Anti-MICA / B antibodies and uses thereof

Abstract

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

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 329,221, filed April 8, 2022.

[0002] The present disclosure relates to antibodies capable of binding to major histocompatibility complex class I chain-related A (MICA), antibodies capable of binding to major histocompatibility complex class I chain-related B (MICA) (collectively referred to as anti-MICA / B antibodies), and uses thereof. [Background technology]

[0003] Major histocompatibility complex class I chain-related A and B (MICA / B) is a highly polymorphic cell surface protein associated with MHC class I glycoproteins and is the stimulatory ligand for the activating receptor NKG2D expressed on NK cells, CD8+ T cells, and gamma delta (GD) T cells. Binding of the NKG2D receptor to the MICA / B protein triggers NK cells and costimulates T cells to eliminate cancer or damaged cells by effector cells expressing the NKG2D receptor. (Bauer S et al., Activation of NK and T cells by NKG2D, a receptor for stress-induced MICA. Science 1999-07-30;285(5428):727-9; Diefenbach A et al., Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nat Immunol 2000-08;1(2):119-26; and Groh V et al., Costimulation of CD8alphabeta T cells by NKG2D via virally infected cell-induced MIC engagement. Nat Immunol 2001-03;2(3):255-60.)

[0004] The MICA / B protein is constitutively expressed at low levels in myeloid, epithelial, endothelial, and fibroblast cells. The MICA / B protein is upregulated or de novo expressed in response to stress, such as during carcinogenesis, infection, DNA damage responses, and various autoimmune conditions. However, as an escape mechanism to prevent NKG2D-mediated responses, tumor cells proteolytically shed MICA / B protein from the cell surface, resulting in both a decrease in MICA / B surface density and the generation of soluble MICA / B (sMICA / B) (Groh V et al., Inhibition of NKG2D expression and T cell activation by tumor-derived soluble MIC ligands. Nature 2002 Oct 17;419(6908):734-8; and Salih HR et al., Cutting edge: Downregulation of MICA in human tumors by proteolytic shedding. J Immunol 2002 Oct 15;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 expressed primarily intracellularly in tumor and normal tissues, Br J Cancer, 2017 Apr 25;116(9):1208-1217.)

[0005] Genome-wide association studies (GWAS) have revealed that MICA / B-associated signals are highly correlated with the incidence and poor prognosis of several human cancers. It is believed that specific inhibition of the shedding of MICA and MICB proteins from cancer cells may restore or enhance the NKG2D-dependent activation of NK cells and T cells in the tumor microenvironment, thereby enhancing anti-tumor activity in cancer patients. Thus, there is a need to generate anti-MICA / B antibodies that bind to and inhibit the shedding of MICA and MICB, as well as enhance NK cells and T cells. The compositions and methods disclosed herein address this need. Summary of the Invention [Problem to be solved by the invention]

[0006] The present disclosure relates to anti-MICA / B antibodies, antigen-binding fragments thereof, and uses thereof. [Means for solving the problem]

[0007] In one aspect, the 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), the antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, and a light chain variable region (VL) comprising CDRs 1, 2, and 3, wherein 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, the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR3 amino acid sequence, and 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, and the VL CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR3 amino acid sequence. and the VL CDR3 comprises an amino acid sequence that is at least 80% identical to a selected VL CDR3 amino acid sequence, and in some embodiments the selected VH CDR1, 2 and 3 amino acid sequences and the selected VL CDR1, 2 and 3 amino acid sequences are selected from the VH CDR1, 2, 3 and VL CDR1, 2, 3 listed in Figures 24A, 24B, 24C, 24D, 24E, 28, 29, 30A, 30B, 30C, 30D and 30E.

[0008] In some embodiments, the selected VH CDR1, 2, and 3 amino acid sequences and the selected VL CDR1, 2, and 3 amino acid sequences are one of the following: (1) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 3, 4, and 5, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 6, 7, and 8, respectively. (2) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 11, 12, and 13, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 14, 15, and 16, respectively. (3) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 19, 20, and 21, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 22, 23, and 24, respectively. (4) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 27, 28, and 29, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 30, 31, and 32, respectively. (5) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 35, 36, and 37, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 38, 39, and 40, respectively. (6) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 43, 44, and 45, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 46, 47, and 48, respectively. (7) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 51, 52, and 53, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 54, 55, and 56, respectively. (8) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 59, 60, and 61, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 62, 63, and 64, respectively. (9) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 67, 68, and 69, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 70, 71, and 72, respectively. (10) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 75, 76, and 77, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 78, 79, and 80, respectively. (11) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 83, 84, and 85, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 86, 87, and 88, respectively. (12) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 91, 92, and 93, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 94, 95, and 96, respectively. (13) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 99, 100, and 101, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 102, 103, and 104, respectively. (14) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 107, 108, and 109, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 110, 111, and 112, respectively. (15) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 115, 116, and 117, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 118, 119, and 120, respectively. (16) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 123, 124, and 125, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 126, 127, and 128, respectively. (17) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 131, 132, and 133, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 134, 135, and 136, respectively. (18) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 139, 140, and 141, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 142, 143, and 144, respectively. (19) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 147, 148, and 149, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 150, 151, and 152, respectively. (20) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 155, 156, and 157, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 158, 159, and 160, respectively. (21) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 815, 816, and 817, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 818, 819, and 820, respectively. (22) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 821, 822, and 823, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 824, 825, and 826, respectively. (23) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 827, 828, and 829, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 830, 831, and 832, respectively. (24) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 833, 834, and 835, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 836, 837, and 838, respectively. (25) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 839, 840, and 841, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 842, 843, and 844, respectively. (26) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 845, 846, and 847, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 848, 849, and 850, respectively. (27) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 851, 852, and 853, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 854, 855, and 856, respectively. (28) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 857, 858, and 859, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 860, 861, and 862, respectively. (29) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 863, 864, and 865, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 866, 867, and 868, respectively. (30) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 869, 870, and 871, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 872, 873, and 874, respectively. (31) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 875, 876, and 877, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 878, 879, and 880, respectively. (32) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 881, 882, and 883, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 884, 885, and 886, respectively. (33) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 887, 888, and 889, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 890, 891, and 892, respectively. (34) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 893, 894, and 895, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 896, 897, and 898, respectively. (35) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 899, 900, and 901, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 902, 903, and 904, respectively. (36) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 905, 906, and 907, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 908, 909, and 910, respectively. (37) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 911, 912, and 913, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 914, 915, and 916, respectively. (38) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 917, 918, and 919, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 920, 921, and 922, respectively. (39) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 923, 924, and 925, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 926, 927, and 928, respectively. (40) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 929, 930, and 931, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 932, 933, and 934, respectively.

[0009] In some embodiments, the CDRs are determined by the IMGT definition.

[0010] In some embodiments, the selected VH CDR1, 2, and 3 amino acid sequences and the selected VL CDR1, 2, and 3 amino acid sequences are one of the following: (1) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 161, 162, and 163, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 164, 165, and 166, respectively. (2) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 167, 168, and 169, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 170, 171, and 172, respectively. (3) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 173, 174, and 175, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 176, 177, and 178, respectively. (4) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 179, 180, and 181, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 182, 183, and 184, respectively. (5) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 185, 186, and 187, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 188, 189, and 190, respectively. (6) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 191, 192, and 193, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 194, 195, and 196, respectively. (7) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 197, 198, and 199, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 200, 201, and 202, respectively. (8) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 203, 204, and 205, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 206, 207, and 208, respectively. (9) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 209, 210, and 211, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 212, 213, and 214, respectively. (10) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 215, 216, and 217, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 218, 219, and 220, respectively. (11) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 221, 222, and 223, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 224, 225, and 226, respectively. (12) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 227, 228, and 229, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 230, 231, and 232, respectively. (13) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 233, 234, and 235, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 236, 237, and 238, respectively. (14) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 239, 240, and 241, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 242, 243, and 244, respectively. (15) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 245, 246, and 247, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 248, 249, and 250, respectively. (16) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 251, 252, and 253, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 254, 255, and 256, respectively. (17) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 257, 258, and 259, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 260, 261, and 262, respectively. (18) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 263, 264, and 265, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 266, 267, and 268, respectively. (19) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 269, 270, and 271, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 272, 273, and 274, respectively. (20) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 275, 276, and 277, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 278, 279, and 280, respectively. (21) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 935, 936, and 937, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 938, 939, and 940, respectively. (22) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 941, 942, and 943, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 944, 945, and 946, respectively. (23) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 947, 948, and 949, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 950, 951, and 952, respectively. (24) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 953, 954, and 955, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 956, 957, and 958, respectively. (25) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 959, 960, and 961, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 962, 963, and 964, respectively. (26) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 965, 966, and 967, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 968, 969, and 970, respectively. (27) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 971, 972, and 973, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 974, 975, and 976, respectively. (28) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 977, 978, and 979, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 980, 981, and 982, respectively. (29) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 983, 984, and 985, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 986, 987, and 988, respectively. (30) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 989, 990, and 991, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 992, 993, and 994, respectively. (31) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 995, 996, and 997, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 998, 999, and 1000, respectively. (32) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1001, 1002, and 1003, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1004, 1005, and 1006, respectively. (33) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1007, 1008, and 1009, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1010, 1011, and 1012, respectively. (34) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1013, 1014, and 1015, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1016, 1017, and 1018, respectively. (35) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1019, 1020, and 1021, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1022, 1023, and 1024, respectively. (36) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1025, 1026, and 1027, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1028, 1029, and 1030, respectively. (37) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1031, 1032, and 1033, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1034, 1035, and 1036, respectively. (38) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1037, 1038, and 1039, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1040, 1041, and 1042, respectively. (39) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1043, 1044, and 1045, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1046, 1047, and 1048, respectively. (40) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1049, 1050, and 1051, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1052, 1053, and 1054, respectively.

[0011] In some embodiments, the CDRs are determined by the Kabat definition.

[0012] In some embodiments, the selected VH CDR1, 2, and 3 amino acid sequences and the selected VL CDR1, 2, and 3 amino acid sequences are one of the following: (1) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 281, 282, and 283, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 284, 285, and 286, respectively. (2) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 287, 288, and 289, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 290, 291, and 292, respectively. (3) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 293, 294, and 295, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 296, 297, and 298, respectively. (4) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 299, 300, and 301, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 302, 303, and 304, respectively. (5) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 305, 306, and 307, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 308, 309, and 310, respectively. (6) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 311, 312, and 313, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 314, 315, and 316, respectively. (7) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 317, 318, and 319, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 320, 321, and 322, respectively. (8) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 323, 324, and 325, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 326, 327, and 328, respectively. (9) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 329, 330, and 331, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 332, 333, and 334, respectively. (10) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 335, 336, and 337, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 338, 339, and 340, respectively. (11) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 341, 342, and 343, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 344, 345, and 346, respectively. (12) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 347, 348, and 349, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 350, 351, and 352, respectively. (13) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 353, 354, and 355, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 356, 357, and 358, respectively. (14) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 359, 360, and 361, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 362, 363, and 364, respectively. (15) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 365, 366, and 367, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 368, 369, and 370, respectively. (16) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 371, 372, and 373, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 374, 375, and 376, respectively. (17) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 377, 378, and 379, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 380, 381, and 382, ​​respectively. (18) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 383, 384, and 385, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 386, 387, and 388, respectively. (19) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 389, 390, and 391, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 392, 393, and 394, respectively. (20) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 395, 396, and 397, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 398, 399, and 400, respectively. (21) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1055, 1056, and 1057, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1058, 1059, and 1060, respectively. (22) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1061, 1062, and 1063, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1064, 1065, and 1066, respectively. (23) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1067, 1068, and 1069, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1070, 1071, and 1072, respectively. (24) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1073, 1074, and 1075, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1076, 1077, and 1078, respectively. (25) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1079, 1080, and 1081, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1082, 1083, and 1084, respectively. (26) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1085, 1086, and 1087, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1088, 1089, and 1090, respectively. (27) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1091, 1092, and 1093, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1094, 1095, and 1096, respectively. (28) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1097, 1098, and 1099, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1100, 1101, and 1102, respectively. (29) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1103, 1104, and 1105, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1106, 1107, and 1108, respectively. (30) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1109, 1110, and 1111, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1112, 1113, and 1114, respectively. (31) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1115, 1116, and 1117, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1118, 1119, and 1120, respectively. (32) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1121, 1122, and 1123, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1124, 1125, and 1126, respectively. (33) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1127, 1128, and 1129, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1130, 1131, and 1132, respectively. (34) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1133, 1134, and 1135, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1136, 1137, and 1138, respectively. (35) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1139, 1140, and 1141, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1142, 1143, and 1144, respectively. (36) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1145, 1146, and 1147, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1148, 1149, and 1150, respectively. (37) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1151, 1152, and 1153, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1154, 1155, and 1156, respectively. (38) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1157, 1158, and 1159, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1160, 1161, and 1162, respectively. (39) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1163, 1164, and 1165, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1166, 1167, and 1168, respectively. (40) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1169, 1170, and 1171, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1172, 1173, and 1174, respectively.

[0013] In some embodiments, the CDRs are determined by the Chothia definition.

[0014] In some embodiments, the selected VH CDR1, 2, and 3 amino acid sequences and the selected VL CDR1, 2, and 3 amino acid sequences are one of the following: (1) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 401, 402, and 403, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 404, 405, and 406, respectively. (2) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 407, 408, and 409, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 410, 411, and 412, respectively. (3) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 413, 414, and 415, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 416, 417, and 418, respectively. (4) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 419, 420, and 421, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 422, 423, and 424, respectively. (5) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 425, 426, and 427, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 428, 429, and 430, respectively. (6) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 431, 432, and 433, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 434, 435, and 436, respectively. (7) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 437, 438, and 439, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 440, 441, and 442, respectively. (8) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 443, 444, and 445, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 446, 447, and 448, respectively. (9) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 449, 450, and 451, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 452, 453, and 454, respectively. (10) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 455, 456, and 457, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 458, 459, and 460, respectively. (11) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 461, 462, and 463, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 464, 465, and 466, respectively. (12) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 467, 468, and 469, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 470, 471, and 472, respectively. (13) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 473, 474, and 475, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 476, 477, and 478, respectively. (14) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 479, 480, and 481, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 482, 483, and 484, respectively. (15) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 485, 486, and 487, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 488, 489, and 490, respectively. (16) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 491, 492, and 493, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 494, 495, and 496, respectively. (17) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 497, 498, and 499, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 500, 501, and 502, respectively. (18) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 503, 504, and 505, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 506, 507, and 508, respectively. (19) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 509, 510, and 511, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 512, 513, and 514, respectively. (20) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 515, 516, and 517, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 518, 519, and 520, respectively. (21) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1175, 1176, and 1177, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1178, 1179, and 1180, respectively. (22) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1181, 1182, and 1183, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1184, 1185, and 1186, respectively. (23) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1187, 1188, and 1189, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1190, 1191, and 1192, respectively. (24) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1193, 1194, and 1195, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1196, 1197, and 1198, respectively. (25) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1199, 1200, and 1201, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1202, 1203, and 1204, respectively. (26) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1205, 1206, and 1207, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1208, 1209, and 1210, respectively. (27) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1211, 1212, and 1213, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1214, 1215, and 1216, respectively. (28) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1217, 1218, and 1219, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1220, 1221, and 1222, respectively. (29) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1223, 1224, and 1225, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1226, 1227, and 1228, respectively. (30) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1229, 1230, and 1231, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1232, 1233, and 1234, respectively. (31) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1235, 1236, and 1237, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1238, 1239, and 1240, respectively. (32) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1241, 1242, and 1243, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1244, 1245, and 1246, respectively. (33) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1247, 1248, and 1249, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1250, 1251, and 1252, respectively. (34) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1253, 1254, and 1255, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1256, 1257, and 1258, respectively. (35) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1259, 1260, and 1261, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1262, 1263, and 1264, respectively. (36) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1265, 1266, and 1267, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1268, 1269, and 1270, respectively. (37) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1271, 1272, and 1273, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1274, 1275, and 1276, respectively. (38) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1277, 1278, and 1279, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1280, 1281, and 1282, respectively. (39) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1283, 1284, and 1285, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1286, 1287, and 1288, respectively. (40) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1289, 1290, and 1291, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1292, 1293, and 1294, respectively.

[0015] In some embodiments, the CDRs are determined by the Aho definition.

[0016] In some embodiments, the selected VH CDR1, 2, and 3 amino acid sequences and the selected VL CDR1, 2, and 3 amino acid sequences are one of the following: (1) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 521, 522, and 523, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 524, 525, and 526, respectively. (2) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 527, 528, and 529, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 530, 531, and 532, respectively. (3) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 533, 534, and 535, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 536, 537, and 538, respectively. (4) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 539, 540, and 541, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 542, 543, and 544, respectively. (5) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 545, 546, and 547, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 548, 549, and 550, respectively. (6) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 551, 552, and 553, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 554, 555, and 556, respectively. (7) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 557, 558, and 559, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 560, 561, and 562, respectively. (8) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 563, 564, and 565, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 566, 567, and 568, respectively. (9) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 569, 570, and 571, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 572, 573, and 574, respectively. (10) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 575, 576, and 577, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 578, 579, and 580, respectively. (11) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 581, 582, and 583, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 584, 585, and 586, respectively. (12) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 587, 588, and 589, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 590, 591, and 592, respectively. (13) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 593, 594, and 595, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 596, 597, and 598, respectively. (14) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 599, 600, and 601, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 602, 603, and 604, respectively. (15) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 605, 606, and 607, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 608, 609, and 610, respectively. (16) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 611, 612, and 613, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 614, 615, and 616, respectively. (17) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 617, 618, and 619, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 620, 621, and 622, respectively. (18) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 623, 624, and 625, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 626, 627, and 628, respectively. (19) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 629, 630, and 631, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 632, 633, and 634, respectively. (20) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 635, 636, and 637, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 638, 639, and 640, respectively. (21) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1295, 1296, and 1297, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1298, 1299, and 1300, respectively. (22) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1301, 1302, and 1303, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1304, 1305, and 1306, respectively. (23) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1307, 1308, and 1309, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1310, 1311, and 1312, respectively. (24) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1313, 1314, and 1315, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1316, 1317, and 1318, respectively. (25) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1319, 1320, and 1321, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1322, 1323, and 1324, respectively. (26) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1325, 1326, and 1327, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1328, 1329, and 1330, respectively. (27) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1331, 1332, and 1333, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1334, 1335, and 1336, respectively. (28) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1337, 1338, and 1339, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1340, 1341, and 1342, respectively. (29) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1343, 1344, and 1345, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1346, 1347, and 1348, respectively. (30) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1349, 1350, and 1351, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1352, 1353, and 1354, respectively. (31) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1355, 1356, and 1357, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1358, 1359, and 1360, respectively. (32) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1361, 1362, and 1363, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1364, 1365, and 1366, respectively. (33) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1367, 1368, and 1369, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1370, 1371, and 1372, respectively. (34) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1373, 1374, and 1375, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1376, 1377, and 1378, respectively. (35) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1379, 1380, and 1381, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1382, 1383, and 1384, respectively. (36) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1385, 1386, and 1387, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1388, 1389, and 1390, respectively. (37) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1391, 1392, and 1393, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1394, 1395, and 1396, respectively. (38) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1397, 1398, and 1399, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1400, 1401, and 1402, respectively. (39) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1403, 1404, and 1405, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1406, 1407, and 1408, respectively. (40) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1409, 1410, and 1411, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1412, 1413, and 1414, respectively.

[0017] In some embodiments, the CDRs are determined by the North definition.

[0018] In some embodiments, the selected VH CDR1, 2, and 3 amino acid sequences and the selected VL CDR1, 2, and 3 amino acid sequences are one of the following: (1) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 708, 709, and 710, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 711, 712, and 713, respectively. (2) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 714, 715, and 716, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 717, 718, and 719, respectively. (3) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 720, 721, and 722, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 723, 724, and 725, respectively. (4) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 726, 727, and 728, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 729, 730, and 731, respectively. (5) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 732, 733, and 734, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 735, 736, and 737, respectively. (6) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 738, 739, and 740, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 741, 742, and 743, respectively. (7) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 744, 745, and 746, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 747, 748, and 749, respectively. (8) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 750, 751, and 752, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 753, 754, and 755, respectively. (9) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 756, 757, and 758, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 759, 760, and 761, respectively. (10) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 762, 763, and 764, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 765, 766, and 767, respectively. (11) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 768, 769, and 770, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 771, 772, and 773, respectively. (12) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 774, 775, and 776, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 777, 778, and 779, respectively. (13) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 780, 781, and 782, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 783, 784, and 785, respectively. (14) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 786, 787, and 788, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 789, 790, and 791, respectively. (15) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 792, 793, and 794, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 795, 796, and 797, respectively. (16) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 798, 799, and 800, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 801, 802, and 803, respectively. (17) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 804, 805, and 806, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 807, 808, and 809, respectively. (18) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 810, 811, and 812, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 813, 814, and 815, respectively.

[0019] In some embodiments, the antibody or antigen-binding fragment thereof specifically binds to human MICA and / or human MICB. In some embodiments, the antibody or antigen-binding fragment thereof specifically binds to monkey MICA and / or monkey MICB. In some embodiments, the antibody or antigen-binding fragment thereof can inhibit shedding of MICA and / or MICB polypeptides from the surface of cancer cells. In some embodiments, the antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof is a single chain variable fragment (scFV) or a multispecific antibody (e.g., a bispecific antibody).

[0020] In one aspect, the disclosure relates to an antibody or antigen-binding fragment thereof that binds to MICA and / or MICB, the antibody or antigen-binding fragment thereof 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 in some embodiments, the selected VH sequence and the selected VL sequence are selected from Figures 23, 25, 26, 27, 28, or 29.

[0021] In some embodiments, the selected VH sequence and the selected VL sequence are one of the following: (1) the selected VH sequence is SEQ ID NO:1 and the selected VL sequence is SEQ ID NO:2. (2) the selected VH sequence is SEQ ID NO: 9 and the selected VL sequence is SEQ ID NO: 10. (3) the selected VH sequence is SEQ ID NO: 17 and the selected VL sequence is SEQ ID NO: 18. (4) the selected VH sequence is SEQ ID NO:25 and the selected VL sequence is SEQ ID NO:26. (5) the selected VH sequence is SEQ ID NO: 33 and the selected VL sequence is SEQ ID NO: 34. (6) the selected VH sequence is SEQ ID NO: 41 and the selected VL sequence is SEQ ID NO: 42. (7) the selected VH sequence is SEQ ID NO: 49 and the selected VL sequence is SEQ ID NO: 50. (8) the selected VH sequence is SEQ ID NO:57 and the selected VL sequence is SEQ ID NO:58. (9) the selected VH sequence is SEQ ID NO: 65 and the selected VL sequence is SEQ ID NO: 66. (10) the selected VH sequence is SEQ ID NO: 73 and the selected VL sequence is SEQ ID NO: 74. (11) The selected VH sequence is SEQ ID NO: 81 and the selected VL sequence is SEQ ID NO: 82. (12) the selected VH sequence is SEQ ID NO: 89 and the selected VL sequence is SEQ ID NO: 90. (13) The selected VH sequence is SEQ ID NO: 97 and the selected VL sequence is SEQ ID NO: 98. (14) The selected VH sequence is SEQ ID NO: 105 and the selected VL sequence is SEQ ID NO: 106. (15) The selected VH sequence is SEQ ID NO: 113 and the selected VL sequence is SEQ ID NO: 114. (16) The selected VH sequence is SEQ ID NO: 121 and the selected VL sequence is SEQ ID NO: 122. (17) The selected VH sequence is SEQ ID NO: 129 and the selected VL sequence is SEQ ID NO: 130. (18) The selected VH sequence is SEQ ID NO: 137 and the selected VL sequence is SEQ ID NO: 138. (19) The selected VH sequence is SEQ ID NO: 145 and the selected VL sequence is SEQ ID NO: 146. (20) The selected VH sequence is SEQ ID NO: 153 and the selected VL sequence is SEQ ID NO: 154.

[0022] In some embodiments, the selected VH sequence is SEQ ID NO: 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 NO: 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651 or 652 and the selected VL sequence is SEQ ID NO: 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 NO: 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 NO: 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, the VH comprises the sequence of SEQ ID NO: 641 and the VL comprises the sequence of SEQ ID NO: 653. In some embodiments, the VH comprises the sequence of SEQ ID NO: 642 and the VL comprises the sequence of SEQ ID NO: 653. In some embodiments, the VH comprises the sequence of SEQ ID NO: 643 and the 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, the VH comprises the sequence of SEQ ID NO:652 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: 658. In some embodiments, the VH comprises the sequence of SEQ ID NO: 652 and the 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, the VH comprises the sequence of SEQ ID NO: 704 and the VL comprises the sequence of SEQ ID NO: 705. In some embodiments, the VH comprises the sequence of SEQ ID NO: 706 and the VL comprises the sequence of SEQ ID NO: 707.

[0023] 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).

[0024] In one aspect, the disclosure relates to antibodies, or antigen-binding fragments thereof, that cross-compete with the antibodies, or antigen-binding fragments thereof, described herein.

[0025] In one aspect, the disclosure relates to an antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, and a light chain variable region (VL) comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein 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.

[0026] In one aspect, the disclosure relates to an antibody-drug conjugate comprising an antibody or antigen-binding fragment thereof described herein covalently linked to a therapeutic agent. In some embodiments, the therapeutic agent is a cytotoxic or cytostatic drug.

[0027] In one aspect, the disclosure relates to a method of treating a subject suffering from cancer, comprising administering to the subject a therapeutically effective amount of a composition comprising an antibody or antigen-binding fragment thereof, or an antibody-drug conjugate described herein. In some embodiments, the subject suffers from a solid tumor or a hematological cancer. In some embodiments, the cancer is melanoma, neuroblastoma, prostate cancer, renal cancer, multiple myeloma, or chronic lymphocytic leukemia.

[0028] In one aspect, the disclosure relates to a method of reducing tumor growth rate comprising contacting tumor cells with an effective amount of a composition comprising an antibody or antigen-binding fragment thereof, or an antibody-drug conjugate described herein.

[0029] In one aspect, the disclosure relates to a method of killing a tumor cell, comprising contacting the tumor cell with an effective amount of a composition comprising an antibody or antigen-binding fragment thereof, or an antibody-drug conjugate described herein.

[0030] In one aspect, the disclosure relates to a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof, or an antibody-drug conjugate described herein, and a pharma- ceutically acceptable carrier.

