Antibodies specific to MHC class I chain-associated protein A (MICA) and uses thereof

Abstract

The present disclosure relates to the treatment of cancer. In particular, the present disclosure provides novel therapeutic antibodies that target MHC class I chain-associated protein A (MICA) in a manner that reduces the ability of tumor cells to escape immune clearance mediated by natural killer cell group 2D (NKG2D) receptors.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority and benefit to U.S. Provisional Patent Application No. 63 / 508,360, filed June 15, 2023, which is incorporated herein by reference in its entirety for all purposes.

[0003] sequence list The accompanying computer-readable sequence list, with the text title "AKHA_41436_601_SequenceListing", was created on June 13, 2024, and has a file size of 945,112 bytes. It is hereby incorporated in its entirety by reference. Technical Field

[0004] The embodiments of this disclosure relate to the treatment of cancer. In particular, this disclosure provides novel therapeutic antibodies that target MHC class chain-associated protein A (MICA) in a manner that reduces the ability of tumor cells to escape immune clearance mediated by the natural killer cell group 2D (NKG2D) receptor. Background Technology

[0005] The immune system plays a crucial role in tumor development. For example, natural killer (NK) cells are important cytotoxic cells in the immune system, and activated NKG2D receptors on the surface of NK cells can bind to NKG2DL expressed on tumor cells, thereby enabling NK cells to activate and kill tumor cells. However, some tumors have developed the ability to evade NKG2D receptor / NKG2DL-mediated immune clearance through various mechanisms. The expression of NKG2D receptors on NK cells can be regulated by cellular, molecular, and hypoxia-related factors within the tumor microenvironment. Tumor cells regulate NKG2DL expression at the transcriptional, translational, and post-translational levels, thereby evading NK cell recognition. In particular, viruses and hormones have specific mechanisms that affect the expression of NKG2D receptors and NKG2DL. Therefore, NKG2D / NKG2DL may have applications as targets for more effective anti-tumor therapies. Furthermore, DNA damage, oncogene activation and overproliferation, chromatin regulation, and oxidative stress are widely recognized as important hallmarks of cancer. Interestingly, all these abnormalities also induce cellular stress responses. By upregulating stress-inducible ligands, damaged or transformed cells (e.g., tumor cells) can be recognized and eliminated by immune cells (e.g., NK cells). Functional stress-inducible ligands include MICA, MICB, and ULBP1–6, all of which are recognized by NKG2D, which is expressed on natural killer (NK) cells, cytotoxic T cells, and other T cell subsets. The NKG2D ligand / NKG2D axis is widely recognized as an important mediator of antitumor activity; however, patient data regarding the role of NKG2D ligands in immune surveillance and escape appear contradictory. Because these ligands are frequently actively transcribed, tumor cells are forced to manipulate their expression at the post-transcriptional or post-translational level. Although our understanding of the regulation of NKG2D ligand expression remains incomplete, recent studies have revealed multiple cellular mechanisms by which tumor cells reduce the expression of stress-inducible ligands and thus escape immune recognition. Therefore, alternative therapeutic strategies targeting NKG2D-mediated tumor cell immune escape are needed. Summary of the Invention

[0006] Embodiments of this disclosure include an antibody or an antigen-binding fragment thereof that specifically binds to MHC class I chain-associated protein A (MICA), optionally said MICA being human MICA, optionally being a polypeptide comprising an amino acid sequence comprising any one of SEQ ID NO: 837-839.

[0007] According to these embodiments, the antibody or its fragments exhibit any one or more of the following functional characteristics: reducing and / or attenuating the hydrolysis of membrane-bound MICA proteins into soluble MICA; and / or reducing and / or attenuating NKG2D-mediated tumor cell escape; enhancing NK cell-mediated tumor cell killing; cross-reactivity with at least one of cynomolgus monkey MICA (cyMICA), human MICB, human MICA-α3 and / or human MICB-α3; and / or no cross-reactivity with at least one of cynomolgus monkey MICA (cyMICA), human MICB, human MICA-α3 and / or human MICB-α3; and / or at about 1.0 μM or lower K+. D Binds to human MICA; and / or binds to the same epitope on human MICA as an antibody containing the VH and VL sequences of any of the exemplary antibodies (sequences provided in Table 6); and / or competes with an antibody containing the VH and VL sequences of any of the exemplary antibodies (sequences provided in Table 6) for binding to human MICA.

[0008] In some embodiments, the antibodies or antibody fragments of this disclosure are monoclonal, optionally recombinant. In some embodiments, the antibodies or antibody fragments of this disclosure are human, humanized, or chimeric. In some embodiments, the antibodies or antibody fragments of this disclosure are full-length antibodies, single-chain antibodies, single-chain variable fragments (scFv), variable fragments (Fv), fragment antigen-binding regions (Fab), Fab-C, Fab'-SH, (Fab')2, single-domain antibodies (sdAb), VHH antibodies, nanobodies, camel-derived single-domain antibodies, shark IgNAR-derived single-domain antibody fragments (VNAR), diabody, triabody, anti-carrier protein, or aptamer, optionally said antibody is a full-length antibody containing an Fc region (such as human IgG1, IgG2, IgG3, or IgG4 region), and optionally said antibody contains a modified Fc region.

[0009] In some embodiments, the antibody or antibody fragment of this disclosure is conjugated to at least one additional portion, said additional portion optionally selected from: an antigen-binding portion, such as an antibody or an antigen-binding fragment thereof, which is capable of specifically binding to a non-human MICA target; and / or a therapeutic or cytotoxic portion; and / or a detection portion; and / or a purification portion; and / or a half-life extension portion.

