0625] For example, the CDR sequences of "#40" and "#40" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 155, 156, 157 and CDRs of the light chain variable domain, SEQ ID NOs: 158, 159, 160, e.g., as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0626] For example, the CDR sequences of "h36 template" and "h36 template" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 815, 816, 817 and CDRs of the light chain variable domain, SEQ ID NOs: 818, 819, 820, for example, as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0627] For example, "h36B3" and "h36B3" derived antibodies (e.g., humanized antibodies) have CDR sequences including heavy chain variable domain CDRs, SEQ ID NOs: 821, 822, 823 and light chain variable domain CDRs, SEQ ID NOs: 824, 825, 826, e.g., as defined by IMGT numbering. Other defined CDRs for these antibodies are shown in Figures 30B-30E.

[0628] For example, "h36B3 (GS)" and "h36B3 (GS)" derived antibodies (e.g., humanized antibodies) have CDR sequences including heavy chain variable domain CDRs, SEQ ID NOs: 827, 828, 829 and light chain variable domain CDRs, SEQ ID NOs: 830, 831, 832, e.g., as defined by IMGT numbering. Other defined CDRs for these antibodies are shown in Figures 30B-30E.

[0629] For example, "h36B3 (DE)" and "h36B3 (DE)" derived antibodies (e.g., humanized antibodies) have CDR sequences including heavy chain variable domain CDRs, SEQ ID NOs: 833, 834, 835 and light chain variable domain CDRs, SEQ ID NOs: 836, 837, 838, e.g., as defined by IMGT numbering. Other defined CDRs for these antibodies are shown in Figures 30B-30E.

[0630] For example, "h36B3 (GA)" and "h36B3 (GA)" derived antibodies (e.g., humanized antibodies) have CDR sequences including heavy chain variable domain CDRs, SEQ ID numbers: 839, 840, 841 and light chain variable domain CDRs, SEQ ID numbers: 842, 843, 844, e.g., defined by IMGT numbers. Other defined CDRs for these antibodies are shown in Figures 30B-30E.

[0631] For example, "h36D26" and "h36D26" derived antibodies (e.g., humanized antibodies) CDR sequences include heavy chain variable domain CDRs, SEQ ID NOs: 845, 846, 847 and light chain variable domain CDRs, SEQ ID NOs: 848, 849, 850, e.g., defined by IMGT numbering. Other defined CDRs for these antibodies are shown in Figures 30B-30E.

[0632] For example, "h36D28" and "h36D28" derived antibodies (e.g., humanized antibodies) have CDR sequences including heavy chain variable domain CDRs, SEQ ID NOs: 851, 852, 853 and light chain variable domain CDRs, SEQ ID NOs: 854, 855, 856, e.g., as defined by IMGT numbering. Other defined CDRs for these antibodies are shown in Figures 30B-30E.

[0633] For example, "D2M001-201" and "D2M001-201" derived antibodies (e.g., humanized antibodies) include CDRs of heavy chain variable domains, SEQ ID NOs: 857, 858, 859 and CDRs of light chain variable domains, SEQ ID NOs: 860, 861, 862, e.g., defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0634] For example, "D2M001-202" and "D2M001-202" derived antibodies (e.g., humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 863, 864, 865 and CDRs of the light chain variable domain, SEQ ID NOs: 866, 867, 868, e.g., defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0635] For example, "D2M001-203" and "D2M001-203" derived antibodies (e.g., humanized antibodies) include CDRs of heavy chain variable domains, SEQ ID NOs: 869, 870, 871 and CDRs of light chain variable domains, SEQ ID NOs: 872, 873, 874, e.g., defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0636] For example, "D2M001-204" and "D2M001-204" derived antibodies (e.g., humanized antibodies) include CDRs of heavy chain variable domains, SEQ ID NOs: 875, 876, 877 and CDRs of light chain variable domains, SEQ ID NOs: 878, 879, 880, for example, as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0637] For example, "D2M001-205" and "D2M001-205" derived antibodies (e.g., humanized antibodies) include CDRs of heavy chain variable domains, SEQ ID NOs: 881, 882, 883 and CDRs of light chain variable domains, SEQ ID NOs: 884, 885, 886, for example, as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0638] For example, "D2M001-206" and "D2M001-206" derived antibodies (e.g., humanized antibodies) include CDRs of heavy chain variable domains, SEQ ID NOs: 887, 888, 889 and CDRs of light chain variable domains, SEQ ID NOs: 890, 891, 892, for example, as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0639] For example, "D2M001-207" and "D2M001-207" derived antibodies (e.g., humanized antibodies) have CDR sequences including heavy chain variable domain CDRs, SEQ ID NOs: 893, 894, 895, and light chain variable domain CDRs, SEQ ID NOs: 896, 897, 898, e.g., as defined by IMGT numbering. Other defined CDRs for these antibodies are shown in Figures 30B-30E.

[0640] For example, "D2M001-208" and "D2M001-208" derived antibodies (e.g., humanized antibodies) include CDRs of heavy chain variable domains, SEQ ID NOs: 899, 900, 901 and CDRs of light chain variable domains, SEQ ID NOs: 902, 903, 904, e.g., defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0641] For example, "D2M001-209" and "D2M001-209" derived antibodies (e.g., humanized antibodies) include CDRs of heavy chain variable domains, SEQ ID NOs: 905, 906, 907 and CDRs of light chain variable domains, SEQ ID NOs: 908, 909, 910, e.g., defined by IMGT numbering. Other defined CDRs of these antibodies are shown in Figures 30B-30E.

[0642] For example, "D2M001-210" and "D2M001-210" derived antibodies (e.g., humanized antibodies) include CDRs of heavy chain variable domains, SEQ ID NOs: 911, 912, 913 and CDRs of light chain variable domains, SEQ ID NOs: 914, 915, 916, for example, as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0643] For example, "D2M001-211" and "D2M001-211" derived antibodies (e.g., humanized antibodies) include CDRs of heavy chain variable domains, SEQ ID NOs: 917, 918, 919 and CDRs of light chain variable domains, SEQ ID NOs: 920, 921, 922, for example, as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0644] For example, "D2M001-212" and "D2M001-212" derived antibodies (e.g., humanized antibodies) include CDRs of heavy chain variable domains, SEQ ID NOs: 923, 924, 925 and CDRs of light chain variable domains, SEQ ID NOs: 926, 927, 928, for example, as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0645] For example, "D2M001-213" and "D2M001-213" derived antibodies (e.g., humanized antibodies) include CDRs of heavy chain variable domains, SEQ ID NOs: 929, 930, 931 and CDRs of light chain variable domains, SEQ ID NOs: 932, 933, 934, for example, as defined by IMGT numbering. CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0646] For example, the CDR sequences of the "h36 template" and "h36 template" derived antibodies (eg, humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 708, 709, 710, and CDRs of the light chain variable domain, SEQ ID NOs: 711, 712, 713.

[0647] For example, the CDR sequences of "h36B3" and "h36B3"-derived antibodies (eg, humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 714, 715, 716 and CDRs of the light chain variable domain, SEQ ID NOs: 717, 718, 719.

[0648] For example, the CDR sequences of “h36B3(GS)” and “h36B3(GS)”-derived antibodies (eg, humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 720, 721, 722 and CDRs of the light chain variable domain, SEQ ID NOs: 723, 724, 725.

[0649] For example, the CDR sequences of "h36B3(DE)" and "h36B3(DE)"-derived antibodies (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain, SEQ ID NOs: 726, 727, 728 and the CDRs of the light chain variable domain, SEQ ID NOs: 729, 730, 731.

[0650] For example, the CDR sequences of "h36B3(GA)" and "h36B3(GA)"-derived antibodies (eg, humanized antibodies) include the CDRs of the heavy chain variable domain, SEQ ID NOs: 732, 733, 734 and the CDRs of the light chain variable domain, SEQ ID NOs: 735, 736, 737.

[0651] For example, the CDR sequences of "h36D26" and "h36D26"-derived antibodies (eg, humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 738, 739, 740, and CDRs of the light chain variable domain, SEQ ID NOs: 741, 742, 743.

[0652] For example, the CDR sequences of "h36D28" and "h36D28"-derived antibodies (eg, humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 744, 745, 746 and CDRs of the light chain variable domain, SEQ ID NOs: 747, 748, 749.

[0653] For example, the CDR sequences of "D2M001-001" and "D2M001-001" derived antibodies (eg, humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 750, 751, 752 and CDRs of the light chain variable domain, SEQ ID NOs: 753, 754, 755.

[0654] For example, the CDR sequences of "D2M001-003" and "D2M001-003" derived antibodies (eg, humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 756, 757, 758 and CDRs of the light chain variable domain, SEQ ID NOs: 759, 760, 761.

[0655] For example, the CDR sequences of "D2M001-010" and "D2M001-010" derived antibodies (eg, humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 762, 763, 764 and CDRs of the light chain variable domain, SEQ ID NOs: 765, 766, 767.

[0656] For example, the CDR sequences of "D2M001-004" and "D2M001-004" derived antibodies (eg, humanized antibodies) include CDRs of the heavy chain variable domain, SEQ ID NOs: 768, 769, 770 and CDRs of the light chain variable domain, SEQ ID NOs: 771, 772, 773.

[0657] For example, the CDR sequences of "hu39-max-E3S-P3-P2#1" and "hu39-max-E3S-P3-P2#1" derived antibodies (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain, SEQ ID NOs: 774, 775, 776 and the CDRs of the light chain variable domain, SEQ ID NOs: 777, 778, 779.

[0658] For example, the CDR sequences of "hu39-max-E3S-P3-P2#4" and "hu39-max-E3S-P3-P2#4" derived antibodies (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain, SEQ ID NOs: 780, 781, 782 and the CDRs of the light chain variable domain, SEQ ID NOs: 783, 784, 785.

[0659] For example, the CDRs of "h39-010F3S-P2-P2#7" and "h39-010F3S-P2-P2#7" derived antibodies (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain, SEQ ID NOs: 786, 787, 788 and the CDRs of the light chain variable domain, SEQ ID NOs: 789, 790, 791.

[0660] For example, the CDR sequences of "h39-010F3F53E1" and "h39-010F3F53E1"-derived antibodies (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain, SEQ ID NOs: 792, 793, 794 and the CDRs of the light chain variable domain, SEQ ID NOs: 795, 796, 797.

[0661] For example, the CDR sequences of "h39-010F3F53E2(GS)" and "h39-010F3F53E2(GS)"-derived antibodies (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain, SEQ ID NOs: 798, 799, 800 and the CDRs of the light chain variable domain, SEQ ID NOs: 801, 802, 803.

[0662] For example, the CDR sequences of "h39-010F3S-P2-P2#4" and "h39-010F3S-P2-P2#4" derived antibodies (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain, SEQ ID NOs: 804, 805, 806 and the CDRs of the light chain variable domain, SEQ ID NOs: 807, 808, 809.

[0663] For example, the CDR sequences of "h39-010F3F53E2" and "h39-010F3F53E2"-derived antibodies (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain, SEQ ID NOs: 810, 811, 812 and the CDRs of the light chain variable domain, SEQ ID NOs: 813, 814, 815.

[0664] Thus, in one aspect, the present disclosure provides an antibody or antigen-binding fragment thereof that binds to MICA and / or MICB, comprising: a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, wherein the VH CDR1 region comprises an amino acid sequence that is at least 70%, 80%, 90% or 100% identical to a selected VH CDR1 amino acid sequence, the VH CDR2 region comprises an amino acid sequence that is at least 70%, 80%, 90% or 100% identical to a selected VH CDR2 amino acid sequence, and the VH CDR3 region comprises an amino acid sequence that is at least 70%, 80%, 90% or 100% identical to a selected VH CDR3 amino acid sequence; and a light chain variable region (VL) comprising CDRs 1, 2, and 3, wherein the VL CDR1 region comprises an amino acid sequence that is at least 70%, 80%, 90% or 100% identical to a selected VL CDR1 amino acid sequence, the VL CDR2 region comprises an amino acid sequence that is at least 70%, 80%, 90% or 100% identical to a selected VL CDR3 amino acid sequence. The VL CDR3 region comprises an amino acid sequence that is at least 70%, 80%, 90% or 100% identical to a selected VL CDR3 amino acid sequence, wherein the selected VH CDRs 1, 2 and 3 amino acid sequences and the selected VL CDR, 1, 2 and 3 amino acid sequences are selected from VH CDRS1, VL CDRS1, 2, 3 listed in Figures 24A, 24B, 24C, 24D, 24E, 28, 29, 30A, 30B, 30C, 30D and 30E.

[0665] Also provided are the amino acid sequences of the heavy chain variable region and light variable region of the anti-MICA / B antibody. These VH and VL sequences are as follows: Fig.23 , 25, 26, 27, 28 or 29.

[0666] For example, the VH and VL of candidate ID21 are set forth in SEQ ID NOs: 1 and 2. For example, the VH and VL of candidate ID22 are set forth in SEQ ID NOs: 9 and 10. For example, the VH and VL of candidate ID23 are set forth in SEQ ID NOs: 17 and 18. For example, the VH and VL of candidate ID24 are set forth in SEQ ID NOs: 25 and 26. For example, the VH and VL of candidate ID25 are set forth in SEQ ID NOs: 33 and 34. For example, the VH and VL of candidate ID26 are set forth in SEQ ID NOs: 41 and 42. For example, the VH and VL of candidate ID27 are set forth in SEQ ID NOs: 49 and 50. For example, the VH and VL of candidate ID28 are set forth in SEQ ID NOs: 57 and 58. For example, the VH and VL of candidate ID29 are set forth in SEQ ID NOs: 65 and 66. For example, the VH and VL of candidate ID30 are set forth in SEQ ID NOs: 73 and 74. For example, the VH and VL of candidate ID31 are set forth in SEQ ID NOs: 81 and 82. For example, the VH and VL of candidate ID32 are set forth in SEQ ID NOs: 89 and 90. For example, the VH and VL of candidate ID33 are set forth in SEQ ID NOs: 97 and 98. For example, the VH and VL of candidate ID34 are set forth in SEQ ID NOs: 105 and 106. For example, the VH and VL of candidate ID35 are set forth in SEQ ID NOs: 113 and 114. For example, the VH and VL of candidate ID36 are set forth in SEQ ID NOs: 121 and 122. For example, the VH and VL of candidate ID37 are set forth in SEQ ID NOs: 129 and 130. For example, the VH and VL of candidate ID38 are set forth in SEQ ID NOs: 137 and 138. For example, the VH and VL of candidate ID39 are set forth in SEQ ID NOs: 145 and 146. For example, the VH and VL of candidate ID40 are set forth in SEQ ID NOs: 153 and 154.

[0667] These antibodies can be humanized. Humanized VH and VL sequences are shown in Figures 25, 26, 27, 28 or 29.

[0668] For humanized antibodies derived from #36, any of these heavy chain variable region sequences (e.g., SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706) can be paired with any of these light chain variable region sequences (e.g., SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707).

[0669] For humanized antibodies derived from #39, any of these heavy chain variable region sequences (e.g., SEQ ID NOs: 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679 or 680) can be paired with any of these light chain variable region sequences (e.g., SEQ ID NOs 681, 682, 683, 684, 685, 686, 687, 688 or 689).

[0670] In some embodiments, humanization percentage refers to the percentage identity of heavy chain or light chain variable region sequence compared with the human antibody sequence in the International Immunogenetics Information System (IMGT) database. The top hit means that the heavy chain or light chain variable region sequence is closer to the particular species rather than other species. For example, the top hit is relative to people, which means that the sequence is closer to people rather than other species. The top hit is to humans and macaques, which means that the sequence has the same percentage identity with human sequences and macaques (Macacafascicularis) sequences, and compared with the sequences of other species, these percentage identities are the highest. In some embodiments, the humanization percentage is greater than 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 90%, 91%, 92%, 93%, 94% or 95%. A detailed description of how to determine the percentage of humanization and how to determine the top candidates is known in the art, for example, described in Jones, Tim D. et al., "INN and Output of Antibody Nonproprietary Names", MAbs, Volume 8, No. 1, Taylor & Francis, 2016, which is incorporated herein by reference in its entirety. A high percentage of humanization generally has various advantages, for example, being safer and more effective in humans, more likely to be tolerated by human subjects, and / or less likely to cause side effects.

[0671] In addition, in some embodiments, the antibodies or antigen-binding fragments thereof described herein may also include one, two or three heavy chain variable region CDRs selected from Figures 24A-24E, 28, 29, Figures 30A-30E; and / or one, two or three light chain variable region CDRs selected from Figures 24A-24E, 28, 29, Figures 30A-30E. In some embodiments, the antibodies or antigen-binding fragments thereof described herein may also include one, two or three heavy chain variable region CDRs and / or one, two or three light chain variable region CDRs as shown in Figures 24A and 30A. In some embodiments, the antibodies or antigen-binding fragments thereof described herein may also include one, two or three heavy chain variable region CDRs and / or one, two or three light chain variable region CDRs as shown in Figures 24B and 30B. In some embodiments, the antibodies or antigen-binding fragments thereof described herein may also include one, two or three heavy chain variable region CDRs and / or one, two or three light chain variable region CDRs, as shown in Figures 24C and 30C, under the Chothia numbering scheme. In some embodiments, the antibodies or antigen-binding fragments thereof described herein may also include one, two or three heavy chain variable region CDRs and / or one, two or three light chain variable region CDRs as shown in Figures 24D and 30D. In some embodiments, the antibodies or antigen-binding fragments thereof described herein may also include one, two or three heavy chain variable region CDRs and / or one, two or three light chain variable region CDRs as shown in Figures 24E and 30E. In some embodiments, the antibodies or antigen-binding fragments thereof described herein may also include one, two or three heavy chain variable region CDRs and / or one, two or three light chain variable region CDRs as shown in Figures 28 and 29, for example, based on sequence prediction functions.

[0672] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a heavy chain variable domain comprising one, two or three of the VH CDR1s shown in Figures 24A-24E, 28, 29, and Figures 30A-30E, with zero, one or two amino acid insertions, deletions or substitutions; any one of the VH CDR2s shown in Figures 24A-24E, Figures 28, 29, and Figures 30A-30E, with zero, one or two amino acid insertions, deletions or substitutions; any one of the VH CDR3s shown in Figures 24A-24E, 28, 29, and Figures 30A-30E, with zero, one or two amino acid insertions, deletions or substitutions.