[0031] In one aspect, the disclosure relates to a nucleic acid comprising a polynucleotide encoding a polypeptide, the nucleic acid 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, comprising VH CDRs 1, 2, 3, as depicted in Figure 24A, 24B, 24C, 24D, 24E, 28, 29, 30A, 30B, 30C, 30D, or 30E; or (2) an immunoglobulin light chain or fragment thereof comprising a VL comprising VL CDRs 1, 2, 3, as depicted in Figure 24A, 24B, 24C, 24D, 24E, 28, 29, 30A, 30B, 30C, 30D, or 30E; in some embodiments, the VH binds MICA and / or MICB when paired with a corresponding light chain variable region (VL), and the VL binds MICA and / or MICB when paired with a corresponding VH.

[0032] In some embodiments, one of the following is true: (1) The immunoglobulin heavy chain or fragment thereof comprises 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, the VH binds to MICA and / or MICB when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 2. (2) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO:11, 12, and 13, 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 NO:10. (3) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 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 NO: 18. (4) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 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 NO: 26. (5) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 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 NO: 34. (6) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 42. (7) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 51, 52, and 53, 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 NO: 50. (8) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 58. (9) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 66. (10) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 74. (11) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 82. (12) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 91, 92, and 93, 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 NO: 90. (13) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 99, 100, and 101, 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 NO: 98. (14) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 107, 108, and 109, 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 NO: 106. (15) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 115, 116, and 117, 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 NO: 114. (16) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 123, 124, and 125, 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 NO: 122. (17) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 131, 132, and 133, 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 NO: 130. (18) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 139, 140, and 141, 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 NO: 138. (19) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 147, 148, and 149, 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 NO: 146. (20) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 155, 156, and 157, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO: 154. (21) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 6, 7, and 8, 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 NO: 1. (22) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 14, 15, and 16, 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 NO: 9. (23) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 22, 23, and 24, 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 NO: 17. (24) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising 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 NO: 25. (25) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising 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 NO: 33. (26) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 46, 47, and 48, 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 NO: 41. (27) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 54, 55, and 56, 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 NO: 49. (28) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising 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 NO: 57. (29) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 70, 71, and 72, 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 NO: 65. (30) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 78, 79, and 80, 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 NO: 73. (31) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 86, 87, and 88, 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 NO: 81. (32) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising 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 NO: 89. (33) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 102, 103, and 104, 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 NO: 97. (34) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising 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 NO: 105. (35) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 118, 119, and 120, 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 NO: 113. (36) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising 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 NO: 121. (37) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 134, 135, and 136, 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 NO: 129. (38) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 142, 143, and 144, 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 NO: 137. (39) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising 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 NO: 145. (40) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 158, 159, and 160, 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 NO: 153. (41) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 815, 816, and 817, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (42) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 821, 822, and 823, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (43) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (44) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (45) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (46) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (47) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (48) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (49) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (50) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (51) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (52) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (53) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (54) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (55) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (56) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (57) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (58) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (59) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (60) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 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 NO: 653, 654, 655, 656, 657, 658, 691, 693, 695, 697, 699, 701, 703, 705, or 707. (61) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (62) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 824, 825, and 826, 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (63) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (64) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (65) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (66) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (67) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 854, 855, and 856, 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (68) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (69) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (70) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (71) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (72) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (73) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (74) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (75) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (76) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (77) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 914, 915, and 916, 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (78) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706. (79) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 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 (80) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth 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 set forth in SEQ ID NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 690, 692, 694, 696, 698, 700, 702, 704, or 706.

[0033] In some embodiments, the VH, when paired with a VL, specifically binds human MICA and / or MICB, or the VL, when paired with a VH, specifically binds human MICA and / or MICB. In some embodiments, 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. 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.

[0034] In one aspect, the disclosure relates to a vector comprising one or more of the nucleic acids described herein. In one aspect, the disclosure relates to a vector comprising two of the nucleic acids described herein, in some embodiments, the vectors encode the VL and VH regions that together bind MICA and / or MICB. In one aspect, the disclosure relates to a pair of vectors, in some embodiments, each vector comprises one of the nucleic acids described herein, in some embodiments, the pair of vectors encode the VL and VH regions that together bind MICA and / or MICB.

[0035] In one aspect, the disclosure relates to a cell comprising a vector or vector pair described herein. In some embodiments, the cell is a CHO cell. In one aspect, the disclosure relates to a cell comprising one or more nucleic acids described herein. In one aspect, the disclosure relates to a cell comprising two nucleic acids described herein. In some embodiments, the two nucleic acids both encode the VL region and the VH region that both bind MICA and / or MICB.

[0036] In one aspect, the disclosure relates to a method of producing an antibody or antigen-binding fragment thereof, comprising: (a) culturing a cell described herein under conditions sufficient for the cell to produce the antibody or antigen-binding fragment; and (b) harvesting the antibody or antigen-binding fragment produced by the cell.

[0037] The term "cancer" as used herein refers to cells that have the ability to grow autonomously. Examples of such cells include cells that have an abnormal state or pathology characterized by rapidly proliferating cell proliferation. The term is meant to include cancerous growths, such as tumors, oncogenic processes, metastatic tissues, and malignantly transformed cells, tissues, or organs, regardless of histopathological type or stage of invasiveness. It also includes malignant tumors of various organ systems, such as the respiratory, cardiovascular, renal, reproductive, hematological, nervous, hepatic, gastrointestinal, and endocrine systems, as well as adenocarcinomas, including malignant tumors, such as most colon cancers, renal cell carcinoma, prostate and / or testicular cancer, non-small cell carcinoma of the lung, and small intestine cancer. "Naturally occurring" cancer includes any cancer that is not experimentally induced by implanting cancer cells in a subject, including, for example, naturally occurring cancers, cancers caused by exposure of a patient to a carcinogen, cancers caused by the insertion of a transgenic oncogene or knockout of a tumor suppressor gene, and cancers caused by infections, such as viral infections. The term "carcinoma" is art-recognized and refers to malignant tumors of epithelial or endocrine tissue. The term also includes carcinosarcomas, which include malignant tumors composed of carcinomatous and sarcomatous tissue. The term "adenocarcinoma" refers to cancers arising in glandular tissue or carcinomas in which the tumor cells form recognizable glandular structures. The term "sarcoma" is art-recognized and refers to malignant tumors of mesenchymal origin. The term "hematopoietic neoplastic disorder" includes diseases involving hyperplastic / neoplastic cells of hematopoietic origin. Hematopoietic neoplastic disorders may arise from myeloid, lymphoid, erythroid, or their precursor cells.

[0038] The term "antibody" as used herein refers to any antigen-binding molecule that comprises at least one (e.g., one, two, three, four, five, or six) complementarity determining regions (CDRs) (e.g., any one of the three CDRs of an immunoglobulin light chain or any one of the three CDRs of an immunoglobulin heavy chain) and can specifically bind 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, an antibody can comprise an Fc region of a human antibody. The term antibody also includes derivatives such as bispecific antibodies, single chain antibodies, diabodies, linear antibodies, and multispecific antibodies formed from antibody fragments.

[0039] The term "antigen-binding fragment" as used herein refers to a portion of a full-length antibody, which 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 heavy chain variable domain or a light chain variable domain). Non-limiting examples of antibody fragments include, for example, Fab, Fab', F(ab')2, and Fv fragments.

[0040] As used herein, the term "human antibody" refers to an antibody that is encoded by endogenous nucleic acid present in a human (e.g., a rearranged human immunoglobulin heavy or light chain locus). In some embodiments, a human antibody is obtained from a human or produced in a human cell culture (e.g., a human hybridoma cell). In some embodiments, a human antibody is produced in a non-human cell (e.g., a mouse or hamster cell line). In some embodiments, a human antibody is produced in a bacterial cell or a yeast cell. In some embodiments, a human antibody is produced in a transgenic non-human animal (e.g., a cow) that includes unrearranged or rearranged human immunoglobulin loci (e.g., a heavy or light chain human immunoglobulin locus).

[0041] The term "chimeric antibody" as used herein refers to an antibody that contains sequences present in at least two different antibodies (e.g., antibodies from two different mammalian species, such as a human antibody and a murine antibody). Non-limiting examples of chimeric antibodies include antibodies that contain variable domain sequences (e.g., all or a portion of the light and / or heavy chain variable domain sequences) of a non-human (e.g., murine) antibody and the constant domain of a human antibody. Further examples of chimeric antibodies are described herein and known in the art.

[0042] The term "humanized antibody" as used herein refers to a non-human antibody that contains minimal sequence derived from non-human (e.g., murine) immunoglobulin and contains sequence derived from human immunoglobulin. In a non-limiting example, a humanized antibody is a human antibody (recipient antibody) in which hypervariable (e.g., CDR) region residues of the recipient antibody are replaced by hypervariable (e.g., CDR) region residues of a non-human antibody (e.g., donor antibody), such as a mouse, rat, or rabbit antibody, having the desired specificity, affinity, and capacity. In some embodiments, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human (e.g., murine) immunoglobulin residues. In some embodiments, humanized antibodies may include residues that are not found in the recipient antibody or the donor antibody. These modifications can be made to further refine antibody performance. In some embodiments, a humanized antibody comprises substantially all of at least one, typically two, variable domains, in which all or substantially all of the hypervariable loops (CDRs) correspond to the CDRs of a non-human (e.g., murine) immunoglobulin and all or substantially all of the framework regions are human immunoglobulin framework regions. The humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), typically a human immunoglobulin constant region. Humanized antibodies can be produced using molecular biology methods known in the art. Non-limiting examples of methods for generating humanized antibodies are described herein.

[0043] As used herein, the term "single chain antibody" refers to a single polypeptide comprising at least two immunoglobulin variable domains (e.g., variable domains of a mammalian immunoglobulin heavy or light chain) capable of specifically binding to an antigen. Non-limiting examples of single chain antibodies are described herein.

[0044] As used herein, the term "multimeric antibody" refers to an antibody that comprises four or more (e.g., six, eight, or ten) immunoglobulin variable domains. In some embodiments, the multimeric antibody is capable of cross-linking one target molecule (e.g., MICA or MICB) to at least one second target molecule (e.g., MICA or MICB) on the surface of a mammalian cell (e.g., a human T cell).

[0045] As used herein, the terms "subject" and "patient" are used interchangeably throughout the specification and refer to an animal, human or non-human, to which treatment according to the methods of the invention is provided. Veterinary and non-veterinary applications are contemplated for the present invention. A human patient can be an adult or adolescent human (e.g., a human under the age of 18). Patients include, but are not limited to, humans, as well as 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, boars (e.g., pigs, minipigs), equines, canines, felines, bovines, and other domestic, farm, and zoo animals.

[0046] As used herein, the phrases "specifically binding" and "specifically binds" when referring to an antibody mean that the antibody interacts with its target molecule (e.g., MICA and / or MICB), and preferably with other molecules, because the interaction is dependent on the presence of a particular structure (i.e., antigenic determinant or epitope) on the target molecule; in other words, the reagent recognizes and binds to a molecule that contains 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.

[0047] As used herein, the terms "polypeptide," "peptide," and "protein" are used interchangeably to refer to polymers of amino acids of any length of at least two amino acids.

[0048] As used herein, the terms "polynucleotide," "nucleic acid molecule," and "nucleic acid sequence" are used interchangeably herein to refer to polymers of nucleotides of any length of at least two nucleotides, including, but not limited to, DNA, RNA, DNA / RNA hybrids, and modifications thereof.

[0049] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Methods and materials for use in the present invention are described herein, but other suitable methods and materials known in the art can also be used. The materials, methods, and examples are for illustrative purposes only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0050] Other features and advantages of the invention will become apparent from the following detailed description and drawings, and from the claims. [Brief description of the drawings]