[0010] In some embodiments, the antibodies or antibody fragments of this disclosure are polypeptides comprising: one, two, or all three HCDRs of any of the exemplary antibodies (sequences provided in Table 6), and optionally also comprising one, two, or all three corresponding LCDRs of the exemplary antibody; and / or a VH sequence having at least 90% identity with the VH sequence of any of the exemplary antibodies (sequences provided in Table 6), and optionally also comprising a VL sequence having at least 90% identity with the corresponding VL sequence of the exemplary antibody, preferably wherein variation in the HCDRs or LCDRs is not permitted; and / or all six CDRs of any of the exemplary antibodies (sequences provided in Table 6); and / or the VH and VL sequences of any of the exemplary antibodies (sequences provided in Table 6); and / or the full-length heavy chain (VH + constant) sequence of any of the exemplary antibodies (sequences provided in Table 6), and optionally comprising the corresponding full-length light chain (VL + constant) sequence of the exemplary antibody.

[0011] Embodiments of this disclosure also include polynucleotides encoding antibodies or antibody fragments of this disclosure, optionally said polynucleotides comprising or consisting of a nucleic acid sequence having at least 70%, 80%, 90%, or 100% identity with a nucleic acid sequence of any of the exemplary antibodies (whose sequences are provided in Table 6).

[0012] Embodiments of this disclosure also include an expression vector comprising any of the polynucleotides disclosed herein, said expression vector optionally being an adeno-associated virus (AAV) vector, a lentiviral (LV) vector, a herpes simplex virus (HSV) vector, or a retroviral vector.

[0013] Embodiments of this disclosure also include a pharmaceutical composition comprising an antibody or antibody fragment, polynucleotide, or expression vector of the present disclosure, and optionally: at least one pharmaceutically acceptable carrier, diluent, or preservative; and / or at least one additional active ingredient. In some embodiments, the pharmaceutical composition is suitable for administration to a subject, optionally via ocular, oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration.

[0014] Embodiments of this disclosure also include methods of using the polynucleotides, expression vectors, or compositions of this disclosure as medicaments, optionally for treating a subject's cancer. In some embodiments, the antibodies, antibody fragments, polynucleotides, expression vectors, or compositions of this disclosure are used as part of a method of treating a subject's cancer, wherein the cancer is characterized by exhibiting the ability to evade immune clearance mediated by natural killer cell group 2D (NKG2D) receptors. In some embodiments, the antibodies, antibody fragments, polynucleotides, expression vectors, or compositions of this disclosure are used as part of a method of treating a subject's cancer, wherein the method includes intravenous administration of the antibody, antibody fragment, polynucleotide, expression vector, or composition, and wherein intravenous administration relieves at least one symptom in the subject. According to these embodiments, the cancers are lung cancer, pancreatic cancer, ovarian cancer, colon cancer, and prostate cancer.

[0015] Embodiments of this disclosure include antibodies against MHC class I chain-associated protein A (MICA) peptides or antigen-binding fragments thereof. According to these embodiments, this disclosure provides a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region comprising complementarity-determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and the light chain variable region comprising complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3. In some embodiments, HCDR1 comprises one of the following amino acid sequences: (a) X1YX2MX3 (SEQ ID NO: 1), wherein X1 is R, S, or T; X2 is S or A; and X3 is N or S; (b) X1X2X3MH (SEQ ID NO: 64), wherein X1 is N, D, or S; X2 is H, Y, or S; and X3 is A or G; (c) X1X2X3X4X5 (SEQ ID NO: 85), wherein X1 is G, S, V, A, N, or T; X2 is N or Y; X3 is Y, D, L, or G; X4 is I, M, or L; and X5 is H, N, E, or S; (d) X1YDX2N (SEQ ID NO: 145), wherein X1 is S, H, or N; X2 is I or V; or (e) X1X2X3X4X5 (SEQ ID NO: 145). 172), wherein X1 is D, N, S or A; X2 is N, Y or Q; X3 is Y, N or A; X4 is I, W or M; and X5 is S, H, Y or N; wherein HCDR2 contains one of the following amino acid sequences: (a) X1IX2X3X4X5X6X7X8X9YADSVKG (SEQ ID NO: 22), wherein X1 is Y, F, S or V; X2 is N, S or T; X3 is S, T, Y or G; X4 is R or S; X5 is S, G or E; X6 is N, S, T, G or D; X7 is T, R or N; X8 is I or T; and X9 is Y or D; (b) X1IX2X3X4GX5X6X7X8YX9DSVKG (SEQ ID NO: 71), where X1 is L, I, G or V; X2 is W or S; X3 is Y or W; X4 is D or S; X5 is S, G or N; X6 is N or S; X7 is K or I; X8 is Y, G or F; X9 is A or E; (c) X1IX2X3X4X5GX6TX7X8X9X 10 X 11 FX 12 X 13 (SEQ ID NO: 105), wherein X1 is W or A; X2 is N, D or S; X3 is P or S; X4 is N, D, G or Y; and X5 is S or N; X6 is A, G or N; X7 is N or H; X8 is S or Y; X9 is A or N; X 10 For Q or E; X 11 For N, K, or E; X12 For Q or K; and X 13 (d) WNMPX1SX2NTGX3AQKFQG (SEQ ID NO: 154), where X1 is N or D; X2 is G or S; and X3 is Y or F; or (e) X1IX2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 (SEQ ID NO: 178), wherein X1 is W, T, Y, or F; X2 is Y, N, E, or F; X3 is A, P, N, or T; X4 is G, S, Y, T, or H; X5 is T, G, or N; X6 is G, V, or I; X7 is G, S, V, T, or D; X8 is S, T, P, or N; X9 is S, M, Y, or T; X 10 For Y or N; X 11 For N, A, or P; X 12 For Q, P, S, or D; X 13 For K, R, L, or D; X 14 For F or K; and X 15The amino acid sequence is R, Q, K, or S; and HCDR3 contains one of the following amino acid sequences: (a) X1X2X3X4X5X6X7 (SEQ ID NO: 43), wherein X1 is V, A, or G; X2 is S, M, or G; X3 is D, S, A, V, I, or Y; X4 is I, V, R, Q, or W; X5 is T, G, L, or F; X6 is G, S, T, W, or D; and X7 is N, G, S, P, or N; (b) X1X2X3X4 (SEQ ID NO: 78), wherein X1 is E or S; X2 is R or Y; X3 is D, F, L, or V; X4 is Y, P, or V; (c) X1X2X3X4X5X6X7X8 (SEQ ID NO: 78) 125), wherein X1 is D, S, A, F or E; X2 is T, A, S, N or L; X3 is F, A, W, Y or G; X4 is K, R, A, G, P or N; and X5 is P, G, A, Y or W; X6 is Y, F, S or N; X7 is Y, F or D; and X8 is Y, S or N; (d) X1X2X3X4X5X6DX7 (SEQ ID NO: 163), wherein X1 is S or G; X2 is A or S; X3 is A or I; X4 is S, A or R; X5 is G or A; X6 is F, V or S; and X7 is Y, N, S or I; or (e) X1X2X3X4X5X6X7X8 (SEQ ID NO: 184), where X1 is H, Y, S, G or T; X2 is D, S, G, M or Y; X3 is Y, W, S, A or G; X4 is Y, G, S, A or N; X5 is G, P, N, R or Y; X6 is T, G, F, P or A; X7 is S, A, D, Y or M; X8 is G, F, Y or D.