[0673] In some embodiments, the antibodies or antigen-binding fragments described herein may comprise a light chain variable domain comprising one, two or three of the VL CDR1s shown in Figures 24A-24E, 28, 29, and 30A-30E with zero, one or two amino acid insertions, deletions or substitutions; any of the VL CDR2s shown in Figures 24A-24E, Figures 28, 29, and 30A-30E with zero, one or two amino acid insertions, deletions or substitutions; any of the VL CDR3s shown in Figures 24A-24E, 28, 29, and 30A-30E with zero, one or two amino acid insertions, deletions or substitutions. Insertions, deletions and substitutions may be within the CDR sequence or at one or both ends of the CDR sequence.

[0674] The present disclosure also provides antibodies or antigen-binding fragments thereof that bind to MICA and / or MICB. The antibodies or antigen-binding fragments thereof comprise a heavy chain variable region (VH) comprising or consisting of an amino acid sequence that is at least 80%, 85%, 90% or 95% identical to a selected VH sequence, and a light chain variable region (VL) comprising or consisting of an amino acid sequence that is at least 80% identical, 85%, 90% or 95% identical to a selected VL sequence. In some embodiments, the selected VH sequence is SEQ ID NO: 1, 9, 17, 25, 33, 41, 49, 57, 65, 73, 81, 89, 97, 105, 113, 121, 129, 137, 145, 153, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, 706, 659, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, or 680. In some embodiments, the selected VL sequence is SEQ ID NO: 2, 10, 18, 26, 34, 42, 50, 58, 66, 74, 82, 90, 98, 106, 114, 122, 130, 138, 146, 154, 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, 707, 660, 681, 682, 683, 684, 685, 686, 687, 688 or 689.

[0675] In order to determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of the first and second amino acid or nucleic acid sequences to achieve optimal alignment, and non-homologous sequences can be ignored for comparison). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecules at that position are identical. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap, which values ​​need to be introduced to achieve optimal alignment of the two sequences. For example, the comparison of sequences and the determination of the percent identity between the two sequences can be accomplished using the Blossum62 scoring matrix, with a gap penalty of 12, a consecutive gap penalty of 4, and a frameshift gap penalty of 5.

[0676] The disclosure also provides a nucleic acid comprising a coded polypeptide comprising an immunoglobulin heavy chain or an immunoglobulin heavy chain. An immunoglobulin heavy chain or an immunoglobulin light chain comprises a CDR (numbered as defined by Kabat, Chothia, IMGT, North or Aho), as shown in Figures 24A-24E, 28, 29, and Figures 30A-30E. When a polypeptide is paired with a corresponding polypeptide (e.g., a corresponding heavy chain variable region or a corresponding light chain variable region), the paired polypeptide is combined with MICA and / or MICB.

[0677] Anti-MICA / B antibodies and antigen-binding fragments can also be antibody variants (including derivatives and conjugates) and multispecific (e.g., bispecific) antibodies or antibody fragments of antibodies or antibody fragments. Other antibodies provided herein are polyclonal antibodies, monoclonal antibodies, multispecific antibodies (polymers, such as bispecific antibodies), human antibodies, chimeric antibodies (e.g., human-mouse chimeras), single-chain antibodies, antibodies made in cells (i.e., in antibodies), and antigen-binding fragments thereof. The antibody or its antigen-binding fragment can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), category (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. In some embodiments, the antibody or its antigen-binding fragment is an IgG antibody or its antigen-binding fragment.

[0678] Antibody fragments are suitable for use in the provided methods as long as they retain the affinity and specificity required for full-length antibodies. Therefore, antibody fragments that bind to MICA and / or MICB will retain the ability to bind to MICA and / or MICB. The Fv fragment is an antibody fragment that contains a complete antigen recognition and binding site. This region consists of a dimer of a tightly associated heavy chain and a light chain variable domain, which can be covalent in nature, such as in scFv. It is in this configuration that the three CDRs of each variable domain interact to define the antigen binding site on the surface of the VH-VL dimer. In general, these 6 CDRs or their subsets give antibodies antigen binding specificity. However, even a single variable domain (or half of an Fv that contains only three CDRs specific to an antigen) can have the ability to recognize and bind to an antigen, although the affinity is usually lower than the entire binding site.

[0679] Single-chain Fv or (scFv) antibody fragments comprise the VH and VL domains (or regions) of an antibody, wherein these domains are present in a single polypeptide chain. Typically, the scFv polypeptide also includes a polypeptide linker between the VH and VL domains, which enables the scFv to form the structure required for antigen binding.

[0680] The Fab fragment contains the variable and constant domains of the light chain, and the variable and first constant domains (CH1) of the heavy chain. The F(ab')2 antibody fragment consists of a pair of Fab fragments, which are usually covalently linked near their carboxyl termini by hinge cysteines between them. Other chemical couplings of antibody fragments are also known in the art.

[0681] Diabodies are small antibody fragments with two antigen-binding sites, which fragments include a VH connected to a VL in the same polypeptide chain (VH and VL). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and form two antigen-binding sites.

[0682] Linear antibodies consist of a pair of tandem Fd fragments (VH-CH1-VH-CH1), which together with complementary light chain polypeptides form a pair of antigen binding regions. Linear antibodies can be bispecific or monospecific.

[0683] The antibodies and antibody fragments of the present disclosure may be modified in the Fc region to provide desired effector function or serum half-life.

[0684] The multimerization of antibodies can be accomplished by natural aggregation of antibodies or by chemical or recombinant connection techniques known in the art. For example, a certain proportion of purified antibody preparations (e.g., purified IgG1 molecules) spontaneously form protein aggregates containing antibody homodimers and other high-order antibody multimers.

[0685] Alternatively, antibody homodimers can be formed by chemical bonding techniques known in the art. For example, heterobifunctional cross-linkers, including but not limited to SMCC (succinimidyl 4-(maleimidomethyl) cyclohexane-1-carboxylate) and SATA (N-succinimidyl S-acetylthioacetate) can be used to form antibody multimers. An exemplary method for the formation of antibody homodimers is described in the study of Ghetie et al. (Proc. Natl. Acad. Sci. USA 94: 7509-7514, 1997). Antibody homodimers can be converted into Fab'2 homodimers by pepsin digestion. Another method for forming antibody homodimers is to use the self-affinity T15 peptide described by Zhao et al. (J. Immunol. 25: 396-404, 2002).

[0686] In some embodiments, the multispecific antibody is a bispecific antibody. Bispecific antibodies can be manufactured by designing the interface between a pair of antibody molecules, to maximize the percentage of heterodimers recovered from recombinant cell culture. For example, the interface can include at least a portion of the CH3 domain of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced by larger side chains (such as tyrosine or tryptophan). On the interface of the second antibody molecule, by replacing the large amino acid side chain with a smaller amino acid side chain (such as alanine or threonine), a compensatory "cavity" identical or similar to the large amino acid side chain size is formed. This provides a mechanism that can improve the output of heterodimers relative to other unwanted end products (such as homodimers). For example, this method is described in WO96 / 27011, which is fully incorporated herein by reference.

[0687] Bispecific antibodies include cross-linked antibodies or "heteroconjugate" antibodies. For example, one antibody in the heteroconjugate can be coupled to avidin and the other antibody can be coupled to biotin. Heteroconjugate antibodies can also be prepared using any convenient cross-linking method. Suitable cross-linking agents and cross-linking techniques are well known in the art and are disclosed in U.S. Patent No. 4,676,980, which is incorporated herein by reference in its entirety.

[0688] Any antibody or antigen-binding fragment described herein can be coupled to a stabilizing molecule (e.g., a molecule that increases the half-life of the antibody or antigen-binding fragment thereof in a subject or solution). Non-limiting examples of stabilizing molecules include: polymers (e.g., polyethylene glycol) or proteins (e.g., serum albumin, such as human serum albumin). Coupling of stabilizing molecules can increase the half-life of the antibody or antigen-binding fragment in vitro (e.g., in tissue culture or when stored as a pharmaceutical composition) or in vivo (e.g., in humans) or extend its biological activity.

[0689] In some embodiments, the antibodies or antigen-binding fragments described herein can be coupled to a therapeutic agent. Antibody-drug conjugates include antibodies or antigen-binding fragments thereof covalently or non-covalently bound to a therapeutic agent. In some embodiments, the therapeutic agent is cytotoxic or cytostatic (e.g., cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenotoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxy anthrax, maytansine compounds such as DM-1 and DM-4, ​​diketones, mitoxantrone, mitramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, epirubicin and cyclophosphamide and the like).

[0690] Antibodies and antigen-binding fragments

[0691] The present disclosure provides anti-MICA / B antibodies and antigen-binding fragments thereof. In general, antibodies (also called immunoglobulins) are composed of two types of polypeptide chains, light chains and heavy chains. The non-limiting antibodies of the present disclosure can be complete four-immunoglobulin chain antibodies comprising two heavy chains and two light chains. The heavy chain of the antibody can be any isotype, including IgM, IgG, IgE, IgA or IgD, and can also be a subtype, including IgG1, IgG2, IgG2a, IgG2b, IgG3, IgG4, IgE1, IgE2, etc. The light chain can be a kappa light chain or a lambda light chain. The antibody can contain two identical copies of the light chain and two identical copies of the heavy chain. Each heavy chain contains a variable domain (or variable region, V H ) and multiple constant domains (or constant regions), which are bound to each other through disulfide bonds within their constant domains to form the "stem" of the antibody. The light chains each contain a variable domain (or variable region, VL) and a constant domain (or constant region), and each light chain is bound to a heavy chain through disulfide bonds. The variable region of each light chain is aligned with the variable region of the heavy chain to which it is bound. The variable regions of both light and heavy chains contain three hypervariable regions sandwiched between more conserved framework regions (FR).

[0692] These hypervariable regions are called complementarity determining regions (CDRs) and form loops that make up the major antigen-binding surface of the antibody. The four framework regions primarily adopt a beta-sheet conformation, and the CDRs form loops that connect, and in some cases form part of, the beta-sheet structure. The CDRs in each chain are bound tightly by the framework regions and, together with the CDRs from the other chain, contribute to the formation of the antigen-binding region.

[0693] Methods for identifying antibody CDR regions by analyzing the amino acid sequence of an antibody are well known, and a number of CDR definition methods are generally available. The Kabat definition is based on sequence variability, while the Chothia definition is based on the position of the structural loop regions. These methods and definitions are described, for example, in Martin, "Protein sequence and structural analysis of antibody variable domains", Antibody engineering, Springer Berlin Heidelberg, 2001, 422-439; Abhinandan et al., "Kabat's analysis and improvement and correct structural numbering of antibody variable domains", Molecular immunology 45.14 (2008): 3832-3839; Wu, TT and Kabat, EA (1970) J. Exp. Med. 132: 211-250; Martin et al., Methods Enzymol. 203:121-53 (1991); Morea et al., Biophys Chem 68(1-3):9-16 (October 1997); Morea et al., J Mol Biol. 275(2):269-94 (January 1998); Chothia et al., Nature 342(6252):877-83 (December 1989); Ponomarenko and Bourne, BMC Structural Biology 7:64 (2007); each of which is incorporated herein by reference in its entirety. Other definitions are known in the art, including, for example, IMGT, Aho (Honneger's Numbering Scheme), and North. In some embodiments, a combination of different CDR definitions is used.

[0694] CDRs are important for recognizing the epitope of an antigen. As used herein, an "epitope" is the smallest portion of a target molecule that can specifically bind to the antigen binding domain of an antibody. The minimum size of an epitope may be about 3, 4, 5, 6, or 7 amino acids, but these amino acids do not need to be in a continuous linear sequence of the primary structure of the antigen, as the epitope may depend on the three-dimensional configuration of the antigen based on the secondary and tertiary structures of the antigen.

[0695] In some embodiments, the antibody is a complete immunoglobulin molecule (e.g., IgG1, IgG2a, IgG2b, IgG3, IgM, IgD, IgE, IgA). IgG subclasses (IgG1, IgG2, IgG3, and IgG4) are highly conserved, with different constant regions, especially the hinge and upper CH2 domains. The sequences and differences of IgG subclasses are known in the art and are described, for example, in Vidarsson et al., "IgG subclasses and isotypes: from structure to effector function", Frontiers in immunology 5 (2014); Irani et al., "Molecular properties of human IgG subclasses and their impact on the design of therapeutic monoclonal antibodies against infectious diseases", Molecular immunology 67.2 (2015): 171-182; Shakib, Farouk, ed., Human IgG subclasses: Molecular analysis of structure, function, and regulation, Elsevier, 2016; each of which is incorporated herein by reference in its entirety.

[0696] Antibodies can also be immunoglobulin molecules derived from any species (e.g., humans, rodents, mice, camelids). Antibodies disclosed herein also include, but are not limited to, polyclonal antibodies, monoclonal antibodies, monospecific antibodies, and chimeric antibodies, which include immunoglobulin binding domains fused to another polypeptide. The term "antigen binding domain" or "antigen binding fragment" is a portion of an antibody that retains the specific binding activity of a complete antibody, i.e., any portion of an antibody that can specifically bind to an epitope on a complete antibody target molecule. It includes Fab, Fab', F(ab')2, etc. and variants of these fragments. Therefore, in some embodiments, an antibody or its antigen binding fragment can be, for example, scFv, Fv, Fd, dAb, bispecific antibodies, bispecific scFv, double antibodies, linear antibodies, single-chain antibody molecules, multispecific antibodies formed by antibody fragments, and any polypeptide including a binding domain that is homologous or homologous to the following: antibody binding domain. Non-limiting examples of antigen binding domains include, e.g., heavy and / or light chain CDRs of an intact antibody, heavy and / or light chain variable regions of an intact antibody, the full length heavy or light chain of an intact antibody, or a single CDR from a heavy or light chain of an intact antibody.

[0697] In some embodiments, the antigen binding fragment may form a part of a chimeric antigen receptor (CAR). In some embodiments, the chimeric antigen receptor is a fusion of a single-chain variable fragment (scFv) as described herein, fused to the CD3-zeta transmembrane and endomembrane domains. In some embodiments, the chimeric antigen receptor also includes intracellular signal transduction domains from various costimulatory protein receptors (e.g., CD28, 41BB, ICOS). In some embodiments, the chimeric antigen receptor comprises multiple signal transduction domains, such as CD3z-CD28-41BB or CD3z-CD28-OX40, to increase effectiveness. Therefore, in one aspect, the present disclosure also provides cells (e.g., T cells) expressing chimeric antigen receptors as described herein.

[0698] In some embodiments, the scFV has one heavy chain variable domain and one light chain variable domain.

[0699] Antibody characteristics

[0700] The antibodies or antigen-binding fragments thereof described herein can block the release of MICA and / or MICB polypeptides from the surface of cancer cells and promote the enhancement of NK and T cells.

[0701] MICA and MICB are ligands of NKG2D and can be expressed in response to cellular stress, such as DNA damage, unfolded protein response, hypoxia, and carcinogenesis. The expression of MICA / B on the surface of cancer cells can be marked for NK cell-mediated killing. However, MICA / B proteins can be downregulated by tumor cells or proteolytically detached from the surface of tumor cells, resulting in effective escape from NKG2D recognition and subsequent cancer proliferation and progression. In some embodiments, by binding to MICA and / or MICB, the antibodies described herein can block the proteolytic detachment of MICA / MICB polypeptides in cancer cells, restoring NKG2D recognition and enhancement of NK cell responses.

[0702] In some embodiments, the antibody or antigen binding fragment thereof can bind to the alpha-1, alpha-2, and / or alpha-3 domain. In some embodiments, the antibody or antigen binding fragment thereof can bind to the alpha-3 domain.

[0703] In some embodiments, antibodies or antigen-binding fragments thereof as described herein can reduce the shedding of MICA / B polypeptides from the surface of cancer cells to less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%. In some embodiments, antibodies or antigen-binding fragments thereof as described herein can stabilize MICA / B on the cell surface by preventing shedding. In some embodiments, antibodies or antigen-binding fragments thereof as described herein can reduce the abundance of soluble MICA / B polypeptides in serum to less than 90%, 80%, 70%, 60%, 50%, 40%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%. In some embodiments, antibodies or antigen-binding fragments thereof as described herein can reduce the abundance of soluble MICA / B polypeptides in the cell culture fluid of cancer cells grown in culture to 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% or less. In some embodiments, antibodies or antigen-binding fragments thereof as described herein can effectively capture shed MICA / B to form immune complexes, thereby stimulating NKG2D and co-activating NK cells and / or T cells. In some embodiments, antibodies or antigen-binding fragments thereof as described herein can enhance the ability of NK cells to kill tumor cells. In some embodiments, antibodies or antigen-binding fragments thereof as described herein can mediate effector functions (e.g., ADCC) to kill tumor cells expressing MICA / B. In some embodiments, the antibodies or antigen-binding fragments thereof as described herein can reduce tumor growth or tumor metastasis to a level of less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%.

[0704] In certain embodiments, the antibody (or antigen-binding fragment thereof) specifically binds to MICA (e.g., human MICA, monkey MICA and / or chimeric MICA) or MICB (e.g., human MICB, monkey MICB and / or chimeric MICB) with an off-rate (koff) of less than 0.1 s -1 Less than 0.01s -1 , less than 0.001s -1 , less than 0.0001s -1 , or less than 0.0001s -1 In some embodiments, the dissociation rate (koff) is greater than 0.01 s -1 , greater than 0.001s -1、 More than 0.0001s -1、More than 0.0001s -1 or greater than 0.00001 s-1 .

[0705] In some embodiments, the kinetic association rate (kon) is greater than 1×10 2 / Ms, greater than 1×10 3 / Ms, greater than 1×10 4 / Ms, greater than 1×10 5 / Ms, or greater than 1×10 6 / Ms. In some embodiments, the kinetic association rate (kon) is less than 1×10 5 / Ms, less than 1×10 6 / Ms, or less than 1×10 7 / Ms.

[0706] Affinity can be derived from the quotient of the kinetic rate constants (KD = koff / kon). In some embodiments, KD is less than 1×10 -6 M, less than 1×10 -7 M, less than 1×10 -8 M, less than 1×10 -9 M, or less than 1×10 -10 In some embodiments, the KD is less than 30 nM, 20 nM, 15 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM. In some embodiments, the KD is greater than 1×10 -7M , greater than 1×10 -8 M, greater than 1×10 -9 M, greater than 1×10 -10 M, greater than 1×10 -11 M, or greater than 1×10 -12 M.