[0051] [Figure 1A] 1 shows the binding affinity of chimeric anti-MICA / B antibodies to MICB005, MICA002, MICA004 and MICA008 polypeptides as measured by the Carterra® high-throughput antibody characterization platform. Anti-MICA / B antibodies 1D5, 3F9, 13A9, 6E1.1.12, B10G5 are reference antibodies and are used for benchmarking purposes. [Figure 1B] Binding affinities of humanized anti-MICA / B antibodies to MICB005, MICA002, MICA004 and MICA008 polypeptides as measured by the Carterra® high-throughput antibody characterization platform. Anti-MICA / B antibodies 1D5, 3F9 and 13A9 are reference antibodies. [Figure 1C] Summary of the binding affinities of humanized and optimized anti-MICA / B antibodies to MICB005, MICA002, MICA004, MICA008, MICA009 and cynomolgus monkey MICA (cynoMICA) polypeptides as measured by the GatorPrime™ biolayer interferometry platform. Anti-MICA / B antibodies 1D5, 3F9, 13A9, 6E1.1.12, and B10G5-2 are reference antibodies and are used for benchmarking purposes. [Figure 2A] Chimeric anti-MICA / B antibodies binding to MICA / B polypeptide in CHO-MICA002 cells. CHO-MICA002 cells were incubated with titrated anti-MICA / B antibodies followed by 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). Antibody binding signals to MICA / B on APC (gMFI) were measured by flow cytometry. [Figure 2B]Chimeric anti-MICA / B antibodies binding to MICA / B polypeptide in CHO-MICA004 cells. CHO-MICA004 cells were incubated with titrated anti-MICA / B antibodies followed by 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). Antibody binding signals to MICA / B on APC (gMFI) were measured by flow cytometry. [Figure 2C] Chimeric anti-MICA / B antibodies binding to MICA / B polypeptide in CHO-MICA008 cells. CHO-MICA008 cells were incubated with titrated anti-MICA / B antibodies followed by 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). Antibody binding signals to MICA / B on APC (gMFI) were measured by flow cytometry. [Figure 2D] 1 shows chimeric anti-MICA / B antibodies binding to MICA / B polypeptide in CHO-MICB005 cells. CHO-MICB005 cells were incubated with titrated anti-MICA / B antibodies followed by 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). Antibody binding signals to MICA / B on APC (gMFI) were measured by flow cytometry. [Figure 2E] Chimeric anti-MICA / B antibodies binding to MICA / B polypeptide in HeLa cells expressing MICA008. HeLa cells were incubated with titrated anti-MICA / B antibodies followed by 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). Antibody binding signals to MICA / B on APC (gMFI) were measured by flow cytometry. [Figure 2F]1 is a table showing the maximum MFI and calculated EC50 of chimeric anti-MICA / B antibodies against MICA / B polypeptides. [Figure 3A] Figure 1 shows humanized anti-MICA / B antibodies binding to MICA / B polypeptide in CHO-MICA002 cells incubated with titrated anti-MICA / B antibodies followed by APC-labeled anti-human Fc antibodies. Anti-MICA / B antibody 1D5 is the reference antibody. IgG1 is the isotype control (IgG). Antibody binding signals to MICA / B on APC (gMFI) were measured by flow cytometry. [Figure 3B] Figure 1 shows humanized anti-MICA / B antibodies binding to MICA / B polypeptide in CHO-MICA004 cells incubated with titrated anti-MICA / B antibodies followed by APC-labeled anti-human Fc antibodies. Anti-MICA / B antibody 1D5 is the reference antibody. IgG1 is the isotype control (IgG). Antibody binding signals to MICA / B on APC (gMFI) were measured by flow cytometry. [Figure 3C] Figure 1 shows humanized anti-MICA / B antibody binding to MICA / B polypeptide in CHO-MICA008 cells incubated with titrated anti-MICA / B antibody followed by APC-labeled anti-human Fc antibody. Anti-MICA / B antibody 1D5 is the reference antibody. IgG1 is the isotype control (IgG). Antibody binding signal to MICA / B on APC (gMFI) was measured by flow cytometry. [Figure 3D] Figure 1 shows humanized anti-MICA / B antibody binding to MICA / B polypeptide in CHO-MICA005 cells incubated with titrated anti-MICA / B antibody followed by APC-labeled anti-human Fc antibody. Anti-MICA / B antibody 1D5 is the reference antibody. IgG1 is the isotype control (IgG). Antibody binding signal to MICA / B on APC (gMFI) was measured by flow cytometry. [Figure 3E]Figure 1 shows humanized anti-MICA / B antibodies binding to MICA / B polypeptide in CHO-MICA002 cells incubated with titrated anti-MICA / B antibodies followed by APC-labeled anti-human Fc antibodies. Anti-MICA / B antibodies 1D5 and 3F9 are reference antibodies. IgG1 is an isotype control (IgG). Antibody binding signals to MICA / B on APC (gMFI) were measured by flow cytometry. [Figure 3F] Figure 1 shows humanized anti-MICA / B antibodies binding to MICA / B polypeptide in CHO-MICB004 cells incubated with titrated anti-MICA / B antibodies followed by APC-labeled anti-human Fc antibodies. Anti-MICA / B antibodies 1D5 and 3F9 are reference antibodies. IgG1 is an isotype control (IgG). Antibody binding signals to MICA / B on APC (gMFI) were measured by flow cytometry. [Figure 3G] Figure 1 shows humanized anti-MICA / B antibodies binding to MICA / B polypeptide in CHO-MICA008 cells incubated with titrated anti-MICA / B antibodies followed by APC-labeled anti-human Fc antibodies. Anti-MICA / B antibodies 1D5 and 3F9 are reference antibodies. IgG1 is an isotype control (IgG). Antibody binding signals to MICA / B on APC (gMFI) were measured by flow cytometry. [Figure 3H] Figure 1 shows humanized anti-MICA / B antibodies binding to MICA / B polypeptide in CHO-MICB005 cells incubated with titrated anti-MICA / B antibodies followed by APC-labeled anti-human Fc antibodies. Anti-MICA / B antibodies 1D5 and 3F9 are reference antibodies. IgG1 is an isotype control (IgG). Antibody binding signals to MICA / B on APC (gMFI) were measured by flow cytometry. [Figure 3I] Optimized h36B3 mutants binding to MICA / B polypeptide in CHO-MICA002 cells incubated with titrated anti-MICA / B antibodies followed by APC-labeled anti-human Fc antibodies. IgG1 is an isotype control (IgG). Antibody binding signal to MICA / B on APC (gMFI) was measured by flow cytometry. [Figure 3J] Optimized h36B3 mutants binding to MICA / B polypeptide in CHO-MICA004 cells incubated with titrated anti-MICA / B antibodies followed by APC-labeled anti-human Fc antibodies. IgG1 is an isotype control (IgG). Antibody binding signal to MICA / B on APC (gMFI) was measured by flow cytometry. [Figure 3K] Optimized h36B3 mutants binding to MICA / B polypeptide in CHO-MICA008 cells incubated with titrated anti-MICA / B antibodies followed by APC-labeled anti-human Fc antibodies. IgG1 is an isotype control (IgG). Antibody binding signal to MICA / B on APC (gMFI) was measured by flow cytometry. [Figure 3L] Optimized h36B3 mutants binding to MICA / B polypeptide in CHO-MICB005 cells incubated with titrated anti-MICA / B antibodies followed by APC-labeled anti-human Fc antibodies. IgG1 is the isotype control (IgG). Antibody binding signal to MICA / B on APC (gMFI) was measured by flow cytometry. [Figure 3M] Figure 1 shows humanized anti-MICA / B antibodies binding to MICA / B polypeptide in HeLa cells incubated with titrated anti-MICA / B antibodies followed by APC-labeled anti-human Fc antibodies. Anti-MICA / B antibodies 1D5 and 3F9 are reference antibodies. IgG1 is an isotype control (IgG). Antibody binding signals to MICA / B on APC (gMFI) were measured by flow cytometry. [Figure 3N] Optimized h36B3 variants binding to MICA / B polypeptide in HeLa cells incubated with titrated anti-MICA / B antibodies followed by APC-labeled anti-human Fc antibodies are shown. Antibody binding signals to MICA / B on APC (gMFI) were measured by flow cytometry. [Figure 3O]Optimized h36B3 mutants binding to MICA / B polypeptide in CHO-MICA002 cells incubated with titrated anti-MICA / B antibodies followed by APC-labeled anti-human Fc antibodies. IgG1 is an isotype control (IgG). Antibody binding signal to MICA / B on APC (gMFI) was measured by flow cytometry. [Figure 3P] Optimized h36B3 mutants binding to MICA / B polypeptide in CHO-MICA004 cells incubated with titrated anti-MICA / B antibodies followed by APC-labeled anti-human Fc antibodies. IgG1 is an isotype control (IgG). Antibody binding signal to MICA / B on APC (gMFI) was measured by flow cytometry. [Figure 3Q] Optimized h36B3 mutants binding to MICA / B polypeptide in CHO-MICA008 cells incubated with titrated anti-MICA / B antibodies followed by APC-labeled anti-human Fc antibodies. IgG1 is an isotype control (IgG). Antibody binding signal to MICA / B on APC (gMFI) was measured by flow cytometry. [Figure 3R] Optimized h36B3 mutants binding to MICA / B polypeptide in CHO-MICB005 cells incubated with titrated anti-MICA / B antibodies followed by APC-labeled anti-human Fc antibodies. IgG1 is the isotype control (IgG). Antibody binding signal to MICA / B on APC (gMFI) was measured by flow cytometry. [Figure 3S] 1 is a table showing the maximum MFI and calculated EC50 of humanized anti-MICA / B antibodies against MICA / B polypeptides expressed by CHO cells. [Figure 3T] 1 is a table showing the maximum MFI and calculated EC50 of humanized anti-MICA / B antibodies against MICA / B polypeptides expressed by CHO cells or HeLa cells. [Figure 3U]1 is a table showing the maximum MFI and calculated EC50 of optimized h36B3 variants against MICA / B polypeptide expressed by CHO cells. [Figure 4A] 1 is a plot showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptide from CHO-MICA002 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 4B] 1 is a plot showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptide from C1R-MICA004 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 4C] 1 is a plot showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptide from C1R-MICA008 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 4D] 1 is a plot showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptide from C1R-MICB005 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 4E] 1 is a plot showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptide from HeLa cells expressing MICA008 polypeptide. Shed MICA / B polypeptide in cell culture medium was quantified by sandwich ELISA. [Figure 4F] 1 is a table showing the maximum shedding inhibition and calculated IC50 of chimeric anti-MICA / B antibodies against MICA / B polypeptides. [Figure 5A] Plot showing surface MICA / B expression on C1R-MICA002 cells treated with chimeric anti-MICA / B antibody. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4, which does not compete with our anti-MICA / B. [Figure 5B] FIG. 13 is a plot showing surface MICA / B expression on C1R-MICA004 cells treated with chimeric anti-MICA / B antibodies. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4, which does not compete with our anti-MICA / B. [Figure 5C] Plot showing surface MICA / B expression on C1R-MICA008 cells treated with chimeric anti-MICA / B antibody. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4, which does not compete with our anti-MICA / B. [Figure 5D] FIG. 13 is a plot showing surface MICA / B expression on C1R-MICA005 cells treated with chimeric anti-MICA / B antibodies. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4, which does not compete with our anti-MICA / B. [Figure 5E] Plot showing surface MICA / B expression on HeLa cells treated with chimeric anti-MICA / B antibodies. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4, which does not compete with our anti-MICA / B. [Figure 5F] 1 is a table showing increased expression of MICA / B and the calculated EC50 of chimeric anti-MICA / B antibodies against MICA / B polypeptides. [Figure 6A] 1 is a plot showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptide from C1R-MICA002 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 6B] 1 is a plot showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptide from C1R-MICA004 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 6C]1 is a plot showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptide from C1R-MICA008 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 6D] 1 is a plot showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptide from C1R-MICB005 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 6E] 1 is a plot showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptide from C1R-MICA002 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 6F] 1 is a plot showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptide from C1R-MICA004 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 6G] 1 is a plot showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptide from C1R-MICA008 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 6H] 1 is a plot showing that anti-MICA / B antibodies can inhibit the shedding of MICA / B polypeptide from C1R-MICB005 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 6I] 1 is a plot showing that the optimized h36B3 mutant can inhibit the shedding of MICA / B polypeptide from C1R-MICA002 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 6J]1 is a plot showing that the optimized h36B3 mutant can inhibit the shedding of MICA / B polypeptide from C1R-MICA004 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 6K] 1 is a plot showing that the optimized h36B3 mutant can inhibit the shedding of MICA / B polypeptide from C1R-MICA008 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 6L] 1 is a plot showing that the optimized h36B3 mutant can inhibit the shedding of MICA / B polypeptide from C1R-MICB005 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 6M] 1 is a plot showing that the optimized h36B3 mutant can inhibit the shedding of MICA / B polypeptide from C1R-MICA002 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 6N] 1 is a plot showing that the optimized h36B3 mutant can inhibit the shedding of MICA / B polypeptide from C1R-MICA004 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 6O] 1 is a plot showing that the optimized h36B3 mutant can inhibit the shedding of MICA / B polypeptide from C1R-MICA008 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 6P] 1 is a plot showing that the optimized h36B3 mutant can inhibit the shedding of MICA / B polypeptide from C1R-MICB005 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. [Figure 6Q]1 is a table showing the maximum shedding inhibition and calculated IC50 of humanized anti-MICA / B antibodies against several MICA / B polypeptides. [Figure 6R] 1 is a table showing the maximum shedding inhibition and calculated IC50 of humanized anti-MICA / B antibodies against several MICA / B polypeptides. [Figure 6S] 1 is a table showing the maximum shedding inhibition and calculated IC50 of optimized h36B3 variants against several MICA / B polypeptides. [Figure 6T] 1 is a table showing the maximum shedding inhibition and calculated IC50 of optimized h36B3 variants against several MICA / B polypeptides. [Figure 6U] FIG. 1 is a plot comparing the ability of D2M001-209 and benchmark anti-MICA / B to inhibit the shedding of MICA / B polypeptide from C1R-MICB005 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. Maximum shedding inhibition and calculated IC50 are shown below the plot. [Figure 6V] FIG. 1 is a plot comparing the ability of D2M001-209 and benchmark anti-MICA / B to inhibit the shedding of MICA / B polypeptide from C1R-MICA002 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. Maximum shedding inhibition and calculated IC50 are shown below the plot. [Figure 6W] FIG. 1 is a plot comparing the ability of D2M001-209 and benchmark anti-MICA / B to inhibit the shedding of MICA / B polypeptide from C1R-MICA004 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. Maximum shedding inhibition and calculated IC50 are shown below the plot. [Figure 6X]FIG. 1 is a plot comparing the ability of D2M001-209 and benchmark anti-MICA / B to inhibit the shedding of MICA / B polypeptide from C1R-MICA008 cells. Shed MICA / B polypeptide in the cell culture medium was quantified by sandwich ELISA. Maximum shedding inhibition and calculated IC50 are shown below the plot. [Figure 7A] FIG. 1 is a plot showing surface MICA / B expression on C1R-MICA002 cells treated with humanized anti-MICA / B antibody. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. [Figure 7B] FIG. 1 is a plot showing surface MICA / B expression on C1R-MICA004 cells treated with humanized anti-MICA / B antibody. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. [Figure 7C] FIG. 1 is a plot showing surface MICA / B expression on C1R-MICA008 cells treated with humanized anti-MICA / B antibody. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. [Figure 7D] FIG. 1 is a plot showing surface MICA / B expression on C1R-MICB005 cells treated with humanized anti-MICA / B antibody. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. [Figure 7E] FIG. 1 is a plot showing surface MICA / B expression on C1R-MICA002 cells treated with humanized anti-MICA / B antibody. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. [Figure 7F] FIG. 1 is a plot showing surface MICA / B expression on C1R-MICA004 cells treated with humanized anti-MICA / B antibody. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. [Figure 7G]FIG. 1 is a plot showing surface MICA / B expression on C1R-MICA008 cells treated with humanized anti-MICA / B antibody. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. [Figure 7H] FIG. 1 is a plot showing surface MICA / B expression on C1R-MICB005 cells treated with humanized anti-MICA / B antibody. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. [Figure 7I] FIG. 13 is a plot showing surface MICA / B expression in C1R-MICA002 cells treated with optimized h36B3 mutants. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. [Figure 7J] FIG. 13 is a plot showing surface MICA / B expression in C1R-MICA004 cells treated with optimized h36B3 mutants. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. [Figure 7K] FIG. 13 is a plot showing surface MICA / B expression in C1R-MICA008 cells treated with optimized h36B3 mutants. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. [Figure 7L] FIG. 1 is a plot showing surface MICA / B expression in C1R-MICB005 cells treated with optimized h36B3 mutants. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. [Figure 7M] FIG. 13 is a plot showing surface MICA / B expression in C1R-MICA002 cells treated with optimized h36B3 mutants. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. [Figure 7N]FIG. 13 is a plot showing surface MICA / B expression in C1R-MICA004 cells treated with optimized h36B3 mutants. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. [Figure 7O] FIG. 13 is a plot showing surface MICA / B expression in C1R-MICA008 cells treated with optimized h36B3 mutants. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. [Figure 7P] FIG. 13 is a plot showing surface MICA / B expression in C1R-MICB005 cells treated with optimized h36B3 mutants. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. [Figure 7Q] 1 is a table showing the maximum increase in expression of MICA / B and the calculated EC50 of humanized anti-MICA / B antibodies against several MICA / B polypeptides. [Figure 7R] 1 is a table showing the maximum increase in expression of MICA / B and the calculated EC50 of humanized anti-MICA / B antibodies against several MICA / B polypeptides. [Figure 7S] 1 is a table showing the maximum expression increase of MICA / B and the calculated EC50 of optimized h36B3 variants against several MICA / B polypeptides. [Figure 7T] 1 is a table showing the maximum expression increase of MICA / B and the calculated EC50 of optimized h36B3 variants against several MICA / B polypeptides. [Figure 7U] FIG. 1 is a plot comparing the ability of D2M001-209 and benchmark anti-MICA / B to stabilize surface MICA / B polypeptides on C1R-MICB005 cells. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. The calculated EC50, TopMFI and % increase in surface MICB005 are shown below the plot. [Figure 7V]Figure 1 is a plot comparing the ability of D2M001-209 and benchmark anti-MICA / B to stabilize surface MICA / B polypeptide on C1R-MICA002 cells. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. The calculated EC50, TopMFI and % increase in surface MICA002 are shown below the plot. [Figure 7W] Figure 1 is a plot comparing the ability of D2M001-209 and benchmark anti-MICA / B to stabilize surface MICA / B polypeptide on C1R-MICA004 cells. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. The calculated EC50, TopMFI and % increase in surface MICA004 are shown below the plot. [Figure 7X] Figure 1 is a plot comparing the ability of D2M001-209 and benchmark anti-MICA / B to stabilize surface MICA / B polypeptide on C1R-MICA008 cells. MICA / B signal was quantified by flow cytometry using PE-anti-MICA / B 6D4. The calculated EC50, TopMFI and % increase in surface MICA008 are shown below the plot. [Figure 8A] 1 is a plot showing that chimeric anti-MICA / B antibodies can capture MICA002 polypeptides shed from cells. The shed / bound MICA / B polypeptides were derived from conditioned growth media of CHO-MICA002 cells. [Figure 8B] 1 is a plot showing that chimeric anti-MICA / B antibodies can capture MICA004 polypeptides shed from cells. The shed / bound MICA / B polypeptides were derived from conditioned growth media of CHO-MICA004 cells. [Figure 8C] 1 is a plot showing that chimeric anti-MICA / B antibodies can capture MICA008 polypeptides shed from cells. The shed / bound MICA / B polypeptides were derived from conditioned growth media of CHO-MICA008 cells. [Figure 8D]1 is a plot showing that chimeric anti-MICA / B antibodies can capture MICB005 polypeptides shed from cells. The shed / bound MICA / B polypeptides were derived from conditioned growth media of CHO-MICB005 cells. [Figure 8E] 1 is a table showing the maximum OD450 and calculated EC50 of chimeric anti-MICA / B antibodies against various shed MICA / B polypeptides. [Figure 9A] Figure 13 is a plot showing that humanized anti-MICA / B antibody (#39 variant) can capture MICA002 polypeptide shed from cells. The shed / bound MICA / B polypeptide was derived from conditioned growth media of CHO-MICA002 cells. [Figure 9B] Figure 13 is a plot showing that humanized anti-MICA / B antibody (#39 variant) can capture MICA004 polypeptide shed from cells. The shed / bound MICA / B polypeptide was derived from conditioned growth media of CHO-MICA004 cells. [Figure 9C] Figure 13 is a plot showing that humanized anti-MICA / B antibody (#39 variant) can capture MICA008 polypeptide shed from cells. The shed / bound MICA / B polypeptide was derived from conditioned growth media of CHO-MICA008 cells. [Figure 9D] Figure 13 is a plot showing that humanized anti-MICA / B antibody (#39 variant) can capture MICB005 polypeptide shed from cells. The shed / bound MICA / B polypeptide was derived from conditioned growth media of CHO-MICB005 cells. [Figure 9E] 1 is a plot showing that humanized anti-MICA / B antibodies can capture soluble MICA002 polypeptides shed from cells. The shed / bound MICA / B polypeptides were derived from conditioned growth media of CHO-MICA002 cells. [Figure 9F] 1 is a plot showing that humanized anti-MICA / B antibodies can capture soluble MICA004 polypeptides shed from cells. The shed / bound MICA / B polypeptides were derived from conditioned growth media of CHO-MICA004 cells. [Figure 9G] 1 is a plot showing that humanized anti-MICA / B antibodies can capture soluble MICA008 polypeptides shed from cells. The shed / bound MICA / B polypeptides were derived from conditioned growth media of CHO-MICA008 cells. [Figure 9H] 1 is a plot showing that humanized anti-MICA / B antibodies can capture soluble MICB005 polypeptides shed from cells. The shed / bound MICA / B polypeptides were derived from conditioned growth media of CHO-MICB005 cells. [Figure 9I] 1 is a table showing the maximum OD450 and calculated EC50 of a humanized anti-MICA / B antibody (#39 variant) against several truncated MICA / B polypeptides. [Figure 9J] 1 is a table showing the maximum OD450 and calculated EC50 of humanized anti-MICA / B antibodies against several shed MICA / B polypeptides. [Figure 9K] Figure 13 is a plot showing that humanized anti-MICA / B antibody (optimized h36B3 variant) can capture soluble MICA002 polypeptide shed from cells. The shed / bound MICA / B polypeptide was derived from conditioned growth media of CHO-MICA008 cells. [Figure 9L] Figure 13 is a plot showing that humanized anti-MICA / B antibody (optimized h36B3 variant) can capture soluble MICA004 polypeptide shed from cells. The shed / bound MICA / B polypeptide was derived from conditioned growth medium of CHO-MICB005 cells. [Figure 9M] Figure 1 is a plot showing that humanized anti-MICA / B antibody (optimized h36B3 variant) can capture soluble MICA008 polypeptide shed from cells. The shed / bound MICA / B polypeptide was derived from conditioned growth media of CHO-MICA008 cells. [Figure 9N]Figure 1 is a plot showing that humanized anti-MICA / B antibody (optimized h36B3 variant) can capture soluble MICB005 polypeptide shed from cells. The shed / bound MICA / B polypeptide was derived from conditioned growth medium of CHO-MICB005 cells. [Figure 9O] 1 is a table showing the maximum OD450 and calculated EC50 of humanized anti-MICA / B antibodies (optimized h36B3 variants) against several truncated MICA / B polypeptides. [Figure 10A] 1 is a plot showing the interaction of NKG2D with synthetic MICA / B polypeptides as measured by ELISA. [Figure 10B] 1 is a plot showing the interaction of NKG2D with immune complexes of a humanized anti-MICA / B antibody (#39 variant) and shed MICA002 polypeptide as measured by ELISA. [Figure 10C] 1 is a plot showing the interaction of NKG2D with immune complexes of a humanized anti-MICA / B antibody (#39 variant) and shed MICA004 polypeptide as measured by ELISA. [Figure 10D] 1 is a table showing the maximum OD450 and calculated EC50 of humanized anti-MICA / B antibodies (#39 variant) against sheared MICA002 and MICA004 polypeptides. [Figure 10E] 1 is a plot showing IL2 concentrations in Hut-78T cells treated with immune complexes of chimeric anti-MICA / B antibodies and shed MICA002 polypeptide in the presence of anti-CD3 stimulation. [Figure 10F] 1 is a plot showing IL2 concentrations in Hut-78T cells treated with immune complexes of chimeric anti-MICA / B antibodies and shed MICB005 polypeptide in the presence of anti-CD3 stimulation. [Figure 10G] 1 is a plot showing IL2 concentrations in Hut-78T cells treated with immune complexes of humanized anti-MICA / B antibodies and shed soluble MICA002 polypeptide in the presence of anti-CD3 stimulation. [Figure 10H]1 is a plot showing IL2 concentrations in Hut-78T cells treated with immune complexes of humanized anti-MICA / B antibodies and shed soluble MICA004 polypeptide in the presence of anti-CD3 stimulation. [Figure 10I] 1 is a plot showing IL2 concentrations in Hut-78T cells treated with immune complexes of humanized anti-MICA / B antibodies and shed soluble MICA008 polypeptides in the presence of anti-CD3 stimulation. [Figure 10J] 1 is a plot showing IL2 concentrations in Hut-78T cells treated with immune complexes of humanized anti-MICA / B antibodies and shed soluble MICB005 polypeptide in the presence of anti-CD3 stimulation. [Figure 10K] 1 is a plot showing IL2 concentrations in Hut-78T cells treated with immune complexes of humanized anti-MICA / B antibody (h36B3 variant) and shed soluble MICA002 polypeptide in the presence of anti-CD3 stimulation. [Figure 10L] 1 is a plot showing IL2 concentrations in Hut-78T cells treated with immune complexes of humanized anti-MICA / B antibody (h36B3 variant) and shed soluble MICA004 polypeptide in the presence of anti-CD3 stimulation. [Figure 10M] 1 is a plot showing IL2 concentrations in Hut-78T cells treated with immune complexes of humanized anti-MICA / B antibody (h36B3 variant) and shed soluble MICA008 polypeptide in the presence of anti-CD3 stimulation. [Figure 10N] 1 is a plot showing IL2 concentrations in Hut-78T cells treated with immune complexes of humanized anti-MICA / B antibodies and shed soluble MICB005 polypeptide in the presence of anti-CD3 stimulation. [Figure 11A] 1 is a plot showing IFN-γ production in human primary NK cells from multiple donors treated with immunoconjugates of humanized anti-MICA / B antibody and shed soluble MICA002 polypeptide. Each data point represents NK cells from one donor. [Figure 11B]1 is a plot showing IFN-γ production in human primary NK cells from multiple donors treated with immunoconjugates of humanized anti-MICA / B antibody and shed soluble MICA004 polypeptide. Each data point represents NK cells from one donor. [Figure 11C] 1 is a plot showing IFN-γ production in human primary NK cells from multiple donors treated with immunoconjugates of humanized anti-MICA / B antibody and shed soluble MICA008 polypeptide. Each data point represents NK cells from one donor. [Figure 11D] 1 is a plot showing IFN-γ production in human primary NK cells from multiple donors treated with immune complexes of humanized anti-MICA / B antibody and shed soluble MICB005 polypeptide. Each data point represents NK cells from one donor. [Figure 11E] 1 is a plot showing IFN-γ production in human primary NK cells from multiple donors treated with immunocomplexes of humanized anti-MICA / B antibody (h36B3 variant) and shed soluble MICA002 polypeptide. Each data point represents NK cells from one donor. [Figure 11F] 1 is a plot showing IFN-γ production in human primary NK cells from multiple donors treated with immunocomplexes of humanized anti-MICA / B antibody (h36B3 variant) and shed soluble MICA004 polypeptide. Each data point represents NK cells from one donor. [Figure 11G] 1 is a plot showing IFN-γ production in human primary NK cells from multiple donors treated with immunocomplexes of humanized anti-MICA / B antibody (h36B3 variant) and shed soluble MICA008 polypeptide. Each data point represents NK cells from one donor. [Figure 11H] 1 is a plot showing IFN-γ production in human primary NK cells from multiple donors treated with immunocomplexes of humanized anti-MICA / B antibody (h36B3 variant) and shed soluble MICB005 polypeptide. Each data point represents NK cells from one donor. [Figure 12A]1 is a plot showing IFN-γ expression levels in NK cells co-cultured with C1R tumor cells expressing MICA004 polypeptide in the presence of a chimeric anti-MICA / B antibody. [Figure 12B] 1 is a plot showing IFN-γ expression levels in NK cells co-cultured with C1R tumor cells expressing MICA008 polypeptide in the presence of a chimeric anti-MICA / B antibody. [Figure 12C] 1 is a plot showing IFN-γ expression levels in NK cells co-cultured with C1R tumor cells expressing the MICB005 polypeptide in the presence of a chimeric anti-MICA / B antibody. [Figure 12D] 1 is a plot showing the expression levels of CD107a on NK cells co-cultured with C1R tumor cells expressing MICA004 polypeptide in the presence of a chimeric anti-MICA / B antibody. [Figure 12E] 1 is a plot showing the expression levels of CD107a on NK cells co-cultured with C1R tumor cells expressing MICA008 polypeptide in the presence of a chimeric anti-MICA / B antibody. [Figure 12F] 1 is a plot showing the expression levels of CD107a on NK cells co-cultured with C1R tumor cells expressing the MICB005 polypeptide in the presence of a chimeric anti-MICA / B antibody. [Figure 12G] 1 is a plot showing IFN-γ expression levels in NK cells co-cultured with C1R tumor cells expressing MICA002 polypeptide in the presence of humanized anti-MICA / B antibody. [Figure 12H] 1 is a plot showing IFN-γ expression levels in NK cells co-cultured with C1R tumor cells expressing MICA004 polypeptide in the presence of humanized anti-MICA / B antibody. [Figure 12I] 1 is a plot showing IFN-γ expression levels in NK cells co-cultured with C1R tumor cells expressing MICA008 polypeptide in the presence of humanized anti-MICA / B antibody. [Figure 12J]1 is a plot showing IFN-γ expression levels in NK cells co-cultured with C1R tumor cells expressing the MICB005 polypeptide in the presence of humanized anti-MICA / B antibody. [Figure 12K] 1 is a plot showing the expression levels of CD107a on NK cells co-cultured with C1R tumor cells expressing MICA002 polypeptide in the presence of humanized anti-MICA / B antibody. [Figure 12L] 1 is a plot showing the expression levels of CD107a on NK cells co-cultured with C1R tumor cells expressing MICA004 polypeptide in the presence of humanized anti-MICA / B antibody. [Figure 12M] 1 is a plot showing the expression levels of CD107a on NK cells co-cultured with C1R tumor cells expressing MICA008 polypeptide in the presence of humanized anti-MICA / B antibody. [Figure 12N] 1 is a plot showing the expression levels of CD107a on NK cells co-cultured with C1R tumor cells expressing the MICB005 polypeptide in the presence of humanized anti-MICA / B antibody. [Figure 12O] 1 is a plot showing IFN-γ expression levels in NK cells co-cultured with C1R tumor cells expressing MICA002 polypeptide in the presence of humanized anti-MICA / B antibodies (h36B3 mutant) from two independent donors. [Figure 12P] 1 is a plot showing IFN-γ expression levels in NK cells co-cultured with C1R tumor cells expressing MICA004 polypeptide in the presence of humanized anti-MICA / B antibodies (h36B3 mutant) from two independent donors. [Figure 12Q] 1 is a plot showing IFN-γ expression levels in NK cells co-cultured with C1R tumor cells expressing MICA008 polypeptide in the presence of humanized anti-MICA / B antibodies (h36B3 mutant) from two independent donors. [Figure 12R]1 is a plot showing IFN-γ expression levels in NK cells co-cultured with C1R tumor cells expressing the MICB005 polypeptide in the presence of humanized anti-MICA / B antibodies (h36B3 variant) from two independent donors. [Figure 12S] 1 is a plot showing the expression levels of CD107a on NK cells co-cultured with C1R tumor cells expressing MICA002 polypeptide in the presence of humanized anti-MICA / B antibody (h36B3 variant) from two independent donors. [Figure 12T] 1 is a plot showing the expression levels of CD107a in NK cells co-cultured with C1R tumor cells expressing MICA004 polypeptide in the presence of humanized anti-MICA / B antibodies (h36B3 variant) from two independent donors. [Figure 12U] 1 is a plot showing the expression levels of CD107a in NK cells co-cultured with C1R tumor cells expressing MICA008 polypeptide in the presence of humanized anti-MICA / B antibody (h36B3 variant) from two independent donors. [Figure 12V] 1 is a plot showing the expression levels of CD107a in NK cells co-cultured with C1R tumor cells expressing the MICB005 polypeptide in the presence of humanized anti-MICA / B antibodies (h36B3 variant) from two independent donors. [Figure 13A] 1 is a plot showing the percentage of C1R tumor cells expressing MICA004 polypeptide that were killed by human NK cells in the presence of chimeric anti-MICA / B antibody. [Figure 13B] 1 is a plot showing the percentage of C1R tumor cells expressing MICA008 polypeptide that were killed by human NK cells in the presence of chimeric anti-MICA / B antibody. [Figure 13C] 1 is a plot showing the percentage of C1R tumor cells expressing the MICB005 polypeptide that were killed by human NK cells in the presence of chimeric anti-MICA / B antibody. [Figure 13D]1 is a plot showing the percentage of C1R tumor cells expressing MICA002 polypeptide that were killed by human NK cells in the presence of humanized anti-MICA / B antibodies. [Figure 13E] 1 is a plot showing the percentage of C1R tumor cells expressing MICA004 polypeptide that were killed by human NK cells in the presence of humanized anti-MICA / B antibodies. [Figure 13F] 1 is a plot showing the percentage of C1R tumor cells expressing MICA008 polypeptide that were killed by human NK cells in the presence of humanized anti-MICA / B antibodies. [Figure 13G] 1 is a plot showing the percentage of C1R tumor cells expressing the MICB005 polypeptide that were killed by human NK cells in the presence of humanized anti-MICA / B antibodies. [Figure 13H] 1 is a plot showing the percentage of C1R tumor cells expressing MICA002 polypeptide that were killed by human NK cells in the presence of humanized anti-MICA / B antibody (h36B3 mutant). [Figure 13I] 1 is a plot showing the percentage of C1R tumor cells expressing MICA004 polypeptide that were killed by human NK cells in the presence of a humanized anti-MICA / B antibody (h36B3 mutant). [Figure 13J] 1 is a plot showing the percentage of C1R tumor cells expressing MICA008 polypeptide that were killed by human NK cells in the presence of humanized anti-MICA / B antibody (h36B3 mutant). [Figure 13K] 1 is a plot showing the percentage of C1R tumor cells expressing the MICB005 polypeptide that were killed by human NK cells in the presence of a humanized anti-MICA / B antibody (h36B3 mutant). [Figure 14A] Figure 1 shows a plot of thermal stability of humanized anti-MICA / B antibody full IgG. Melting curves were measured with a protein thermal shift dye kit using a qPCR thermocycler. Fluorescence intensity was subtracted at the lowest intensity (bottom) before the peak and normalized to the amplitude from the peak to the bottom. [Figure 14B]Figure 1 shows a plot of thermal stability of F(ab')2 fragment of humanized anti-MICA / B antibody. Melting curves were measured with a protein thermal shift dye kit using a qPCR thermocycler. Fluorescence intensity was subtracted at the lowest intensity (bottom) before the peak and normalized to the amplitude from the peak to the bottom. [Figure 14C] Figure 1 shows a plot of thermal stability of humanized anti-MICA / B antibody full IgG. Melting curves were measured with a protein thermal shift dye kit using a qPCR thermocycler. Fluorescence intensity was subtracted at the lowest intensity (bottom) before the peak and normalized to the amplitude from the peak to the bottom. [Figure 14D] Figure 1 shows a plot of thermal stability of F(ab')2 fragment of humanized anti-MICA / B antibody. Melting curves were measured with a protein thermal shift dye kit using a qPCR thermocycler. Fluorescence intensity was subtracted at the lowest intensity (bottom) before the peak and normalized to the amplitude from the peak to the bottom. [Figure 14E] The Tm of the humanized anti-MICA / B antibody, the reference antibody, and the isotype control IgG1 full IgG and F(ab)2 fragments are summarized based on the temperature of 50% of the amplitude from the base to the peak of the plots shown in Figures 14A-14D. The mean and + / - standard deviation were calculated from two experiments, each repeated in duplicate. [Figure 15] 1 is a table showing the binding affinity of humanized anti-MICA / B antibodies stressed with low and high pH buffers, respectively, to various MICA / B polypeptides. The antibodies were stressed in pH 5.5 or pH 8.5 buffers, respectively, for 2 weeks at 40° C. The binding kinetics were measured by GatorPrime™ Biolayer Interferometry. [Figure 16] 1 is a table showing the clonal self-interactions (CSI) of humanized and optimized anti-MICA / B antibodies as measured by GatorPrime™ Biolayer Interferometry. [Figure 17A]The antibodies were tested at a concentration of 15 μg / mL by sandwich ELISA and are plotted against background non-specific binding of humanized and optimized anti-MICA / B antibodies to whole cell lysates produced from CHO cells. [Figure 17B] The antibodies were tested at a concentration of 1.5 μg / mL by sandwich ELISA and are plotted against background non-specific binding of humanized and optimized anti-MICA / B antibodies to whole cell lysates produced from CHO cells. [Figure 17C] The antibodies were tested at a concentration of 15 μg / mL by sandwich ELISA and are plotted against background non-specific binding of humanized and optimized anti-MICA / B antibodies to whole cell lysates produced from C1R cancer cells. [Figure 17D] The antibodies were tested at a concentration of 1.5 μg / mL by sandwich ELISA and are plotted against background non-specific binding of humanized and optimized anti-MICA / B antibodies to whole cell lysates produced from C1R cancer cells. [Figure 18A] 1 is a plot showing the binding affinity of humanized and optimized anti-MICA / B antibodies in CHO-MICB005 stressed in human serum at 37° C. for 1 week. [Figure 18B] FIG. 13 is a plot showing the binding affinity of humanized and optimized anti-MICA / B antibodies in CHO-MICB005 stressed in human serum at 37° C. for 2 weeks. [Figure 18C] FIG. 18C is a table showing the calculated EC50s of the humanized and optimized anti-MICA / B antibodies plotted in FIGS. 18A and 18B. [Figure 18D] 13 is a plot showing the binding affinity of D2M001-209 in CHO-MICA002 stressed in human plasma or PBS for 2 weeks at 37° C. [Figure 18E] 1 is a plot showing the binding affinity of D2M001-209 in CHO-MICA004 stressed in human plasma or PBS for 2 weeks at 37° C. [Figure 18F]13 is a plot showing the binding affinity of D2M001-209 in CHO-MICA008 stressed in human plasma or PBS for 2 weeks at 37° C. [Figure 18G] 1 is a plot showing the binding affinity of D2M001-209 in CHO-MICB005 stressed in human plasma or PBS for 2 weeks at 37° C. [Figure 19A] 1 is a plot showing the time course of the amount of humanized anti-MICB antibody (D2M001-010) in vivo in mice over the course of a 10-day experiment. The antibody was quantified by sandwich ELISA using MICB recombinant protein or anti-human Fab as the capture reagent and anti-human FC as the detection reagent. [Figure 19B] 1 is a plot showing the time course of the amount of humanized anti-MICB antibody (D2M001-h39F53GS) in vivo in mice over a 10-day experiment. The antibody was quantified by sandwich ELISA using MICB recombinant protein or anti-human Fab as the capture reagent and anti-human FC as the detection reagent. [Figure 19C] 1 is a plot showing the time course of the amount of humanized anti-MICB antibody (D2M001-h36B3) in vivo in mice over a 10-day experiment. The antibody was quantified by sandwich ELISA using MICB recombinant protein or anti-human Fab as the capture reagent and anti-human FC as the detection reagent. [Figure 19D] 1 is a plot showing the time course of the amount of humanized anti-MICB antibody (D2M001-h36B3GS) in vivo in mice over a 10-day experiment. The antibody was quantified by sandwich ELISA using MICB recombinant protein or anti-human Fab as the capture reagent and anti-human FC as the detection reagent. [Figure 19E]Figure 19 is a plot of the kinetics of D2M001-209 in vivo in B16F10-MICAB tumor-bearing mice. Blood samples were collected over time over the 9-day experiment at a single dose of 10 mg / kg or 30 mg / kg. Antibodies were quantified by sandwich ELISA using anti-human F(ab)2 as the capture reagent and anti-human F(ab) as the detection reagent. Samples were used for MICB quantification in Figure 19F. [Figure 19F] Figure 19 shows a kinetic plot of plasma soluble MICB in tumor-bearing mice treated with D2M001-209 normalized to mice treated with PBS (untreated). B16F10-MICAB tumor-bearing mice were treated with a single dose of PBS or 10 mg / kg or 30 mg / kg. Blood samples were taken over the course of the 9-day experiment at the same time points as described in Figure 19E. MICB in plasma was quantified by sandwich ELISA. [Figure 20A] Figure 13 is a plot showing that transgenic mouse tumor cells can shed MICA in vitro and that the shedding of MICA polypeptide from transgenic mouse tumor cells is inhibited in vitro by a humanized and optimized anti-MICA / B antibody. [Figure 20B] FIG. 1 is a plot showing that transgenic mouse tumor cells can shed MICB in vitro and that humanized and optimized anti-MICA / B antibodies inhibit the shedding of MICB polypeptide from transgenic mouse tumor cells in vitro. [Figure 20C] FIG. 1 is a plot showing the reduction in soluble MICA polypeptide shedding (as measured by soluble MICA polypeptide) from transgenic mouse tumor cells by the humanized and optimized anti-MICA / B antibody h36B3 in vivo. [Figure 20D] FIG. 1 is a plot showing the reduction in soluble MICA polypeptide shedding (as measured by soluble MICB polypeptide) from transgenic mouse tumor cells by the humanized and optimized anti-MICA / B antibody h36B3 in vivo. [Figure 21A]Plot of tumor area (mm2) upon treatment with humanized and optimized anti-MICA / B antibody D2M001-010, control IgG alone, anti-PD1 antibody alone, or the combination of anti-MICA / B antibody D2M001-010 and anti-PD1 antibody. Statistical analysis was performed using t-test. P values ​​were calculated by t-test. * denotes P<0.05, ** denotes P<0.01, *** denotes P<0.001, **** denotes P<0.0001, and ns denotes not significant. [Figure 21B] Figure 1 is a plot showing the inhibition of soluble MICB polypeptide shedding from transgenic mouse tumor cells by humanized and optimized anti-MICA / B antibodies in vivo. Statistical analysis was performed using t-test. P values ​​were calculated by t-test. * denotes P<0.05, ** denotes P<0.01, *** denotes P<0.001, **** denotes P<0.0001, and ns denotes not significant. [Figure 21C] Plot of tumor area (mm2) following treatment with humanized-optimized anti-MICA / B antibody h36B3, control IgG alone, anti-PD1 antibody alone, or the combination of anti-MICA / B antibody h36B3 and anti-PD1 antibody. Statistical analysis was performed using t-test. P values ​​were calculated by t-test. * denotes P<0.05, ** denotes P<0.01, and ns denotes not significant. [Figure 21D] FIG. 1 is a plot showing the inhibition of soluble MICB polypeptide shedding from transgenic mouse tumor cells by humanized and optimized anti-MICA / B antibodies in vivo. [Figure 21E] Plot of tumor area (mm2) upon treatment with Fc function null anti-MICA / B antibody h36B3 (h36B3-LALAPA), control IgG alone, anti-PD1 antibody alone, or the combination of h36B3-LALAPA and anti-PD1 antibody. Statistical analysis was performed using t-test. P values ​​were calculated by t-test. * denotes P<0.05, ** denotes P<0.01, and ns denotes not significant. [Figure 21F]Figure 1 is a plot showing the inhibition of soluble MICB polypeptide shedding from transgenic mouse tumor cells by humanized and optimized anti-MICA / B antibodies in vivo. Statistical analysis was performed using t-test. P values ​​were calculated by t-test. * denotes P<0.05, ** denotes P<0.01, and ns denotes not significant. [Figure 21G] Plot of tumor volume (mm3) in response to treatment with a single dose of 30 mg / kg D2M001-209, reference antibody 3F9 or control PBS. Statistical analysis was performed using two-way ANOVA, Tukey's comparison test. [Fig. 21H] Plot of tumor volume (mm3) in response to treatment with humanized and optimized anti-MICA / B antibody D2M001-209, PBS alone, anti-PD1 antibody alone, or the combination of D2M001-209 and anti-PD1 antibody. P values ​​were calculated by two-way ANOVA. * denotes P<0.05, **** denotes P<0.0001, and ns denotes not significant. [Figure 21I] Figure 21 shows that D2M001-209 increased 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 in Figure 21H. P values ​​were calculated by t-test. * is P<0.05, *** is P<0.001. [Figure 21J] Figure 21 shows that D2M001-209 increased 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 in Figure 21H. P values ​​were calculated by t-test. * is P<0.05, *** is P<0.001. [Figure 21K]D2M001-209 reduced the concentration of soluble MICA peptide in plasma of animals treated with anti-MICA / B D2M001-209 antibody, PBS alone, anti-PD1 antibody alone, or the combination of anti-MICA / B antibody D2M001-209 and anti-PD1 antibody in Figure 21H. P values ​​were calculated by t-test. *, P<0.05, **, P<0.01, ***, P<0.001. [Figure 21L] D2M001-209 reduced the concentration of soluble MICB peptide in plasma of animals treated with anti-MICA / B D2M001-209 antibody, PBS alone, anti-PD1 antibody alone, or the combination of anti-MICA / B antibody D2M001-209 and anti-PD1 antibody in Figure 21H. P values ​​were calculated by t-test. *, P<0.05, **, P<0.01, ***, P<0.001. [Figure 22A] Figure 1 shows a series of photographs of lungs taken 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 14 days after treatment and photographs were taken. [Figure 22B] The number of lung tumor nodules in animals treated with anti-MICA / B D2M001-010 antibody, animals treated with anti-MICA / B h36B3 antibody, and control animals treated with IgG isotype control are shown. P values ​​were calculated by t-test. **** is P<0.0001. [Figure 22C] Plasma concentrations of soluble MICA peptides in animals treated with anti-MICA / B D2M001-010 antibody and in control animals treated with IgG isotype control are shown. P values ​​were calculated by t-test. *, P<0.05, **, P<0.01, ****, P<0.0001. [Figure 22D]Plasma concentrations of soluble MICB peptides in animals treated with anti-MICA / B D2M001-010 antibody and in control animals treated with IgG isotype control are shown. P values ​​were calculated by t-test. * is P<0.05, ** is P<0.01, and **** is P<0.0001. [Figure 22E] Figure 1 shows the number of lung tumor nodules in B6 mice bearing metastatic B16F10-MICA / B tumor cells. Treatment animals were treated with anti-MICA / B h36B3 antibody, Fc functional null h36B3 antibody (h36B3-LALAPA), and IgG1 isotype control. P values ​​were calculated by t-test. * is P<0.05, **** is P<0.0001. [Figure 22F] Plasma concentrations of soluble MICA peptides in animals treated with anti-MICA / B h36B3 antibody, Fc function null 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. [Figure 22G] Plasma concentrations of soluble MICB peptides in animals treated with anti-MICA / B h36B3 antibody, Fc function null h36B3 antibody (h36B3-LALAPA), and IgG1 isotype control are shown. P values ​​were calculated by t-test. * is P<0.05, **** is P<0.0001. [Fig. 22H] Plot of tumor volume (mm3) in A375 tumor-bearing SCID mice in response to treatment with humanized and optimized anti-MICA / B antibody D2M001-209 and IgG1 isotype control. Statistical analysis was performed using t-test. P values ​​were calculated by t-test. ** denotes P<0.01, *** denotes P<0.001, **** denotes P<0.0001, and ns denotes not significant. [Figure 22I] Figure 1 shows the number of lung tumor nodules in SCID mice bearing metastatic A375 tumor cells. 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. [Figure 23] The VH and VL sequences of several antibodies are shown. [Figure 24A] The CDR sequences of several antibodies are provided. [Figure 24B] The CDR sequences of several antibodies are provided. [Figure 24C] The CDR sequences of several antibodies are provided. [Figure 24D] The CDR sequences of several antibodies are provided. [Figure 24E] The CDR sequences of several antibodies are provided. [Figure 25-1] FIG. 25 shows the humanized VH and VL sequences. [Figure 25-2] This is a continuation of Figure 25-1. [Figure 26-1] FIG. 26 shows the humanized VH and VL sequences of hit IDs #38 and #39. [Figure 26-2] This is a continuation of Figure 26-1. [Figure 27-1] FIG. 27 shows the humanized VH and VL sequences of hit ID#36. [Figure 27-2] This is a continuation of Figure 27-1. [Figure 28] The CDR sequences for humanization of hit ID#36 are shown. [Figure 29] The CDR sequences for humanization of hit IDs #38 and #39 are shown. [Figure 30A] The CDR sequences of several humanized antibodies are provided. [Figure 30B] The CDR sequences of several humanized antibodies are provided. [Figure 30C] The CDR sequences of several humanized antibodies are provided. [Figure 30D] The CDR sequences of several humanized antibodies are provided. [Figure 30E] The CDR sequences of several humanized antibodies are provided. [Diagram 31] The protein sequence of the reference antibody is provided. [Diagram 32] The protein sequence of full-length MICA / B stably expressed by a transgenic cell line is provided. [Diagram 33] The protein sequence expressed by the DNA immunogen used for immunization is provided. [Diagram 34] The sequences of the protein immunogens used for immunization are provided. [Diagram 35] The sequence of the recombinant ECD protein used in the affinity measurements is provided. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0052] The present disclosure provides examples of antibodies, or antigen-binding fragments thereof, that bind to MICA (major histocompatibility complex class I chain-related A) and / or MICB (major histocompatibility complex class I chain-related B). In some embodiments, the antibodies or antigen-binding fragments thereof bind to MICA. In some embodiments, the antibodies or antigen-binding fragments thereof bind to MICB. In some embodiments, the antibodies or antigen-binding fragments thereof bind to both MICA and MICB.