[0016] According to the above implementation scheme, the LCDR1 of the anti-MICA antibody disclosed herein contains the amino acid sequence of any one of SEQ ID NO: 191-213, SEQ ID NO: 263-284 or SEQ ID NO: 332-344; the LCDR2 contains the amino acid sequence of any one of SEQ ID NO: 215-237, SEQ ID NO: 286-306 or SEQ ID NO: 346-358; and the LCDR3 contains the amino acid sequence of any one of SEQ ID NO: 239-261, SEQ ID NO: 309-330 or SEQ ID NO: 360-372.

[0017] In some embodiments, this disclosure provides an antibody or antigen-binding fragment thereof targeting the MICA peptide, the antibody or antigen-binding fragment comprising VH and VL, the VH comprising complementarity-determining regions HCDR1, HCDR2, and HCDR3, and the VL comprising complementarity-determining regions LCDR1, LCDR2, and LCDR3, wherein LCDR1 comprises one of the following amino acid sequences: (a) X1X2X3X4X5X6X7X8X9 (SEQ ID NO: 190), wherein X1 is R or S; X2 is A or S; X3 is Q or S; X4 is S, T, R, or G; X5 is H, S, N, T, or R; X6 is N, S, Y, I, or D; X7 is Y, F, D, or H; X8 is L, F, or Y; and X9 is N, G, A, or L; (b) X1X2X3X4X5X6X7X8X9X 10 (SEQ ID NO: 262), wherein X1 is R, S, or K; X2 is T, A, or S; X3 is Q or G; X4 is G, A, V, N, D, H, S, or R; X5 is V or I; X6 is N, G, S, H, R, V, or L; X7 is S, N, H, or Y; X8 is W, Y, or S; X9 is L, N, or S; and X 10为A, N, or E; or (c) RX1SQSX2X3X4X5X6X7 (SEQ ID NO: 331), wherein X1 is A or T; X2 is V or I; X3 is I, S, or N; X4 is I, T, or S; X5 is N, K, S, W, or Y; X6 is Q, Y, H, or L; and X7 is L or A; wherein LCDR2 contains one of the following amino acid sequences: (a) X1X2X3X4LX5S (SEQ ID NO: 214), wherein X1 is A, S, G, or R; X2 is A or T; X3 is S or F; X4 is S, T, G, or N; and X5 is Q or A; (b) X1X2X3X4X5X6X7 (SEQ ID NO: 214) 285), wherein X1 is A, Y, D, T, K or W; X2 is A, T or V; X3 is S or E; X4 is S, T, I or N; X5 is L or R; X6 is Q, A, H, L, F or E; and X7 is S, D or L; or (c) X1X2SX3X4X5X6X7 (SEQ ID NO: 345), wherein X1 is G, K or D; X2 is A or T; X3 is S, T or N; X4 is R or L; X5 is A, E, V or Q; and X6 is T or S; and wherein LCDR3 contains one of the following amino acid sequences: (a) X1X2X3X4X5X6X7X8 (SEQ ID NO: (b) X1QX2X3X4X5PX6X7 (SEQ ID NO: 308), wherein X1 is F or Q; X2 is A, F, Y, G or S; X3 is N, W, S or Y; X4 is I, S, T, K or H; X5 is F, V, T or Y; X6 is L, I, Y, R or W; and X7 is S or T; or (c) QQX1X2X3X4PX5X6 (SEQ ID NO: 359), wherein X1 is Y, A or R; X2 is G, N or S; X3 is S, V, N or I; X4 is S, F or W; X5 is R, L or I; and X6 is T or S.