[0707] Common techniques for measuring antibody affinity for an antigen include ELISA, RIA, and surface plasmon resonance (SPR). SPR imaging system or Gator Prime BLI system for measurement. In some embodiments, the antibody binds to human MICA, monkey MICA (e.g., cynomolgus monkey MICA) and / or chimeric MICA. In some embodiments, the antibody binds to human MICB, monkey MICB (e.g., cynomolgus monkey MICB) and / or chimeric MICB.

[0708] In some embodiments, the antibodies described herein can bind to human or monomeric MICA or MICB with an EC50 value of less than 10 μg / mL, less than 9 μg / mL, less than 8 μg / mL, less than 7 μg / mL, less than 6 μg / mL, less than 5 μg / mL, less than 4 μg / mL, less than 3 μg / mL, less than 2 μg / mL, less than 1 μg / mL, less than 0.9 μg / mL, less than 0.8 μg / mL, less than 0.7 μg / mL, less than 0.6 μg / mL, less than 0.5 μg / mL, less than 0.4 μg / mL, less than 0.3 μg / mL, less than 0.2 μg / mL, less than 0.1 μg / mL, less than 0.09 μg / mL, less than 0.08 μg / mL, less than 0.07 μg / mL, less than 0.06 μg / mL, less than 0.05 μg / mL, less than 0.04 μg / mL, less than 0.03 μg / mL, less than 0.02 μg / mL or less than 0.01 μg / mL. In some embodiments, EC50 is less than 0.01 μg / mL. In some embodiments, EC50 is less than 0.02 μg / mL. In some embodiments, EC50 is less than 0.03 μg / mL. In some embodiments, thermal stability is determined. The Tm of the antibodies or antigen-binding fragments described herein may be greater than 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94 or 95°C. Since IgG can be described as a multi-domain protein, the melting curve sometimes shows two transitions, a first denaturation temperature Tm D1 and a second denaturation temperature Tm D2. The presence of these two peaks usually indicates the denaturation of the Fc domain (Tm D1) and the Fab domain (Tm D2), respectively. When there are two peaks, Tm usually refers to Tm D2.

[0709] Thus, in some embodiments, the antibodies or antigen binding fragments as described herein have a Tm D1 of greater than 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, or 95°C. In some embodiments, the antibodies or antigen binding fragments as described herein have a Tm D2 of greater than 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, or 95°C.

[0710] In some embodiments, Tm, Tm Dl, Tm D2 is less than 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, or 95 °C.

[0711] In some embodiments, the antibodies have greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190% or 200%. In some embodiments, the antibodies have a tumor growth inhibition percentage of less than 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190% or 200%. TGI% can be determined, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days after initiation of treatment, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after initiation of treatment. As used herein, tumor growth inhibition percentage (TGI%) is calculated using the following formula:

[0712] TGI(%)=[1-(Ti-T0) / (Vi-V0)]×100

[0713] Ti is the mean tumor volume of the treatment group on day i. T0 is the mean tumor volume of the treatment group on day 0. Vi is the mean tumor volume of the control group on day i. V0 is the mean tumor volume of the control group on day 0.

[0714] In some embodiments, antibodies or antigen-binding fragments thereof described herein have functional Fc. In some embodiments, Fc is from human IgG1, human IgG2, human IgG3 or human IgG4. In some embodiments, the effector function of functional Fc is antibody-dependent cell-mediated cytotoxicity (ADCC). In some embodiments, the effector function of functional Fc is phagocytosis (e.g., antibody-dependent cellular phagocytosis, or ADCP). In some embodiments, the effector function of functional Fc is ADCC and phagocytosis. In some embodiments, antibodies or antigen-binding fragments thereof as described herein have Fc regions without effector functions. In some embodiments, Fc is human IgG4Fc. In some embodiments, Fc is human IgG1Fc. In some embodiments, Fc does not have a functional Fc region. For example, the Fc region has a LALA mutation (L234A and L235A mutations in EU numbering), a LALAPA mutation (L234A, L235A, P329A mutations in EU numbering), or a LALAPG mutation (L234A, L235A, P329G mutations in EU numbering). In some embodiments, the Fc region includes an amino acid sequence that is at least 80%, at least 90%, or 100% identical to SEQ ID NO: 801, 802, 803, 804, or 805%. For example, the antibody or antigen-binding fragment is a Fab, Fab', F(ab')2, and Fv fragment.

[0715] In some embodiments, the anti-MICA / B antibodies described herein can only bind to MICA, and thus can also be named anti-MICA antibodies. In some embodiments, the anti-MICA / B antibodies described herein can only bind to MICB, and thus can also be named anti-MICB antibodies.

[0716] In some embodiments, the anti-MICA / B antibodies described herein can inhibit the shedding of MICA / B polypeptides from the surface of tumor cells. Thus, NKG2D-dependent activation of NK cells can be increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% compared to negative control cells.

[0717] In some embodiments, the anti-MICA / B antibodies described herein can increase the anti-tumor activity (e.g., destruction of tumor cells by NK cells or T cells) in a cancer patient after treatment with a therapeutically effective amount of the anti-MICA / B antibody by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% compared to not being treated with the anti-MICA / B antibody.

[0718] In some embodiments, the anti-MICA / B antibodies described herein are more potent (e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 1-fold, 2-fold, 5-fold, or 10-fold more potent) than a reference antibody. Some reference antibodies (e.g., 3F9, 6E.1.1.12, ID5, 13A9, P2B10G5, or CM33322) such as Fig.31 shown.

[0719] Method for preparing anti-MICA / B antibodies

[0720] The isolated fragments of human MICA and / or MICB can be used as immunogens to generate antibodies using standard polyclonal and monoclonal antibody preparation techniques. Polyclonal antibodies can be produced in animals by multiple injections (e.g., subcutaneous or intraperitoneal injections) of antigenic peptides or proteins. In some embodiments, the antigenic peptides or proteins are injected with at least one adjuvant. In some embodiments, the antigenic peptides or proteins can be coupled with an immunogenic agent in the species to be immunized. Animals can be injected with antigenic peptides or proteins multiple times (e.g., twice, three times, or four times).

[0721] The full-length polypeptide or protein can be used, or an antigenic peptide fragment thereof can be used as an immunogen. The antigenic peptide of the protein comprises at least 8 (e.g., at least 10, 15, 20 or 30) amino acid residues of the amino acid sequence of MICA and / or MICB, and comprises an epitope of the protein, so that antibodies raised against the peptide form a specific immune complex with the protein. As described above, the full-length sequence of human MICA is known in the art (e.g., SEQ ID NO: 1427, 1428 or 1429), and the full-length sequence of human MICB is known in the art (e.g., SEQ ID NO: 11430).

[0722] Immunogens are typically used to prepare antibodies by immunizing a suitable subject (e.g., a human or transgenic animal expressing at least one human immunoglobulin locus). Suitable immunogenic preparations may include, for example, recombinantly expressed or chemically synthesized polypeptides (e.g., fragments of human MICA and / or MICB). The preparation may also include an adjuvant, such as Freund's complete or incomplete adjuvant, or a similar immunostimulant.

[0723] As described above, polyclonal antibodies can be prepared by immunizing a suitable subject using MICA and / or MICB polypeptides or their antigenic peptides (e.g., a part of MICA and / or MICB) as an immunogen. Antibody titers in immune subjects can be monitored over time by standard techniques, such as enzyme-linked immunosorbent assay (ELISA) using immobilized MICA and / or MICB polypeptides or peptides. If desired, antibody molecules can be isolated from mammals (e.g., from blood) and further purified by well-known techniques, such as protein A of protein G chromatography, to obtain IgG components. At an appropriate time after immunization, for example, when specific antibody titers are highest, antibody-producing cells can be obtained from the subject and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique originally described by Kohler et al. (Nature 256: 495-497, 1975), human B cell hybridoma technique (Kozbor et al., Immunol. Today 4: 72, 1983), EBV hybridoma technique (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96, 1985) or trioma technique. Techniques for producing hybridomas are well known (see generally, Current Protocols in Immunology, 1994, Collian et al. (eds.), John Wiley & Sons, Inc., New York, New York). Hybridoma cells producing monoclonal antibodies are detected by screening hybridoma culture supernatants for antibodies that bind the polypeptide or epitope of interest, for example, using a standard ELISA assay.

[0724] Variants of antibodies or antigen-binding fragments described herein can be prepared by introducing appropriate nucleotide changes into DNA encoding human, humanized or chimeric antibodies or their antigen-binding fragments, or by peptide synthesis. For example, such variants include deletions, insertions or substitutions of residues in the amino acid sequence constituting the antibody antigen-binding site or antigen-binding domain. In a population of such variants, the affinity of some antibodies or antigen-binding fragments to target proteins (e.g., MICA and / or MICB) will increase. Any combination of deletions, insertions and / or combinations can be performed to obtain antibodies or their antigen-binding fragments with increased binding affinity to the target. Amino acid changes introduced into antibodies or antigen-binding fragments can also change or introduce post-translational modifications of antibodies or antigen-binding fragments, such as changing (e.g., increasing or decreasing) the number of glycosylation sites, changing the type of glycosylation sites (e.g., changing the amino acid sequence so that enzymes present in the cell are connected to different sugars), or introducing new glycosylation sites.

[0725] The antibodies disclosed herein can be derived from any species of animal, including mammals. Non-limiting examples of natural antibodies include antibodies derived from humans, primates (e.g., monkeys and apes), cattle, pigs, horses, sheep, camelids (e.g., camels and llamas), chickens, goats, and rodents (e.g., rats, mice, hamsters, and rabbits), including transgenic rodents that have been genetically engineered to produce human antibodies.

[0726] Human antibodies and humanized antibodies include antibodies with variable and constant regions derived from human germline immunoglobulin sequences (or with the same amino acid sequence as the derived antibodies). Human antibodies may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or somatic mutations in vivo), such as in CDRs.

[0727] Humanized antibodies typically graft non-human CDRs to human frameworks (FRs). Thus, humanized antibodies have one or more amino acid sequences introduced from non-human sources. These non-human amino acid residues are often referred to as "import" residues and are typically taken from "imported" variable domains. Humanization can essentially be performed, for example, by replacing the corresponding sequences of human antibodies with rodent CDRs or CDR sequences. These methods are described in Jones et al., Nature, 321: 522-525 (1986); Riechmann et al., Nature, 332: 323-327 (1988); Verhoeyen et al., Science, 239: 1534-1536 (1988); each of which is incorporated herein by reference in its entirety. Therefore, "humanized" antibodies are chimeric antibodies in which antibodies that are much smaller than the complete human V domain have been replaced by corresponding sequences from non-human species. In practice, humanized antibodies are typically mouse antibodies in which some CDR residues and some FR residues are substituted by residues from analogous sites in human antibodies.

[0728] The selection of human VH and VL domains for making humanized antibodies is very important for reducing immunogenicity. According to the so-called "best fit" method, the V domain sequence of mouse antibodies is screened according to the entire known human domain sequence library. Then, the human sequence closest to the mouse is accepted as the human FR of the humanized antibody (Sims et al., J.Immunol., 151: 2296 (1993); Chothia et al., J.Mol.Biol., 196: 901 (1987)).

[0729] In some embodiments, yeast display is performed to achieve affinity maturation. Detailed information can be found in reports by Boder, ET et al., for example, "Yeast surface display for screening combinatorial polypeptide libraries", Nature Biotechnology 15.6 (1997): 553-557; Feldhaus, MJ, et al. "Flow cytometric separation of human antibodies from non-immune Saccharomyces cerevisiae surface display libraries" Nature Biotechnology 21.2 (2003): 163-170; and Chao, G. et al., "Separation and engineering of human antibodies using yeast surface display", Nature Protocols 1.2 (2006): 755-768; each of which is incorporated herein by reference in its entirety.

[0730] More importantly, antibody humanization should retain high specificity and affinity for antigens and other favorable biological properties. In order to achieve this goal, three-dimensional models of parental and humanized sequences can be used to prepare humanized antibodies by analyzing parental sequences and various conceptual humanized products. Three-dimensional immunoglobulin models are common and familiar to those skilled in the art. Computer programs can be used to illustrate and display the possible three-dimensional conformational structures of selected candidate immunoglobulin sequences. Examining these displays can analyze the possible role of residues in the function of candidate immunoglobulin sequences, i.e., analyze the residues that affect the ability of candidate immunoglobulins to bind to their antigens. In this way, FR residues can be selected and combined from receptor and imported sequences to obtain desired antibody properties, such as increasing affinity for target antigens.

[0731] In some embodiments, humanization of an anti-MICA / B antibody or antigen-binding fragment thereof described herein is achieved computationally, for example, using MOE computer software.

[0732] Generally, the amino acid sequence variants of a humanized or chimeric anti-MICA / B antibody will comprise an amino acid sequence that is at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to a sequence in the light or heavy chain of the original antibody.

[0733] Identity or homology to a native sequence is generally the percentage of amino acid residues present in a candidate sequence that are identical to the sequence present in a human, humanized or chimeric anti-MICA / B antibody or fragment, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity.

[0734] Other modifications may be made to the anti-MICA / B antibody or antigen-binding fragment. For example, cysteine ​​residues may be introduced into the Fc region, thereby allowing the formation of interchain disulfide bonds in this region. The homodimeric antibodies thus produced may have any extended half-life in vitro and / or in vivo. Homodimeric antibodies with increased half-life in vitro and / or in vivo may also be prepared using heterobifunctional cross-linkers, for example, in Wolff et al. (Cancer Res. 53: 2560-2565, 1993). Alternatively, antibodies with dual Fc regions may be designed (e.g., see Stevenson et al., Anti-Cancer Drug Design 3: 219-230, 1989).

[0735] In some embodiments, the anti-MICA / B antibody or antigen-binding fragment thereof may be covalently modified. These covalent modifications may be achieved by chemical or enzymatic synthesis, or by enzymatic or chemical cleavage. Other types of covalent modifications of antibodies or antibody fragments are introduced into the molecule by reacting targeted amino acid residues of the antibody or antibody fragment with an organic derivatizing agent that reacts with selected side chains or N-terminal or C-terminal residues.

[0736] In some embodiments, the antibody variant has a carbohydrate structure that lacks fucose (directly or indirectly) attached to the Fc region. For example, the amount of fucose in such an antibody may be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose in the Asn297 sugar chain relative to the sum of all sugar structures measured by MALDI-TOF mass spectrometry (e.g., complex, mixed and high mannose structures measured by MALDI-TOF mass spectrometry), such as WO2008 / 077546. Asn297 refers to an asparagine residue located at about position 297 in the Fc region (Eu numbering of residues in the Fc region; or position 314 in Kabat numbering); however, due to minor sequence variations in antibodies, Asn297 may also be located about ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300. Such fucosylated variants may have improved ADCC function. In some embodiments, to reduce glycan heterogeneity, the Fc region of the antibody can be further designed to replace the asparagine at position 297 with alanine (N297A).

[0737] Recombinant vector

[0738] The present disclosure also provides a recombinant vector (e.g., an expression vector) comprising an isolated polynucleotide disclosed herein (e.g., a polynucleotide encoding a polypeptide disclosed herein), introducing the recombinant vector into a host cell thereof (i.e., causing the host cell to contain the polynucleotide and / or a vector comprising the polynucleotide), and producing a recombinant antibody polypeptide or fragment thereof by recombinant technology.

[0739] As used herein, "vector" refers to any construct capable of delivering one or more target polynucleotides to a host cell when the vector is introduced into the host cell. "Expression vector" is capable of delivering and expressing one or more target polynucleotides encoding a polypeptide in a host cell into which the expression vector is introduced. Therefore, in order to achieve expression in a vector, the target polynucleotide is operably connected to a regulatory element tail such as a promoter, an enhancer and / or poly-A and positioned in the vector or in the genome of the host cell or near or on both sides of the integration site of the target polynucleotide, so that the target polynucleotide is translated in the host cell into which the expression vector is introduced.

[0740] The vector can be introduced into the host cell by methods known in the art, such as electroporation, chemical transfection (e.g., DEAE-dextran), transformation, transfection, and infection and / or transduction (e.g., using recombinant viruses). Therefore, non-limiting examples of vectors include viral vectors (which can be used to generate recombinant viruses), naked DNA or RNA, plasmids, cosmids, phage vectors, and DNA or RNA expression vectors associated with cationic condensing agents.

[0741] In some embodiments, polynucleotides disclosed herein (e.g., polynucleotides encoding polypeptides disclosed herein) are introduced using a viral expression system (e.g., vaccinia or other poxviruses, retroviruses, or adenoviruses), which may involve the use of non-pathogenic (defective), replication-competent viruses, or may use replication-defective viruses. In the latter case, viral propagation generally occurs only in complementing viral packaging cells. Suitable systems are disclosed, for example, in Fisher-Hoch et al., 1989, Proc. Natl. Acad. Sci. USA 86:317-321; Flexner et al., 1989, Ann. NY Acad Sci 569:86-103; Flexner et al., 1990, Vaccine, 8:17-21; U.S. Pat. Nos. 4,603,112, 4,769,330 and 5,017,487; WO 89 / 01973; U.S. Pat. No. 4,777,127; GB 2,200,651; EP 0,345,242; WO 91 / 02805; Berkner-Biotechniques, 6:616-627, 1988; Rosenfeld et al., 1991, Science, 252:431-434; Kolls et al., 1994, Proc. Natl. Acad. Sci. USA, 91:215-219; Kass-Eisler et al., 1993, Proc. Natl. Acad. Sci. USA, 90:11498-11502; Guzman et al., 1993, Circulation, 88:2838-2848; and Guzman et al., 1993, Cir. Res., 73:1202-1207. Techniques for incorporating DNA into such expression systems are well known to those of ordinary skill in the art. The DNA may also be "naked" as described in Ulmer et al., 1993, Science, 259: 1745-1749 and Cohen, 1993, Science, 259: 1691-1692. Uptake of naked DNA can be increased by coating the DNA onto biodegradable microbeads that can be efficiently transported into cells.