[0053] MICA and MICB Major histocompatibility complex (MHC) class I polypeptide-related A and B (MICA / B) is a highly polymorphic cell surface protein associated with MHC class I glycoproteins and is a stimulatory ligand 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 to co-stimulate T cells and eliminate cancer or damaged cells by effector cells expressing the NKG2D receptor.

[0054] MICA / B protein is constitutively expressed at low levels in myeloid, epithelial, endothelial, and fibroblast cells. MICA / B protein is upregulated or de novo expressed in response to stresses such as during carcinogenesis, infections, DNA damage responses, and various autoimmune conditions. MICA / B expression can tag cells for elimination by cytotoxic lymphocytes via activation of the NKG2D receptor. However, as an escape mechanism to prevent NKG2D-mediated responses, tumor cells proteolytically shed MICA / B protein from the cell surface, resulting in both 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. MICA / B expression has also been reported in a variety of tumor types with high expression associated with poor patient prognosis.

[0055] It is believed that specific inhibition of shedding of MICA and MICB proteins from cancer cells may restore or enhance NKG2D-dependent activation of NK cells and T cells in the tumor microenvironment, thereby enhancing antitumor activity in cancer patients. Within the MICA / B polypeptide, the extracellular domain of MICA / B is composed of three C-type Ig-like domains, called alpha1, alpha2, and alpha3 domains. The alpha1 and alpha2 domains are distant from the cell membrane, whereas the alpha3 domain is close to the cell membrane. A six amino acid motif within the alpha3 domain has been reported to be a proteolytic cleavage site that allows MICA / B polypeptide to be shed from the surface of cancer cells. A detailed description is provided, for example, in Wang, X. et al., "A six amino acid motif within the alpha3 domain of MICA is a cancer therapeutic target that inhibits shedding," Biochemical and Biophysical Research Communications 387.3 (2009): 476-481, the entire contents of which are incorporated herein by reference.

[0056] The function of MICA / B and its relationship to various diseases have been reviewed in, for example, Groh V et al., Inhibition of NKG2D expression and T cell activation by tumor-derived soluble MIC ligands, Nature, 2002 Oct 17, 419(6908):734-8.; Salih HR et al., Cutting edge: Downregulation of MICA in human tumors by proteolytic shedding, J Immunol, 2002 Oct 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 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; Xing S, Ferrari de Andrade L, NKG2D and MICA / B shedding: a "game of tag" between NK cells and malignant cells, Clin Transl Immunology. 2020 Dec 22;9(12):e123, each of which is incorporated herein by reference.

[0057] Antibodies that recognize MICA / B polypeptide on the surface of cancer cells, particularly specific epitopes required for initiation of proteolytic shedding, i.e., the alpha 3 domain, can inhibit shedding of MICA / B polypeptide from the surface of cancer cells and reduce the amount of soluble MICA / B polypeptide released from cancer cells. The present disclosure provides several anti-MICA / B antibodies, antigen-binding fragments thereof, and methods of using these antibodies and antigen-binding fragments to inhibit shedding of MICA / B polypeptide from cancer cells, inhibit tumor growth, and treat cancer.

[0058] Anti-MICA / B antibodies and antigen-binding fragments 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 can bind to MICA and / or MICB polypeptides, bind to MICA / B polypeptides and inhibit their shedding from the surface of cancer cells, and can potentiate NK cells and T cells.The present disclosure relates to, 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, D2M 001-011, D2M001-201, D2M001-202, D2M001-203, D2M001-204, D2M001-205, D2M001-206, D2M001-207, D2M001-208, D2M001-209, D2M00 1-210, D2M001-211, D2M001-212, D2M001-213, h36, h36B3, h36B3GS, h36B3(DE), h36B3(GA), h36D26, h36D28, h39F53, h39F53GS, h39-ma x-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, their chimeric antibodies, and their humanized antibodies are provided. The CDR sequences, VH, and VL of these antibodies or antibodies derived therefrom are shown in Figures 23 to 30.

[0059] For example, the CDR sequences of "#21" and antibodies derived from "#21" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 3, 4, 5) and the CDRs of the light chain variable domain (SEQ ID NOs: 6, 7, 8) as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0060] For example, the CDR sequences of "#22" and antibodies derived from "#22" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 11, 12, 13) and the CDRs of the light chain variable domain (SEQ ID NOs: 14, 15, 16) as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0061] For example, the CDR sequences of "#23" and antibodies derived from "#23" (e.g., humanized antibodies), as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 19, 20, 21) and the CDRs of the light chain variable domain (SEQ ID NOs: 22, 23, 24). The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0062] For example, the CDR sequences of "#24" and antibodies derived from "#24" (e.g., humanized antibodies), as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 27, 28, 29) and the CDRs of the light chain variable domain (SEQ ID NOs: 30, 31, 32). The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0063] For example, the CDR sequences of "#25" and antibodies (e.g., humanized antibodies) derived from "#25", as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 35, 36, 37) and the CDRs of the light chain variable domain (SEQ ID NOs: 38, 39, 40). The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0064] For example, the CDR sequences of "#26" and antibodies derived from "#26" (e.g., humanized antibodies), as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 43, 44, 45) and the CDRs of the light chain variable domain (SEQ ID NOs: 46, 47, 48). The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0065] For example, the CDR sequences of "#27" and antibodies (e.g., humanized antibodies) derived from "#27", as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 51, 52, 53) and the CDRs of the light chain variable domain (SEQ ID NOs: 54, 55, 56). The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0066] For example, the CDR sequences of "#28" and antibodies derived from "#28" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 59, 60, 61) and the CDRs of the light chain variable domain (SEQ ID NOs: 62, 63, 64), as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0067] For example, the CDR sequences of "#29" and antibodies derived from "#29" (e.g., humanized antibodies), as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 67, 68, 69) and the CDRs of the light chain variable domain (SEQ ID NOs: 70, 71, 72). The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0068] For example, the CDR sequences of "#30" and antibodies derived from "#30" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 75, 76, 77) and the CDRs of the light chain variable domain (SEQ ID NOs: 78, 79, 80), as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0069] For example, the CDR sequences of "#31" and antibodies derived from "#31" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 83, 84, 85) and the CDRs of the light chain variable domain (SEQ ID NOs: 86, 87, 88), as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0070] For example, the CDR sequences of "#32" and antibodies derived from "#32" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 91, 92, 93) and the CDRs of the light chain variable domain (SEQ ID NOs: 94, 95, 96), as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0071] For example, the CDR sequences of "#33" and antibodies derived from "#33" (e.g., humanized antibodies), as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 99, 100, 101) and the CDRs of the light chain variable domain (SEQ ID NOs: 102, 103, 104). The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0072] For example, the CDR sequences of "#34" and antibodies (e.g., humanized antibodies) derived from "#34", as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 107, 108, 109) and the CDRs of the light chain variable domain (SEQ ID NOs: 110, 111, 112). The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0073] For example, the CDR sequences of "#35" and antibodies (e.g., humanized antibodies) derived from "#35", as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 115, 116, 117) and the CDRs of the light chain variable domain (SEQ ID NOs: 118, 119, 120). The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0074] For example, the CDR sequences of "#36" and antibodies derived from "#36" (e.g., humanized antibodies), as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 123, 124, 125) and the CDRs of the light chain variable domain (SEQ ID NOs: 126, 127, 128). The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0075] For example, the CDR sequences of "#37" and antibodies derived from "#37" (e.g., humanized antibodies), as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 131, 132, 133) and the CDRs of the light chain variable domain (SEQ ID NOs: 134, 135, 136). The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0076] For example, the CDR sequences of "#38" and antibodies derived from "#38" (e.g., humanized antibodies), as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 139, 140, 141) and the CDRs of the light chain variable domain (SEQ ID NOs: 142, 143, 144). The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0077] For example, the CDR sequences of "#39" and antibodies derived from "#39" (e.g., humanized antibodies), as defined, for example, by IMGT numbering, 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). The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0078] For example, the CDR sequences of "#40" and antibodies derived from "#40" (e.g., humanized antibodies), as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 155, 156, 157) and the CDRs of the light chain variable domain (SEQ ID NOs: 158, 159, 160). The CDRs of these antibodies based on other definitions are shown in Figures 24B-24E.

[0079] For example, the CDR sequences of the "h36 template" and antibodies (e.g., humanized antibodies) derived from the "h36 template" include the CDRs of the heavy chain variable domain (SEQ ID NOs: 815, 816, 817) and the CDRs of the light chain variable domain (SEQ ID NOs: 818, 819, 820), as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0080] For example, the CDR sequences of "h36B3" and antibodies derived from "h36B3" (e.g., humanized antibodies), as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 821, 822, 823) and the CDRs of the light chain variable domain (SEQ ID NOs: 824, 825, 826). The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0081] For example, the CDR sequences of "h36B3(GS)" and antibodies derived from "h36B3(GS)" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 827, 828, 829) and the CDRs of the light chain variable domain (SEQ ID NOs: 830, 831, 832), as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0082] For example, the CDR sequences of "h36B3(DE)" and antibodies derived from "h36B3(DE)" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 833, 834, 835) and the CDRs of the light chain variable domain (SEQ ID NOs: 836, 837, 838), as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0083] For example, the CDR sequences of "h36B3(GA)" and antibodies derived from "h36B3(GA)" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 839, 840, 841) and the CDRs of the light chain variable domain (SEQ ID NOs: 842, 843, 844), as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0084] For example, the CDR sequences of "h36D26" and antibodies derived from "h36D26" (e.g., humanized antibodies), as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 845, 846, 847) and the CDRs of the light chain variable domain (SEQ ID NOs: 848, 849, 850). The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0085] For example, the CDR sequences of "h36D28" and antibodies derived from "h36D28" (e.g., humanized antibodies), as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 851, 852, 853) and the CDRs of the light chain variable domain (SEQ ID NOs: 854, 855, 856). The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0086] For example, the CDR sequences of "D2M001-201" and antibodies (e.g., humanized antibodies) derived from "D2M001-201" include the CDRs of the heavy chain variable domain (SEQ ID NOs: 857, 858, 859) and the CDRs of the light chain variable domain (SEQ ID NOs: 860, 861, 862), as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0087] For example, the CDR sequences of "D2M001-202" and antibodies (e.g., humanized antibodies) derived from "D2M001-202" include the CDRs of the heavy chain variable domain (SEQ ID NOs: 863, 864, 865) and the CDRs of the light chain variable domain (SEQ ID NOs: 866, 867, 868), as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0088] For example, the CDR sequences of "D2M001-203" and antibodies (e.g., humanized antibodies) derived from "D2M001-203" include the CDRs of the heavy chain variable domain (SEQ ID NOs: 869, 870, 871) and the CDRs of the light chain variable domain (SEQ ID NOs: 872, 873, 874), as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0089] For example, the CDR sequences of "D2M001-204" and antibodies (e.g., humanized antibodies) derived from "D2M001-204" include the CDRs of the heavy chain variable domain (SEQ ID NOs: 875, 876, 877) and the CDRs of the light chain variable domain (SEQ ID NOs: 878, 879, 880), as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0090] For example, the CDR sequences of "D2M001-205" and antibodies (e.g., humanized antibodies) derived from "D2M001-205" include the CDRs of the heavy chain variable domain (SEQ ID NOs: 881, 882, 883) and the CDRs of the light chain variable domain (SEQ ID NOs: 884, 885, 886), as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0091] For example, the CDR sequences of "D2M001-206" and antibodies (e.g., humanized antibodies) derived from "D2M001-206", as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 887, 888, 889) and the CDRs of the light chain variable domain (SEQ ID NOs: 890, 891, 892). The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0092] For example, the CDR sequences of "D2M001-207" and antibodies (e.g., humanized antibodies) derived from "D2M001-207", as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 893, 894, 895) and the CDRs of the light chain variable domain (SEQ ID NOs: 896, 897, 898). The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0093] For example, the CDR sequences of "D2M001-208" and antibodies (e.g., humanized antibodies) derived from "D2M001-208" include the CDRs of the heavy chain variable domain (SEQ ID NOs: 899, 900, 901) and the CDRs of the light chain variable domain (SEQ ID NOs: 902, 903, 904), as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0094] For example, the CDR sequences of "D2M001-209" and antibodies (e.g., humanized antibodies) derived from "D2M001-209" include the CDRs of the heavy chain variable domain (SEQ ID NOs: 905, 906, 907) and the CDRs of the light chain variable domain (SEQ ID NOs: 908, 909, 910), as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0095] For example, the CDR sequences of "D2M001-210" and antibodies (e.g., humanized antibodies) derived from "D2M001-210", as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 911, 912, 913) and the CDRs of the light chain variable domain (SEQ ID NOs: 914, 915, 916). The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0096] For example, the CDR sequences of "D2M001-211" and antibodies (e.g., humanized antibodies) derived from "D2M001-211", as defined, for example, by IMGT numbering, include the CDRs of the heavy chain variable domain (SEQ ID NOs: 917, 918, 919) and the CDRs of the light chain variable domain (SEQ ID NOs: 920, 921, 922). The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0097] For example, the CDR sequences of "D2M001-212" and antibodies (e.g., humanized antibodies) derived from "D2M001-212" include the CDRs of the heavy chain variable domain (SEQ ID NOs: 923, 924, 925) and the CDRs of the light chain variable domain (SEQ ID NOs: 926, 927, 928), as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0098] For example, the CDR sequences of "D2M001-213" and antibodies (e.g., humanized antibodies) derived from "D2M001-213" include the CDRs of the heavy chain variable domain (SEQ ID NOs: 929, 930, 931) and the CDRs of the light chain variable domain (SEQ ID NOs: 932, 933, 934), as defined, for example, by IMGT numbering. The CDRs of these antibodies based on other definitions are shown in Figures 30B-30E.

[0099] For example, the CDR sequences of the "h36 template" and antibodies (e.g., humanized antibodies) derived from the "h36 template" include the CDRs of the heavy chain variable domain (SEQ ID NOs: 708, 709, 710) and the CDRs of the light chain variable domain (SEQ ID NOs: 711, 712, 713).

[0100] For example, the CDR sequences of "h36B3" and antibodies derived from "h36B3" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 714, 715, 716) and the CDRs of the light chain variable domain (SEQ ID NOs: 717, 718, 719).

[0101] For example, the CDR sequences of "h36B3(GS)" and antibodies derived from "h36B3(GS)" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 720, 721, 722) and the CDRs of the light chain variable domain (SEQ ID NOs: 723, 724, 725).

[0102] For example, the CDR sequences of "h36B3(DE)" and antibodies derived from "h36B3(DE)" (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).

[0103] For example, the CDR sequences of "h36B3(GA)" and antibodies derived from "h36B3(GA)" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (sequence numbers 732, 733, 734) and the CDRs of the light chain variable domain (sequence numbers 735, 736, 737).

[0104] For example, the CDR sequences of "h36D26" and antibodies derived from "h36D26" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 738, 739, 740) and the CDRs of the light chain variable domain (SEQ ID NOs: 741, 742, 743).

[0105] For example, the CDR sequences of "h36D28" and antibodies derived from "h36D28" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 744, 745, 746) and the CDRs of the light chain variable domain (SEQ ID NOs: 747, 748, 749).

[0106] For example, the CDR sequences of "D2M001-001" and antibodies derived from "D2M001-001" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (sequence numbers 750, 751, 752) and the CDRs of the light chain variable domain (sequence numbers 753, 754, 755).

[0107] For example, the CDR sequences of "D2M001-003" and antibodies derived from "D2M001-003" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (sequence numbers 756, 757, 758) and the CDRs of the light chain variable domain (sequence numbers 759, 760, 761).

[0108] For example, the CDR sequences of "D2M001-010" and antibodies derived from "D2M001-010" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (sequence numbers 762, 763, 764) and the CDRs of the light chain variable domain (sequence numbers 765, 766, 767).

[0109] For example, the CDR sequences of "D2M001-004" and antibodies derived from "D2M001-004" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (sequence numbers 768, 769, 770) and the CDRs of the light chain variable domain (sequence numbers 771, 772, 773).

[0110] For example, the CDR sequences of "hu39-max-E3S-P3-P2#1" and antibodies (e.g., humanized antibodies) derived from "hu39-max-E3S-P3-P2#1" include the CDRs of the heavy chain variable domain (sequence numbers 774, 775, 776) and the CDRs of the light chain variable domain (sequence numbers 777, 778, 779).

[0111] For example, the CDR sequences of "hu39-max-E3S-P3-P2#4" and antibodies (e.g., humanized antibodies) derived from "hu39-max-E3S-P3-P2#4" include the CDRs of the heavy chain variable domain (sequence numbers 780, 781, 782) and the CDRs of the light chain variable domain (sequence numbers 783, 784, 785).

[0112] For example, the CDR sequences of "h39-010F3S-P2-P2#7" and antibodies (e.g., humanized antibodies) derived from "h39-010F3S-P2-P2#7" include the CDRs of the heavy chain variable domain (sequence numbers 786, 787, 788) and the CDRs of the light chain variable domain (sequence numbers 789, 790, 791).

[0113] For example, the CDR sequences of "h39-010F3F53E1" and antibodies derived from "h39-010F3F53E1" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (sequence numbers 792, 793, 794) and the CDRs of the light chain variable domain (sequence numbers 795, 796, 797).

[0114] For example, the CDR sequences of "h39-010F3F53E2(GS)" and antibodies derived from "h39-010F3F53E2(GS)" (e.g., humanized antibodies) include the CDRs of the heavy chain variable domain (sequence numbers 798, 799, 800) and the CDRs of the light chain variable domain (sequence numbers 801, 802, 803).