[0018] According to the above implementation scheme, the HCDR1 of the anti-MICA antibody disclosed herein contains the amino acid sequence of any one of SEQ ID NO: 2-21, SEQ ID NO: 65-70, SEQ ID NO: 86-104, SEQ ID NO: 147-153 or SEQ ID NO: 173-177; HCDR2 contains the amino acid sequence of any one of SEQ ID NO: 23-42, SEQ ID NO: 72-77, SEQ ID NO: 106-124, SEQ ID NO: 153-162 or SEQ ID NO: 179-183; and HCDR3 contains the amino acid sequence of any one of SEQ ID NO: 44-63, SEQ ID NO: 79-84, SEQ ID NO: 126-143, SEQ ID NO: 163-171 or SEQ ID NO: 185-189.

[0019] In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 2; HCDR2 comprises the amino acid sequence of SEQ ID NO: 23; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 44. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 24; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 45. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 4; HCDR2 comprises the amino acid sequence of SEQ ID NO: 25; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 46. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 5; HCDR2 comprises the amino acid sequence of SEQ ID NO: 26; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 6; HCDR2 comprises the amino acid sequence of SEQ ID NO: 27; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 48. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 7; HCDR2 comprises the amino acid sequence of SEQ ID NO: 28; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 49. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 8; HCDR2 comprises the amino acid sequence of SEQ ID NO: 29; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 50. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 9; HCDR2 comprises the amino acid sequence of SEQ ID NO: 30; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 51. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 10; HCDR2 comprises the amino acid sequence of SEQ ID NO: 31; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 52. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 11; HCDR2 comprises the amino acid sequence of SEQ ID NO: 32; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 53. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 12; HCDR2 comprises the amino acid sequence of SEQ ID NO: 33; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 54.In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; HCDR2 comprises the amino acid sequence of SEQ ID NO: 34; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 55. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 14; HCDR2 comprises the amino acid sequence of SEQ ID NO: 35; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 56. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 15; HCDR2 comprises the amino acid sequence of SEQ ID NO: 36; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 57. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 16; HCDR2 comprises the amino acid sequence of SEQ ID NO: 37; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 58. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 17; HCDR2 comprises the amino acid sequence of SEQ ID NO: 38; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 59. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 18; HCDR2 comprises the amino acid sequence of SEQ ID NO: 39; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 60. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 19; HCDR2 comprises the amino acid sequence of SEQ ID NO: 40; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 61. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 20; HCDR2 comprises the amino acid sequence of SEQ ID NO: 41; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 62. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 21; HCDR2 comprises the amino acid sequence of SEQ ID NO: 42; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 63. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 65; HCDR2 comprises the amino acid sequence of SEQ ID NO: 72; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 79.In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 66; HCDR2 comprises the amino acid sequence of SEQ ID NO: 73; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 80. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 67; HCDR2 comprises the amino acid sequence of SEQ ID NO: 74; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 80. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 68; HCDR2 comprises the amino acid sequence of SEQ ID NO: 75; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 81. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 69; HCDR2 comprises the amino acid sequence of SEQ ID NO: 76; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 82. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 70; HCDR2 comprises the amino acid sequence of SEQ ID NO: 77; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 84. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 86; HCDR2 comprises the amino acid sequence of SEQ ID NO: 106; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 126. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 87; HCDR2 comprises the amino acid sequence of SEQ ID NO: 107; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 127. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 88; HCDR2 comprises the amino acid sequence of SEQ ID NO: 108; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 128. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 89; HCDR2 comprises the amino acid sequence of SEQ ID NO: 109; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 129. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 90; HCDR2 comprises the amino acid sequence of SEQ ID NO: 110; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 130.In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 91; HCDR2 comprises the amino acid sequence of SEQ ID NO: 111; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 131. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 92; HCDR2 comprises the amino acid sequence of SEQ ID NO: 112; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 132. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 93; HCDR2 comprises the amino acid sequence of SEQ ID NO: 113; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 133. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 94; HCDR2 comprises the amino acid sequence of SEQ ID NO: 114; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 134. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 95; HCDR2 comprises the amino acid sequence of SEQ ID NO: 115; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 135. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 96; HCDR2 comprises the amino acid sequence of SEQ ID NO: 116; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 136. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 97; HCDR2 comprises the amino acid sequence of SEQ ID NO: 117; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 137. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 98; HCDR2 comprises the amino acid sequence of SEQ ID NO: 118; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 138. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 99; HCDR2 comprises the amino acid sequence of SEQ ID NO: 119; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 139. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 100; HCDR2 comprises the amino acid sequence of SEQ ID NO: 120; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 140.In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 101; HCDR2 comprises the amino acid sequence of SEQ ID NO: 121; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 141. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 102; HCDR2 comprises the amino acid sequence of SEQ ID NO: 122; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 142. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 103; HCDR2 comprises the amino acid sequence of SEQ ID NO: 123; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 143. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 104; HCDR2 comprises the amino acid sequence of SEQ ID NO: 124; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 144. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 146; HCDR2 comprises the amino acid sequence of SEQ ID NO: 155; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 164. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 147; HCDR2 comprises the amino acid sequence of SEQ ID NO: 156; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 165. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 148; HCDR2 comprises the amino acid sequence of SEQ ID NO: 157; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 166. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 149; HCDR2 comprises the amino acid sequence of SEQ ID NO: 158; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 167. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 150; HCDR2 comprises the amino acid sequence of SEQ ID NO: 159; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 168. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 151; HCDR2 comprises the amino acid sequence of SEQ ID NO: 160; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 169.In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 152; HCDR2 comprises the amino acid sequence of SEQ ID NO: 161; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 170. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 153; HCDR2 comprises the amino acid sequence of SEQ ID NO: 162; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 171. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 173; HCDR2 comprises the amino acid sequence of SEQ ID NO: 179; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 185. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 174; HCDR2 comprises the amino acid sequence of SEQ ID NO: 180; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 186. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 175; HCDR2 comprises the amino acid sequence of SEQ ID NO: 181; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 187. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 176; HCDR2 comprises the amino acid sequence of SEQ ID NO: 182; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 189. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 191; LCDR2 comprises the amino acid sequence of SEQ ID NO: 215; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 239. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 192; LCDR2 comprises the amino acid sequence of SEQ ID NO: 216; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 240. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 193; LCDR2 comprises the amino acid sequence of SEQ ID NO: 217; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 241. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 194; LCDR2 comprises the amino acid sequence of SEQ ID NO: 218; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 242.In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 195; LCDR2 comprises the amino acid sequence of SEQ ID NO: 219; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 243. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 196; LCDR2 comprises the amino acid sequence of SEQ ID NO: 220; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 244. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 197; LCDR2 comprises the amino acid sequence of SEQ ID NO: 221; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 245. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 198; LCDR2 comprises the amino acid sequence of SEQ ID NO: 222; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 246. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 199; LCDR2 comprises the amino acid sequence of SEQ ID NO: 223; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 247. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 200; LCDR2 comprises the amino acid sequence of SEQ ID NO: 224; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 248. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 201; LCDR2 comprises the amino acid sequence of SEQ ID NO: 225; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 249. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 202; LCDR2 comprises the amino acid sequence of SEQ ID NO: 226; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 250. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 203; LCDR2 comprises the amino acid sequence of SEQ ID NO: 227; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 251. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 204; LCDR2 comprises the amino acid sequence of SEQ ID NO: 228; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 252.In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 205; LCDR2 comprises the amino acid sequence of SEQ ID NO: 229; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 253. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 206; LCDR2 comprises the amino acid sequence of SEQ ID NO: 230; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 254. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 207; LCDR2 comprises the amino acid sequence of SEQ ID NO: 231; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 255. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 208; LCDR2 comprises the amino acid sequence of SEQ ID NO: 232; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 256. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 209; LCDR2 comprises the amino acid sequence of SEQ ID NO: 233; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 257. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 210; LCDR2 comprises the amino acid sequence of SEQ ID NO: 234; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 258. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 211; LCDR2 comprises the amino acid sequence of SEQ ID NO: 235; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 259. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 212; LCDR2 comprises the amino acid sequence of SEQ ID NO: 236; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 260. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 213; LCDR2 comprises the amino acid sequence of SEQ ID NO: 237; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 261. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 263; LCDR2 comprises the amino acid sequence of SEQ ID NO: 286; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 309.In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 264; LCDR2 comprises the amino acid sequence of SEQ ID NO: 287; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 310. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 265; LCDR2 comprises the amino acid sequence of SEQ ID NO: 288; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 311. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 266; LCDR2 comprises the amino acid sequence of SEQ ID NO: 289; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 312. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 267; LCDR2 comprises the amino acid sequence of SEQ ID NO: 290; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 313. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 268; LCDR2 comprises the amino acid sequence of SEQ ID NO: 291; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 314. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 269; LCDR2 comprises the amino acid sequence of SEQ ID NO: 292; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 315. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 270; LCDR2 comprises the amino acid sequence of SEQ ID NO: 293; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 316. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 271; LCDR2 comprises the amino acid sequence of SEQ ID NO: 294; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 317. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 272; LCDR2 comprises the amino acid sequence of SEQ ID NO: 295; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 318. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 273; LCDR2 comprises the amino acid sequence of SEQ ID NO: 296; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 319.In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 274; LCDR2 comprises the amino acid sequence of SEQ ID NO: 297; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 320. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 275; LCDR2 comprises the amino acid sequence of SEQ ID NO: 298; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 321. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 276; LCDR2 comprises the amino acid sequence of SEQ ID NO: 299; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 322. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 277; LCDR2 comprises the amino acid sequence of SEQ ID NO: 300; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 323. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 278; LCDR2 comprises the amino acid sequence of SEQ ID NO: 301; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 324. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 279; LCDR2 comprises the amino acid sequence of SEQ ID NO: 302; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 325. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 280; LCDR2 comprises the amino acid sequence of SEQ ID NO: 303; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 326. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 281; LCDR2 comprises the amino acid sequence of SEQ ID NO: 304; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 327. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 282; LCDR2 comprises the amino acid sequence of SEQ ID NO: 305; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 328. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 283; LCDR2 comprises the amino acid sequence of SEQ ID NO: 306; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 329.In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 284; LCDR2 comprises the amino acid sequence of SEQ ID NO: 307; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 330. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 332; LCDR2 comprises the amino acid sequence of SEQ ID NO: 346; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 360. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 333; LCDR2 comprises the amino acid sequence of SEQ ID NO: 347; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 361. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 334; LCDR2 comprises the amino acid sequence of SEQ ID NO: 348; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 362. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 335; LCDR2 comprises the amino acid sequence of SEQ ID NO: 349; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 363. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 336; LCDR2 comprises the amino acid sequence of SEQ ID NO: 350; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 364. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 337; LCDR2 comprises the amino acid sequence of SEQ ID NO: 351; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 365. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 338; LCDR2 comprises the amino acid sequence of SEQ ID NO: 352; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 366. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 339; LCDR2 comprises the amino acid sequence of SEQ ID NO: 353; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 367. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 340; LCDR2 comprises the amino acid sequence of SEQ ID NO: 354; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 368.In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 341; LCDR2 comprises the amino acid sequence of SEQ ID NO: 355; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 369. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 342; LCDR2 comprises the amino acid sequence of SEQ ID NO: 356; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 370. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 343; LCDR2 comprises the amino acid sequence of SEQ ID NO: 357; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 371. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 344; LCDR2 comprises the amino acid sequence of SEQ ID NO: 358; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 372.