[0742] For expression, the DNA insert comprising a polynucleotide encoding an antibody or polypeptide disclosed herein can be operably linked to an appropriate promoter (e.g., a heterologous promoter), such as the bacteriophage lambda PL promoter, the E. coli lac, trp and tac promoters, the SV40 early and late promoters, and the promoters of the retroviral LTR, to name a few. Other suitable promoters are known to the skilled artisan. The expression construct may further comprise sites for transcription initiation, termination, and a ribosome binding site for translation in the transcribed region. The coding portion of the mature transcript expressed by the construct may include a start codon at the beginning of the polypeptide to be translated and a stop codon (UAA, UGA or UAG) appropriately located at the end of the polypeptide to be translated.

[0743] As noted, the expression vector may contain at least one selectable marker. These markers include dihydrofolate reductase or neomycin resistance for eukaryotic cell culture, and tetracycline or ampicillin resistance genes for culture in Escherichia coli and other bacteria. Representative examples of suitable hosts include, but are not limited to, bacterial cells, such as Escherichia coli, Streptomyces, and Salmonella typhimurium cells; fungal cells, such as yeast cells; insect cells, such as Drosophila S2 and Spodoptera exigua Sf9 cells; animal cells, such as CHO, COS, Bowes melanoma, and HK293 cells; and plant cells. Culture media and conditions suitable for host cells described herein are known in the art.

[0744] Non-limiting vectors for bacteria include pQE70, pQE60, and pQE-9 provided by Qiagen; pBS vectors, phage vectors, Bluescript vectors, pNH8A, pNH16a, pNH18A, pNH46A, available from Stratagene; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5, available from Pharmacia. Non-limiting eukaryotic vectors include pWLNEO, pSV2CAT, pOG44, pXT1, and pSG provided by Stratagene; and pSVK3, pBPV, pMSG, and pSVL, available from Pharmacia. Other suitable vectors will be apparent to the skilled artisan.

[0745] Non-limiting bacterial promoters suitable for use include E. coli lacI and lacZ promoters, T3 and T7 promoters, gpt promoter, lambdaPR and PL promoters, and trp promoter. Suitable eukaryotic promoters include CMV immediate early promoter, HSV thymidine kinase promoter, early and late SV40 promoter, promoters of retroviral LTRs, such as the promoter of Rous sarcoma virus (RSV), and metallothionein promoters, such as mouse metallothionein-I promoter.

[0746] In Saccharomyces cerevisiae, a number of vectors containing constitutive or inducible promoters (e.g., alpha factor, alcohol oxidase, and PGH) are available. For reviews, see Ausubel et al., (1989) Current Protocols in Molecular Biol, John Wiley & Sons, New York, NY and Grant et al., Methods Enzymol., 153:516-544 (1997).

[0747] Transduction of the vector construct into host cells can be accomplished by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic liposome mediated transfection, electroporation, transduction, infection or other methods. These methods are described in many standard laboratory manuals, such as Basic Methods In Molecular Biology (1986) by Davis et al.

[0748] Transcription of DNA encoding the disclosed antibodies of higher eukaryotic organisms can be increased by inserting enhancer sequences into the vector. Enhancers are cis-acting elements of DNA, usually about 10 to 300 bp, that increase the transcriptional activity of a promoter in a given host cell type. Examples of enhancers include the SV40 enhancer, located about 100 to 270 bp on the late side of the replication origin, the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, and adenovirus enhancers.

[0749] In order to secrete the translated protein into the lumen of the endoplasmic reticulum, the periplasmic space or the extracellular environment, appropriate secretion signals can be incorporated into the expressed polypeptide. These signals may be endogenous signals of the polypeptide or heterologous signals.

[0750] Polypeptides (e.g., antibodies) can be expressed in modified forms, such as fusion proteins (e.g., GST fusions) or with histidine tags, and may include not only secretion signals, but also other heterologous functional regions. For example, other amino acid regions, particularly charged amino acids, can be added to the N-terminus of the polypeptide to improve stability and durability in host cells, during purification, or during subsequent processing and storage. In addition, peptide moieties can be added to the polypeptide to facilitate purification. These regions can be removed before the final preparation of the polypeptide. Adding peptide groups to polypeptides to promote secretion or exocytosis, improve stability, and promote purification, etc., is a conventional technique familiar in the art.

[0751] Treatment

[0752] The antibodies or antibodies or antigen-binding fragments thereof disclosed herein can be used for various therapeutic purposes. On the one hand, the disclosure provides a method for treating a subject's cancer, a method for reducing the rate of increase of a subject's tumor volume over time, a method for reducing the risk of metastasis, or a method for reducing the risk of additional metastasis. In some embodiments, treatment can stop, slow down, delay or inhibit the progression of cancer. In some embodiments, treatment can result in a reduction in the quantity, severity and / or duration of one or more symptoms of cancer in a subject.

[0753] In one aspect, the present disclosure introduces methods for administering a therapeutically effective amount of an antibody or antigen-binding fragment thereof disclosed herein to a subject in need (e.g., a subject suffering from or determined or diagnosed to have cancer), such as breast cancer (e.g., triple-negative breast cancer), carcinoid cancer, cervical cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, small cell lung cancer, lymphoma, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, colorectal cancer, gastric cancer, testicular cancer, thyroid cancer, bladder cancer, urethral cancer, or hematological malignancies. In some embodiments, the cancer is unresectable melanoma or metastatic melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bladder cancer, or metastatic hormone-refractory prostate cancer. In some embodiments, the subject suffers from a solid tumor or a blood cancer. In some embodiments, the cancer is squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma (RCC), triple-negative breast cancer (TNBC), or colorectal cancer. In some embodiments, the subject has melanoma, neuroblastoma, prostate cancer, renal cancer, multiple myeloma, or chronic lymphocytic leukemia.

[0754] In some embodiments, the cancer is glioma, thyroid cancer, lung cancer, colorectal cancer, head and neck cancer, gastric cancer, liver cancer, pancreatic cancer, kidney cancer, urothelial cancer, prostate cancer, testicular cancer, breast cancer, cervical cancer, endometrial cancer, ovarian cancer, or melanoma.

[0755] In some embodiments, the combination components and methods disclosed herein can be used to treat patients at risk for cancer.Cancer patients can be identified using various methods known in the art.

[0756] As used herein, "effective amount" refers to an amount or dosage sufficient to achieve a beneficial or desired result, including stopping, slowing, delaying or inhibiting the progression of a disease (e.g., cancer). The effective amount will depend, for example, on the age and weight of the subject to whom the antibody, antigen-binding fragment, antibody encoding polynucleotide, vector constituting the polynucleotide and / or its composition is to be administered, the severity of the symptoms, and the route of administration, and thus administration can be determined on an individual basis.

[0757] The effective amount can be administered in one or more administrations. For example, the effective amount of the antibody or antigen binding fragment is sufficient to improve, stop, stabilize, reverse, inhibit, slow down and / or delay the progression of the patient's cancer, or the amount sufficient to improve, stop, stabilize, reverse, slow down and / or delay cell proliferation (e.g., biopsy cells, any cancer cell described herein, or in vitro cell line (e.g., cancer cell line)). As understood in the art, the effective amount of the antibody or antigen binding fragment may vary, depending on, among other things, the patient's medical history and other factors, such as the type (and / or dosage) of the antibody used.

[0758] The effective amount and schedule of using antibodies, antibody encoding polynucleotides and / or compositions disclosed herein can be determined by experience, and making such a decision is within the skill of the art. It will be understood by those skilled in the art that the dosage that must be applied will depend on, for example, the mammals that will receive the antibodies, the polynucleotides encoding the antibodies and / or the compositions disclosed herein, the routes of administration, the antibodies of a particular type, the polynucleotides encoding the antibodies, the antigen binding fragments and / or the compositions disclosed herein used, and other drugs being administered to the mammals. For guidance on selecting an appropriate dosage for an antibody or antigen binding fragment, please refer to the literature on the therapeutic use of antibodies and antigen binding fragments, for example, Handbook of Monoclonal Antibodies, edited by Ferrone et al., Noges Publications, Park Ridge, New Jersey, 1985, Chapter 22 and pages 303-357; Smith et al., Antibodies in Human Diagnosis and Therapy, edited by Haber et al., Raven Press, New York, 1977, pages 365-389.

[0759] The typical daily dosage of an effective amount of an antibody is 0.01 mg / kg to 100 mg / kg. In some embodiments, the dosage can be less than 100 mg / kg, 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, 0.5 mg / kg or 0.1 mg / kg. In some embodiments, the dosage can be greater than 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, 0.5 mg / kg, 0.1 mg / kg, 0.05 mg / kg or 0.01 mg / kg. In some embodiments, the amount is about 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, 0.9 mg / kg, 0.8 mg / kg, 0.7 mg / kg, 0.6 mg / kg, 0.5 mg / kg, 0.4 mg / kg, 0.3 mg / kg, 0.2 mg / kg, or 0.1 mg / kg.

[0760] In any of the methods described herein, at least one antibody, antigen-binding fragment thereof, or pharmaceutical composition (e.g., any antibody, antigen-binding fragment, or pharmaceutical composition described herein) may be administered to a subject at least once a week (e.g., once a week, twice a week, three times a week, four times a week, once a day, twice a day, or three times a day) optionally with at least one additional therapeutic agent. In some embodiments, at least two different antibodies and / or antigen-binding fragments are administered in the same composition (e.g., a liquid composition). In some embodiments, at least one antibody or antigen-binding fragment and at least one additional therapeutic agent are administered in the same composition (e.g., a liquid composition). In some embodiments, at least one antibody or antigen-binding fragment and at least one additional therapeutic agent are administered in two different compositions (e.g., a liquid composition containing at least one antibody or antigen-binding fragment and a solid oral composition containing at least one additional therapeutic agent). In some embodiments, at least one additional therapeutic agent is administered in the form of a pill, tablet, or capsule. In some embodiments, at least one additional therapeutic agent is administered in a sustained-release oral formulation.

[0761] In some embodiments, one or more additional therapeutic agents may be administered to a subject before or after administration of at least one antibody, antigen-binding antibody fragment, or pharmaceutical composition (e.g., any antibody, antigen-binding antibody fragment, or pharmaceutical composition described herein). In some embodiments, one or more additional therapeutic agents and at least one antibody, antigen-binding antibody fragment, or pharmaceutical composition (e.g., any antibody, antigen-binding antibody fragment, or pharmaceutical composition described herein) are administered to a subject such that the one or more additional therapeutic agents overlap with the biological activity period of the at least one antibody or antigen-binding fragment (e.g., any antibody or antigen-binding fragment described herein) in the subject.

[0762] In some embodiments, the subject can be administered at least one antibody, antigen-binding antibody fragment, or pharmaceutical composition over a longer period of time (e.g., at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, 2 years, 3 years, 4 years, or 5 years). A skilled medical professional can determine the length of the treatment period using any of the methods described herein to diagnose or track the effectiveness of the treatment (e.g., to observe at least one symptom of cancer). As described herein, a skilled medical professional can also change the type and amount (e.g., increase or decrease) of the antibody or antigen-binding antibody fragment (and / or one or more other therapeutic agents) administered to the subject, and can also adjust (e.g., increase or decrease) the dosage or frequency of administration of at least one antibody or antigen-binding antibody fragment (and / or one or more other therapeutic agents) based on an evaluation of the effectiveness of the subject's treatment (e.g., using any of the methods described herein and known in the art).

[0763] In some embodiments, one or more additional therapeutic agents may be administered to a subject. The one or more additional therapeutic agents may be selected from a group of drugs including B-Raf inhibitors, EGFR inhibitors, MEK inhibitors, ERK inhibitors, K-Ras inhibitors, c-Met inhibitors, anaplastic lymphoma kinase (ALK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, Akt inhibitors, mTOR inhibitors, PI3K / mTOR dual inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, and isocitrate dehydrogenase 1 (IDH1) and / or isocitrate dehydrogenase 2 (IDH2) inhibitors.

[0764] In some embodiments, the additional therapeutic agent may include one or more inhibitors selected from the group consisting of HER3 inhibitors, LSD1 inhibitors, MDM2 inhibitors, BCL2 inhibitors, CHK1 inhibitors, activated hedgehog signaling pathway inhibitors, and agents that selectively degrade estrogen receptors.

[0765] In some embodiments, the additional therapeutic agent may include one or more additional therapeutic agents selected from the group consisting of trabectedin, nab-paclitaxel, trabantib, pazopanib, cediranib, palbociclib, everolimus, fluoropyrimidine, IFL, regorafenib, riolysin, alimta, zikadia, sutent, temsirolimus, axitinib, everolimus, sorafenib, Votrient, pazopanib, IMA-901, AGS-003, cabozantinib, vinflunine, Hsp90 inhibitors, Ad-GM-CSF, temazolomide, IL-2, IFNa, vinblastine, salidomide, dacarbazine, cyclophosphamide, lenalidomide, azacytidine, lenalidomide, bortezomib, ampicillin, carfilzomib, pralatrexate, and enzastaurin.

[0766] In some embodiments, the additional therapeutic agents may include one or more additional therapeutic agents selected from the group consisting of adjuvants, TLR agonists, tumor necrosis factor (TNF) α, IL-1, HMGB1, IL-10 antagonists, IL-4 antagonists, IL-13 antagonists, IL-17 antagonists, HVEM antagonists, ICOS agonists, therapeutic agents targeting CX3CL1, therapeutic agents targeting CXCL9, a group of drugs targeting CXCL10, a group of drugs targeting CCL5, LFA-1 agonists, ICAM1 agonists and Selectin agonists.

[0767] In some embodiments, carboplatin, nab-paclitaxel, paclitaxel, cisplatin, pemetrexed, gemcitabine, FOLFOX, or FOLFIRI is administered to the subject.

[0768] In some embodiments, the additional therapeutic agent is an anti-PD1 antibody, an anti-PD-L1 antibody, an anti-LAG-3 antibody, an anti-TIGIT antibody, an anti-BTLA antibody, an anti-CTLA-4 antibody, or an anti-GITR antibody.

[0769] Pharmaceutical compositions and routes of administration

[0770] Also provided herein are pharmaceutical compositions containing at least one (e.g., one, two, three, or four) of the antibodies or antigen-binding fragments described herein. Two or more (e.g., two, three, or four) of any of the antibodies or antigen-binding fragments described herein may be present in any combination in the pharmaceutical composition. The pharmaceutical composition may be formulated in any manner known in the art.

[0771] The pharmaceutical composition is formulated to be compatible with its intended route of administration (e.g., intravenous, intraarterial, intramuscular, intradermal, subcutaneous or intraperitoneal). The composition may include a sterile diluent (e.g., sterile water or saline); fixed oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents, antibacterial or antifungal agents (e.g., benzyl alcohol or methyl paraben, chlorobutanol, phenol, ascorbic acid, thimerosal, etc.), antioxidants (e.g., ascorbic acid or sodium bisulfite), chelating agents (e.g., ethylenediaminetetraacetic acid), buffers (e.g., acetates, citrates or phosphates), and isotonic agents (e.g., sugars, (e.g., glucose), polyols (e.g., mannitol or sorbitol) or salts (e.g., sodium chloride) or any combination thereof. Liposomal suspensions may also be used as pharmaceutically acceptable carriers (e.g., see U.S. Pat. No. 5,434,867). No. 4,522,811). Formulations of the composition can be formulated and packaged in ampoules, disposable syringes, or multiple dose vials. If desired (e.g., injectable formulations), appropriate fluidity can be maintained by using a coating (e.g., lecithin) or a surfactant. Absorption of the antibody or antigen-binding fragment thereof can be prolonged by adding agents that delay absorption (e.g., aluminum monostearate and gelatin). Alternatively, controlled release can be achieved by implants and microencapsulated delivery systems, which can include biodegradable, biocompatible polymers (e.g., ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid; Alza Corporation and Nova Pharmaceutical, Inc.).

[0772] Compositions containing one or more of any of the antibodies or antigen-binding fragments described herein can be formulated for parenteral (e.g., intravenous, intraarterial, intramuscular, intradermal, subcutaneous or intraperitoneal) administration in dosage unit form (i.e., physically discrete units containing predetermined quantities of active compound to facilitate administration and uniformity of dosage).

[0773] The toxicity and therapeutic efficacy of the composition can be determined by standard pharmaceutical procedures in cell culture or experimental animals (e.g., monkeys). For example, the LD50 (the dose lethal to 50% of the population) and the ED50 (the therapeutic dose effective to 50% of the population) can be determined: the therapeutic index is the ratio of LD50:ED50. Drugs with high therapeutic indices are preferred. When a drug exhibits adverse side effects, care should be taken to minimize potential damage (i.e., reduce unwanted side effects). Toxicity and therapeutic efficacy can be determined by other standard pharmaceutical procedures.

[0774] The data obtained from cell culture assays and animal studies can be used to formulate an appropriate dose of any given drug for use in a subject (e.g., human). The therapeutically effective amount of one or more (e.g., one, two, three, or four) antibodies or antigen-binding fragments thereof (e.g., any antibody or antibody fragment described herein) will be a dose that treats the subject's disease (e.g., kills cancer cells), a subject (e.g., a human subject determined to have cancer), or a subject determined to be at risk of illness (e.g., a subject who previously had cancer but is now cured), reduces the severity, frequency, and / or duration of one or more disease symptoms in a subject (e.g., human). The effectiveness and dosage of any antibody or antigen-binding fragment described herein can be determined by a healthcare professional or veterinary professional using methods known in the art, or by observing one or more disease symptoms in a subject (e.g., human). Certain factors may affect the dose and time required to effectively treat a subject (e.g., the severity of the disease or condition, previous treatment, the general health and / or age of the subject, and the presence or absence of other diseases).

[0775] Exemplary dosages include any antibody or antigen-binding fragment in milligram or microgram amounts per kilogram of subject body weight (e.g., about 1 μg / kg to about 500 mg / kg; about 100 μg / kg to about 500 mg / kg; about 100 μg / kg to about 50 mg / kg; about 100 μg / kg to about 50 mg / kg; about 10 μg / kg to about 5 mg / kg; about 10 μg / kg to about 0.5 mg / kg; or about 1 μg / kg to about 50 μg / kg). Although these dosages cover a wide range, one of ordinary skill in the art will appreciate that therapeutic agents, including antibodies and antigen-binding fragments thereof, vary in potency and that effective amounts can be determined by methods known in the art. Typically, a relatively low dose is initially administered, and the attending healthcare professional or veterinary professional (in the case of therapeutic applications) or researcher (when still working in the development phase) can then gradually increase the dose until an appropriate response is obtained. Furthermore, it will be appreciated that the specific dosage level for any particular subject will depend on a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex and diet of the subject, time of administration, route of administration, rate of excretion and half-life of the antibody or antibody fragment in vivo.