[0115] For example, the CDR sequences of "h39-010F3S-P2-P2#4" and antibodies (e.g., humanized antibodies) derived from "h39-010F3S-P2-P2#4" include the CDRs of the heavy chain variable domain (sequence numbers 804, 805, 806) and the CDRs of the light chain variable domain (sequence numbers 807, 808, 809).

[0116] For example, the CDR sequences of "h39-010F3F53E2" and antibodies derived from "h39-010F3F53E2" (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).

[0117] Accordingly, in one aspect, the disclosure provides an antibody or antigen-binding fragment thereof that binds to MICA and / or MICB, the antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, and a light chain variable region (VL) comprising 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, 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 the VL CDR1 region comprises an amino acid sequence that is at least 70%, 80%, 90% or 100% identical to a selected VL CDR3 amino acid sequence. and wherein the VL CDR2 region comprises an amino acid sequence that is at least 70%, 80%, 90% or 100% identical to a selected VL CDR2 amino acid sequence, and 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, and the selected VH CDR1, 2 and 3 amino acid sequences and the selected VL CDR1, 2 and 3 amino acid sequences are selected from the VH CDR1, 2, 3 and VL CDR1, 2, 3 listed in Figures 24A, 24B, 24C, 24D, 24E, 28, 29, 30A, 30B, 30C, 30D and 30E.

[0118] The amino acid sequences of the heavy and light chain variable regions of the anti-MICA / B antibodies are also provided, and these VH and VL sequences are shown in Figures 23, 25, 26, 27, 28 or 29.

[0119] For example, the VH and VL of Hit ID 21 are shown in SEQ ID NOs: 1 and 2. For example, the VL and VH of Hit ID 22 are shown in SEQ ID NOs: 9 and 10. For example, the VH and VL of Hit ID 23 are shown in SEQ ID NOs: 17 and 18. For example, the VH and VL of Hit ID 24 are shown in SEQ ID NOs: 25 and 26. For example, the VH and VL of Hit ID 25 are shown in SEQ ID NOs: 33 and 34. For example, the VH and VL of Hit ID 26 are shown in SEQ ID NOs: 41 and 42. For example, the VH and VL of Hit ID 27 are shown in SEQ ID NOs: 49 and 50. For example, the VH and VL of Hit ID 28 are shown in SEQ ID NOs: 57 and 58. For example, the VH and VL of Hit ID 29 are shown in SEQ ID NOs: 65 and 66. For example, the VH and VL of Hit ID 30 are shown in SEQ ID NOs: 73 and 74. For example, the VH and VL of Hit ID 31 are shown in SEQ ID NOs: 81 and 82. For example, the VH and VL of Hit ID 32 are set forth in SEQ ID NOs: 89 and 90. For example, the VH and VL of Hit ID 33 are set forth in SEQ ID NOs: 97 and 98. For example, the VH and VL of Hit ID 34 are set forth in SEQ ID NOs: 105 and 106. For example, the VH and VL of Hit ID 35 are set forth in SEQ ID NOs: 113 and 114. For example, the VH and VL of Hit ID 36 are set forth in SEQ ID NOs: 121 and 122. For example, the VH and VL of Hit ID 37 are set forth in SEQ ID NOs: 129 and 130. For example, the VH and VL of Hit ID 38 are set forth in SEQ ID NOs: 137 and 138. For example, the VH and VL of Hit ID 39 are set forth in SEQ ID NOs: 145 and 146. For example, the VH and VL of Hit ID 40 are set forth in SEQ ID NOs: 153 and 154.

[0120] These antibodies can be humanized. The humanized VH and VL sequences are shown in Figures 25, 26, 27, 28 or 29.

[0121] 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).

[0122] 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).

[0123] In some embodiments, the humanization percentage refers to the percentage of identity of a heavy or light chain variable region sequence compared to human antibody sequences in the International Immunogenetic Information System (IMGT) database. A top hit means that a heavy or light chain variable region sequence is closer to a particular species than to other species. For example, a top hit to human means that the sequence is closer to human than to other species. A top hit to human and cynomolgus monkey means that the sequence has the same percentage of identity to human sequences and cynomolgus monkey sequences, and these percentages of identity are the highest compared to sequences of other species. In some embodiments, the humanization percentage is greater than 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% or 95%. Detailed descriptions of how to determine the humanization percentage and how to determine the top hits are known in the art and are described, for example, in Jones, Tim D. et al., "Inns and Details of Antibody Common Names," MAbs. Vol. 8. No. 1. Taylor & Francis, 2016, which is incorporated herein by reference in its entirety. A high humanization percentage often provides various advantages, such as being safer and more effective in humans, more likely to be tolerated by human subjects, and / or less likely to cause side effects.

[0124] Further, in some embodiments, the antibodies or antigen-binding fragments thereof described herein may also comprise one, two or three heavy chain variable region CDRs selected from Figures 24A-24E, 28, 29, and Figures 30A-30E, or one, two or three light chain variable region CDRs selected from Figures 24A-24E, 28, 29, and Figures 30A-30E. In some embodiments, the antibodies or antigen-binding fragments thereof described herein may also comprise 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 according to the IMGT numbering scheme. In some embodiments, the antibodies or antigen-binding fragments thereof described herein may also comprise 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 according to the Kabat numbering scheme. In some embodiments, the antibodies or antigen-binding fragments thereof described herein can comprise one, two or three heavy chain variable region CDRs and / or one, two or three light chain variable region CDRs according to the Chothia numbering scheme, as shown in Figures 24C and 30C. In some embodiments, the antibodies or antigen-binding fragments thereof described herein can comprise one, two or three heavy chain variable region CDRs and / or one, two or three light chain variable region CDRs according to the Aho numbering scheme, as shown in Figures 24D and 30D. In some embodiments, the antibodies or antigen-binding fragments thereof described herein can comprise one, two or three heavy chain variable region CDRs and / or one, two or three light chain variable region CDRs according to the North numbering scheme, as shown in Figures 24E and 30E. In some embodiments, the antibodies or antigen-binding fragments thereof described herein can comprise 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, also according to the IMGT or combined numbering scheme, e.g., based on predicted functionality of the sequences.

[0125] In some embodiments, the antibodies or antigen-binding fragments described herein can comprise a heavy chain variable domain comprising any one of the VH CDR1s shown in Figures 24A-24E, 28, 29, and 30A-30E having zero, one or two amino acid insertions, deletions or substitutions, any one of the VH CDR2s shown in Figures 24A-24E, 28, 29, and 30A-30E having two or three, zero, one or two amino acid insertions, deletions or substitutions, and any one of the VH CDR3s shown in Figures 24A-24E, 28, 29, and 30A-30E having zero, one or two amino acid insertions, deletions or substitutions.

[0126] In some embodiments, the antibodies or antigen-binding fragments described herein can comprise a light chain variable domain comprising any one of the VL CDR1s shown in Figures 24A-24E, 28, 29, and 30A-30E having zero, one or two amino acid insertions, deletions or substitutions, any one of the VL CDR2s shown in Figures 24A-24E, 28, 29, and 30A-30E having two or three, zero, one or two amino acid insertions, deletions or substitutions, and any one of the VL CDR3s shown in Figures 24A-24E, 28, 29, and 30A-30E having zero, one or two amino acid insertions, deletions or substitutions.

[0127] Insertions, deletions and substitutions can be made within the CDR sequences or at one or both termini of the CDR sequences.

[0128] The invention also provides an antibody or antigen-binding fragment thereof that binds to MICA and / or MICB, the antibody or antigen-binding fragment thereof comprising 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%, 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.

[0129] 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 into one or both of the first and second amino acid or nucleic acid sequences for optimal alignment, and non-homologous sequences can be ignored for comparison purposes). The amino acid residues or nucleotides at corresponding amino acid or nucleotide positions are then compared. If 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 are identical at that position. 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 that need to be introduced to optimally align the two sequences and the length of each gap. For example, comparison of sequences and determination of the percent identity between the two sequences can be accomplished using a Blossum62 scoring matrix with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5.

[0130] The invention also provides a nucleic acid comprising a polynucleotide encoding an immunoglobulin heavy chain or a polypeptide comprising an immunoglobulin heavy chain. The immunoglobulin heavy chain or immunoglobulin light chain comprises CDRs (based on Kabat, Chothia, IMGT, North, or Aho numbering) as shown in Figures 24A-24E, 28, 29, and 30A-30E. When the 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 binds to MICA and / or MICB.

[0131] Anti-MICA / B antibodies and antigen-binding fragments can also include antibody variants (including derivatives and conjugates) of antibodies or antibody fragments, and multispecific (e.g., bispecific) antibodies or antibody fragments. Additional antibodies provided herein are polyclonal, monoclonal, multispecific (multimeric, e.g., bispecific), human, chimeric (e.g., human-mouse chimeras), single chain, intracellularly produced antibodies (i.e., intrabodies), and antigen-binding fragments thereof. The antibodies or antigen-binding fragments thereof can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. In some embodiments, the antibodies or antigen-binding fragments thereof are IgG antibodies or antigen-binding fragments thereof.

[0132] Fragments of antibodies are suitable for use in the methods provided, so long as they retain the desired affinity and specificity of the full-length antibody. Thus, fragments of antibodies that bind MICA and / or MICB retain the ability to bind MICA and / or MICB. Fv fragments are antibody fragments that contain a complete antigen recognition and binding site. This region consists of a tightly associated (which may essentially be covalently linked, e.g., in scFv) dimer of one heavy and one light chain variable domain. In this configuration, the three CDRs of each variable domain interact to define an antigen binding site on the surface of the VH-VL dimer. Collectively, the six CDRs or a subset thereof confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three CDRs specific for an antigen) can be capable of recognizing and binding to an antigen, although usually with a lower affinity than the entire binding site.

[0133] 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. Generally, the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen binding.

[0134] The Fab fragment contains the variable and constant domains of the light chain and the variable and first constant domain (CH1) of the heavy chain. F(ab')2 antibody fragments usually comprise a pair of Fab fragments covalently linked by hinge cysteines near the carboxy terminus. Other chemical linkages of antibody fragments are known in the art.

[0135] Diabodies are small antibody fragments with two antigen-binding sites, which consist of 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, creating two antigen-binding sites.

[0136] Linear antibodies contain a pair of tandem Fd segments (VH-CH1-VH-CH1) that form a pair of antigen-binding regions with complementary light chain polypeptides. Linear antibodies can be bispecific or monospecific.

[0137] The antibodies and antibody fragments of the disclosure can be modified in the Fc region to provide desired effector functions or serum half-life.

[0138] Antibody multimerization can be achieved by natural aggregation of antibodies, or by chemical or recombinant conjugation techniques known in the art. For example, a proportion of purified antibody preparations (e.g., purified IgG1 molecules) spontaneously form protein aggregates that include antibody homodimers and other higher order antibody multimers.

[0139] Alternatively, antibody homodimers can be formed by chemical coupling techniques known in the art. For example, heterobifunctional cross-linkers can be used to form antibody multimers, including but not limited to SMCC (succinimidyl 4-(maleimidomethyl)cyclohexane-1-carboxylate) and SATA (N-succinimidyl S-acetylthioacetate). An exemplary protocol for the formation of antibody homodimers is described in Ghetie et al. (Proc. Natl. Acad. Sci. USA 94:7509-7514, 1997). Antibody homodimers can be converted to Fab'2 homodimers through digestion with pepsin. Another method for forming antibody homodimers is to use the autophilic T15 peptide described in Zhao et al. (J. Immunol. 25:396-404, 2002).

[0140] In some embodiments, the multispecific antibody is a bispecific antibody. Bispecific antibodies can be generated by engineering the interface between a pair of antibody molecules to maximize the percentage of heterodimers recovered from recombinant cell culture. For example, the interface can comprise at least a portion of the CH3 domain of an antibody constant domain. In this method, one or more small amino acid side chains at the interface of a first antibody molecule are replaced with larger side chains (e.g., tyrosine or tryptophan). Compensatory "cavities" of identical or similar size to the large side chains are created at the interface of a second antibody molecule by replacing the large amino acid side chains with smaller ones (e.g., alanine or threonine). This provides a mechanism for increasing the yield of heterodimers over other unwanted end-products such as homodimers. This method is described, for example, in WO 96 / 27011, incorporated by reference in its entirety.

[0141] Bispecific antibodies include cross-linked or "heteroconjugate" antibodies. For example, one of the antibodies of the heteroconjugate can be coupled to avidin and the other to biotin. Heteroconjugate antibodies may be made using any convenient cross-linking method. Suitable cross-linking agents and techniques are well known in the art and are disclosed in U.S. Pat. No. 4,676,980, which is incorporated herein by reference in its entirety.

[0142] Any of the antibodies or antigen-binding fragments described herein can be conjugated to a stabilizing molecule (e.g., a molecule that extends the half-life of the antibody or antigen-binding fragment thereof in a subject or in solution). Non-limiting examples of stabilizing molecules include polymers (e.g., polyethylene glycol) or proteins (e.g., serum albumins such as human serum albumin). Conjugation to a stabilizing molecule can extend the half-life or enhance the biological activity of the antibody or antigen-binding fragment in vitro (e.g., when stored in tissue culture or as a pharmaceutical composition) or in vivo (e.g., in the human body).

[0143] In some embodiments, the antibodies or antigen-binding fragments described herein can be conjugated to a therapeutic agent. The antibody-drug conjugates comprising the antibodies or antigen-binding fragments thereof can be covalently or non-covalently conjugated to a therapeutic agent. In some embodiments, the therapeutic agent is a cytotoxic or cytostatic drug (e.g., cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracin, maytansinoids such as DM-1 and DM-4, ​​dione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, epirubicin, and cyclophosphamide and analogs).

[0144] Antibodies and antigen-binding fragments The present invention provides anti-MICA / B antibodies and antigen-binding fragments thereof. Generally, antibodies (also called immunoglobulins) are composed of two classes of polypeptide chains: light chains and heavy chains. A non-limiting antibody of the present disclosure can be a complete four immunoglobulin chain antibody, including two heavy chains and two light chains. The heavy chain of the antibody can be of any isotype, including IgM, IgG, IgE, IgA, or IgD, or a subisotype, 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 include two identical copies of the light chain and two identical copies of the heavy chain. The heavy chains each contain one variable domain (or variable region, V H ) and multiple constant domains (or constant regions), which are linked together via disulfide bonds within the constant domains to form the "stem" of the antibody. The light chains each contain one variable domain (or variable region, V L ) and one constant domain (or constant region), each bound to one heavy chain via disulfide bonds. The variable region of each light chain is aligned with the variable region of the heavy chain to which it is bound. Both the light and heavy chain variable regions contain three hypervariable regions flanked by more conserved framework regions (FR).

[0145] These hypervariable regions, known as complementarity determining regions (CDRs), form the loops that comprise the major antigen-binding surface of the antibody. The four framework regions adopt a predominantly β-sheet structure, and the CDRs form loops that connect to, and in some cases form part of, the β-sheet structure. The CDRs of each chain are held in close proximity by the framework regions and contribute to the formation of the antigen-binding region with the CDRs from the other chain.

[0146] Methods for identifying CDR regions of an antibody by analyzing the amino acid sequence of the antibody are well known, and a number of definitions of CDRs are in common use: the Kabat definition is based on sequence variability, and the Chothia definition is based on the location of 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., "Analysis and improvement of Kabat and structurally correct 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 (Oct. 1997); Morea et al., J Mol Biol. 275(2): 269-94 (Jan 1998); Chothia et al., Nature 1999. 342(6252):877-83 (Dec. 1989); Ponomarenko and Bourne, BMC Structural Biology 7:64 (2007), each of which is incorporated herein by reference. Other definitions are known in the art, including, for example, IMGT, Aho (Honneger numbering scheme), and North. In some embodiments, a combination of CDR definitions is used.

[0147] CDR is important for recognizing the epitope of an antigen. As used herein, "epitope" is the smallest part of a target molecule that the antigen-binding domain of an antibody can specifically bind to. The smallest size of an epitope can be about 3, 4, 5, 6, or 7 amino acids, but these amino acids do not need to be a continuous linear sequence of the primary structure of an antigen, because an epitope can depend on the three-dimensional configuration of an antigen based on the secondary and tertiary structure of the antigen.

[0148] 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, IgG4) are highly conserved and differ in their constant regions, particularly their hinge and upper CH2 domains. The sequences and differences of IgG subclasses are known in the art and described, for example, in Vidarsson et al., "IgG Subclasses and Allotypes: From Structure to Effector Functions," Frontiers in immunology 5 (2014); Irani et al., "Molecular Properties of Human IgG Subclasses and Implications for the Design of Therapeutic Monoclonal Antibodies for 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.

[0149] An antibody can be an immunoglobulin molecule from any species (e.g., human, rodent, murine, camelid). Antibodies disclosed herein also include, but are not limited to, polyclonal antibodies, monoclonal antibodies, monospecific antibodies, multispecific antibodies, and chimeric antibodies comprising an immunoglobulin binding domain fused to another polypeptide. The term "antigen-binding domain" or "antigen-binding fragment" refers to any portion of an antibody that retains the specific binding activity of the intact antibody, i.e., any portion of an antibody that can specifically bind to an epitope on the intact antibody's target molecule. It includes, for example, Fab, Fab', F(ab')2, and variants of these fragments. Thus, in some embodiments, an antibody or antigen-binding fragment thereof can be, for example, an scFv, Fv, Fd, dAb, bispecific antibodies, bispecific scFv, diabodies, linear antibodies, single chain antibody molecules, multispecific antibodies formed from antibody fragments, and any polypeptide that comprises a binding domain that is an antibody binding domain or is homologous to an antibody binding domain. Non-limiting examples of antigen-binding domains include, for example, the heavy and / or light chain CDRs of a complete antibody, the heavy and / or light chain variable regions of a complete antibody, the full-length heavy or light chain of a complete antibody, or individual CDRs from either the heavy or light chain of a complete antibody.

[0150] In some embodiments, the antigen-binding fragment can form part of a chimeric antigen receptor (CAR). In some embodiments, the chimeric antigen receptor is a fusion of a single chain variable fragment (scFv) described herein fused to a CD3 zeta transmembrane domain and endodomain. In some embodiments, the chimeric antigen receptor also comprises the intracellular signaling domains of various co-stimulatory protein receptors (e.g., CD28, 41BB, ICOS). In some embodiments, the chimeric antigen receptor comprises multiple signaling domains, such as CD3z-CD28-41BB or CD3z-CD28-OX40, to enhance potency. Thus, in one aspect, the invention further provides a cell (e.g., a T cell) expressing a chimeric antigen receptor described herein.

[0151] In some embodiments, the scFV has one heavy chain variable domain and one light chain variable domain.

[0152] Antibody properties The antibodies or antigen-binding fragments thereof described herein can inhibit the shedding of MICA and / or MICB polypeptides from the surface of cancer cells and promote the recruitment of NK cells and T cells.

[0153] MICA and MICB are ligands for NKG2D and can be expressed in response to cellular stresses, including DNA damage, endoplasmic reticulum stress response, hypoxia, and carcinogenesis. Expression of MICA / B on the surface of cancer cells can tag the cancer cells for NK cell-mediated destruction. However, MICA / B proteins can be downregulated by tumor cells or proteolytically shed from the surface of tumor cells, resulting in effective evasion from NKG2D recognition and subsequent progression of cancer growth. In some embodiments, the antibodies described herein can bind to MICA and / or MICB, thereby inhibiting proteolytic shedding of MICA / MICB polypeptides from cancer cells and restoring enhanced NKG2D recognition and NK cell responses.

[0154] In some embodiments, the antibody or antigen-binding fragment thereof is capable of binding to the alpha 1, alpha 2, and / or alpha 3 domains. In some embodiments, the antibody or antigen-binding fragment thereof is capable of binding to the alpha 3 domain.

[0155] In some embodiments, the antibodies or antigen-binding fragments thereof described herein can reduce shedding of MICA / B polypeptide 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, the antibodies or antigen-binding fragments thereof described herein can stabilize MICA / B on the cell surface by preventing shedding. In some embodiments, the antibodies or antigen-binding fragments thereof described herein can reduce the amount of soluble MICA / B polypeptide in serum 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, the antibodies or antigen-binding fragments thereof described herein can reduce the amount of soluble MICA / B polypeptide in cell culture medium of cancer cells grown in culture 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, the antibodies or antigen-binding fragments thereof described herein can efficiently capture shed MICA / B to form immune complexes, thereby stimulating NKG2D and coactivating NK cells and / or T cells. In some embodiments, the antibodies or antigen-binding fragments thereof described herein can potentiate NK cells to kill tumor cells. In some embodiments, the antibodies or antigen-binding fragments thereof described herein can mediate effector functions (e.g., ADCC) to kill MICA / B-expressing tumor cells. In some embodiments, the antibodies or antigen-binding fragments thereof described herein can reduce tumor growth or tumor metastasis by less than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1%.

[0156] In some embodiments, the antibody (or antigen-binding fragment thereof) is -1 Less than 0.01s -1 Less than 0.001s -1 Less than 0.0001s -1Less than or equal to 0.0001s -1 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 a k of less than 0.01 s. In some embodiments, the k is less than 0.01 s. -1 Greater than 0.001s - Greater than 1, 0.0001s -1 Greater than 0.0001s -1 Greater than or equal to 0.00001s -1 Greater than.

[0157] In some embodiments, the kinetic association rate (k) is greater than or equal to 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 (k) is greater than 1×10 5 / Ms, less than 1×10 6 / Ms or less than 1×10 7 / Ms.

[0158] Affinity can be estimated from the quotient of kinetic rate constants (K = k / k). In some embodiments, K is greater than or equal to 1 x 10 -6 Less than M, 1×10 -7 Less than M, 1×10 -8 Less than M, 1×10 -9 Less than M or 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 less than 1 x 10 -7 Larger than M, 1×10 -8 Larger than M, 1×10 -9 Larger than M, 1×10 -10 Larger than M, 1×10 -11 Larger than M or 1×10-12 Bigger than M.

[0159] Common techniques for measuring the affinity of an antibody to an antigen include, for example, ELISA, RIA, and surface plasmon resonance (SPR). In some embodiments, measurements are performed using a Carterra® SPR Imaging System or a Gator Prime BLI System. In some embodiments, the antibody binds to human MICA, monkey MICA (e.g., cynomolgus MICA), and / or chimeric MICA. In some embodiments, the antibody binds to human MICB, monkey MICB (e.g., cynomolgus MICB), and / or chimeric MICB.

[0160] In some embodiments, the antibodies described herein have a concentration 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, the EC50 is less than 0.01 μg / mL. In some embodiments, the EC50 is less than 0.02 μg / mL. In some embodiments, the EC50 is less than 0.03 μg / mL. In some embodiments, the thermal stability is determined. The antibodies or antigen-binding fragments described herein may have a Tm of more 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 may show two transitions, a first denaturation temperature Tm D1 and a second denaturation temperature Tm D2. The presence of these two peaks often indicates the denaturation of the Fc domain (Tm D1) and the Fab domain (Tm D2), respectively. When there are two peaks, the Tm usually refers to Tm D2.

[0161] Thus, in some embodiments, the antibodies or antigen-binding fragments 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 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.

[0162] In some embodiments, the Tm, Tm D1, Tm D2 are 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.

[0163] In some embodiments, the antibody has a tumor growth inhibition (TGI%) of 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 antibody has a tumor growth inhibition 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 the start of treatment, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after the start of treatment. As used herein, tumor growth inhibition (TGI%) is calculated using the following formula: TGI(%)=[1-(Ti-T0) / (Vi-V0)]×100 Ti is the mean tumor volume on day i of the treatment group. T0 is the mean tumor volume on day 0 of the treatment group. Vi is the mean tumor volume on day i of the control group. V0 is the mean tumor volume on day 0 of the control group.

[0164] In some embodiments, the antibodies or antigen-binding fragments thereof described herein have a functional Fc. In some embodiments, the Fc is from human IgG1, human IgG2, human IgG3, or human IgG4. In some embodiments, the effector function of the functional Fc is antibody-dependent cell-mediated cytotoxicity (ADCC). In some embodiments, the effector function of the functional Fc is phagocytosis (e.g., antibody-dependent cellular phagocytosis, or ADCP). In some embodiments, the effector function of the functional Fc is ADCC and phagocytosis. In some embodiments, the antibodies or antigen-binding fragments thereof described herein have an Fc region without effector function. In some embodiments, the Fc is a human IgG4 Fc. In some embodiments, the Fc is a human IgG1 Fc. In some embodiments, the 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 comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, 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, or Fv fragment.

[0165] In some embodiments, the anti-MICA / B antibodies described herein can bind only to MICA and therefore may also be referred to as anti-MICA antibodies. In some embodiments, the anti-MICA / B antibodies described herein can bind only to MICB and therefore may also be referred to as anti-MICB antibodies.

[0166] In some embodiments, the anti-MICA / B antibodies described herein can inhibit shedding of MICA / B polypeptides from the surface of tumor cells, such that 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.

[0167] In some embodiments, the anti-MICA / B antibodies described herein can increase anti-tumor activity (e.g., destruction of tumor cells by NK cells or T cells) in a cancer patient following treatment with a therapeutically effective amount of an 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 an anti-MICA / B antibody.

[0168] In some embodiments, the anti-MICA / B antibodies described herein are more effective (e.g., at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 1-fold, 2-fold, 5-fold, or 10-fold more effective) than a reference antibody. Some of the reference antibodies (e.g., 3F9, 6E.1.1.12, ID5, 13A9, P2B10G5, or CM33322) are shown in FIG.

[0169] Method for producing anti-MICA / B antibodies Isolated fragments of human MICA and / or MICB can be used as immunogens to generate antibodies using standard techniques for the preparation of polyclonal and monoclonal antibodies. Polyclonal antibodies can be raised in animals by multiple injections (e.g., subcutaneous or intraperitoneal) of the antigenic peptide or protein. In some embodiments, the antigenic peptide or protein is injected with at least one adjuvant. In some embodiments, the antigenic peptide or protein can be conjugated to an agent that is immunogenic in the species being immunized. Animals can be injected multiple times (e.g., 2, 3, or 4 times) with the antigenic peptide or protein.

[0170] Full-length polypeptides or proteins may be used, or antigenic peptide fragments thereof may be used as immunogens. An antigenic peptide of a 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 encompasses an epitope of the protein such that antibodies raised against the peptide form specific immune complexes with the protein. As mentioned 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).

[0171] An immunogen is typically used to prepare antibodies by immunizing a suitable subject (e.g., a human or transgenic animal expressing at least one human immunoglobulin locus). An appropriate immunogenic formulation can include, for example, a recombinantly expressed or chemically synthesized polypeptide (e.g., a fragment of human MICA and / or MICB). The formulation can further include an adjuvant, such as Freund's complete or incomplete adjuvant, or a similar immunostimulant.