[0020] In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NO: 373-430. In some embodiments, VL comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NO: 489-546.

[0021] In some embodiments, the heavy chain Fc domain of the antibody contains at least 90% of the same amino acid sequence as SEQ ID NO: 845, and contains at least one amino acid substitution selected from S239D, A330L, and / or I332E. In some embodiments, the antibody contains at least two amino acid substitutions selected from S239D, A330L, and / or I332E. In some embodiments, the antibody contains all three amino acid substitutions selected from S239D, A330L, and / or I332E. In some embodiments, the antibody contains at least one additional amino acid substitution relative to SEQ ID NO: 845.

[0022] In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 373, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 489. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 374, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 490. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 375, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 491. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 376, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 492. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 377, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 493. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 378, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 494. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 379, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 495. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 380, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 496. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 381, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 497. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 382, ​​and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 498. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 383, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 499. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 384, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 500. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 385, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 501.In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 386, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 502. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 387, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 503. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 388, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 504. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 389, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 505. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 390, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 506. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 391, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 507. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 392, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 508. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 393, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 509. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 394, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 510. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 395, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 511. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 396, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 512. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 397, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 513. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 398, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 514.In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 399, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 515. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 400, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 516. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 401, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 517. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 402, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 518. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 403, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 519. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 404, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 520. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 405, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 521. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 406, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 522. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 407, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 523. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 408, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 524. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 409, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 525. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 410, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 526. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 411, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 527.In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 412, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 528. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 413, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 529. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 414, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 530. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 415, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 531. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 416, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 532. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 417, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 533. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 418, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 534. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 419, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 535. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 420, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 536. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 421, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 537. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 422, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 538. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 423, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 539. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 424, and VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 540.In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 425, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 541. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 426, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 542. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 427, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 543. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 428, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 544. In some embodiments, VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 429, and VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 545. In some embodiments, VH contains at least 90% of the same amino acid sequence as SEQ ID NO: 430, and VL contains at least 90% of the same amino acid sequence as SEQ ID NO: 546.

[0023] In some embodiments, the heavy chain Fc domain of the antibody contains at least 90% of the same amino acid sequence as SEQ ID NO: 845, and contains at least one amino acid substitution selected from S239D, A330L, and / or I332E. In some embodiments, the antibody contains at least two amino acid substitutions selected from S239D, A330L, and / or I332E. In some embodiments, the antibody contains all three amino acid substitutions selected from S239D, A330L, and / or I332E. In some embodiments, the antibody contains at least one additional amino acid substitution relative to SEQ ID NO: 845.

[0024] Based on the above embodiments, this disclosure provides anti-MICA antibodies including various functional characteristics. In some embodiments, the anti-MICA antibodies described herein bind to an antigen on MICA or a variant or isotype thereof (e.g., SEQ ID NO: 837-844) (via interaction with its antigenic determinant (epitope). In some embodiments, the binding of the anti-MICA antibody to MICA reduces the proteolytic cleavage of MICA (e.g., inhibits MICA shedding). In some embodiments, the binding of the anti-MICA antibody to MICA attenuates NKG2D-mediated tumor cell escape. In some embodiments, the anti-MICA antibody is administered at about 1.0 μM or lower K+. D Combined with human MICA ( Figure 4).

[0025] In some embodiments, the anti-MICA antibody cross-reacts with one or more of cynomolgus monkey MICA (cyMICA), human MICA-α3, and human MICB-α3. In some embodiments, the anti-MICA antibody does not cross-react with one or more of cyMICA, human MICA-α3, and human MICB-α3. In some embodiments, the anti-MICA antibody comprises a VH region and a VL region, said VH region and VL region being at least 90% identical to the VH region and VL region of an antibody selected from the group consisting of: AHA-P-1, AHA-P-2, AHA-P-3, AHA-P-4, AHA-P-5, AHA-P-6, AHA-P-7, AHA-P-8, ATX-P-1550, ATX-P-1551, ATX-P-1552, and ATX-P-1. 553, ATX-P-1554, ATX-P-1555, ATX-P-1556, ATX-P-1563, ATX-P-1564, ATX-P-1565, ATX-P-1568, ATX -P-1569, ATX-P-1572, ATX-P-1678, ATX-P-1680, ATX-P-1684, ATX-P-1820, ATX-P-1822, ATX-P-1825, ATX-P-1826, ATX-P-1827, ATX-P-1828, ATX-P-1829, ATX-P-1831, ATX-P-1832, ATX-P-1833, ATX-P-1 835, ATX-P-1838, ATX-P-1839, ATX-P-1840, ATX-P-1841, ATX-P-1842, ATX-P-1843, ATX-P-1844, ATX -P-1845, ATX-P-1846, ATX-P-1847, ATX-P-1848, ATX-P-1850, ATX-P-1852, ATX-P-1853, ATX-P-1856 , ATX-P-1857, ATX-P-1858, ATX-P-1860, ATX-P-1861, ATX-P-791, ATX-P-792, ATX-P-793 and ATX-P-794.