[0776] The pharmaceutical composition can be packaged in a container, package or dispenser, together with instructions for administration. The present disclosure also provides methods for making antibodies or antigen-binding fragments thereof for the various uses described herein.

[0777] Example

[0778] The present invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0779] Example 1: Generation of anti-MICA / B antibodies

[0780] This example describes a strategy for generating anti-MICA / B antibodies. Two immunization strategies were used to generate a panel of antibodies that selectively bind to human and cynomolgus (cyno) monkey MICA / B antigens in BALB / c mice. Due to genetic polymorphisms in the human population, the choice of DNA or protein antigens maximizes coverage in the human population (Tables 1 and 2). In these experiments, DNA immunization was followed by protein immunization. For DNA immunization, DNA encoding human MICA*002, MICA*004, MICA*008, MICA*009, and MICB*05 MICA / B and cMICA (cynomolgus, cynomolgus) MICA α3 domain and fused mouse IgG2a Fc region (exact sequence is in Fig.33 After this step, a group of human MICA-ECD (extracellular domain) human Fc fusion protein (Sino Biological, Catalog #: 12302-H02H), human MICA-ECD-HIS (Sino Biological, Catalog #: HPLC-12302-H08H), human MICB-ECD-HIS (Sino Biological, Catalog #: 10759-H08H) and recombinant human MICA / B-α3 mouse Fc fusion protein (human MICA*002, 004, 008 and MICB*05) (sequences in Fig.34 The protein immunogen was resuspended in PBS with RIBI adjuvant and injected intraperitoneally.

[0781] Table 1

[0782]

[0783]

[0784] a. The polymorphic residue occurs in MICA*002, MICA*004, MICA*008, or MICA*009, so the antibody is likely to recognize MICA*010.

[0785] Table 2

[0786]

[0787] A: The unique residues are located at the end of the α3 domain and are therefore unlikely to affect antibody recognition.

[0788] Mice with serum titers that meet the requirements are euthanized. Spleen and bone marrow are collected. Splenocytes or B plasma cells are isolated using a mouse CD138+ plasma cell isolation kit (Miltenyi Biotec Inc., catalog #: 130-092-530) and processed separately to isolate single cells. mRNA is isolated from single cells. Nucleic acid sequences encoding the heavy chain variable region (VH) and light chain variable region (VL) are amplified by RT-PCR. PCR amplification products encoding MICA / B specific single chain variable fragments (scFV) are constructed into yeast libraries.

[0789] The two yeast libraries were expressed by Miltenyi MidiMACS using biotinylated immunogens. TM Four rounds of selection were performed using the system and fluorescence activated cell sorting (FACS) using biotinylated antigen or native protein or whole cell screening. These methods are described in reports such as Chao et al., Isolation and engineering of human antibodies using yeast surface display technology, Nat Protoc. 2006; 1(2): 755-68, which is incorporated herein by reference in its entirety. Briefly, the MiltenyiMidiMACS TM Systematic separation of libraries. The isolated yeast was sorted by two rounds of sorting using a FACSARIAII sorter (BD Biosciences) using biotinylated MICA and MICB-α3-mFc fusion antigens. The sorted MICA / MICB-binding yeast cells were incubated with CHO cells expressing MICA / B. After washing away unbound cells, the CHO cells bound to yeast were treated, resuspended in yeast growth medium, and inoculated on standard yeast growth medium to form single yeast colonies.

[0790] Single yeast colonies were picked and inoculated into 96-well plates containing yeast growth medium to produce scFv. Yeast culture supernatants were harvested and analyzed using ELISA and Screening for protein binding. Nucleic acid sequences encoding the heavy chain variable region (VH) and light chain variable region (VL) of MICA / B specific antibodies were amplified by RT-PCR. Nucleic acid sequences encoding candidate VH and VL were obtained by sequencing. Afterwards, the sequences encoding VH and VL were cloned into a vector expressing human IgG1 (containing mouse variable regions and human constant regions) and expressed in HEK or CHO cells. The expressed antibodies were further screened and characterized. Some of these antibodies, such as Fig.23 Their CDR sequences are shown in Figures 24A-24E.

[0791] In order to humanize the above antibodies, two methods were used. First, humanization templates were designed on a computer using MOE (Molecular Operating Environment) software; second, humanization templates were designed by grafting 6 CDRs onto human germline VH and VL frameworks (FRs) and keeping a limited number of mouse FR residues near the CDRs. The selection of human germline was determined based on homology with mice. CDRs were defined based on one or a combination of numbering schemes known in the art. Humanization templates were synthesized. DNA fragments of humanization templates were amplified and constructed into yeast for display.

[0792] To improve affinity and control challenges for industrial production, mutant libraries are constructed by mutagenesis in CDRs using MOE design or by random mutagenesis via error-prone PCR. The designed library is synthesized. DNA fragments including the library sequences are amplified and constructed into yeast for display. Yeast screening is performed in a similar manner to the selection process described above, except that a more stringent threshold is used to select for higher binding affinity.

[0793] A selected number of humanized and optimized candidates with desirable properties are further engineered to reduce production challenges through user-defined mutation points and / or to be deimmunized through regression germline mutations on the framework, and to maximize retention of desirable properties. The sequences of humanized and / or optimized antibodies are shown in Figures 25, 26, and 27. Their CDR sequences are listed in Figures 28, 29, and 30A-30E.

[0794] Example 2: Biochemical Characterization of Anti-MICA / B Antibodies

[0795] The binding kinetics of the antibodies identified in Example 1 were determined using SPR imaging system (Carterra USA) was used for measurement. Specifically, anti-MICA / B antibodies were captured by anti-human Fc (SouthernBiotech, Cat#: 2047-01) immobilized on HC200M-polycarboxylate chips (CarterraBio, Cat#: HC200M) or by amine coupling on HC30M-polycarboxylate chips (Carterra Bio, Cat#: HC30M). Next, as Fig.35As shown, the corresponding monomeric antigen MICA002-ECD-HISAvi (BioIntron, project code #: B662201), MICA004-ECD-HISAvi (BioIntron, project code #: B662202), MICA008-ECD-HISAvi (SinoBio, Cat #: 12302-H08H1) or MICB005-ECD-HISAvi (SinoBio Cat #: 10759-H08H) was injected for 2-3 minutes in a flow buffer at 25°C. The dissociation kinetics were monitored for about 10 minutes. The chip surface was regenerated with 10mM glycine hydrochloride (pH 1.7) between binding cycles. The binding kinetics were analyzed using the software provided by the manufacturer.

[0796] The binding kinetics of the antibodies were also measured using the GatorPrime BLI (biofilm interferometry) system (Gator Bio, USA). Specifically, the anti-MICA / B antibodies were loaded via HFC (Anti-hIgGFc, Gator Bio, Cat#: 160003) probes. Next, the probes were incubated with the corresponding monomeric antigens MICA002-ECD-HISAvi (BioIntron, project code #: B662201), MICA004-ECD-HISAvi (BioIntron project code #: B662202), MICA008-ECD-HISAvi (BioIntron project code #: B21016107), MICB005-ECD-HISAvi (BioIntron project code #: B21016109), MICA009Avi (BioIntron project code #: B21016108), as described above. Fig.35 As indicated, or cynoMICA (cynoMICA) (SinoBio, Cat#: 90924-C08H) was incubated in K buffer (Gator Bio, Cat#: 120011) at 25°C for 3-4 minutes. The dissociation kinetics were monitored for approximately 10 minutes. The probe was regenerated with regeneration buffer (Gator Bio, Cat#: 120012) between binding cycles. The binding kinetics were analyzed using the software provided by the manufacturer.

[0797] Depend on The binding affinity of the chimeric antibody measured by the system is as Figure 1A As shown, the binding affinities of humanized and optimized antibodies from lineages #38 and #39 are shown in Figure 1B As shown. The binding affinities of humanized antibody #36 variant and D2M001-010 variant measured by the system, as Figure 1CTheir sequences are listed in Figures 26-27.

[0798] These data demonstrate that the optimized and humanized #36 lineage antibodies and D2M001-010 variants exhibit at least low single-digit nM affinities to all major human MICA / B alleles as well as cynomolgus monkey MICA. Recurrent germline mutations in the framework regions did not significantly alter binding affinity.

[0799] Figure 1C The binding profiles of the in-house optimized and humanized anti-MICA / B antibodies and the reference anti-MICAB antibodies are summarized. Figure 1C As shown, the lead candidate D2M001-209 exhibited a broad binding profile compared to CM33322 (LC: SEQ ID NO: 1444, HC: SEQ ID NO: 1445), 6E1.1.12 (LC: SEQ ID NO: 1417, HC: SEQ ID NO: 1418), and B10G5 (LC: SEQ ID NO: 1423, HC: SEQ ID NO: 1424). Binding of CM33322 to all tested alleles of MICA and MICB could not be detected in our experiments. 6E1.1.12 and B10G5 appeared to bind to MICB005, MICA004, and MICA008, but not to MICA002 and cynoMICA.

[0800] Among all the reference antibodies tested, 1D5 (LC: SEQ ID NO: 1419, HC: SEQ ID NO: 1420) showed good binding affinity to all the allotypes tested. However, 1D5 is still a mouse anti-human MICA / B antibody and there is no information indicating that it has been successfully humanized. Considering its performance among the reference antibodies, it was selected as the reference benchmark. Figure 1C As shown, D2M001-209 displayed comparable binding affinity characteristics relative to 1D5.

[0801] 3F9 (LC: SEQ ID NO: 1415, HC: SEQ ID NO: 1416) is speculated to represent the only anti-MICA / B (CLN-619) currently being evaluated in clinical trials. Therefore, 3F9 was selected as the reference benchmark. Figure 1C As shown, D2M001-209 exhibited better binding affinity characteristics than the benchmark 3F9 for all tested allotypes except MICA008.

[0802] D2M001-209 has the best binding affinity for cynoMIC protein compared to all reference anti-MICA / B antibodies. For example, 3F9 and 13A9 (LC: SEQ ID NO: 1421, HC: SEQ ID NO: 1422) have double-digit nM affinities for cynomolgus monkey MIC, an order of magnitude lower than the affinity of D2M001-209. More importantly, the difference in binding affinity between human and monkey orthologs of D2M001-209 is minimal compared to the differences among all reference antibodies. For example, the difference is within 5-fold. Comparability of binding affinity between human and monkey orthologs is important for immunotherapeutic antibody drugs in drug discovery and development because it can determine whether non-clinical studies in non-human primates are relevant.

[0803] Overall, D2M001-209 exhibited superior binding characteristics to the reference anti-MICA / B antibodies. In particular, the binding kinetics data well distinguished D2M001-209 from all reference anti-MICAB antibodies.

[0804] Example 3: Cell-based characterization assay of anti-MICA / B antibodies binding to MICA / B variants

[0805] Cell-based antibody binding affinity was measured by incubating serial dilutions of anti-MICA / B antibodies, reference antibodies, or isotype control antibodies (IgG1) with CHO cells engineered to overexpress human MICA002, MICA004, MICA008, or MICB005 (CHO-MICA002, CHO-MICA004, CHO-MICA008, and CHO-MICB005, respectively) or Hela cells known to be homozygous for the MICA008 allele. 50 μL of CHO-MICA, CHO-MICB, or Hela cells (4.0 × 10 4 Cells were added to each well of a 96-well U-bottom microplate. Then, 50 μL of serially diluted anti-MICA / B antibodies were added to the wells to a final concentration of 30 μg / mL, 10 μg / mL, 3.33 μg / mL, 1.11 μg / mL, 0.370 μg / mL, 0.123 μg / mL, 0.041 μg / mL, 0.0137 μg / mL, 0.0046 μg / mL, 0.0015 μg / mL, or 0 μg / mL at room temperature. After incubation for 30 minutes, the plate was centrifuged and the cells were washed three times with PBS. 50 μL of Alexa Fluor 500 μL was added to each well. 647AffiniPure F(ab')2 goat anti-human IgG fragment, Fcγ fragment specific (Jackson ImmunoResearch Laboratories Inc., Catalog #: 109-606-098). After shaking for 30 minutes at room temperature, the cells were washed twice with PBS. Flow cytometry (Attune TM CytPix TM , ThermoFisher) to detect and quantify fluorescent signals in living cell populations (negative for the viability dye PI).

[0806] like Figure 2A-2E As shown, chimeric anti-MICA / B antibodies and reference antibodies (1D5, 3F9.13A9 and 6E1.1.12) had an effect on CHO cells ( Figures 2A-2D ) and HeLa cells ( Figure 2E All four MICA / B alleles expressed on ) showed strong binding ability, while the isotype control antibody IgG1 did not. EC50 values ​​are shown in Figure 2F As shown, and calculated by GraphPad Prism software based on the nonlinear fitting curve.

[0807] like Figure 3A-3R As shown in Figure 2, humanized anti-MICA / B antibodies and reference antibodies (1D5 and 3F9) showed strong binding affinity to all four MICA / B alleles expressed on CHO cells and Hela cells, while the isotype control antibody IgG1 did not. EC50 values ​​are shown in Figure 2. Figure 3S-3U Shown is calculated by GraphPad Prism software based on nonlinear fitting curves. The humanized and optimized #36 variant "h36B3" showed high binding affinity to cells expressing MICA / B, comparable to the reference mouse antibody 1D5. In addition, H36B3 and D2M001-209 bind to cells expressing MICA / B significantly better than the reference antibody 3F9, especially to cells expressing MICA008 or MICB005. The superior binding to MICB is important and well distinguishes D2M001-209 from 3F9, as shown in Example 6, which may play a more important role in NKG2D biology.

[0808] Example 4: Anti-MICA / B antibodies inhibit shedding of MICA / B polypeptides in tumor cell lines

[0809] It is speculated that anti-MICA / B antibodies inhibit the shedding of MICA / B polypeptides possibly by binding to MICA and MICBα3 domains, which triggers the initiation of cell surface shedding. To investigate the ability of anti-MICA / B antibodies to inhibit the shedding of MICA / B polypeptides from cells, shedding assays were performed using serial dilutions of anti-MICA / B antibodies, reference antibodies (1D5 and 3F9) or isotype control antibodies (IgG1) and engineered C1R cells overexpressing four human MICA / B variants (C1R-MICA002; C1R-MICA004; C1R-MICA008; or C1R-MICB005) or Hela cells expressing the MICA008 variant. The concentration of shed MICA / B polypeptides in the growth medium was measured by homemade and commercially available sandwich ELISA kits. The surface expression of MICA / B on cells was detected by flow cytometry using PE anti-MICA / B mAb 6D4 (BioLegend, Cat#: 320906). Anti-MICA / B 6D4 was used to detect total MICA / B as well as shed MICA / B because it binds outside the MICA / B α3 domain and does not inhibit MICA / B shedding.

[0810] 50 μL of C1R-MICA / B or Hela cells (approximately 1.0×10 5 cells) or CHO-MICA002 cells (about 5×10 4cells). 50 μL of serially diluted antibodies were added to a final concentration of 30 μg / mL, 10 μg / mL, 3.33 μg / mL, 1.11 μg / mL, 0.370 μg / mL, 0.123 μg / mL, 0.041 μg / mL, 0.0137 μg / mL, 0.0046 μg / mL, 0.0015 μg / mL, and 0 μg / mL. After incubation for 24 hours at room temperature, the plate was centrifuged and 60 μL of the medium was sampled to measure the concentration of soluble MICA or / and MICB, respectively, by ELISA. The shed MICA / B concentration was measured by sandwich ELISA assay: 100 μL of 2 μg / mL AMO1 anti-human MICA antibody (BAMOMAB, Cat. #: BOB-AMO1-500) was added to a 96-well assay plate and coated overnight. The plates were then washed twice with PBS and blocked with 300 μL 1% BSA for 1 hour at room temperature. After two more PBS washes, 100 μL dilution medium was added and the plates were incubated for 2 hours at room temperature. Next, the plates were washed twice with PBS, 100 μL 1 μg / mL biotinylated anti-MICA / B 6D4 (BioLegend, Catalog #: 320904) was added, and incubated for 90 minutes at room temperature. 100 μL 1:100 diluted streptavidin-HRP solution (R&D Systems, Catalog #: DY998) was added and incubated for 1 hour at room temperature. After washing, the microplates were developed with TMB (Surmodics, Catalog #: TMBS-1000-01) and stopped with BioFX 450 nM liquid stop solution (Surmodics, Catalog #: LSTP-1000-01). TM OD 450 was measured in a Lux plate reader (ThermoFisher Scientific, Cat#: VLBL00D1, SN#: 3020-80467), and the concentration of shed MICA polypeptide was detected using MICA018-ECD-His synthetic protein (Sino Biological, Cat#: HPLC-12302-H08H) as a standard.

[0811] The concentration of shed MICB was measured by human MICB sandwich ELISA kit (R&D Systems, Catalog #: DY1599). The remaining cells in the plate were then washed once with PBS, and 100 μL of diluted phycoerythrin (PE)-conjugated anti-MICA / B6D4 (BioLegend, Catalog #: 320906) was added. After mixing and incubation at room temperature for 30 minutes, the plate was washed twice with PBS. The plate was analyzed by flow cytometry (Attune TM CytPix TM , ThermoFisher) was used to measure PE signal within live cell populations (negative for the viability dye DAPI).

[0812] like Figures 4A-4E As shown, the results of chimeric anti-MICA / B treatment of CHO-MICA002, C1R-MICA / B or Hela cells are described. Due to the treatment with anti-MICA / B antibody, the shed MICA / B polypeptide in the cell culture medium was significantly reduced. In addition, as Figures 5A-5E As shown in Figure 2, the surface expression of MICA / B polypeptides in C1R-MICA / B cells or Hela cells was significantly increased, indicating that the chimeric anti-MICA / B antibody and the reference anti-MICA / B antibody showed strong inhibition of the shedding of all four MICA / B variants expressed on C1R cells and Hela cells, while the isotype control antibody IgG1 did not. The maximum shedding inhibition and IC50 value of MICA / B shedding were calculated by GraphPadPrism software according to the nonlinear fitting curve (as shown in Figure 2). Figure 4F The maximum change in surface MICA / B expression and EC50 (as shown) Fig. 5F The results are shown in Figure 3 and were calculated by GraphPad Prism software based on nonlinear fitting curves.