[0172] Polyclonal antibodies can be prepared by immunizing a suitable subject with a MICA and / or MICB polypeptide, or an antigenic peptide thereof (e.g., a portion of MICA and / or MICB), as described above, as an immunogen. The antibody titer of the immunized subject can be monitored over time by standard techniques, such as enzyme-linked immunosorbent assay (ELISA) using immobilized MICA and / or MICB polypeptide or peptide. If desired, the antibody molecules can be isolated from the mammal (e.g., from the blood) and further purified by well-known techniques, such as protein A / protein G chromatography to obtain an IgG fraction. At an appropriate time after immunization, e.g., when the specific antibody titer is highest, antibody-producing cells can be obtained from the subject and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique first described by Kohler et al. (Nature 256:495-497, 1975), the human B cell hybridoma technique (Kozbor et al., Immunol. Today 4:72, 1983), the EBV hybridoma technique (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp.77-96, 1985), or the trioma technique. Techniques for producing hybridomas are well known (see generally Current Protocols in Immunology, 1994, Coligan et al. (Eds.), John Wiley & Sons, Inc., New York, NY). Hybridoma cells producing a monoclonal antibody can be detected by screening the hybridoma culture supernatants for antibodies that bind the polypeptide or epitope of interest, e.g., using a standard ELISA assay.

[0173] Variants of the antibodies or antigen-binding fragments described herein can be prepared by introducing appropriate nucleotide changes into the DNA encoding the human, humanized, or chimeric antibodies or antigen-binding fragments thereof described herein, or by peptide synthesis. Such variants include, for example, deletions, insertions, or substitutions of residues within the amino acid sequence that constitutes the antigen-binding site or domain of the antibody. In such a population of variants, some antibodies or antigen-binding fragments will have increased affinity for the target protein, e.g., MICA and / or MICB. Deletions, insertions, and / or combinations can be made to obtain antibodies or antigen-binding fragments thereof with improved binding affinity for the target. Amino acid changes introduced into the antibody or antigen-binding fragment can also alter or introduce new post-translational modifications to the antibody or antigen-binding fragment, such as changing the number (e.g., increasing or decreasing) of glycosylation sites, changing the type of glycosylation site (e.g., changing the amino acid sequence so that different sugars are added by enzymes present in the cell), or introducing new glycosylation sites.

[0174] The antibodies disclosed herein can be derived from any animal species, including mammals. Non-limiting examples of natural antibodies include antibodies derived from humans, primates such as monkeys and apes, cows, 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.

[0175] Human and humanized antibodies include antibodies having variable and constant regions derived from (or with the same amino acid sequences as) human germline immunoglobulin sequences. Human antibodies can include amino acid residues, for example in the CDRs, that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).

[0176] A humanized antibody usually has a human framework (FR) into which non-human CDRs have been grafted. Thus, a humanized antibody contains one or more amino acid sequences introduced from a source that is non-human. These non-human amino acid residues are often referred to as "import" residues, and are usually taken from an "import" variable domain. Humanization can be essentially performed, for example, by replacing rodent CDRs or CDR sequences with the corresponding sequences of a human antibody. These methods are described, for example, 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. Thus, a "humanized" antibody is a chimeric antibody in which a portion of a human V domain is replaced by the corresponding sequence from a non-human species. In practice, humanized antibodies are usually murine antibodies in which some CDR residues and some FR residues are substituted by residues from analogous sites in human antibodies.

[0177] The selection of human VH and VL domains used to generate humanized antibodies is very important to reduce immunogenicity. According to the so-called "best-fit" method, the sequence of the V domain of mouse antibody is screened against the entire library of known human domain sequences. The human sequence that is closest to the mouse sequence 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)).

[0178] In some embodiments, yeast display is performed to achieve affinity maturation. Details are described, for example, in Boder, E. T. et al., "Yeast surface display for screening combinatorial collision wrinkles," Nature Biotechnology 15.6 (1997): 553-557; Feldhaus, M. J. et al., "Flow cytometric isolation of human antibodies from non-immune Saccharomyces cerevisiae surface display libraries," Nature Biotechnology 21.2 (2003): 163-170; and Chao, G. et al., "Isolation 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.

[0179] It is further important that antibodies be humanized while retaining high specificity and affinity for the antigen, as well as other favorable biological properties. To achieve this goal, humanized antibodies can be prepared by a process of analyzing the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays allows analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., residues that influence the ability of the candidate immunoglobulin to bind to the antigen. In this way, FR residues can be selected and combined from the recipient and import sequences to achieve desired antibody properties, such as improved affinity for the target antigen.

[0180] In some embodiments, humanization of the anti-MICA / B antibodies or antigen-binding fragments thereof described herein is accomplished in silicon using, for example, MOE computer software.

[0181] Typically, amino acid sequence variants of a human, humanized, or chimeric anti-MICA / B antibody contain an amino acid sequence that has at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% percent identity to a sequence present in the light or heavy chain of the original antibody.

[0182] Identity or homology to a source sequence is typically the percentage of amino acid residues present in a candidate sequence that are identical to sequences 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; any conservative substitutions are not taken into account as part of the sequence identity.

[0183] Additional modifications can be made to the anti-MICA / B antibody or antigen-binding fragment. For example, cysteine ​​residues can be introduced into the Fc region to allow interchain disulfide bond formation in this region. The homodimeric antibodies thus generated may have extended half-lives in vitro and / or in vivo. Homodimeric antibodies with extended half-lives in vitro and / or in vivo can also be prepared using heterobifunctional cross-linkers, for example as described in Wolff et al. (Cancer Res. 53:2560-2565, 1993). Alternatively, antibodies with dual Fc regions can be engineered (see, for example, Stevenson et al., Anti-Cancer Drug Design 3:219-230, 1989).

[0184] In some embodiments, covalent modifications can be made to the anti-MICA / B antibody or antigen-binding fragment thereof. These covalent modifications can be made 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 fragment with organic derivatizing agents capable of reacting with selected side chains or the N- or C-terminal residues.

[0185] In some embodiments, antibody variants are provided that have carbohydrate structures that lack fucose attached (directly or indirectly) to the Fc region. For example, the amount of fucose in such antibodies can be between 1% and 80%, between 1% and 65%, between 5% and 65%, or between 20% and 40%. The amount of fucose is determined by calculating the average amount of fucose in the glycan of Asn297 relative to the sum of all glycan structures (e.g., complex, hybrid, high mannose structures) attached to Asn297 as measured by MALDI-TOF mass spectrometry, e.g., as described in WO 2008 / 077546. Asn297 refers to an asparagine residue located at approximately position 297 (position 314 in the Eu numbering of Fc region residues, or Kabat numbering), in the Fc region, although due to minor sequence variations in antibodies, Asn297 can also be located approximately ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300. Such fucosylation variants may have improved ADCC function. In some embodiments, the Fc region of the antibody can be further engineered to replace asparagine at position 297 with alanine (N297A) to reduce glycan heterogeneity.

[0186] Recombinant Vectors The present disclosure also provides recombinant vectors (e.g., expression vectors) comprising the isolated polynucleotides disclosed herein (e.g., polynucleotides encoding the polypeptides disclosed herein), host cells into which the recombinant vectors are introduced (i.e., such that the host cell contains the polynucleotides and / or vectors containing the polynucleotides), and the production of recombinant antibody polypeptides or fragments thereof by recombinant techniques.

[0187] As used herein, a "vector" is any construct capable of delivering one or more polynucleotides of interest to a host cell when the vector is introduced into the host cell. An "expression vector" is capable of delivering and expressing one or more polynucleotides of interest as encoded polypeptides in a host cell into which the expression vector is introduced. Thus, in an expression vector, a polynucleotide of interest is positioned for expression in the vector by being operably linked to regulatory elements, such as promoters, enhancers, and / or polyA tails, located at or near or on either side of the integration site of the polynucleotide of interest within the vector or within the genome of the host cell, such that the polynucleotide of interest is translated in the host cell into which it is introduced with the expression vector.

[0188] Vectors can be introduced into host cells by methods known in the art, such as, for example, electroporation, chemical transfection (e.g., DEAE-dextran), transformation, transfection, and infection and / or transduction (e.g., by recombinant viruses). Thus, 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.

[0189] In some embodiments, a polynucleotide disclosed herein (e.g., a polynucleotide encoding a polypeptide disclosed herein) is introduced using a viral expression system (e.g., vaccinia virus or other poxvirus, retrovirus, or adenovirus), which may involve the use of a non-pathogenic (defective), replication-competent virus, or may use a replication-deficient virus. In the latter case, viral propagation generally occurs only in complementary viral packaging cells. Suitable systems are described, 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; US ​​Pat. Nos. 4,603,112, 4,769,330 and 5,017,487, WO 89 / 01973, US 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 skilled in the art. The DNA may be "naked" DNA, for example as described in Ulmer et al., 1993, Science, 259:1745-1749, and Cohen, 1993, Science, 259:1691-1692. Uptake of naked DNA may be increased by coating the DNA onto biodegradable beads that are efficiently transported into cells.

[0190] For expression, a DNA insert comprising a polynucleotide encoding an antibody or a polynucleotide encoding a polypeptide disclosed herein can be operably linked to a suitable promoter (e.g., a heterologous promoter), such as the phage lambda PL promoter, the E. coli lac, trp and tac promoters, the SV40 early and late promoters, and the promoters of retroviral LTRs, to name a few. Other suitable promoters are known to those of skill in the art. The expression construct can further comprise sites for transcription initiation, transcription termination, and a ribosome binding site for translation within the transcribed region. The coding portion of the mature transcript expressed by the construct can include a stop codon (UAA, UGA, or UAG) appropriately positioned for translation to begin at the beginning and at the end of the polypeptide to be translated.

[0191] As mentioned above, the expression vector may include at least one selectable marker. Such markers include dihydrofolate reductase or neomycin resistance for eukaryotic cell culture, and tetracycline or ampicillin resistance genes for culturing in E. coli and other bacteria. Representative examples of suitable hosts include, but are not limited to, bacterial cells such as E. coli cells, Streptomyces cells and Salmonella typhimurium cells, fungal cells such as yeast cells, insect cells such as Drosophila S2 cells and Spodoptera Sf9 cells, animal cells such as CHO cells, COS cells, Bowes melanoma cells, HK293 cells, and plant cells. Culture media and conditions suitable for the host cells described herein are known in the art.

[0192] Non-limiting vectors for use in bacteria include pQE70, pQE60 and pQE-9 available from Qiagen, pBS vectors available from Stratagene, Phagescript vectors, Bluescript vectors, pNH8A, pNH16a, pNH18A, pNH46A, ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 available from Pharmacia. Non-limiting eukaryotic vectors include pWLNEO, pSV2CAT, pOG44, pXT1, pSG available from Stratagene, and pSVK3, pBPV, pMSG, pSVL available from Pharmacia. Other suitable vectors will be readily apparent to one of skill in the art.

[0193] Non-limiting bacterial promoters suitable for use include the E. coli lacI and lacZ promoters, the T3 and T7 promoters, the gpt promoter, the lambda PR and PL promoters, and the trp promoter. Suitable eukaryotic promoters include the CMV immediate early promoter, the HSV thymidine kinase promoter, the SV40 early and late promoters, promoters of retroviral LTRs such as Rous sarcoma virus (RSV), and metallothionein promoters such as the mouse metallothionein I promoter.

[0194] In the yeast Saccharomyces cerevisiae, a number of vectors containing constitutive or inducible promoters such as alpha factor, alcohol oxidase, and PGH can be used. For reviews, see Ausubel et al., (1989) Current Protocols in Molecular Biology, John Wiley & Sons, New York, NY, and Grant et al., Methods Enzymol., 153:516-544 (1997).

[0195] Introduction of the construct into the host cell can be accomplished by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid mediated transfection, electroporation, transduction, infection or other methods, which are described in many standard laboratory manuals, such as Davis et al., Basic Methods In Molecular Biology (1986).

[0196] Transcription of DNA encoding the antibody of the present invention by higher eukaryotes can be increased by inserting an enhancer sequence into the vector. Enhancers are cis elements of DNA, usually about 10-300 bp, that serve to increase the transcriptional activity of a promoter in a given host cell type. Examples of enhancers include the SV40 enhancer located 100-270 base pairs 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.

[0197] For secretion of the translated protein into the lumen of the endoplasmic reticulum, into the periplasmic space or into the extracellular environment, appropriate secretion signals may be incorporated into the expressed polypeptide. The signals may be endogenous to the polypeptide or they may be heterologous signals.

[0198] Polypeptides (e.g., antibodies) can be expressed in modified forms, such as fusion proteins (e.g., GST fusion proteins) or histidine-tagged, and can contain secretion signals as well as additional heterologous functional regions. For example, a region of additional amino acids, particularly charged amino acids, can be added to the N-terminus of the polypeptide to improve stability and persistence in the host cell during purification or during subsequent handling and storage. Also, peptide moieties can be added to the polypeptide to facilitate purification. Such regions can be removed before the final preparation of the polypeptide. Adding peptide moieties to polypeptides to effect secretion or excretion, improve stability, and facilitate purification is a routine technique well known in the art.

[0199] Treatment method The antibodies or antigen-binding fragments thereof of the present disclosure can be used for various therapeutic purposes. In one aspect, the present disclosure provides a method of treating cancer in a subject, reducing the rate of increase in tumor volume in a subject over time, reducing the risk of developing metastasis, or reducing the risk of developing further metastasis in a subject. In some embodiments, the treatment can stop, slow, prevent, or inhibit the progression of cancer. In some embodiments, the treatment can result in a reduction in the number, severity, and / or duration of one or more symptoms of cancer in a subject.

[0200] In one aspect, the disclosure features a method comprising administering a therapeutically effective amount of an antibody or antigen-binding fragment thereof disclosed herein to a subject in need thereof (e.g., a subject suffering from or identified or diagnosed as suffering from 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, colon cancer, gastric cancer, testicular cancer, thyroid cancer, bladder cancer, urethral cancer, or hematological malignancies. In some embodiments, the cancer is unresectable 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 is suffering from a solid tumor or hematological 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.

[0201] In some embodiments, the cancer is glioma, thyroid cancer, lung cancer, colon 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.

[0202] In some embodiments, the compositions and methods disclosed herein can be used to treat patients at risk for cancer. Cancer patients can be identified by a variety of methods known in the art.

[0203] As used herein, an "effective amount" refers to an amount or dosage sufficient to bring about beneficial or desired results, including halting, slowing, preventing or inhibiting the progression of a disease such as cancer. Since the effective amount will vary depending on, for example, the age and weight of the subject to whom the antibody, antigen-binding fragment, polynucleotide encoding the antibody, vector comprising the polynucleotide, and / or composition thereof is administered, the severity of the symptoms, and the route of administration, administration can be determined on an individual basis.

[0204] An effective amount can be administered once or multiple times. By way of example, an effective amount of an antibody or antigen-binding fragment is an amount sufficient to improve, stop, stabilize, reverse, inhibit, slow down and / or delay the progression of a cancer in a patient, or to improve, stop, stabilize, reverse, slow down and / or delay the proliferation of a cell (e.g., a biopsy cell, any of the cancer cells described herein, or a cell line (e.g., a cancer cell line)) in vitro. As is understood in the art, the effective amount of an antibody or antigen-binding fragment can vary depending on other factors, such as, inter alia, the medical history of the patient, and the type (and / or dosage) of the antibody used.

[0205] Effective amounts and schedules for administering the antibodies, antibody-encoding polynucleotides, and / or compositions disclosed herein can be determined empirically, and making such determinations is within the skill of the art. One of ordinary skill in the art will appreciate that the dosage that must be administered will vary depending, for example, on the mammal receiving the antibodies, antibody-encoding polynucleotides, and / or compositions disclosed herein, the route of administration, the particular type of antibodies, antibody-encoding polynucleotides, antigen-binding fragments, and / or compositions disclosed herein that are used, and other drugs administered to the mammal. Guidelines for selecting appropriate dosages of antibodies or antigen-binding fragments can be found in the literature on therapeutic uses of antibodies and antigen-binding fragments, such as, for example, Handbook of Monoclonal Antibodies, Ferrone et al., eds., Noges Publications, Park Ridge, NJ, 1985, ch. 22 and pp. 303-357; Smith et al., Antibodies in Human Diagnosis and Therapy, Haber et al., eds., Raven Press, New York, 1977, pp. 365-389.

[0206] A typical daily dosage of an effective amount of an antibody is between 0.01 mg / kg and 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 dosage 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.

[0207] In any of the methods described herein, at least one antibody, antigen-binding fragment thereof, or pharmaceutical composition (e.g., any of the antibodies, antigen-binding fragments, or pharmaceutical compositions described herein), and optionally at least one additional therapeutic agent, can 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). 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 comprising at least one antibody or antigen-binding fragment and a solid oral composition comprising at least one additional therapeutic agent). In some embodiments, at least one additional therapeutic agent is administered as a pill, tablet, or capsule. In some embodiments, the at least one additional therapeutic agent is administered as a sustained release oral formulation.

[0208] In some embodiments, the one or more additional therapeutic agents can be administered to the subject before or after administration of at least one antibody, antigen-binding antibody fragment, or pharmaceutical composition (e.g., any of the antibodies, antigen-binding antibody fragments, or pharmaceutical compositions described herein). In some embodiments, the one or more additional therapeutic agents and the at least one antibody, antigen-binding antibody fragment, or pharmaceutical composition (e.g., any of the antibodies, antigen-binding antibody fragments, or pharmaceutical compositions described herein) are administered to the subject such that there is an overlap in the period of biological activity of the one or more additional therapeutic agents and the at least one antibody or antigen-binding fragment (e.g., any of the antibodies or antigen-binding fragments described herein) in the subject.

[0209] In some embodiments, a subject may be administered at least one antibody, antigen-binding antibody fragment, or pharmaceutical composition (e.g., any of the antibodies, antigen-binding antibody fragments, or pharmaceutical compositions described herein) for an extended period of time (e.g., for a period of 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 may determine the length of time for treatment using any of the methods of diagnosis or tracking the effectiveness of treatment (e.g., observation of at least one symptom of cancer) described herein. As described herein, a skilled medical professional may also vary the identity and number (e.g., increase or decrease) of antibodies or antigen-binding antibody fragments (and / or one or more additional therapeutic agents) administered to a subject, and may 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 additional therapeutic agents) to a subject based on an evaluation of the effectiveness of the treatment (e.g., using any of the methods described herein and known in the art).

[0210] In some embodiments, one or more additional therapeutic agents can be administered to the subject. The additional therapeutic agents can include one or more inhibitors selected from the group consisting of 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, dual PI3K / mTOR inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, and isocitrate dehydrogenase 1 (IDH1) and / or isocitrate dehydrogenase 2 (IDH2) inhibitors.

[0211] In some embodiments, the additional therapeutic agent can include one or more inhibitors selected from the group consisting of a HER3 inhibitor, an LSD1 inhibitor, an MDM2 inhibitor, a BCL2 inhibitor, a CHK1 inhibitor, an activated Hedgehog signaling pathway inhibitor, and an agent that selectively degrades the estrogen receptor.

[0212] In some embodiments, the additional therapeutic agent is selected from the group consisting of trabectedin, nab-paclitaxel, trebananib, pazopanib, cediranib, palbociclib, everolimus, fluoropyrimidine, IFL, regorafenib, leolysin, Alimta, Zykadia, Sutent, temsirolimus, axitinib, everolimus, sorafenib, Votrient, pazopanib, IMA-901, AGS-003, The therapeutic agents may include one or more selected from the group consisting of cabozantinib, vinflunine, Hsp90 inhibitors, Ad-GM-CSF, temazolomide, IL-2, IFNa, vinblastine, talomide, dacarbazine, cyclophosphamide, lenalidomide, azacitidine, lenalidomide, bortezomib, amrubicin, carfilzomib, pralatrexate, and enzastaurin.

[0213] In some embodiments, the additional therapeutic agent can include one or more therapeutic agents selected from the group consisting of an adjuvant, a TLR agonist, a tumor necrosis factor (TNF) alpha, IL-1, HMGB1, an IL-10 antagonist, an IL-4 antagonist, an IL-13 antagonist, an IL-17 antagonist, an HVEM antagonist, an ICOS agonist, a CX3CL1 targeted therapy, a CXCL9 targeted therapy, a CXCL10 targeted therapy, a CCL5 targeted therapy, an LFA-1 agonist, an ICAM1 agonist, and a selectin agonist.

[0214] In some embodiments, carboplatin, nab-paclitaxel, paclitaxel, cisplatin, pemetrexed, gemcitabine, FOLFOX, or FOLFIRI are administered to the subject.

[0215] 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.

[0216] Pharmaceutical Compositions and Routes of Administration Also provided herein is a pharmaceutical composition comprising 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 the antibodies or antigen-binding fragments described herein can be present in the pharmaceutical composition in any combination. The pharmaceutical composition can be formulated by any method known in the art.

[0217] Pharmaceutical compositions are formulated to suit the intended route of administration (e.g., intravenous, intraarterial, intramuscular, intradermal, subcutaneous, or intraperitoneal). The compositions can include sterile diluents (e.g., sterile water or saline), fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents, antibacterial or antifungal agents such as benzyl alcohol or methylparabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, buffers such as acetates, citrates, or phosphates, and isotonic agents such as sugars (e.g., dextrose), polyalcohols (e.g., mannitol or sorbitol), or salts (e.g., sodium chloride, and the like), or any combination thereof. Liposomal suspensions can also be used as pharma-ceutically acceptable carriers (see, e.g., U.S. Pat. No. 4,522,811). The composition formulations can be formulated and enclosed in ampoules, disposable syringes, or multiple dose vials. Where necessary (e.g., injectable formulations), proper fluidity can be maintained by the use of a coating such as lecithin or a surfactant. Absorption of the antibody or antigen-binding fragment thereof can be prolonged by including an agent that delays 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.).

[0218] Compositions comprising any one or more 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 (e.g., a physically discrete unit containing a predetermined amount of active compound for ease of administration and uniformity of dosage).

[0219] Toxicity and therapeutic efficacy of the compositions can be determined by standard pharmaceutical procedures in cell cultures or experimental animals (e.g., monkeys). For example, the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population) can be determined. The therapeutic index is the ratio of LD50:ED50. Drugs that exhibit a high therapeutic index are preferred. If a drug exhibits undesirable side effects, care should be taken to minimize potential harm (i.e., reduce undesirable side effects). Toxicity and therapeutic efficacy can be determined by other standard pharmaceutical procedures.

[0220] Data obtained from cell culture assays and animal studies can be used in formulating the appropriate dosage of any given agent for use in a subject (e.g., a human). A therapeutically effective amount of one or more (e.g., one, two, three, or four) antibodies or antigen-binding fragments thereof (e.g., any of the antibodies or antibody fragments described herein) is an amount that treats the disease (e.g., kills cancer cells) in a subject (e.g., a human subject identified as having cancer) or a subject identified as at risk for developing the disease (e.g., a subject who previously developed cancer but has now been cured) and reduces the severity, frequency, and / or duration of one or more symptoms of the disease in the subject (e.g., a human). The efficacy and dosage of the antibodies or antigen-binding fragments described herein can be determined by a medical or veterinary professional using methods known in the art, as well as by observation of one or more symptoms of the disease in a subject (e.g., a human). Certain factors can affect the dosage and timing required to effectively treat a subject (e.g., the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and the presence of other diseases).

[0221] Exemplary dosage amounts include milligram or microgram amounts per kilogram of subject body weight of any of the antibodies or antigen-binding fragments described herein (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 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). These dosage amounts will vary widely, but one of skill in the art will recognize 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 dosage is administered initially, and the attending medical or veterinary professional (for therapeutic applications) or researcher (when working in the development stages) can then gradually increase the dosage until an appropriate response is obtained. It is further understood that the specific dosage level for any particular subject will depend on a variety of factors, including the activity of the particular compound used, the subject's age, weight, general health, sex, and diet, the time of administration, the route of administration, the rate of excretion, and the half-life of the antibody or antibody fragment in the body.

[0222] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.The present disclosure also provides methods for making the antibodies or antigen-binding fragments thereof for the various uses described herein.

[0223] Working Example The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0224] Example 1. Generation of anti-MICA / B antibodies In this example, the strategy used to generate anti-MICA / B antibodies is described. A panel of antibodies selectively binding to human and cynomolgus (cyno) monkey MICA / B antigens was generated in BALB / c mice using two immunization strategies. DNA or protein antigens were selected to maximize coverage in the human population due to genetic polymorphisms in the human population (Tables 1 and 2). In these experiments, DNA immunization was followed by protein immunization. For DNA immunization, a pool of DNA encoding the MICA / B alpha 3 domain of human MICA*002, MICA*004, MICA*008, MICA*009, and MICB*05, as well as cMICA fused to the Fc region of mouse IgG2a (cynoMICA, Macaca fascicularis MICA (the exact sequence is disclosed in Figure 33)) was injected into mice as immunogens using the Helios gene gun system (Bio-rad). Following this step, human MICA-ECD (Sino Biologicals, Catalog Number: 12302-H02H), human MICA-ECD-HIS (Sino Biologicals, Catalog Number: HPLC-12302-H08H), human MICB-ECD-HIS (Sino Biologicals, Catalog Number: 10759-H08H), and a pool of recombinant human MICA / B-alpha3 (human MICA*002, 004, 008 and MICB*05) fused to mouse Fc protein (sequences disclosed in Figure 34) were injected. Protein immunogens were resuspended in PBS with RIBI adjuvant and injected intraperitoneally.

[0225] [Table 1]

[0226] [Table 2]

[0227] Mice that showed sufficient serum titers were sacrificed. Spleens and bone marrow were harvested. Spleen cells or plasma B cells were isolated using a Mouse CD138+ Plasma Cell Isolation Kit (Miltenyi Biotec Inc., Cat. No.: 130-092-530) and processed separately to isolate single cells. mRNA was isolated from single cells. Nucleic acid sequences encoding the heavy chain variable region (VH) and light chain variable region (VL) were amplified by RT-PCR. Amplified PCR products encoding MICA / B-specific single chain variable fragments (scFVs) were assembled into a yeast library.