[0026] According to the above embodiments, the anti-MICA antibody disclosed herein can be a monoclonal antibody, a human antibody, a humanized antibody, and / or a chimeric antibody. In some embodiments, the antibody is a fragment selected from the group consisting of: Fab, Fab-C, Fab'-SH, Fv, scFv, and (Fab')2 fragments. In some embodiments, the anti-MICA antibody is a monospecific antibody. In some embodiments, the anti-MICA antibody is a bispecific antibody. In some embodiments, the anti-MICA antibody comprises two or more single-domain antibodies, said single-domain antibodies forming bivalent, trivalent, or quadrivalent antibodies that recognize different epitopes on the same or different antigens.

[0027] In some embodiments, the antibody includes a detection portion. In some embodiments, the antibody includes a purification portion. In some embodiments, the antibody includes a half-life extension portion.

[0028] The anti-MICA antibody of this disclosure can be administered as part of a pharmaceutical composition in a therapeutically effective amount to treat tumors or tumor-related diseases or disorders (e.g., cancer). In some embodiments, the composition is suitable for delivery by a single bolus injection, by multiple bolus injections, or by continuous infusion. Compositions containing an anti-MICA antibody or its antigen-binding fragment can be administered to mammals using standard administration techniques, including ocular, oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration. In some embodiments, administration includes delivery of the anti-MICA antibody using needles, gels, nanoparticles, mucosal adhesion polymers, ointments, solutions, suspensions, drops, and / or implants. In some embodiments, the pharmaceutical composition containing a therapeutically effective amount of the anti-MICA antibody of this disclosure is administered at a dose ranging from about 0.0001 mg / dose to about 100 mg / dose. In some embodiments, the pharmaceutical composition is administered at a dose ranging from about 0.0001 mg / ml to about 100 mg / ml.

[0029] Embodiments of this disclosure also include polynucleotides encoding any anti-MICA antibody of this disclosure. In some embodiments, the polynucleotide comprises a sequence that is at least 70% identical to any one of SEQ ID NO: 431-488 or SEQ ID NO: 547-604. In some embodiments, the polynucleotide comprises a sequence that is at least 80% identical to any one of SEQ ID NO: 431-488 or SEQ ID NO: 547-604. In some embodiments, the polynucleotide comprises a sequence that is at least 90% identical to any one of SEQ ID NO: 431-488 or SEQ ID NO: 547-604. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 70% identical to any one of SEQ ID NO: 431-488; and a nucleic acid sequence that is at least 70% identical to any one of SEQ ID NO: 547-604. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 80% identical to any one of SEQ ID NO: 431-488; and a nucleic acid sequence that is at least 80% identical to any one of SEQ ID NO: 547-604. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 90% identical to any one of SEQ ID NO: 431-488; and a nucleic acid sequence that is at least 90% identical to any one of SEQ ID NO: 547-604.

[0030] In some implementations, the polynucleotide comprises a nucleic acid sequence having at least 70% identity with any of the following: (a) SEQ ID NO: 663-720; (b) SEQ ID NO: 779-836; (c) SEQ ID NO: 663-720; (d) SEQ ID NO: 779-836; (e) SEQ ID NO: 663-720; or (f) SEQ ID NO: 779-836.

[0031] In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 70% identical to any one of SEQ ID NO: 663-720; and a nucleic acid sequence that is at least 70% identical to any one of SEQ ID NO: 779-836. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 80% identical to any one of SEQ ID NO: 663-720; and a nucleic acid sequence that is at least 80% identical to any one of SEQ ID NO: 779-836. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 90% identical to any one of SEQ ID NO: 663-720; and a nucleic acid sequence that is at least 90% identical to any one of SEQ ID NO: 779-836.

[0032] According to these embodiments, this disclosure includes expression vectors comprising any polynucleotide encoding an anti-MICA antibody of this disclosure. In some embodiments, the expression vector is adapted to manufacture the anti-MICA antibody of this disclosure for delivery to a subject. In some embodiments, the expression vector is suitable for gene therapy (e.g., an expression vector for delivering a polynucleotide encoding an anti-MICA antibody of this disclosure to a subject). In some embodiments, the expression vector is an adeno-associated virus (AAV) vector or contains an AAV backbone. In some embodiments, the expression vector is a lentiviral vector (LV) or contains an LV backbone. In some embodiments, the expression vector is a herpes simplex virus (HSV) vector or a retroviral vector.

[0033] According to these embodiments, this disclosure also provides a method of administering gene therapy to a subject in need, the method comprising injecting a pharmaceutical composition comprising an effective amount of the expression vector described herein (e.g., an expression vector comprising a polynucleotide encoding an anti-MICA antibody of this disclosure). According to these embodiments, this disclosure also provides a method of treating cancer, the method comprising administering a pharmaceutical composition comprising an effective amount of the expression vector described herein (e.g., an expression vector comprising a polynucleotide encoding an anti-MICA antibody of this disclosure). In some embodiments, administering the pharmaceutical composition treats at least one symptom present in a subject suffering from cancer. Attached Figure Description

[0034] Figure 1 Representative ELISA results used to determine the antigen-positive serum titers of mice immunized with human MICA, depending on the different immunization protocols / cohorts.