[0813] like Figures 6A-6X As shown in Figure 2, after C1R-MICA / B was treated with humanized anti-MICA / B antibody, the MICA / B polypeptide shed in the cell culture medium was significantly reduced. Figures 7A-7P As shown in Figure 3, the surface expression of MICA / B alleles was significantly increased in C1R-MICA / B cells, indicating that the humanized anti-MICA / B antibody and the reference antibodies (1D5 and 3F9) showed strong inhibition of shedding of all four MICA / B alleles expressed on C1R cells, while the isotype control antibody IgG1 did not. The maximum shedding inhibition and IC50 values ​​of shedding MICA / B were calculated by GraphPadPrism software based on the nonlinear fitting curve (Figure 3). Figure 6Q-6T The maximum change and EC50 value of surface MICA / B expression (as shown) Figure 7Q-7T The results are shown in Table 1. The results are calculated by GraphPad Prism software based on the nonlinear fitting curve.

[0814] like Figure 6U-6X As shown, D2M001-209 was further compared with reference anti-MICA / B for their ability to inhibit MICA / B polypeptide shedding and stabilize MICA / B surface expression. D2M001-209 showed an ability to inhibit MICA / B shedding comparable to 1D5 and was more potent than 3F9 in terms of IC50 and maximum effect.

[0815] like Figure 7U-7XAs shown, D2M001-209 was further compared with the reference anti-MICA / B in terms of its ability to inhibit MICA / B polypeptide shedding and stabilize MICA / B surface expression. D2M001-209 showed superior ability to stabilize surface MICA / B over 1D5 and 3F9 in terms of EC50 and / or percentage increase.

[0816] Example 5: Anti-MICA / B antibodies capture MICA / B polypeptides shed from the cell surface

[0817] As discussed in further detail below, the anti-MICA / B antibodies identified in Example 1 not only inhibit MICA / B polypeptide shedding from cells, but also bind to shed MICA / B polypeptides released from tumor cells. To investigate the binding affinity of the anti-MICA / B antibodies to shed MICA / B polypeptides, shed MICA / B polypeptides were concentrated from the conditioned medium of CHO-MICA002, CHO-MICA004, CHO-MICA008, and CHO-MICB005 using a Spin-X concentrator (Corning, Cat#: 431489). Each well of a 96-well plate was coated overnight with 100 μL of 5 μg / mL anti-hFc (Jackson ImmunoResearch, Cat#: 109-005-098), washed twice with PBS, and blocked with 1% BSA for 1 hour at room temperature. After washing with PBS twice more, the anti-MICA / B antibody, reference antibody (1D5, 13A9, 6E1.1.12 and 3F9) or isotype control antibody (IgG1) diluted in series were added to the plate wells, with final concentrations of 15 μg / mL, 5 μg / mL, 1.667 μg / mL, 0.556 μg / mL, 0.185 μg / mL, 0.062 μg / mL, 0.021 μg / mL, 0.007 μg / mL and 0 μg / mL, and incubated at room temperature for 30 minutes. The plate was washed twice with PBS, and 100 μL of shed MICA / B polypeptide at a concentration of 80 ng / mL was added to each well of the plate and incubated at room temperature for 2 hours. After two more PBS washes, 100 μL of 1 μg / mL biotinylated anti-MICA / B 6D4 (BioLegend, Catalog #: 320904) was added to each well of the plate and incubated for 1.5 hours at room temperature. 100 μL of streptavidin-HRP solution (R&D Systems, Catalog #: DY998, 200×) was added and incubated for 1 hour at room temperature. After washing, the microplate was developed with TMB and stopped with BioFX 450 nM liquid stop solution. Varioskan TM OD 450 was measured using a Lux plate reader.

[0818] like Figures 8A-8EAs shown, the chimeric anti-MICA / B antibody and the reference antibody showed strong binding affinity to all four shed MICA / B polypeptide variants released from CHO cells overexpressing MICA / B alleles, while the isotype control antibody IgG1 did not. The maximum binding signal (OD 450) and EC50 value (as shown in Figure 5) of shed MICA / B binding were calculated by GraphPadPrism software based on the nonlinear fitting curve. Fig. 8E ).

[0819] like Figures 9A-9H and Figure 9K-9N As shown, humanized anti-MICA / B antibodies and reference antibodies (1D5, 13A9, and 3F9) exhibited strong binding affinity to all four shed MICA / B variants released from CHO cells overexpressing MICA / B alleles, whereas the isotype control antibody IgG1 did not. Figures 9I-9J and Fig.9O The maximum binding signal (OD 450) and EC50 values ​​of shed MICA / B binding shown in were calculated based on nonlinear fitting curves using GraphPad Prism software.

[0820] like Figure 9K-9N As shown in Example 6, D2M001-209 exhibits a strong ability to capture soluble MICA / B, comparable to 1D5 and more effective than 3F9 for all tested alleles. In particular, D2M001-209 can not only capture MICB005 more effectively than 3F9, but also capture more MICB than 3F9. Even when reaching the plateau, 3F9 can only capture less than half of MICB compared to D2M001-209. The superior ability to capture soluble MICB is important and well distinguishes D2M001-209 from 3F9, as sho...

Claims

1. An antibody or antigen-binding fragment thereof that binds to MICA (major histocompatibility complex class I chain-associated A) and / or MICB (major histocompatibility complex class I chain-associated B), comprising: A heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, wherein VH the CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR1 amino acid sequence, the VH CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR2 amino acid sequence, and the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR3 amino acid sequence; and a light chain variable region (VL) comprising CDRs 1, 2, and 3, wherein the VL CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR1 amino acid sequence, the VL CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR2 amino acid sequence, and the VL CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR3 amino acid sequence, Wherein, the selected VH CDRs 1, 2 and 3 amino acid sequences and the selected VL CDRS1, 2 and 3 amino acid sequences are selected from the VH CDRs 1, 2, 3 and VLCDRS1, 2, 3 sequences listed in Figures 24A, 24B, 24C, 24D, 24E, 28, 29, 30A, 30B, 30C, 30D and 30E.

2. The antibody or antigen-binding fragment thereof according to claim 1, wherein the selected VH CDRs 1, 2 and 3 amino acid sequences and the selected VL CDRs 1, 2 and 3 amino acid sequences are one of the following: (1) The selected amino acid sequences of VH CDRs 1, 2, and 3 are listed in SEQ ID NOs: 3, 4, and 5, respectively, and the selected amino acid sequences of VLCDRS 1, 2, and 3 are listed in SEQ ID NOs: 6, 7, and 8, respectively; (2) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 11, 12, and 13, respectively, and the selected VLCDRS 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 14, 15, and 16, respectively; (3) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 19, 20, and 21, respectively, and the selected VLCDRS 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 22, 23, and 24, respectively; (4) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 27, 28, and 29, respectively, and the selected VLCDRS 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 30, 31, and 32, respectively; (5) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 35, 36, and 37, respectively, and the selected VLCDRS 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 38, 39, and 40, respectively; (6) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 43, 44, and 45, respectively, and the selected VLCDRS 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 46, 47, and 48, respectively; (7) The selected amino acid sequences of VH CDRs 1, 2, and 3 are represented by SEQ ID NOs: 51, 52, and 53, respectively, and the selected amino acid sequences of VLCDRS 1, 2, and 3 are represented by SEQ ID NOs: 54, 55, and 56, respectively. Show; (8) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 59, 60, and 61, respectively, and the selected VLCDRS 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 62, 63, and 64, respectively; (9) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 67, 68, and 69, respectively, and the selected VLCDRS 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 70, 71, and 72, respectively; (10) The selected amino acid sequences of VH CDRs 1, 2, and 3 are listed in SEQ ID NOs: 75, 76, and 77, respectively, and the selected amino acid sequences of VLCDRS 1, 2, and 3 are listed in SEQ ID NOs: 78, 79, 80 listed; (11) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 83, 84, and 85, respectively, and the selected VLCDRS 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 86, 87, and 88, respectively; (12) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 91, 92, and 93, respectively, and the selected VLCDRS 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 94, 95, and 96, respectively; (13) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 99, 100, and 101, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 102, 103, and 104, respectively; (14) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 107, 108, and 109, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 110, 111, and 112, respectively; (15) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 115, 116, and 117, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 118, 119, and 120, respectively; (16) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 123, 124, and 125, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 126, 127, and 128, respectively; (17) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 131, 132, and 133, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 134, 135, and 136, respectively; (18) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 139, 140, and 141, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 142, 143, and 144, respectively; (19) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 147, 148, and 149, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 150, 151, and 152, respectively; (20) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 155, 156, and 157, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 158, 159, and 160, respectively; (21) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 815, 816, and 817, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 818, 819, and 820, respectively; (22) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 821, 822, and 823, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 824, 825, and 826, respectively; (23) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 827, 828, and 829, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 830, 831, and 832, respectively; (24) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 833, 834, and 835, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 836, 837, and 838, respectively; (25) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 839, 840, and 841, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 842, 843, and 844, respectively; (26) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 845, 846, and 847, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 848, 849, and 850, respectively; (27) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 851, 852, and 853, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 854, 855, and 856, respectively; (28) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 857, 858, and 859, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 860, 861, and 862, respectively; (29) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 863, 864, and 865, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 866, 867, and 868, respectively; (30) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 869, 870, and 871, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 872, 873, and 874, respectively; (31) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 875, 876, and 877, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 878, 879, and 880, respectively; (32) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 881, 882, and 883, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 884, 885, and 886, respectively; (33) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 887, 888, and 889, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 890, 891, and 892, respectively; (34) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 893, 894, and 895, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 896, 897, and 898, respectively; (35) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 899, 900, and 901, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 902, 903, and 904, respectively; (36) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 905, 906, and 907, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 908, 909, and 910, respectively; (37) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 911, 912, and 913, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 914, 915, and 916, respectively; (38) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 917, 918, and 919, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 920, 921, and 922, respectively; (39) The selected amino acid sequences of VH CDRs 1, 2, and 3 are listed in SEQ ID NOs: 923, 924, and 925, respectively. The selected amino acid sequences of VL CDRs 1, 2, and 3 are listed in SEQ ID NOs: 926, listed in 927, 928; and (40) The selected amino acid sequences of VH CDRs 1, 2, and 3 are listed in SEQ ID NOs: 929, 930, and 931, respectively. The selected amino acid sequences of VL CDRs 1, 2, and 3 are listed in SEQ ID NOs: 932, Listed in 933 and 934.

3. The antibody or antigen-binding fragment thereof according to claim 1 or 2, wherein the CDRs are determined by the IMGT definition method.

4. The antibody or antigen-binding fragment thereof according to claim 1, wherein the selected VH CDRs 1, 2 and 3 amino acid sequences and the selected VL CDRs 1, 2 and 3 amino acid sequences are one of the following: (1) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 161, 162, and 163, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 164, 165, and 166, respectively; (2) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 167, 168, and 169, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 170, 171, and 172, respectively; (3) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 173, 174, and 175, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 176, 177, and 178, respectively; (4) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 179, 180, and 181, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 182, 183, and 184, respectively; (5) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 185, 186, and 187, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 188, 189, and 190, respectively; (6) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 191, 192, and 193, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 194, 195, and 196, respectively; (7) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 197, 198, and 199, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 200, 201, and 202, respectively; (8) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 203, 204, and 205, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOz: 206, 207, and 208, respectively; (9) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 209, 210, and 211, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 212, listed in 213 and 214; (10) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 215, 216, and 217, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 218, 219, and 220, respectively; (11) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 221, 222, and 223, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 224, 225, and 226, respectively; (12) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 227, 228, and 229, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 230, 231, and 232, respectively; (13) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 233, 234, and 235, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 236, 237, and 238, respectively; (14) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 239, 240, and 241, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 242, 243, and 244, respectively; (15) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 245, 246, and 247, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 248, 249, and 250, respectively; (16) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 251, 252, and 253, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 254, 255, and 256, respectively; (17) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 257, 258, and 259, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 260, 261, and 262, respectively; (18) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 263, 264, and 265, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 266, 267, and 268, respectively; (19) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 269, 270, and 271, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 272, 273, and 274, respectively; (20) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 275, 276, and 277, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 278, 279, and 280, respectively; (21) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 935, 936, and 937, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 938, 939, and 940, respectively; (22) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 941, 942, and 943, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 944, 945, and 946, respectively; (23) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 947, 948, and 949, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 950, 951, and 952, respectively; (24) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 953, 954, and 955, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 956, 957, and 958, respectively; (25) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 959, 960, and 961, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 962, 963, and 964, respectively; (26) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 965, 966, and 967, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 968, 969, and 970, respectively; (27) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 971, 972, and 973, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 974, 975, and 976, respectively; (28) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 977, 978, and 979, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 980, 981, and 982, respectively; (29) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 983, 984, and 985, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 986, 987, and 988, respectively; (30) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 989, 990, and 991, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 992, 993, and 994, respectively; (31) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 995, 996, and 997, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 998, 999, and 1000, respectively; (32) The selected VH CDRs 1, 2, and 3 amino acid sequences are in SEQ ID NOs: 1001, 1002, 1003, the selected VL CDRS1, 2, 3 amino acid sequences are respectively in SEQ ID NOs: Listed in 1004, 1005, 1006; (33) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1007, 1008, and 1009, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1010, 1011, and 1012, respectively; (34) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1013, 1014, and 1015, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1016, 1017, and 1018, respectively; (35) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1019, 1020, and 1021, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1022, 1023, and 1024, respectively; (36) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1025, 1026, and 1027, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1028, 1029, and 1030, respectively; (37) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1031, 1032, and 1033, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1034, 1035, and 1036, respectively; (38) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1037, 1038, and 1039, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1040, 1041, and 1042, respectively; (39) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1043, 1044, and 1045, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1046, 1047, and 1048, respectively; and (40) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1049, 1050, and 1051, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1052, 1053, and 1054, respectively.

5. The antibody or antigen-binding fragment thereof according to claim 1 or 4, wherein the CDRs are determined by the Kabat definition.

6. The antibody or antigen-binding fragment thereof according to claim 1, wherein the selected VH CDRs 1, 2 and 3 amino acid sequences and the selected VL CDRs 1, 2 and 3 amino acid sequences are one of the following: (1) The selected amino acid sequences of VH CDRs 1, 2, and 3 are listed in SEQ ID NOs: 281, 282, and 283, respectively, and the selected amino acid sequences of VL CDRs 1, 2, and 3 are listed in SEQ ID NOs: 284, listed in 285 and 286; (2) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 287, 288, and 289, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 290, listed in 291 and 292; (3) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 293, 294, and 295, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 296, listed in 297 and 298; (4) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 299, 300, and 301, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 302, Listed in 303 and 304; (5) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 305, 306, and 307, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 308, listed in 309 and 310; (6) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 311, 312, and 313, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 314, Listed in 315 and 316; (7) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 317, 318, and 319, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 320, listed in 321 and 322; (8) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 323, 324, and 325, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 326, listed in 327 and 328; (9) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 329, 330, and 331, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 332, listed in 333, 334; (10) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 335, 336, and 337, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 338, 339, and 340, respectively; (11) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 341, 342, and 343, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 344, 345, and 346, respectively; (12) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 347, 348, and 349, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 350, 351, and 352, respectively; (13) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 353, 354, and 355, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 356, 357, and 358, respectively; (14) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 359, 360, and 361, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 362, 363, and 364, respectively; (15) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 365, 366, and 367, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 368, 369, and 370, respectively; (16) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 371, 372, and 373, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 374, 375, and 376, respectively; (17) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 377, 378, and 379, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 380, 381, and 382, ​​respectively; (18) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 383, 384, and 385, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 386, 387, and 388, respectively; (19) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 389, 390, and 391, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 392, 393, and 394, respectively; (20) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 395, 396, and 397, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 398, 399, and 400, respectively; (21) The selected VH CDRs 1, 2, and 3 amino acid sequences are in SEQ ID NOs: 1055, 1056, 1057, the selected VL CDRS1, 2, 3 amino acid sequences are respectively in SEQ ID NOs: listed in 1058, 1059, 1060; (22) The selected VH CDRs 1, 2, and 3 amino acid sequences are in SEQ ID NOs: 1061, 1062, 1063, the selected VL CDRS1, 2, 3 amino acid sequences are respectively in SEQ ID NOs: Listed in 1064, 1065, 1066; (23) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1067, 1068, and 1069, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1070, 1071, and 1072, respectively; (24) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1073, 1074, and 1075, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1076, 1077, and 1078, respectively; (25) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1079, 1080, and 1081, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1082, 1083, and 1084, respectively; (26) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1085, 1086, and 1087, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1088, 1089, and 1090, respectively; (27) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1091, 1092, and 1093, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1094, 1095, and 1096, respectively; (28) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1097, 1098, and 1099, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1100, 1101, and 1102, respectively; (29) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1103, 1104, and 1105, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1106, 1107, and 1108, respectively; (30) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1109, 1110, and 1111, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1112, 1113, and 1114, respectively; (31) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1115, 1116, and 1117, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1118, 1119, and 1120, respectively; (32) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1121, 1122, and 1123, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1124, 1125, and 1126, respectively; (33) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1127, 1128, and 1129, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1130, 1131, and 1132, respectively; (34) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1133, 1134, and 1135, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1136, 1137, and 1138, respectively; (35) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1139, 1140, and 1141, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1142, 1143, and 1144, respectively; (36) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1145, 1146, and 1147, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1148, 1149, and 1150, respectively; (37) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1151, 1152, and 1153, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1154, 1155, and 1156, respectively; (38) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1157, 1158, and 1159, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1160, 1161, and 1162, respectively; (39) The selected VH CDRs 1, 2, and 3 amino acid sequences are in SEQ ID NOs: 1163, 1164, 1165, the selected VL CDRS1, 2, 3 amino acid sequences are respectively in SEQ ID NOs: 1166, 1167, 1168; and (40) The selected VH CDRs 1, 2, and 3 amino acid sequences are in SEQ ID NOs: 1169, 1170, 1171, the selected VL CDRS1, 2, 3 amino acid sequences are respectively in SEQ ID NOs: Listed in 1172, 1173, and 1174.