[0228] The above two yeast libraries underwent four rounds of selection using the MiltenyiMi diMACS™ system using biotinylated immunogens, and fluorescence-activated cell sorting (FACS) using biotinylated Ag or native protein or whole cell selection. These methods are described, for example, in Chao et al., Isolation and Engineering of Human Antibodies Using Yeast Surface Display, Nat Protoc. 2006;1(2):755-68, which is incorporated herein by reference in its entirety. Briefly, the libraries were first isolated using the Miltenyi MidiMACS™ system. The isolated yeast underwent two rounds of selection using a FACSARIAII sorter (BD Biosciences) using biotinylated MICA and MICB-alpha3-mFc fusion antigens. The selected MICA / MICB-binding yeast cells were incubated with CHO cells expressing MICA / B. After washing away unbound cells, the CHO cells with bound yeast were detached, resuspended in yeast growth medium, and plated to form single yeast colonies on standard yeast growth medium.

[0229] Single yeast colonies were picked and inoculated into 96-well plates containing yeast growth medium for scFv production. Yeast culture supernatants were harvested and screened for protein binding using ELISA and Carterra®. 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 VH and VL of hits were obtained by sequencing. The VH and VL encoding sequences were then cloned into a vector expressing human IgG1 (containing mouse variable region and human constant region) and expressed in HEK or CHO cells. The expressed antibodies were further screened and characterized. Some of these antibodies are shown in Figure 23. Their CDR sequences are shown in Figures 24A-24E.

[0230] Two approaches were used to humanize the antibodies identified above. First, a humanization template was designed in silico using a fusion computational chemistry system (MOE). Second, a humanization template was designed by grafting the six CDRs into human germline VH and VL frameworks (FRs) and flanking the CDRs with a limited number of mouse FR residues. The human germline was selected based on homology with mouse. The CDRs were defined based on one or a combination of numbering schemes known in the art. The humanization template was synthesized. The DNA fragment of the humanization template was amplified and introduced into yeast for display.

[0231] To improve control over affinity and manufacturing challenges, mutation libraries were constructed by mutating the CDRs by design using MOE or by random mutagenesis by error-prone PCR. Designed libraries were synthesized. DNA fragments of library sequences were amplified and introduced into yeast for display. Yeast screening was performed similarly to the selection process described above, except that a more stringent threshold was used to select for higher binding affinity.

[0232] A selected number of humanized-optimized hits with desirable properties were further engineered to mitigate manufacturing challenges by user-defined point mutations, to eliminate immunity by framework reversion germline mutations, and to maximally maintain desirable properties. The sequences of the 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.

[0233] Example 2. Biochemical characterization of anti-MICA / B antibodies The binding kinetics of the antibodies identified in Example 1 were measured using a Carterra® SPR Imaging System (Carterra USA). Specifically, anti-MICA / B antibodies were captured by anti-human Fc (SouthernBiotech, Catalog No.: 2047-01) immobilized to a HC200M-polycarboxylate chip (Carterra Bio, Catalog No.: HC200M) or HC30M-polycarboxylate chip (Carterra Bio, Catalog No.: HC30M) via amine-based coupling. Then, the corresponding monomeric antigens MICA002-ECD-HISAvi (BioIntron, project code number: B662201), MICA004-ECD-HISAvi (BioIntron, project code number: B662202), MICA008-ECD-HISAvi (Sino Bio, catalog number: 12302-H08H1), or MICB005-ECD-HISAvi (Sino Bio, catalog number: 10759-H08H) were injected in running buffer for 2-3 min at 25 °C, as shown in Figure 35. Dissociation kinetics were monitored for approximately 10 min. The chip surface was regenerated with 10 mM glycine HCl, pH 1.7 between binding cycles. Binding kinetics were analyzed using software provided by the manufacturer.

[0234] The binding kinetics of the antibodies was also measured using the GatorPrime BLI (biolayer interference) system (Gator Bio, USA). Specifically, anti-MICA / B antibodies were loaded with HFC (Anti-hIgG Fc, Gator Bio, Cat. No.: 160003). The probes were then incubated with the corresponding monomeric antigens MICA002-ECD-HISAvi (BioIntron, project code number: B662201), MICA004-ECD-HISAvi (BioIntron, project code number: B662202), MICA008-ECD-HISAvi (BioIntron, project code number: B21016107), MICB005-ECD-HISAvi (BioIntron, project code number: B21016109), MICA009Avi (BioIntron, project code number: B21016108), or cynomolgus MICA (cynoMICA) (Sino Bio, catalog number: 90924-C08H) as disclosed in FIG. 35 for 3-4 min at 25° C. in K buffer (Gator Bio, catalog number: 120011). Dissociation kinetics were monitored for approximately 10 min. Probes were regenerated between binding cycles using regeneration buffer (Gator Bio, Cat. No.: 120012). Binding kinetics were analyzed using software provided by the manufacturer.

[0235] The binding affinities of the chimeric antibodies measured by the Carterra® system are shown in Figure 1A. The binding affinities of the humanized-optimized antibodies from the #38 and #39 lines are shown in Figure 1B. The binding affinities of the humanized antibody #36 and D2M001-010 variants measured by the GatorPrime® system are shown in Figure 1C. Their sequences are listed in Figures 26-27.

[0236] As shown by these data, the optimized and humanized #36 antibody lineage and D2M001-010 variants exhibited at least low single-digit nM affinity across all major human MICA / B alleles and cynomolgus MICA. Germline mutations in the framework regions did not significantly alter binding affinity.

[0237] Figure 1C summarizes the binding profiles of the in-house optimized and humanized anti-MICA / B and reference anti-MICAB antibodies. As shown in Figure 1C, lead candidate D2M001-209 showed a broader 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 was not detected in our experiments. 6E1.1.12 and B10G5 appeared to bind to MICB005, MICA004, and MICA008, but not to MICA002 and cynoMICA.

[0238] Among all the tested reference antibodies, 1D5 (LC: SEQ ID NO: 1419, HC: SEQ ID NO: 1420) showed good binding affinity to all the tested allotypes. However, 1D5 is still a mouse anti-human MICA / B antibody, and there is no information that it has been successfully humanized. Considering its performance among the reference antibodies, it was selected as a benchmark. As shown in Figure 1C, D2M001-209 showed a comparable binding affinity profile compared to 1D5.

[0239] It is speculated that 3F9 (LC: SEQ ID NO: 1415, HC: SEQ ID NO: 1416) is likely to be the only anti-MICA / B (CLN-619) currently being evaluated in clinical trials. Therefore, 3F9 was selected as the benchmark. As shown in Figure 1C, D2M001-209 showed a better binding affinity profile than the benchmark 3F9 for all tested allotypes except MICA008.

[0240] D2M001-209 shows the highest binding affinity to cyno MIC protein compared to all reference anti-MICA / B antibodies. For example, 3F9 and 13A9 (LC: SEQ ID NO: 1421, HC: SEQ ID NO: 1422) showed 2-digit nM affinity to cyno MIC, which was one order of magnitude lower than that of D2M001-209. More importantly, the difference in binding affinity between human and monkey orthologues of D2M001-209 is minimal compared to that of all reference antibodies. For example, the difference is within 5-fold. Comparable binding affinity between human and monkey orthologues is important for immunotherapeutic antibody drugs in drug discovery and development, since nonclinical studies in nonhuman primates can determine whether they are relevant.

[0241] Overall, D2M001-209 exhibited a superior binding profile to the reference anti-MICA / B antibodies. In particular, the binding kinetics data well distinguished D2M001-209 from all reference anti-MICAB antibodies.

[0242] Example 3. Cell-Based Characterization of Anti-MICA / B Antibodies Binding to MICA / B Mutants Cell-based antibody binding affinity was measured by incubating titrated anti-MICA / B antibodies, reference antibodies, or isotype control antibodies (IgG1) with engineered CHO cells overexpressing human MICA002, MICA004, MICA008, or MICB005 (i.e., 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 4 100 cells) were added to each well of a 96-well U-bottom plate. 50 μL of titrated anti-MICA / B antibody was then added to the wells at room temperature 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. After 30 minutes of incubation, the plate was centrifuged and the cells were washed three times with PBS. 50 μL of Alexa Fluor® 647 AffiniPure F(ab')2 Fragment Goat Anti-Human IgG, Fcγ-Specific Fragment (Jackson ImmunoResearch Laboratories Inc., Catalog Number: 109-606-098) was added to each well. After mixing for 30 min at room temperature, cells were washed twice with PBS. Fluorescent signals were detected and quantified by flow cytometry (Attune™ CytPix™, Thermo Fisher) within the live cell population (viability dye PI negative).

[0243] As shown in Figures 2A-2E, the chimeric anti-MICA / B antibodies and reference antibodies (1D5, 3F9, 13A9, and 6E1.1.12) showed strong binding ability to all four MICA / B alleles expressed in both CHO cells (Figures 2A-2D) and HeLa cells (Figure 2E), but the isotype control antibody IgG1 did not. The EC50 values ​​are shown in Figure 2F. They were calculated based on the nonlinear fitting curves by GraphPad Prism software.

[0244] As shown in Figures 3A-3R, the humanized anti-MICA / B antibodies and the reference antibodies (1D5 and 3F9) showed strong binding affinity to all four MICA / B alleles expressed in both CHO and Hela cells, but the isotype control antibody IgG1 did not. The EC50 values ​​shown in Figures 3S-3U were calculated based on nonlinear fitting curves by GraphPad Prism software. The humanized and optimized #36 variant "h36B3" showed high binding affinity to MICA / B expressing cells, comparable to the reference mouse antibody 1D5. Furthermore, H36B3 and D2M001-209 bound significantly better to MICA / B expressing cells, especially MICA008 or MICB005 expressing cells, than the reference antibody 3F9. The superior binding to MICB was important and distinguished D2M001-209 and 3F9 well, as shown in Example 6, indicating that MICB may play a more important role in NKG2D biology.

[0245] Example 4: Inhibition of MICA / B polypeptide shedding in tumor cell lines by anti-MICA / B antibodies It is hypothesized that anti-MICA / B antibodies may inhibit shedding of MICA / B polypeptides by binding to the MICA and MICB alpha 3 domains, which promote the initiation of shedding from the cell surface. To examine the ability of anti-MICA / B antibodies to inhibit shedding of MICA / B polypeptides from cells, shedding assays were performed using titrated anti-MICA / B antibodies, reference antibodies (1D5 and 3F9), or an isotype control antibody (IgG1), and modified C1R cells overexpressing four human MICA / B mutants (C1R-MICA002, C1R-MICA004, C1R-MICA008, or C1R-MICB005), or HeLa cells expressing the MICA008 mutant. The concentration of shed MICA / B polypeptides was measured in the growth medium by a proprietary assay and a commercially available sandwich ELISA kit. Surface expression of MICA / B on cells was detected by flow cytometry using PE anti-MICA / B mAb 6D4 (BioLegend, Cat. No.: 320906). Anti-MICA / B 6D4 binds to the outside of the MICA / B alpha 3 domain and does not inhibit shedding of MICA / B, so it was used to detect total and shed MICA / B.

[0246] 50 μL of C1R-MICA / B or HeLa cells (approximately 1.0 × 10 5 cells), or CHO-MICA002 cells (approximately 5 × 10 4Cells) were added to each well of a 96-well U-bottom plate. 50 μL of titrated antibodies were added to final concentrations 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 24 h of incubation at room temperature, the plates were centrifuged and 60 μL of culture medium was sampled to measure the concentrations of soluble MICA and / or MICB individually by ELISA. The concentrations of shed MICA / B were measured by sandwich ELISA assay. Briefly, 96-well assay plates were coated overnight with 100 μL of 2 μg / mL AMO1 anti-human MICA antibody (BAMOMAB, Cat. No.: BOB-AMO1-500). Plates were then washed twice with PBS and blocked with 300 μL of 1% BSA for 1 h at room temperature. After two further washes with PBS, 100 μL of titrated diluted medium was added and plates were incubated for 2 h at room temperature. Plates were then washed twice with PBS and 100 μL of 1 μg / mL biotinylated anti-MICA / B 6D4 (BioLegend, Cat. No.: 320904) was added and incubated for 90 min at room temperature. 100 μL of 1:100 diluted streptavidin-HRP solution (R&D systems, Cat. No.: DY998) was added and incubated for 1 h at room temperature. After washing, the plate was developed with TMB (Surmodics, Catalog No.: TMBS-1000-01) and stopped with BioFX 450 nM Stop Solution (Surmodics, Catalog No.: LSTP-1000-01). OD450 was measured using a Varioskan™ Lux plate reader (ThermoFisher Scientific, Catalog No.: VLBL00D1, SN No.: 3020-80467) to detect the concentration of shed MICA polypeptide based on the synthetic protein standard of MICA018-ECD-His (Sino Biological, Catalog No.: HPLC-12302-H08H).

[0247] The concentration of shed MICB was measured by Human MICB Sandwich ELISA Kit (R&D Systems, Cat. No.: DY1599). The remaining cells in the plate were then washed once with PBS and 100 μL of diluted Phycoerythrin (PE) anti-MICA / B 6D4 (BioLegend, Cat. No.: 320906) was added. After mixing and incubation for 30 min at room temperature, the plate was washed twice with PBS. The signal of PE was measured by flow cytometry (Attune™ CytPix™, Thermo Fisher) in the live cell population (viability dye DAPI negative).

[0248] As shown in Figures 4A-4E, the results of treatment with chimeric anti-MICA / B on CHO-MICA002, C1R-MICA / B, or Hela cells are shown, and the shed MICA / B polypeptide in the cell culture medium was significantly reduced as a result of treatment with anti-MICA / B antibody. Furthermore, as shown in Figures 5A-5E, the surface expression of MICA / B polypeptide 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 potently inhibited the shedding of all four MICA / B variants expressed in both C1R and Hela cells, but the isotype control antibody IgG1 did not. The maximum shedding inhibition and IC50 values ​​(shown in Figure 4F) of shed MICA / B were calculated based on nonlinear fitting curves by GraphPad Prism software. The maximum change in surface MICA / B expression and EC50 values ​​(shown in Figure 5F) were calculated based on nonlinear fitting curves by GraphPad Prism software.

[0249] As shown in Figures 6A-6X, after C1R-MICA / B was treated with humanized anti-MICA / B antibody, the shed MICA / B polypeptide in the cell culture medium was significantly reduced. Furthermore, as shown in Figures 7A-7P, 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 antibody (1D5 and 3F9) strongly inhibited the shedding of all four MICA / B alleles expressed in C1R cells, but the isotype control antibody IgG1 did not. The maximum shedding inhibition value and IC50 value (shown in Figures 6Q-6T) of shed MICA / B were calculated based on the nonlinear fitting curve by GraphPad Prism software. The maximum change in surface MICA / B expression and EC50 value (shown in Figures 7Q-7T) were calculated based on the nonlinear fitting curve by GraphPad Prism software.

[0250] As shown in Figures 6U-6X, D2M001-209 was further compared to the benchmark anti-MICA / B for its ability to inhibit shedding of MICA / B polypeptide and stabilize surface expression of MICA / B. D2M001-209 demonstrated a comparable ability to 1D5 and a more potent ability to inhibit shedding of MICA / B than 3F9 in terms of IC50 and maximal effect.

[0251] As shown in Figures 7U-7X, D2M001-209 was further compared to the benchmark anti-MICA / B for its ability to inhibit shedding of MICA / B polypeptide and stabilize surface expression of MICA / B. D2M001-209 demonstrated a superior ability to stabilize surface MICA / B compared to 1D5 and 3F9 in terms of EC50 and / or percent increase.

[0252] Example 5. Anti-MICA / B antibody captures MICA / B polypeptide shed from the cell surface As described in more detail below, the anti-MICA / B antibodies identified in Example 1 not only inhibit the shedding of MICA / B polypeptide from cells, but also bind to shed MICA / B polypeptide released from tumor cells. To examine the binding affinity of anti-MICA / B antibodies to shed MICA / B polypeptide, shed MICA / B polypeptide was concentrated from conditioned medium of CHO-MICA002, CHO-MICA004, CHO-MICA008, and CHO-MICB005 using Spin-X concentrators (Corning, Cat. No.: 431489). Each well of a 96-well plate was coated overnight with 100 μL of 5 μg / mL anti-hFc (Jackson ImmunoResearch, Cat. No.: 109-005-098), and the plate was washed twice with PBS and blocked with 1% BSA for 1 hour at room temperature. After two further washes with PBS, 100 μL of titrated anti-MICA / B antibodies, reference antibodies (1D5, 13A9, 6E1.1.12, and 3F9), or isotype control antibodies (IgG1) were added to the wells of the plate and incubated at room temperature for 30 minutes to achieve 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. 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 further washes with PBS, 100 μL of 1 μg / mL biotinylated anti-MICA / B 6D4 (BioLegend, Cat. No.: 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, Cat. No.: DY998, 200×) was added and incubated for 1 hour at room temperature. After washing, the plate was developed with TMB and stopped with BioFX 450 nM stop solution. OD450 was measured using a Varioskan™ Lux plate reader.

[0253] As shown in Figures 8A-8E, the chimeric anti-MICA / B antibody and the reference antibody, but not the isotype control antibody IgG1, showed strong binding affinity to all four shed MICA / B polypeptide variants released from CHO cells overexpressing MICA / B alleles. The maximum binding signals (OD450) and EC50 values ​​(shown in the left panel of Figure 8E) of shed MICA / B binding were calculated based on nonlinear fitting curves by GraphPad Prism software.

[0254] As shown in Figures 9A-9H and 9K-9N, the humanized anti-MICA / B antibodies and reference antibodies (1D5, 13A9, and 3F9), but not the isotype control antibody IgG1, showed strong binding affinity to all four shed MICA / B mutants released from CHO cells overexpressing MICA / B alleles. The maximum binding signals (OD450) and EC50 values ​​of shed MICA / B binding shown in Figures 9I-9J and 9O were calculated based on nonlinear fitting curves by GraphPad Prism software.

[0255] As shown in Figures 9K-9N, D2M001-209 shows a strong ability to capture soluble MICA / B, which is comparable to 1D5 and more potent than 3F9 for all tested alleles. Notably, D2M001-209 can capture MICB005 much more efficiently than 3F9, as well as capture more MICB than 3F9. Even when a plateau is reached, 3F9 can capture less than half the amount of MICB compared to D2M001-209. The superior ability to capture soluble MICB is important and distinguishes D2M001-209 from 3F9 well, as shown...

Claims

1. An antibody or an 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), 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 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; a light chain variable region (VL) comprising CDR1, 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; The selected VH CDR1, 2, and 3 amino acid sequences and the selected VL CDR1, 2, and 3 amino acid sequences are selected from the VH CDR1, 2, and 3 and VL CDR1, 2, and 3 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 amino acid sequences of VH CDR1, 2 and 3 and the selected amino acid sequences of VL CDR1, 2 and 3 are any one of the following (1) to (40): (1) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 3, 4, and 5, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 6, 7, and 8, respectively. (2) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 11, 12, and 13, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 14, 15, and 16, respectively. (3) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 19, 20, and 21, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 22, 23, and 24, respectively. (4) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 27, 28, and 29, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 30, 31, and 32, respectively. (5) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 35, 36, and 37, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 38, 39, and 40, respectively. (6) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 43, 44, and 45, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 46, 47, and 48, respectively. (7) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 51, 52, and 53, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 54, 55, and 56, respectively. (8) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 59, 60, and 61, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 62, 63, and 64, respectively. (9) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 67, 68, and 69, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 70, 71, and 72, respectively. (10) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 75, 76, and 77, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 78, 79, and 80, respectively. (11) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 83, 84, and 85, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 86, 87, and 88, respectively. (12) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 91, 92, and 93, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 94, 95, and 96, respectively. (13) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 99, 100, and 101, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 102, 103, and 104, respectively. (14) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 107, 108, and 109, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 110, 111, and 112, respectively. (15) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 115, 116, and 117, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 118, 119, and 120, respectively. (16) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 123, 124, and 125, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 126, 127, and 128, respectively. (17) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 131, 132, and 133, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 134, 135, and 136, respectively. (18) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 139, 140, and 141, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 142, 143, and 144, respectively. (19) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 147, 148, and 149, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 150, 151, and 152, respectively. (20) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 155, 156, and 157, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 158, 159, and 160, respectively. (21) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 815, 816, and 817, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 818, 819, and 820, respectively. (22) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 821, 822, and 823, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 824, 825, and 826, respectively. (23) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 827, 828, and 829, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 830, 831, and 832, respectively. (24) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 833, 834, and 835, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 836, 837, and 838, respectively. (25) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 839, 840, and 841, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 842, 843, and 844, respectively. (26) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 845, 846, and 847, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 848, 849, and 850, respectively. (27) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 851, 852, and 853, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 854, 855, and 856, respectively. (28) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 857, 858, and 859, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 860, 861, and 862, respectively. (29) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 863, 864, and 865, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 866, 867, and 868, respectively. (30) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 869, 870, and 871, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 872, 873, and 874, respectively. (31) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 875, 876, and 877, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 878, 879, and 880, respectively. (32) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 881, 882, and 883, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 884, 885, and 886, respectively. (33) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 887, 888, and 889, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 890, 891, and 892, respectively. (34) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 893, 894, and 895, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 896, 897, and 898, respectively. (35) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 899, 900, and 901, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 902, 903, and 904, respectively. (36) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 905, 906, and 907, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 908, 909, and 910, respectively. (37) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 911, 912, and 913, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 914, 915, and 916, respectively. (38) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 917, 918, and 919, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 920, 921, and 922, respectively. (39) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 923, 924, and 925, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 926, 927, and 928, respectively. (40) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 929, 930, and 931, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 932, 933, and 934, respectively.

3. The antibody or antigen-binding fragment thereof of claim 1 or 2, wherein the CDRs are determined by the IMGT definition.

4. The antibody or antigen-binding fragment thereof according to claim 1, wherein the selected amino acid sequences of VH CDR1, 2 and 3 and the selected amino acid sequences of VL CDR1, 2 and 3 are any one of the following (1) to (40): (1) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 161, 162, and 163, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 164, 165, and 166, respectively. (2) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 167, 168, and 169, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 170, 171, and 172, respectively. (3) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 173, 174, and 175, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 176, 177, and 178, respectively. (4) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 179, 180, and 181, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 182, 183, and 184, respectively. (5) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 185, 186, and 187, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 188, 189, and 190, respectively. (6) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 191, 192, and 193, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 194, 195, and 196, respectively. (7) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 197, 198, and 199, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 200, 201, and 202, respectively. (8) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 203, 204, and 205, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 206, 207, and 208, respectively. (9) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 209, 210, and 211, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 212, 213, and 214, respectively. (10) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 215, 216, and 217, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 218, 219, and 220, respectively. (11) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 221, 222, and 223, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 224, 225, and 226, respectively. (12) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 227, 228, and 229, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 230, 231, and 232, respectively. (13) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 233, 234, and 235, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 236, 237, and 238, respectively. (14) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 239, 240, and 241, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 242, 243, and 244, respectively. (15) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 245, 246, and 247, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 248, 249, and 250, respectively. (16) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 251, 252, and 253, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 254, 255, and 256, respectively. (17) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 257, 258, and 259, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 260, 261, and 262, respectively. (18) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 263, 264, and 265, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 266, 267, and 268, respectively. (19) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 269, 270, and 271, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 272, 273, and 274, respectively. (20) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 275, 276, and 277, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 278, 279, and 280, respectively. (21) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 935, 936, and 937, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 938, 939, and 940, respectively. (22) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 941, 942, and 943, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 944, 945, and 946, respectively. (23) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 947, 948, and 949, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 950, 951, and 952, respectively. (24) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 953, 954, and 955, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 956, 957, and 958, respectively. (25) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 959, 960, and 961, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 962, 963, and 964, respectively. (26) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 965, 966, and 967, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 968, 969, and 970, respectively. (27) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 971, 972, and 973, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 974, 975, and 976, respectively. (28) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 977, 978, and 979, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 980, 981, and 982, respectively. (29) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 983, 984, and 985, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 986, 987, and 988, respectively. (30) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 989, 990, and 991, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 992, 993, and 994, respectively. (31) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 995, 996, and 997, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 998, 999, and 1000, respectively. (32) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1001, 1002, and 1003, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1004, 1005, and 1006, respectively. (33) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1007, 1008, and 1009, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1010, 1011, and 1012, respectively. (34) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1013, 1014, and 1015, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1016, 1017, and 1018, respectively. (35) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1019, 1020, and 1021, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1022, 1023, and 1024, respectively. (36) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1025, 1026, and 1027, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1028, 1029, and 1030, respectively. (37) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1031, 1032, and 1033, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1034, 1035, and 1036, respectively. (38) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1037, 1038, and 1039, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1040, 1041, and 1042, respectively. (39) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1043, 1044, and 1045, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1046, 1047, and 1048, respectively. (40) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1049, 1050, and 1051, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1052, 1053, and 1054, respectively.

5. The antibody or antigen-binding fragment thereof of claim 1 or 4, wherein the CDRs are determined according to the Kabat definition.

6. The antibody or antigen-binding fragment thereof according to claim 1, wherein the selected amino acid sequences of VH CDR1, 2 and 3 and the selected amino acid sequences of VL CDR1, 2 and 3 are any one of the following (1) to (40): (1) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 281, 282, and 283, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 284, 285, and 286, respectively. (2) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 287, 288, and 289, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 290, 291, and 292, respectively. (3) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 293, 294, and 295, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 296, 297, and 298, respectively. (4) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 299, 300, and 301, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 302, 303, and 304, respectively. (5) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 305, 306, and 307, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 308, 309, and 310, respectively. (6) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 311, 312, and 313, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 314, 315, and 316, respectively. (7) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 317, 318, and 319, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 320, 321, and 322, respectively. (8) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 323, 324, and 325, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 326, 327, and 328, respectively. (9) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 329, 330, and 331, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 332, 333, and 334, respectively. (10) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 335, 336, and 337, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 338, 339, and 340, respectively. (11) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 341, 342, and 343, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 344, 345, and 346, respectively. (12) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 347, 348, and 349, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 350, 351, and 352, respectively. (13) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 353, 354, and 355, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 356, 357, and 358, respectively. (14) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 359, 360, and 361, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 362, 363, and 364, respectively. (15) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 365, 366, and 367, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 368, 369, and 370, respectively. (16) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 371, 372, and 373, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 374, 375, and 376, respectively. (17) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 377, 378, and 379, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 380, 381, and 382, ​​respectively. (18) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 383, 384, and 385, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 386, 387, and 388, respectively. (19) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 389, 390, and 391, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 392, 393, and 394, respectively. (20) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 395, 396, and 397, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 398, 399, and 400, respectively. (21) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1055, 1056, and 1057, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1058, 1059, and 1060, respectively. (22) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1061, 1062, and 1063, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1064, 1065, and 1066, respectively. (23) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1067, 1068, and 1069, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1070, 1071, and 1072, respectively. (24) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1073, 1074, and 1075, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1076, 1077, and 1078, respectively. (25) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1079, 1080, and 1081, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1082, 1083, and 1084, respectively. (26) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1085, 1086, and 1087, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1088, 1089, and 1090, respectively. (27) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1091, 1092, and 1093, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1094, 1095, and 1096, respectively. (28) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1097, 1098, and 1099, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1100, 1101, and 1102, respectively. (29) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1103, 1104, and 1105, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1106, 1107, and 1108, respectively. (30) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1109, 1110, and 1111, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1112, 1113, and 1114, respectively. (31) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1115, 1116, and 1117, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1118, 1119, and 1120, respectively. (32) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1121, 1122, and 1123, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1124, 1125, and 1126, respectively. (33) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1127, 1128, and 1129, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1130, 1131, and 1132, respectively. (34) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1133, 1134, and 1135, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1136, 1137, and 1138, respectively. (35) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1139, 1140, and 1141, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1142, 1143, and 1144, respectively. (36) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1145, 1146, and 1147, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1148, 1149, and 1150, respectively. (37) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1151, 1152, and 1153, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1154, 1155, and 1156, respectively. (38) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1157, 1158, and 1159, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1160, 1161, and 1162, respectively. (39) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1163, 1164, and 1165, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1166, 1167, and 1168, respectively. (40) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1169, 1170, and 1171, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1172, 1173, and 1174, respectively.

7. 7. The antibody or antigen-binding fragment thereof of 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 amino acid sequences of VH CDR1, 2 and 3 and the selected amino acid sequences of VL CDR1, 2 and 3 are any one of the following (1) to (40): (1) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 401, 402, and 403, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 404, 405, and 406, respectively. (2) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 407, 408, and 409, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 410, 411, and 412, respectively. (3) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 413, 414, and 415, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 416, 417, and 418, respectively. (4) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 419, 420, and 421, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 422, 423, and 424, respectively. (5) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 425, 426, and 427, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 428, 429, and 430, respectively. (6) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 431, 432, and 433, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 434, 435, and 436, respectively. (7) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 437, 438, and 439, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 440, 441, and 442, respectively. (8) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 443, 444, and 445, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 446, 447, and 448, respectively. (9) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 449, 450, and 451, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 452, 453, and 454, respectively. (10) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 455, 456, and 457, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 458, 459, and 460, respectively. (11) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 461, 462, and 463, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 464, 465, and 466, respectively. (12) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 467, 468, and 469, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 470, 471, and 472, respectively. (13) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 473, 474, and 475, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 476, 477, and 478, respectively. (14) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 479, 480, and 481, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 482, 483, and 484, respectively. (15) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 485, 486, and 487, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 488, 489, and 490, respectively. (16) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 491, 492, and 493, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 494, 495, and 496, respectively. (17) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 497, 498, and 499, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 500, 501, and 502, respectively. (18) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 503, 504, and 505, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 506, 507, and 508, respectively. (19) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 509, 510, and 511, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 512, 513, and 514, respectively. (20) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 515, 516, and 517, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 518, 519, and 520, respectively. (21) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1175, 1176, and 1177, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1178, 1179, and 1180, respectively. (22) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1181, 1182, and 1183, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1184, 1185, and 1186, respectively. (23) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1187, 1188, and 1189, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1190, 1191, and 1192, respectively. (24) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1193, 1194, and 1195, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1196, 1197, and 1198, respectively. (25) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1199, 1200, and 1201, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1202, 1203, and 1204, respectively. (26) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1205, 1206, and 1207, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1208, 1209, and 1210, respectively. (27) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1211, 1212, and 1213, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1214, 1215, and 1216, respectively. (28) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1217, 1218, and 1219, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1220, 1221, and 1222, respectively. (29) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1223, 1224, and 1225, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1226, 1227, and 1228, respectively. (30) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1229, 1230, and 1231, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1232, 1233, and 1234, respectively. (31) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1235, 1236, and 1237, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1238, 1239, and 1240, respectively. (32) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1241, 1242, and 1243, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1244, 1245, and 1246, respectively. (33) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1247, 1248, and 1249, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1250, 1251, and 1252, respectively. (34) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1253, 1254, and 1255, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1256, 1257, and 1258, respectively. (35) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1259, 1260, and 1261, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1262, 1263, and 1264, respectively. (36) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1265, 1266, and 1267, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1268, 1269, and 1270, respectively. (37) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1271, 1272, and 1273, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1274, 1275, and 1276, respectively. (38) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1277, 1278, and 1279, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1280, 1281, and 1282, respectively. (39) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1283, 1284, and 1285, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1286, 1287, and 1288, respectively. (40) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1289, 1290, and 1291, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1292, 1293, and 1294, respectively.

9. The antibody or antigen-binding fragment thereof of 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 amino acid sequences of VH CDR1, 2 and 3 and the selected amino acid sequences of VL CDR1, 2 and 3 are any one of the following (1) to (40): (1) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 521, 522, and 523, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 524, 525, and 526, respectively. (2) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 527, 528, and 529, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 530, 531, and 532, respectively. (3) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 533, 534, and 535, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 536, 537, and 538, respectively. (4) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 539, 540, and 541, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 542, 543, and 544, respectively. (5) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 545, 546, and 547, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 548, 549, and 550, respectively. (6) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 551, 552, and 553, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 554, 555, and 556, respectively. (7) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 557, 558, and 559, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 560, 561, and 562, respectively. (8) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 563, 564, and 565, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 566, 567, and 568, respectively. (9) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 569, 570, and 571, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 572, 573, and 574, respectively. (10) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 575, 576, and 577, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 578, 579, and 580, respectively. (11) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 581, 582, and 583, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 584, 585, and 586, respectively. (12) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 587, 588, and 589, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 590, 591, and 592, respectively. (13) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 593, 594, and 595, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 596, 597, and 598, respectively. (14) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 599, 600, and 601, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 602, 603, and 604, respectively. (15) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 605, 606, and 607, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 608, 609, and 610, respectively. (16) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 611, 612, and 613, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 614, 615, and 616, respectively. (17) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 617, 618, and 619, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 620, 621, and 622, respectively. (18) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 623, 624, and 625, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 626, 627, and 628, respectively. (19) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 629, 630, and 631, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 632, 633, and 634, respectively. (20) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 635, 636, and 637, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 638, 639, and 640, respectively. (21) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1295, 1296, and 1297, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1298, 1299, and 1300, respectively. (22) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1301, 1302, and 1303, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1304, 1305, and 1306, respectively. (23) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1307, 1308, and 1309, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1310, 1311, and 1312, respectively. (24) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1313, 1314, and 1315, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1316, 1317, and 1318, respectively. (25) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1319, 1320, and 1321, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1322, 1323, and 1324, respectively. (26) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1325, 1326, and 1327, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1328, 1329, and 1330, respectively. (27) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1331, 1332, and 1333, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1334, 1335, and 1336, respectively. (28) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1337, 1338, and 1339, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1340, 1341, and 1342, respectively. (29) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1343, 1344, and 1345, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1346, 1347, and 1348, respectively. (30) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1349, 1350, and 1351, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1352, 1353, and 1354, respectively. (31) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1355, 1356, and 1357, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1358, 1359, and 1360, respectively. (32) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1361, 1362, and 1363, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1364, 1365, and 1366, respectively. (33) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1367, 1368, and 1369, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1370, 1371, and 1372, respectively. (34) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1373, 1374, and 1375, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1376, 1377, and 1378, respectively. (35) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1379, 1380, and 1381, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1382, 1383, and 1384, respectively. (36) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1385, 1386, and 1387, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1388, 1389, and 1390, respectively. (37) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1391, 1392, and 1393, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1394, 1395, and 1396, respectively. (38) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1397, 1398, and 1399, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1400, 1401, and 1402, respectively. (39) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1403, 1404, and 1405, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1406, 1407, and 1408, respectively. (40) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 1409, 1410, and 1411, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 1412, 1413, and 1414, respectively.

11. The antibody or antigen-binding fragment thereof of claim 1 or 10, wherein the CDRs are determined according to the North definition.

12. The antibody or antigen-binding fragment thereof according to claim 1, wherein the selected amino acid sequences of VH CDR1, 2 and 3 and the selected amino acid sequences of VL CDR1, 2 and 3 are any one of the following (1) to (18): (1) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 708, 709, and 710, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 711, 712, and 713, respectively. (2) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 714, 715, and 716, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 717, 718, and 719, respectively. (3) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 720, 721, and 722, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 723, 724, and 725, respectively. (4) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 726, 727, and 728, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 729, 730, and 731, respectively. (5) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 732, 733, and 734, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 735, 736, and 737, respectively. (6) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 738, 739, and 740, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 741, 742, and 743, respectively. (7) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 744, 745, and 746, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 747, 748, and 749, respectively. (8) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 750, 751, and 752, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 753, 754, and 755, respectively. (9) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 756, 757, and 758, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 759, 760, and 761, respectively. (10) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 762, 763, and 764, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 765, 766, and 767, respectively. (11) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 768, 769, and 770, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 771, 772, and 773, respectively. (12) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 774, 775, and 776, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 777, 778, and 779, respectively. (13) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 780, 781, and 782, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 783, 784, and 785, respectively. (14) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 786, 787, and 788, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 789, 790, and 791, respectively. (15) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 792, 793, and 794, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 795, 796, and 797, respectively. (16) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 798, 799, and 800, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 801, 802, and 803, respectively. (17) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 804, 805, and 806, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 807, 808, and 809, respectively. (18) The amino acid sequences of the selected VH CDR1, 2, and 3 are shown in SEQ ID NOs: 810, 811, and 812, respectively, and the amino acid sequences of the selected VL CDR1, 2, and 3 are shown in SEQ ID NOs: 813, 814, and 815, respectively.

13. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 12, which 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, which specifically binds to simian MICA and / or simian 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 thereof is capable of inhibiting shedding of MICA and / or MICB polypeptide 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 thereof 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 (e.g., a bispecific antibody).

18. An antibody or antigen-binding fragment thereof that binds to MICA and / or MICB, a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90% identical to the selected VH sequence; a light chain variable region (VL) comprising an amino acid sequence that is at least 90% identical to the selected VL sequence; The selected VH sequence and the selected VL sequence are an antibody or antigen-binding fragment thereof 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) to (20): (1) the selected VH sequence is SEQ ID NO: 1 and the selected VL sequence is SEQ ID NO: 2 (2) the selected VH sequence is SEQ ID NO: 9 and the selected VL sequence is SEQ ID NO: 10 (3) the selected VH sequence is SEQ ID NO: 17 and the selected VL sequence is SEQ ID NO: 18 (4) the selected VH sequence is SEQ ID NO: 25 and the selected VL sequence is SEQ ID NO: 26 (5) the selected VH sequence is SEQ ID NO: 33 and the selected VL sequence is SEQ ID NO:

34. (6) The selected VH sequence is SEQ ID NO: 41 and the selected VL sequence is SEQ ID NO:

42. (7) The selected VH sequence is SEQ ID NO: 49 and the selected VL sequence is SEQ ID NO:

50. (8) The selected VH sequence is SEQ ID NO: 57 and the selected VL sequence is SEQ ID NO:

58. (9) The selected VH sequence is SEQ ID NO: 65 and the selected VL sequence is SEQ ID NO:

66. (10) The selected VH sequence is SEQ ID NO: 73 and the selected VL sequence is SEQ ID NO:

74. (11) The selected VH sequence is SEQ ID NO: 81 and the selected VL sequence is SEQ ID NO:

82. (12) The selected VH sequence is SEQ ID NO: 89 and the selected VL sequence is SEQ ID NO:

90. (13) The selected VH sequence is SEQ ID NO: 97 and the selected VL sequence is SEQ ID NO:

98. (14) The selected VH sequence is SEQ ID NO: 105 and the selected VL sequence is SEQ ID NO:

106. (15) The selected VH sequence is SEQ ID NO: 113 and the selected VL sequence is SEQ ID NO:

114. (16) The selected VH sequence is SEQ ID NO: 121 and the selected VL sequence is SEQ ID NO:

122. (17) The selected VH sequence is SEQ ID NO: 129 and the selected VL sequence is SEQ ID NO:

130. (18) The selected VH sequence is SEQ ID NO: 137 and the selected VL sequence is SEQ ID NO:

138. (19) The selected VH sequence is SEQ ID NO: 145 and the selected VL sequence is SEQ ID NO:

146. (20) The selected VH sequence is SEQ ID NO: 153 and the selected VL sequence is SEQ ID NO:

154.

20. The antibody or antigen-binding fragment thereof of claim 18, wherein the selected VH sequence is SEQ ID NO: 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 NO: 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 NO: 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651 or 652, and the selected VL sequence is SEQ ID NO: 653, 654, 655, 656, 657 or 658.

22. The antibody or antigen-binding fragment thereof of claim 18, wherein the selected VH sequence is SEQ ID NO: 659 and the selected VL sequence is SEQ ID NO:

660.

23. the selected VH sequence is SEQ ID NO: 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, or 680; The antibody or antigen-binding fragment thereof of claim 18, wherein the selected VL sequence is SEQ ID NO: 681, 682, 683, 684, 685, 686, 687, 688 or 689.

24. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 668 and the VL comprises the sequence of SEQ ID NO:

681.

25. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 669 and the VL comprises the sequence of SEQ ID NO:

681.

26. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 671 and the VL comprises the sequence of SEQ ID NO:

681.

27. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 665 and the VL comprises the sequence of SEQ ID NO:

681.

28. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 666 and the VL comprises the sequence of SEQ ID NO:

681.

29. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 670 and the VL comprises the sequence of SEQ ID NO:

681.

30. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 674 and the VL comprises the sequence of SEQ ID NO:

682.

31. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 675 and the VL comprises the sequence of SEQ ID NO:

683.

32. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 676 and the VL comprises the sequence of SEQ ID NO:

682.

33. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 678 and the VL comprises the sequence of SEQ ID NO:

682.

34. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 677 and the VL comprises the sequence of SEQ ID NO:

684.

35. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 672 and the VL comprises the sequence of SEQ ID NO:

681.

36. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 673 and the VL comprises the sequence of SEQ ID NO:

681.

37. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 667 and the VL comprises the sequence of SEQ ID NO:

681.

38. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 659 and the VL comprises the sequence of SEQ ID NO:

660.

39. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 680 and the VL comprises the sequence of SEQ ID NO:

687.

40. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 661 and the VL comprises the sequence of SEQ ID NO:

685.

41. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 662 and the VL comprises the sequence of SEQ ID NO:

685.

42. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 663 and the VL comprises the sequence of SEQ ID NO:

685.

43. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 664 and the VL comprises the sequence of SEQ ID NO:

685.

44. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 665 and the VL comprises the sequence of SEQ ID NO:

685.

45. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 665 and the VL comprises the sequence of SEQ ID NO:

688.

46. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 665 and the VL comprises the sequence of SEQ ID NO:

689.

47. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 665 and the VL comprises the sequence of SEQ ID NO:

686.

48. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 679 and the VL comprises the sequence of SEQ ID NO:

686.

49. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 641 and the VL comprises the sequence of SEQ ID NO:

653.

50. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 642 and the VL comprises the sequence of SEQ ID NO:

653.

51. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 643 and the VL comprises the sequence of SEQ ID NO:

653.

52. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 644 and the VL comprises the sequence of SEQ ID NO:

653.

53. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 647 and the VL comprises the sequence of SEQ ID NO:

654.

54. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 648 and the VL comprises the sequence of SEQ ID NO:

654.

55. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 649 and the VL comprises the sequence of SEQ ID NO:

654.

56. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 650 and the VL comprises the sequence of SEQ ID NO:

654.

57. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 645 and the VL comprises the sequence of SEQ ID NO:

653.

58. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 646 and the VL comprises the sequence of SEQ ID NO:

653.

59. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 651 and the VL comprises the sequence of SEQ ID NO:

654.

60. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 650 and the VL comprises the sequence of SEQ ID NO:

655.

61. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 650 and the VL comprises the sequence of SEQ ID NO:

656.

62. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 650 and the VL comprises the sequence of SEQ ID NO:

657.

63. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 647 and the VL comprises the sequence of SEQ ID NO:

655.

64. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 647 and the VL comprises the sequence of SEQ ID NO:

657.

65. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 651 and the VL comprises the sequence of SEQ ID NO:

656.

66. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 651 and the VL comprises the sequence of SEQ ID NO:

657.

67. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 652 and the VL comprises the sequence of SEQ ID NO:

656.

68. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 652 and the VL comprises the sequence of SEQ ID NO:

657.

69. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 651 and the VL comprises the sequence of SEQ ID NO:

658.

70. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 652 and the VL comprises the sequence of SEQ ID NO:

658.

71. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 647 and the VL comprises the sequence of SEQ ID NO:

658.

72. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 690 and the VL comprises the sequence of SEQ ID NO:

691.

73. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 692 and the VL comprises the sequence of SEQ ID NO:

693.

74. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 694 and the VL comprises the sequence of SEQ ID NO:

695.

75. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 696 and the VL comprises the sequence of SEQ ID NO:

697.

76. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 698 and the VL comprises the sequence of SEQ ID NO:

699.

77. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 700 and the VL comprises the sequence of SEQ ID NO:

701.

78. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 702 and the VL comprises the sequence of SEQ ID NO:

703.

79. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 704 and the VL comprises the sequence of SEQ ID NO:

705.

80. The antibody or antigen-binding fragment thereof of claim 18, wherein the VH comprises the sequence of SEQ ID NO: 706 and the VL comprises the sequence of SEQ ID NO:

707.

81. The antibody or antigen-binding fragment thereof according to any one of claims 18 to 80, which specifically binds to human MICA and / or MICB.

82. The antibody or antigen-binding fragment thereof according to any one of claims 18 to 81, wherein the antibody or antigen-binding fragment thereof is a humanized antibody or antigen-binding fragment thereof.

83. The antibody or antigen-binding fragment thereof according to any one of claims 18 to 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 to 83.

85. 1. An antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3, and a light chain variable region (VL) comprising a VL CDR1, a VL CDR2, and a VL CDR3, 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 the antibody or antigen-binding fragment thereof described in any one of claims 1 to 84.

86. 86. An antibody-drug conjugate comprising the antibody or antigen-binding fragment thereof of any one of claims 1 to 85 covalently linked to a therapeutic agent.

87. The antibody-drug conjugate of claim 86, wherein the therapeutic agent is a cytotoxic or cytostatic drug.

88. 87. A method of treating a subject suffering from cancer, comprising the step of administering to the subject a therapeutically effective amount of a composition comprising an antibody or antigen-binding fragment thereof described in any one of claims 1 to 85, or an antibody-drug conjugate described in claim 86 or 87.

89. 89. The method of claim 88, wherein the subject is suffering from a solid tumor or a hematological cancer.

90. 89. The method of claim 88, wherein the cancer is melanoma, neuroblastoma, prostate cancer, renal cancer, multiple myeloma, or chronic lymphocytic leukemia.

91. 1. A method of reducing tumor growth rate, comprising:

87. A method comprising contacting a tumor cell with an effective amount of a composition comprising an antibody or antigen-binding fragment thereof described in any one of claims 1 to 85, or an antibody-drug conjugate described in claim 86 or 87.

92. 1. A method for killing tumor cells, comprising:

87. A method comprising contacting a tumor cell with an effective amount of a composition comprising an antibody or antigen-binding fragment thereof described in any one of claims 1 to 85, or an antibody-drug conjugate described in claim 86 or 87.

93. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 85, or an antibody-drug conjugate according to claim 86 or 87, and a pharma- ceutically acceptable carrier.

94. A nucleic acid comprising a polynucleotide encoding a polypeptide, (1) An immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) that contains complementarity determining regions (CDRs) 1, 2, and 3, including VH CDRs 1, 2, and 3, as shown in Figures 24A, 24B, 24C, 24D, 24E, 28, 29, 30A, 30B, 30C, 30D, or 30E, and that binds to MICA and / or MICB when paired with a corresponding light chain variable region (VL); or (2) A nucleic acid comprising an immunoglobulin light chain or fragment thereof comprising CDR1, 2, and 3 comprising the VL CDR1, 2, and 3 shown in Figure 24A, 24B, 24C, 24D, 24E, 28, 29, 30A, 30B, 30C, 30D or 30E, and comprising a VL that binds to MICA and / or MICB when paired with a corresponding VH.

95. (1) The immunoglobulin heavy chain or fragment thereof comprises 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 the VH binds to MICA and / or MICB when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 2; (2) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 11, 12, and 13, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

10. (3) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 19, 20, and 21, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

18. (4) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 27, 28, and 29, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

26. (5) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 35, 36, and 37, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

34. (6) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 43, 44, and 45, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

42. (7) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 51, 52, and 53, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

50. (8) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 59, 60, and 61, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

58. (9) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 67, 68, and 69, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

66. (10) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 75, 76, and 77, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

74. (11) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 83, 84, and 85, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

82. (12) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 91, 92, and 93, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

90. (13) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 99, 100, and 101, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

98. (14) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 107, 108, and 109, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

106. (15) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 115, 116, and 117, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

114. (16) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 123, 124, and 125, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

122. (17) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 131, 132, and 133, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

130. (18) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 139, 140, and 141, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

138. (19) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 147, 148, and 149, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

146. (20) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 155, 156, and 157, respectively, and the VH binds to MICA and / or MICB when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:

154. (21) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 6, 7, and 8, respectively, and the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

1. (22) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 14, 15, and 16, respectively, and the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

9. (23) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 22, 23, and 24, respectively, and the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

17. (24) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 30, 31, and 32, respectively, and the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

25. (25) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 38, 39, and 40, respectively, and the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

33. (26) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 46, 47, and 48, respectively, and the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

41. (27) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 54, 55, and 56, respectively, and the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

49. (28) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 62, 63, and 64, respectively, and the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

57. (29) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 70, 71, and 72, respectively, and the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

65. (30) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 78, 79, and 80, respectively, and the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

73. (31) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 86, 87, and 88, respectively, and the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

81. (32) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 94, 95, and 96, respectively, and the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

89. (33) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 102, 103, and 104, respectively, and the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

97. (34) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 110, 111, and 112, respectively, wherein the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

105. (35) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 118, 119, and 120, respectively, wherein the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

113. (36) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 126, 127, and 128, respectively, wherein the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

121. (37) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 134, 135, and 136, respectively, wherein the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

129. (38) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 142, 143, and 144, respectively, wherein the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

137. (39) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 150, 151, and 152, respectively, wherein the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

145. (40) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NO: 158, 159, and 160, respectively, wherein the VL binds to MICA and / or MICB when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:

153. (41) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 815, 816, and 817, respectively, wherein 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. (42) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 821, 822, and 823, respectively, wherein 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. (43) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 827, 828, and 829, respectively, wherein 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. (44) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 833, 834, and 835, respectively, wherein 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. (45) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 839, 840, and 841, respectively, wherein 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. (46) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 845, 846, and 847, respectively, wherein 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. (47) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 851, 852, and 853, respectively, wherein 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. (48) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 857, 858, and 859, respectively, wherein 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. (49) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 863, 864, and 865, respectively, wherein 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. (50) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 869, 870, and 871, respectively, wherein 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. (51) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 875, 876, and 877, respectively, wherein 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. (52) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 881, 882, and 883, respectively, wherein 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. (53) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 887, 888, and 889, respectively, wherein 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. (54) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 893, 894, and 895, respectively, wherein 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. (55) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 899, 900, and 901, respectively, wherein 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. (56) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 905, 906, and 907, respectively, wherein 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. (57) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 911, 912, and 913, respectively, wherein 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. (58) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 917, 918, and 919, respectively, wherein 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. (59) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 923, 924, and 925, respectively, wherein 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. (60) The immunoglobulin heavy chain or fragment thereof comprises a VH comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 929, 930, and 931, respectively, wherein 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. (61) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 818, 819, and 820, respectively, wherein 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; (62) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 824, 825, and 826, respectively, wherein 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; (63) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 830, 831, and 832, respectively, wherein 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; (64) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 836, 837, and 838, respectively, wherein 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; (65) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 842, 843, and 844, respectively, wherein 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; (66) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 848, 849, and 850, respectively, wherein 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; (67) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 854, 855, and 856, respectively, wherein 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; (68) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 860, 861, and 862, respectively, wherein 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; (69) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 866, 867, and 868, respectively, wherein 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; (70) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 872, 873, and 874, respectively, wherein 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; (71) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 878, 879, and 880, respectively, wherein 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; (72) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 884, 885, and 886, respectively, wherein 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; (73) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth 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 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; (74) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 896, 897, and 898, respectively, wherein 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; (75) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 902, 903, and 904, respectively, wherein 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; (76) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 908, 909, and 910, respectively, wherein 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; (77) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 914, 915, and 916, respectively, wherein 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; (78) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 920, 921, and 922, respectively, wherein 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; (79) The immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 926, 927, and 928, respectively, wherein 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 (80) The nucleic acid of claim 94, wherein the immunoglobulin light chain or fragment thereof comprises a VL comprising CDR1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 932, 933, and 934, respectively, and 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.

96. A nucleic acid as described in claim 94 or 95, wherein the VH specifically binds to human MICA and / or MICB when paired with the VL, or the VL specifically binds to human MICA and / or MICB when paired with the VH.

97. 97. The nucleic acid of any one of claims 94 to 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. 98. The nucleic acid of any one of claims 94 to 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 according to any one of claims 94 to 98, wherein the nucleic acid is a cDNA.

100. A vector comprising one or more nucleic acids according to any one of claims 94 to 99.

101. A vector comprising two nucleic acids according to any one of claims 94 to 99, encoding the VL and VH regions which together bind to MICA and / or MICB.

102. A pair of vectors each comprising one of the nucleic acids according to any one of claims 94 to 99, both encoding the VL and VH regions which together bind to MICA and / or MICB.

103. A cell comprising a vector according to claim 100 or 101, or a vector pair according to claim 102.

104. The cell of claim 103, wherein the cell is a CHO cell.

105. A cell comprising one or more of the nucleic acids according to any one of claims 94 to 99.

106. A cell comprising two nucleic acids according to any one of claims 94 to 99.

107. The cell described in claim 106, wherein the two nucleic acids both encode the VL region and the VH region that both bind to MICA and / or MICB.

108. 1. A method for producing an antibody or antigen-binding fragment thereof, comprising: (a) culturing the cell of any one of claims 103 to 107 under conditions sufficient for the cell to produce the antibody or antigen-binding fragment; (b) harvesting the antibody or antigen-binding fragment produced by the cell.

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