7. The antibody or antigen-binding fragment thereof according to claim 1 or 6, wherein the CDRs are determined by the Chothia definition.

8. The antibody or antigen-binding fragment thereof according to claim 1, wherein The selected VH CDRs 1, 2 and 3 amino acid sequences and the selected VL CDRs 1, 2 and 3 amino acid sequences are one of the following: (1) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 401, 402, and 403, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 404, Listed in 405 and 406; (2) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 407, 408, and 409, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 410, Listed in 411 and 412; (3) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 413, 414, and 415, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 416, listed in 417 and 418; (4) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 419, 420, and 421, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 422, listed in 423 and 424; (5) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 425, 426, and 427, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 428, listed in 429 and 430; (6) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 431, 432, and 433, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 434, listed in 435, 436; (7) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 437, 438, and 439, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 440, listed in 441 and 442; (8) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 443, 444, and 445, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 446, listed in 447 and 448; (9) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 449, 450, and 451, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 452, listed in 453 and 454; (10) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 455, 456, and 457, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 458, 459, and 460, respectively; (11) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 461, 462, and 463, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 464, 465, and 466, respectively; (12) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 467, 468, and 469, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 470, 471, and 472, respectively; (13) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 473, 474, and 475, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 476, 477, and 478, respectively; (14) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 479, 480, and 481, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 482, 483, and 484, respectively; (15) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 485, 486, and 487, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 488, 489, and 490, respectively; (16) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 491, 492, and 493, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 494, 495, and 496, respectively; (17) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 497, 498, and 499, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 500, 501, and 502, respectively; (18) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 503, 504, and 505, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 506, 507, and 508, respectively; (19) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 509, 510, and 511, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 512, 513, and 514, respectively; (20) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 515, 516, and 517, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 518, 519, and 520, respectively; (21) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1175, 1176, and 1177, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1178, 1179, and 1180, respectively; (22) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1181, 1182, and 1183, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1184, 1185, and 1186, respectively; (23) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1187, 1188, and 1189, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1190, 1191, and 1192, respectively; (24) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1193, 1194, and 1195, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1196, 1197, and 1198, respectively; (25) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1199, 1200, and 1201, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1202, 1203, and 1204, respectively; (26) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1205, 1206, and 1207, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1208, 1209, and 1210, respectively; (27) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1211, 1212, and 1213, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1214, 1215, and 1216, respectively; (28) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1217, 1218, and 1219, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1220, 1221, and 1222, respectively; (29) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1223, 1224, and 1225, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1226, 1227, and 1228, respectively; (30) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1229, 1230, and 1231, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1232, 1233, and 1234, respectively; (31) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1235, 1236, and 1237, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1238, 1239, and 1240, respectively; (32) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1241, 1242, and 1243, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1244, 1245, and 1246, respectively; (33) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1247, 1248, and 1249, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1250, 1251, and 1252, respectively; (34) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1253, 1254, and 1255, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1256, 1257, and 1258, respectively; (35) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1259, 1260, and 1261, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1262, 1263, and 1264, respectively; (36) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1265, 1266, and 1267, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1268, 1269, and 1270, respectively; (37) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1271, 1272, and 1273, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1274, 1275, and 1276, respectively; (38) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1277, 1278, and 1279, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1280, 1281, and 1282, respectively; (39) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1283, 1284, and 1285, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1286, 1287, and 1288, respectively; and (40) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1289, 1290, and 1291, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1292, 1293, and 1294, respectively.

9. The antibody or antigen-binding fragment thereof according to claim 1 or 8, wherein the CDRs are determined by the Aho definition.

10. The antibody or antigen-binding fragment thereof according to claim 1, wherein The selected VH CDRs 1, 2 and 3 amino acid sequences and the selected VL CDRs 1, 2 and 3 amino acid sequences are one of the following: (1) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 521, 522, and 523, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 524, 525, and 526, respectively; (2) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 527, 528, and 529, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 530, 531, and 532, respectively; (3) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 533, 534, and 535, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 536, listed in 537 and 538; (4) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 539, 540, and 541, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 542, listed in 543 and 544; (5) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 545, 546, and 547, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 548, listed in 549 and 550; (6) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 551, 552, and 553, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 554, listed in 555 and 556; (7) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 557, 558, and 559, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 560, listed in 561 and 562; (8) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 563, 564, and 565, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 566, listed in 567 and 568; (9) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 569, 570, and 571, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 572, listed in 573 and 574; (10) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 575, 576, and 577, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 578, 579, and 580, respectively; (11) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 581, 582, and 583, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 584, 585, and 586, respectively; (12) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 587, 588, and 589, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 590, 591, and 592, respectively; (13) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 593, 594, and 595, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 596, 597, and 598, respectively; (14) the selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 599, 600, and 601, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 602, 603, and 604, respectively; (15) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 605, 606, and 607, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 608, 609, and 610, respectively; (16) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 611, 612, and 613, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 614, 615, and 616, respectively; (17) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 617, 618, and 619, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 620, 621, and 622, respectively; (18) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 623, 624, and 625, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 626, 627, and 628, respectively; (19) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 629, 630, and 631, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 632, 633, and 634, respectively; (20) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 635, 636, and 637, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 638, 639, and 640, respectively; (21) The selected VH CDRs 1, 2, and 3 amino acid sequences are in SEQ ID NOs: 1295, 1296, 1297, the selected VL CDRS1, 2, 3 amino acid sequences are respectively in SEQ ID NOs: listed in 1298, 1299, 1300; (22) The selected VH CDRs 1, 2, and 3 amino acid sequences are in SEQ ID NOs: 1301, 1302, 1303, the selected VL CDRS1, 2, 3 amino acid sequences are respectively in SEQ ID NOs: listed in 1304, 1305, 1306; (23) The selected VH CDRs 1, 2, and 3 amino acid sequences are in SEQ ID NOs: 1307, 1308, 1309, the selected VL CDRS1, 2, 3 amino acid sequences are respectively in SEQ ID NOs: listed in 1310, 1311, 1312; (24) The selected VH CDRs 1, 2, and 3 amino acid sequences are in SEQ ID NOs: 1313, 1314, 1315, the selected VL CDRS1, 2, 3 amino acid sequences are respectively in SEQ ID NOs: listed in 1316, 1317, 1318; (25) The selected VH CDRs 1, 2, and 3 amino acid sequences are in SEQ ID NOs: 1319, 1320, 1321, the selected VL CDRS1, 2, 3 amino acid sequences are respectively in SEQ ID NOs: listed in 1322, 1323, 1324; (26) The selected VH CDRs 1, 2, and 3 amino acid sequences are in SEQ ID NOs: 1325, 1326, 1327, the selected VL CDRS1, 2, 3 amino acid sequences are respectively in SEQ ID NOs: listed in 1328, 1329, 1330; (27) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1331, 1332, and 1333, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 1334, 1335, and 1336, respectively; (28) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1337, 1338, and 1339, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1340, 1341, and 1342, respectively; (29) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1343, 1344, and 1345, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1346, 1347, and 1348, respectively; (30) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1349, 1350, and 1351, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1352, 1353, and 1354, respectively; (31) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1355, 1356, and 1357, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1358, 1359, and 1360, respectively; (32) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1361, 1362, and 1363, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1364, 1365, and 1366, respectively; (33) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1367, 1368, and 1369, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1370, 1371, and 1372, respectively; (34) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1373, 1374, and 1375, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 1376, 1377, and 1378, respectively; (35) The selected VH CDRs 1, 2, and 3 amino acid sequences are in SEQ ID NOs: 1379, 1380, 1381, the selected VL CDRS1, 2, 3 amino acid sequences are respectively in SEQ ID NOs: listed in 1382, 1383, 1384; (36) The selected VH CDRs 1, 2, and 3 amino acid sequences are in SEQ ID NOs: 1385, 1386, 1387, the selected VL CDRS1, 2, 3 amino acid sequences are respectively in SEQ ID NOs: listed in 1388, 1389, 1390; (37) The selected VH CDRs 1, 2, and 3 amino acid sequences are in SEQ ID NOs: 1391, 1392, 1393, the selected VL CDRS1, 2, 3 amino acid sequences are respectively in SEQ ID NOs: listed in 1394, 1395, 1396; (38) The selected VH CDRs 1, 2, and 3 amino acid sequences are in SEQ ID NOs: 1397, 1398, 1399, the selected VL CDRS1, 2, 3 amino acid sequences are respectively in SEQ ID NOs: Listed in 1400, 1401, 1402; (39) The selected VH CDRs 1, 2, and 3 amino acid sequences are in SEQ ID NOs: 1403, 1404, 1405, the selected VL CDRS1, 2, 3 amino acid sequences are respectively in SEQ ID NOs: listed in 1406, 1407, 1408; and (40) The selected VH CDRs 1, 2, and 3 amino acid sequences are in SEQ ID NOs: 1409, 1410, 1411, the selected VL CDRS1, 2, 3 amino acid sequences are respectively in SEQ ID NOs: Listed in 1412, 1413, and 1414.

11. The antibody or antigen-binding fragment thereof according to claim 1 or 10, wherein the CDRs are determined by the Northern definition.

12. The antibody or antigen-binding fragment thereof according to claim 1, wherein the selected VH CDRs 1, 2 and 3 amino acid sequences and the selected VL CDRs 1, 2 and 3 amino acid sequences are one of the following: (1) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 708, 709, and 710, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 711, 712, and 713, respectively; (2) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 714, 715, and 716, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 717, 718, and 719, respectively; (3) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 720, 721, and 722, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 723, 724, and 725, respectively; (4) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 726, 727, and 728, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 729, 730, and 731, respectively; (5) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 732, 733, and 734, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 735, 736, and 737, respectively; (6) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 738, 739, and 740, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 741, 742, and 743, respectively; (7) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 744, 745, and 746, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 747, 748, and 749, respectively; (8) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 750, 751, and 752, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 753, 754, and 755, respectively; (9) The amino acid sequences of the selected VH CDRs 1, 2, and 3 are in SEQ ID NOs: 756, 757, and 758, respectively. The selected VL CDRS1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 759, listed in 760 and 761; (10) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 762, 763, and 764, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 765, listed in 766 and 767; (11) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 768, 769, and 770, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 771, listed in 772 and 773; (12) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 774, 775, and 776, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 777, listed in 778 and 779; (13) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 780, 781, and 782, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 783, listed in 784 and 785; (14) the selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 786, 787, and 788, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 789, 790, and 791, respectively; (15) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 792, 793, and 794, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 795, 796, and 797, respectively; (16) The selected VH CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 798, 799, and 800, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are set forth in SEQ ID NOs: 801, 802, and 803, respectively; (17) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 804, 805, and 806, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 807, listed in 808 and 809; and (18) The selected VH CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 810, 811, and 812, respectively, and the selected VL CDRs 1, 2, and 3 amino acid sequences are listed in SEQ ID NOs: 813, Listed in 814 and 815.

13. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 12, wherein the antibody or antigen-binding fragment specifically binds to human MICA and / or human MICB.

14. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 13, wherein the antibody or antigen-binding fragment specifically binds to monkey MICA and / or monkey MICB.

15. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 14, wherein the antibody or antigen-binding fragment can block the shedding of MICA and / or MICB polypeptides from the surface of cancer cells.

16. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 15, wherein the antibody or antigen-binding fragment is a humanized antibody or antigen-binding fragment thereof.

17. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 16, wherein the antibody or antigen-binding fragment thereof is a single-chain variable fragment (scFV) or a multispecific antibody (eg, a bispecific antibody).

18. An antibody or antigen-binding fragment thereof that binds to MICA and / or MICB, comprising a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90% identical to a selected VH sequence, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90% identical to a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are selected from Figures 23, 25, 26, 27, 28 or 29.

19. The antibody or antigen-binding fragment thereof according to claim 18, wherein the selected VH sequence and the selected VL sequence are one of the following: (1) The selected VH sequence is SEQ ID NOs: 1, and the selected VL sequence is SEQ ID NOs: 2; (2) the selected VH sequence is SEQ ID NOs: 9, and the selected VL sequence is SEQ ID NOs: 10; (3) the selected VH sequence is SEQ ID NOs: 17, and the selected VL sequence is SEQ ID NOs: 18; (4) the selected VH sequence is SEQ ID NOs: 25, and the selected VL sequence is SEQ ID NOs: 26; (5) the selected VH sequence is SEQ ID NOs: 33, and the selected VL sequence is SEQ ID NOs: 34; (6) the selected VH sequence is SEQ ID NOs: 41, and the selected VL sequence is SEQ ID NOs: 42; (7) the selected VH sequence is SEQ ID NOs: 49, and the selected VL sequence is SEQ ID NOs: 50; (8) the selected VH sequence is SEQ ID NOs: 57, and the selected VL sequence is SEQ ID NOs: 58; (9) the selected VH sequence is SEQ ID NOs: 65, and the selected VL sequence is SEQ ID NOs: 66; (10) the selected VH sequence is SEQ ID NOs: 73, and the selected VL sequence is SEQ ID NOs: 74; (11) the selected VH sequence is SEQ ID NOs: 81, and the selected VL sequence is SEQ ID NOs: 82; (12) the selected VH sequence is SEQ ID NOs: 89, and the selected VL sequence is SEQ ID NOs: 90; (13) the selected VH sequence is SEQ ID NOs: 97, and the selected VL sequence is SEQ ID NOs: 98; (14) the selected VH sequence is SEQ ID NOs: 105, and the selected VL sequence is SEQ ID NOs: 106; (15) the selected VH sequence is SEQ ID NOs: 113, and the selected VL sequence is SEQ ID NOs: 114; (16) The selected VH sequence is SEQ ID NOs: 121, and the selected VL sequence is SEQ ID NOs: 122; (17) The selected VH sequence is SEQ ID NOs: 129, and the selected VL sequence is SEQ ID NOs: 130; (18) The selected VH sequence is SEQ ID NOs: 137, and the selected VL sequence is SEQ ID NOs: 138; (19) the selected VH sequence is SEQ ID NOs: 145, and the selected VL sequence is SEQ ID NOs: 146; and (20) The selected VH sequence is SEQ ID NOs: 153, and the selected VL sequence is SEQ ID NOs:

154.

20. The antibody or antigen-binding fragment thereof according to claim 18, wherein the selected VH sequence is SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, and the selected VL sequences are SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707.

21. The antibody or antigen-binding fragment thereof of claim 20, wherein the selected VH sequence is SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651 or 652, and the selected VL sequence is SEQ ID NOs: 653, 654, 655, 656, 657 or 658.

22. The antibody or antigen-binding fragment thereof according to claim 18, wherein the selected VH sequence is SEQ ID NOs: 659 and the selected VL sequence is SEQ ID NOs:

660.

23. The antibody or antigen-binding fragment thereof of claim 18, wherein the selected VH sequence is SEQ ID NOs: 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679 or 680, and the selected VL sequence is SEQ ID NOs: 681, 682, 683, 684, 685, 686, 687, 688, or 689.

24. The antibody or antigen-binding fragment thereof according to claim 18, wherein VH comprises SEQ ID NOs:668, and VL comprises the sequence of SEQ ID NOs:

681.

25. The antibody or antigen-binding fragment thereof according to claim 18, wherein VH comprises SEQ ID NOs:669, and VL comprises the sequence of SEQ ID NOs:

681.

26. The antibody or antigen-binding fragment thereof according to claim 18, wherein VH comprises SEQ ID NOs:671, and VL comprises the sequence of SEQ ID NOs:

681.

27. The antibody or antigen-binding fragment thereof according to claim 18, wherein VH comprises SEQ ID NOs:665, and VL comprises the sequence of SEQ ID NOs:

681.

28. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises SEQ ID NOs:666, and VL comprises the sequence of SEQ ID NOs:

681.

29. The antibody or antigen-binding fragment thereof according to claim 18, wherein VH comprises the sequence of SEQ ID NOs: 670 and VL comprises the sequence of SEQ ID NOs:

681.

30. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 674 and VL comprises the sequence of SEQ ID NOs:

682.

31. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 675 and VL comprises the sequence of SEQ ID NOs:

683.

32. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 676 and VL comprises the sequence of SEQ ID NOs:

682.

33. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 678 and VL comprises the sequence of SEQ ID NOs:

682.

34. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 677 and VL comprises the sequence of SEQ ID NOs:

684.

35. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 672 and VL comprises the sequence of SEQ ID NOs:

681.

36. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 673 and VL comprises the sequence of SEQ ID NOs:

681.

37. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 667 and VL comprises the sequence of SEQ ID NOs:

681.

38. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 659 and VL comprises the sequence of SEQ ID NOs:

660.

39. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 680 and VL comprises the sequence of SEQ ID NOs:

687.

40. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 661 and VL comprises the sequence of SEQ ID NOs:

685.

41. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 662 and VL comprises the sequence of SEQ ID NOs:

685.

42. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 663 and VL comprises the sequence of SEQ ID NOs:

685.

43. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 664 and VL comprises the sequence of SEQ ID NOs:

685.

44. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 665 and VL comprises the sequence of SEQ ID NOs:

685.

45. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 665 and VL comprises the sequence of SEQ ID NOs:

688.

46. ​​The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 665 and VL comprises the sequence of SEQ ID NOs:

689.

47. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 665 and VL comprises the sequence of SEQ ID NOs:

686.

48. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 679 and VL comprises the sequence of SEQ ID NOs:

686.

49. The antibody or antigen-binding fragment thereof according to claim 18, wherein VH comprises the sequence of SEQ ID NOs: 641 and VL comprises the sequence of SEQ ID NOs:

653.

50. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 642 and VL comprises the sequence of SEQ ID NOs:

653.

51. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 643 and VL comprises the sequence of SEQ ID NOs:

653.

52. The antibody or antigen-binding fragment thereof according to claim 18, wherein VH comprises the sequence of SEQ ID NOs: 644 and VL comprises the sequence of SEQ ID NOs:

653.

53. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 647 and VL comprises the sequence of SEQ ID NOs:

654.

54. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 648 and VL comprises the sequence of SEQ ID NOs:

654.

55. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 649 and VL comprises the sequence of SEQ ID NOs:

654.

56. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 650 and VL comprises the sequence of SEQ ID NOs:

654.

57. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 645 and VL comprises the sequence of SEQ ID NOs:

653.

58. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 646 and VL comprises the sequence of SEQ ID NOs:

653.

59. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 651 and VL comprises the sequence of SEQ ID NOs:

654.

60. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 650 and VL comprises the sequence of SEQ ID NOs:

655.

61. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 650 and VL comprises the sequence of SEQ ID NOs:

656.

62. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 650 and VL comprises the sequence of SEQ ID NOs:

657.

63. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 647 and VL comprises the sequence of SEQ ID NOs:

655.

64. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 647 and VL comprises the sequence of SEQ ID NOs:

657.

65. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 651 and VL comprises the sequence of SEQ ID NOs:

656.

66. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 651 and VL comprises the sequence of SEQ ID NOs:

657.

67. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 652 and VL comprises the sequence of SEQ ID NOs:

656.

68. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 652 and VL comprises the sequence of SEQ ID NOs:

657.

69. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 651 and VL comprises the sequence of SEQ ID NOs:

658.

70. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 652 and VL comprises the sequence of SEQ ID NOs:

658.

71. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 647 and VL comprises the sequence of SEQ ID NOs:

658.

72. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 690 and VL comprises the sequence of SEQ ID NOs:

691.

73. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises the sequence of SEQ ID NOs: 692 and VL comprises the sequence of SEQ ID NOs:

693.

74. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises SEQ ID NOs:694, and VL comprises the sequence of SEQ ID NOs:

695.

75. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises SEQ ID NOs:696, and VL comprises the sequence of SEQ ID NOs:

697.

76. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises SEQ ID NOs:698, and VL comprises the sequence of SEQ ID NOs:

699.

77. The antibody or antigen-binding fragment thereof according to claim 18, wherein VH comprises SEQ ID NOs: The sequence of SEQ ID NOs: 700, and VL comprises the sequence of SEQ ID NOs:

701.

78. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises SEQ ID NOs:702, and VL comprises the sequence of SEQ ID NOs:

703.

79. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises SEQ ID NOs:704, and VL comprises the sequence of SEQ ID NOs:

705.

80. The antibody or antigen-binding fragment thereof of claim 18, wherein VH comprises SEQ ID NOs:706, and VL comprises the sequence of SEQ ID NOs:

707.

81. The antibody or antigen-binding fragment thereof according to any one of claims 18-80, wherein the antibody or antigen-binding fragment specifically binds to human MICA and / or MICB.

82. The antibody or antigen-binding fragment thereof according to any one of claims 18-81, wherein the antibody or antigen-binding fragment is a humanized antibody or antigen-binding fragment thereof.

83. The antibody or antigen-binding fragment thereof according to any one of claims 18-82, wherein the antibody or antigen-binding fragment is a single-chain variable fragment (scFV) or a multispecific antibody (e.g., a bispecific antibody).

84. An antibody or antigen-binding fragment thereof that cross-competes with the antibody or antigen-binding fragment thereof of any one of claims 1-83.

85. An antibody or antigen-binding fragment thereof comprising A heavy chain variable region (VH) comprising VH CDR1, VH CDR2 and VH CDR3, and a light chain variable region (VL) comprising VL CDR1, VLCDR2 and VL CDR3, wherein VH The CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 are identical to the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 of the antibody or antigen-binding fragment thereof of any one of claims 1-84.

86. An antibody-drug conjugate comprising the antibody or antigen-binding fragment thereof of any one of claims 1-85 covalently bound to a therapeutic agent.

87. The antibody drug conjugate of claim 86, wherein the therapeutic agent is cytotoxic or cytostatic.

88. A method of treating a subject having cancer, the method comprising administering to the subject an effective dose of a composition consisting of the antibody or antigen-binding fragment thereof of any one of claims 1-85 or the antibody-drug conjugate of claim 86 or 87.

89. The method of claim 88, wherein the subject has a solid tumor or a hematological cancer.

90. The method of claim 88, wherein the cancer is melanoma, neuroblastoma, prostate cancer, renal cancer, multiple myeloma, or chronic lymphocytic leukemia.

91. A method for reducing tumor growth rate, the method comprising contacting tumor cells with an effective amount of a composition consisting of the antibody or antigen-binding fragment thereof of any one of claims 1-85 or the antibody-drug conjugate of claim 86 or 87.

92. A method for killing tumor cells, the method comprising contacting the tumor cells with an effective dose of a composition consisting of the antibody or antigen-binding fragment thereof of any one of claims 1-85 or the antibody-drug conjugate of claim 86 or 87.

93. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 85, or the antibody-drug conjugate according to claim 86 or 87, and a pharmaceutically acceptable carrier.

94. A nucleic acid comprising a polynucleotide encoding a polypeptide comprising: (1) an immunoglobulin heavy chain or fragment thereof, comprising a heavy chain variable region (VH) containing complementarity determining regions (CDRs) 1, 2 and 3, comprising the VH CDRs 1, 2, 3 shown in Figures 24A, 24B, 24C, 24D, 24E, 28, 29, 30A, 30B, 30C, 30D or 30E, and wherein the VH binds to MICA and / or MICB when paired with a corresponding light chain variable region (VL); or (2) an immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising as shown in Figures 24A, 24B, 24C, 24D, 24E, 28, 29, 30A, 30B, 30C, 30D or 30E VL CDR1, 2, 3 shown, bind to MICA and / or MICB when paired with the corresponding VH.

95. The nucleic acid of claim 94, wherein (1) An immunoglobulin heavy chain or a fragment thereof, comprising a heavy chain variable region (VH) containing complementary determining regions (CDRs) 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 3, 4 and 5, respectively, wherein when VH is combined with a light chain comprising SEQ ID NO: 2 shown in SEQ ID NO When the variable regions (VL) are paired, they bind to MICA and / or MICB; (2) an immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 11, 12 and 13, respectively, wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 10, it binds to MICA and / or MICB; (3) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 19, 20 and 21, respectively, wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 18, it binds to MICA and / or MICB. combine; (4) an immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 27, 28 and 29, respectively, and wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 26, it binds to MICA and / or MICB; (5) an immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 35, 36 and 37, respectively, and wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 34, it binds to MICA and / or MICB; (6) An immunoglobulin heavy chain or a fragment thereof, comprising a VH containing CDR1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 43, 44 and 45, respectively, wherein the VH and the amino acid sequences containing SEQ ID NOs: When the VL of the amino acid sequence shown in ID NO: 42 is paired with MICA and / or MICB combine; (7) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 51, 52 and 53, respectively, wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 50, it binds to MICA and / or MICB. combine; (8) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 59, 60 and 61, respectively, wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 58, it binds to MICA and / or MICB. combine; (9) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 67, 68 and 69, respectively, wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 66, it binds to MICA and / or MICB. combine; (10) an immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 75, 76 and 77, respectively, wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 74, it binds to MICA and / or MICB; (11) an immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 83, 84 and 85, respectively, and wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 82, it binds to MICA and / or MICB; (12) an immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 91, 92 and 93, respectively, wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 90, it binds to MICA and / or MICB; (13) an immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 99, 100 and 101, respectively, wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 98, it binds to MICA and / or MICB; (14) an immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 107, 108 and 109, respectively, wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 106, it binds to MICA and / or MICB; (15) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 115, 116 and 117, respectively, wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 114, it binds to MICA and / or MICB; (16) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 123, 124 and 125, respectively, wherein the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 122; (17) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 131, 132 and 133, respectively, wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 130, it binds to MICA and / or MICB; (18) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 139, 140 and 141, respectively, wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 138, it binds to MICA and / or MICB; (19) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 147, 148 and 149, respectively, wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 146, it binds to MICA and / or MICB; (20) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDR1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 155, 156 and 157, respectively, wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NO: 154, it binds to MICA and / or MICB; (21) an immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 6, 7 and 8, respectively, and wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 1, it binds to MICA and / or MICB; (22) an immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 14, 15 and 16, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 9, it binds to MICA and / or MICB; (23) an immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 22, 23 and 24, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 17, it binds to MICA and / or MICB; (24) An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 30, 31 and 32, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 25, it binds to MICA and / or MICB; (25) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDR1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 38, 39 and 40, respectively, and wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 33, it binds to MICA and / or MICB; (26) An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 46, 47 and 48, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 41, it binds to MICA and / or MICB; (27) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 54, 55 and 56, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 49, it binds to MICA and / or MICB; (28) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 62, 63 and 64, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 57, it binds to MICA and / or MICB; (29) An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 70, 71 and 72, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 65, it binds to MICA and / or MICB; (30) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 78, 79 and 80, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 73, it binds to MICA and / or MICB; (31) an immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 86, 87 and 88, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 81, it binds to MICA and / or MICB; (32) an immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 94, 95 and 96, respectively, wherein the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 89; (33) an immunoglobulin light chain or fragment thereof comprising a VL comprising CDRs 1, 2 and 3, wherein the VL comprises the amino acid sequences shown in SEQ ID NOs: 102, 103 and 104, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 97, it binds to MICA and / or MICB; (34) An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 110, 111 and 112, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 105, it binds to MICA and / or MICB; (35) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 118, 119 and 120, respectively, and wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 113, it binds to MICA and / or MICB; (36) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 126, 127 and 128, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 121, it binds to MICA and / or MICB; (37) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 134, 135 and 136, respectively, and wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 129, it binds to MICA and / or MICB; (38) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDR1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 142, 143 and 144, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 137, it binds to MICA and / or MICB; (39) An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDR1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 150, 151 and 152, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 145, it binds to MICA and / or MICB; (40) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDR1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 158, 159 and 160, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NO: 153, it binds to MICA and / or MICB; (41) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 815, 816 and 817, respectively, and wherein when VH is combined with a VH comprising SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, binds to MICA and / or MICB when paired with a VL having the amino acid sequence shown in 697, 699, 701, 703, 705 or 707; (42) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 821, 822 and 823, respectively, wherein when VH is combined with a VH comprising SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, binds to MICA and / or MICB when paired with a VL having the amino acid sequence shown in 699, 701, 703, 705 or 707; (43) An immunoglobulin heavy chain or a fragment thereof, comprising a VH containing CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 827, 828 and 829, respectively, and wherein when the VH is combined with a VH containing SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707 in combination with MICA and / or MICB; (44) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 833, 834 and 835, respectively, wherein when VH is combined with a VH comprising SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, binds to MICA and / or MICB when paired with a VL having the amino acid sequence shown in 699, 701, 703, 705 or 707; (45) an immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences shown in SEQ ID NOs: 839, 840, and 841, respectively, and wherein the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence shown in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707; (46) An immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 845, 846 and 847, respectively, wherein when VH is combined with a VH comprising SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, binds to MICA and / or MICB when paired with a VL having the amino acid sequence shown in 699, 701, 703, 705 or 707; (47) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 851, 852 and 853, respectively, wherein when VH is combined with a VH comprising SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, binds to MICA and / or MICB when paired with a VL having the amino acid sequence shown in 699, 701, 703, 705 or 707; (48) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 857, 858 and 859, respectively, wherein when VH is combined with a VH comprising SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, binds to MICA and / or MICB when paired with a VL having the amino acid sequence shown in 699, 701, 703, 705 or 707; (49) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 863, 864 and 865, respectively, wherein when VH is combined with a VH comprising SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, binds to MICA and / or MICB when paired with a VL having the amino acid sequence shown in 699, 701, 703, 705 or 707; (50) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 869, 870 and 871, respectively, wherein when VH is combined with a VH comprising SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, binds to MICA and / or MICB when paired with a VL having the amino acid sequence shown in 699, 701, 703, 705 or 707; (51) An immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 875, 876 and 877, respectively, wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, it binds to MICA and / or MICB; (52) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 881, 882 and 883, respectively, wherein when VH is combined with a VH comprising SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, binds to MICA and / or MICB when paired with a VL having the amino acid sequence shown in 699, 701, 703, 705 or 707; (53) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 887, 888 and 889, respectively, wherein when VH is combined with a VH comprising a CDR comprising SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, binds to MICA and / or MICB when paired with a VL having the amino acid sequence shown in 699, 701, 703, 705 or 707; (54) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 893, 894 and 895, respectively, wherein the VH is bound to a VH comprising SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, binds to MICA and / or MICB when paired with a VL having the amino acid sequence shown in 699, 701, 703, 705 or 707; (55) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 899, 900 and 901, respectively, wherein when VH is combined with a VH comprising SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, binds to MICA and / or MICB when paired with a VL having the amino acid sequence shown in 699, 701, 703, 705 or 707; (56) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 905, 906 and 907, respectively, wherein the VH is bound to a fragment thereof comprising a CDR comprising SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, binds to MICA and / or MICB when paired with a VL having the amino acid sequence shown in 699, 701, 703, 705 or 707; (57) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 911, 912 and 913, respectively, wherein the VH is bound to a VH comprising a CDR comprising SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, binds to MICA and / or MICB when paired with a VL having the amino acid sequence shown in 699, 701, 703, 705 or 707; (58) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 917, 918 and 919, respectively, wherein when VH is combined with a VH comprising SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, binds to MICA and / or MICB when paired with a VL having the amino acid sequence shown in 699, 701, 703, 705 or 707; (59) An immunoglobulin heavy chain or fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 923, 924 and 925, respectively, wherein when the VH is paired with a VL comprising the amino acid sequence shown in SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, it binds to MICA and / or MICB; (60) An immunoglobulin heavy chain or a fragment thereof, comprising a VH comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 929, 930 and 931, respectively, wherein when VH is combined with a VH comprising SEQ ID NOs: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705 or 707, binds to MICA and / or MICB when paired with a VL having the amino acid sequence shown in 699, 701, 703, 705 or 707; (61) An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 818, 819 and 820, respectively, wherein when the VL is combined with a CDR comprising SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, binds to MICA and / or MICB when paired with a VH having the amino acid sequence shown in 651; (62) an immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 824, 825 and 826, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, it binds to MICA and / or MICB; (63) An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 830, 831 and 832, respectively, and wherein when the VL is combined with a CDR comprising SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, binds to MICA and / or MICB when paired with a VH having the amino acid sequence shown in 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706; (64) An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 836, 837 and 838, respectively, and wherein when the VL is combined with a CDR comprising SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, binds to MICA and / or MICB when paired with a VH having the amino acid sequence shown in 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706; (65) An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 842, 843 and 844, respectively, wherein when the VL is combined with a VL comprising SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, binds to MICA and / or MICB when paired with a VH having the amino acid sequence shown in 651; (66) An immunoglobulin light chain or a fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 848, 849 and 850, respectively, wherein when the VL is combined with a VL comprising SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, binds to MICA and / or MICB when paired with a VH having the amino acid sequence shown in 651; (67) an immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 854, 855 and 856, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, it binds to MICA and / or MICB; (68) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 860, 861 and 862, respectively, and wherein when combined with a VL comprising SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, binds to MICA and / or MICB when paired with a VH having the amino acid sequence shown in 651; (69) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 866, 867 and 868, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, it binds to MICA and / or MICB; (70) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 872, 873 and 874, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, it binds to MICA and / or MICB; (71) an immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 878, 879 and 880, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, it binds to MICA and / or MICB; (72) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 884, 885 and 886, respectively, wherein when the VL is combined with a VL comprising SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, binds to MICA and / or MICB when paired with a VH having the amino acid sequence shown in 651; (73) an immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences shown in SEQ ID NOs: 890, 891, and 892, respectively, wherein the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence shown in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706; (74) an immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 896, 897 and 898, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, it binds to MICA and / or MICB; (75) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 902, 903 and 904, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, it binds to MICA and / or MICB; (76) an immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3 comprising the amino acid sequences shown in SEQ ID NOs: 908, 909 and 910, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, it binds to MICA and / or MICB; (77) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 914, 915 and 916, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, it binds to MICA and / or MICB; (78) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 920, 921 and 922, respectively, wherein when the VL is paired with a VH comprising the amino acid sequence shown in SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, it binds to MICA and / or MICB; (79) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 926, 927 and 928, respectively, and wherein when the VL is combined with a VL comprising SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, binds to MICA and / or MICB; or (80) An immunoglobulin light chain or fragment thereof, comprising a VL comprising CDRs 1, 2 and 3, comprising the amino acid sequences shown in SEQ ID NOs: 932, 933 and 934, respectively, wherein when the VL is combined with a CDR comprising SEQ ID NOs: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, When paired with a VH having the amino acid sequence shown in 651, 652, 690, 692, 694, 696, 698, 700, 702, 704 or 706, it binds to MICA and / or MICB.

96. The nucleic acid of claim 94 or 95, wherein VH, when paired with VL, specifically binds to human MICA and / or MICB; or VL, when paired with VH, specifically binds to human MICA and / or MICB.

97. The nucleic acid of any one of claims 94-96, wherein the immunoglobulin heavy chain or fragment thereof is a humanized immunoglobulin heavy chain or fragment thereof, and the immunoglobulin light chain or fragment thereof is a humanized immunoglobulin light chain or fragment thereof.

98. The nucleic acid of any one of claims 94-97, wherein the nucleic acid encodes a single-chain variable fragment (scFv) or a multispecific antibody (e.g., a bispecific antibody).

99. The nucleic acid of any one of claims 94-98, wherein the nucleic acid is cDNA.

100. A vector comprising one or more of the nucleic acids of any one of claims 94-99.

101. A vector comprising two nucleic acids of any one of claims 94-99, wherein the vector encodes a VL region and a VH region that together bind to MICA and / or MICB.

102. A pair of vectors, wherein each vector comprises one of the nucleic acids of any one of claims 94-99, the pair of vectors encoding a VL region and a VH region that together bind to MICA and / or MICB.

103. A cell comprising the vector of claim 100 or 101 or the vector pair of claim 102.

104. The cell of claim 103, wherein the cell is a CHO cell.

105. A cell comprising one or more nucleic acids of any one of claims 94-99.

106. A cell comprising two nucleic acids of any one of claims 94-99.

107. The cell of claim 106, wherein the two nucleic acids together encode a VL region and a VH region that together bind MICA and / or MICB.

108. A method for producing an antibody or an antigen-binding fragment thereof, the method comprising (1) culturing the cell according to any one of claims 103-107 under conditions sufficient for the cell to produce the antibody or antigen-binding fragment; and (2) Collecting the antibodies or antigen-binding fragments produced by the cells.

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