[0035] Figure 2 Representative results of cell binding assays using Raji cells expressing the anti-MICA antibody disclosed herein.

[0036] Figure 3 The representative thermal stability of the anti-MICA antibody of this disclosure was determined by protein thermal shift (PTS) and assessed by differential scanning fluorescence (DSF).

[0037] Figure 4 : Representative tables of various anti-MICA antibody characteristics (including epitope binning analysis, binding affinity, and cross-reactivity).

[0038] Figures 5A to 5C Representative results from anti-MICA antibody cross-blocking experiments, including data from progressively grouping antibodies with similar competitive characteristics. Figure 5A Includes representative particle size binning network diagrams (antibodies are highlighted with a blue asterisk). Figure 5B Including representative group binning network diagrams, and Figure 5C This includes representative combined binary tree diagrams (color indicates the boxes in the network diagram).

[0039] Figures 6A to 6C Representative functional data of the anti-MICA antibodies disclosed herein include comparisons with baseline antibodies (i.e., 791, 792, 793, 794, 3F9, C16F10, and C619 are control MICA antibodies). Figure 6A This includes results demonstrating the ability of anti-MICA antibodies to stabilize MICA on the surface of cancer cells. Figure 6B This includes results demonstrating the ability of anti-MICA antibodies to inhibit MICA shedding. Figure 6C This includes data comparing cell surface MICA stability and shedding inhibition at various concentrations of anti-MICA antibodies.

[0040] Figures 7A to 7D Representative functional data for four anti-MICA antibodies disclosed herein, including comparisons with benchmark antibodies (i.e., 7C6, 1D5, and CLN-619 antibodies). Figure 7A This includes results demonstrating the ability of four anti-MICA antibodies to stabilize MICA on the surface of cancer cells. Figure 7B This includes results demonstrating the ability of four anti-MICA antibodies to inhibit MICA shedding. Figure 7C This includes data demonstrating that four anti-MICA antibodies enhance the ability of A375 melanoma target cells to be killed by primary human NK cells at different effector cell to target cell ratios. Figure 7D This includes data demonstrating that four anti-MICA antibodies enhance the ability of different concentrations of MICA antibodies to kill A375 melanoma target cells via primary human NK cells.

[0041] Figure 8Representative results of the binding kinetics of the fully humanized anti-MICA antibody (ATX-P-1826) tested against human MICA, human MICB, and cynomolgus monkey MICA. Similar binding affinity was demonstrated for MICA, MICB, and cynomolgus monkey MICA.

[0042] Figures 9A to 9B FcγRIIIa activation assay used to test the efficacy of AHA-P-1031, ATX-P-1826, and ATX-P-1826 (defucosylated) antibodies in killing cancer cells. Figure 9A ) and ADCC measurement ( Figure 9B Representative results.

[0043] Figure 10 Representative results from in vivo experiments testing the antitumor efficacy of AHA-P-1031 (Fc enhanced) in human xenografts (A375 melanoma cell line).

[0044] Figures 11A to 11C Representative results of experiments testing the ability of AHA-P-1031 to inhibit MICA shedding in different tumor cell lines: lung cancer cell lines (A549, H2030, NCI-H226 and Calu-3); Figure 11A ); pancreatic cancer cell lines (PANC1 and Capan-2); Figure 11B ); Ovarian cancer cell line (OVCAR3); Figure 11B ); colon cancer cell line (HCT116); Figure 11B ); and prostate cancer cell lines (22Rv1, PC3, and LNCaP); Figure 11C ).

[0045] Figure 12 Representative results of cytokine release assays used to test the safety profile of AHA-P-1031. Detailed Implementation

[0046] The embodiments of this disclosure relate to the treatment of cancer. In particular, this disclosure provides novel therapeutic antibodies that target MHC class chain-associated protein A (MICA) in a manner that reduces the ability of tumor cells to escape immune clearance mediated by the natural killer cell group 2D (NKG2D) receptor.

[0047] MHC class I chain-associated proteins A (MICA) and B (MICB) are surface molecules of cancer cells, reflecting both cancer cell-centric biological behavior and the host's immune status. The major histocompatibility complex (MHC) class I chain-associated (MIC) gene family, located within the HLA region, consists of five members: MICA, MICB, MICC, MICD, and MICE. Of these five members, MICA and MICB are the only functional genes, frequently expressed in breast, lung, colon, ovarian, kidney, and prostate cancers, as well as in melanoma, glioma, and leukemia. MICA and MICB act as cellular stress signals, binding to natural killer cell group 2D (NKG2D). This binding activates the cytolytic response of γδ T cells and NK cells against epithelial tumor cells.

[0048] In addition to the membrane-bound form, a soluble isoform of MICA / B (sMICA / B) exists in serum. This serum-soluble form originates from the protein hydrolysis of the membrane-bound molecule. Surface-present MICA forms a complex with a disulfide isomerase / chaperone (ERp5). This complex induces a conformational change, enabling MICA to be proteasically cleaved by integrin and metalloproteinase (ADAM) proteins. Subsequently, the interaction of sMICA / B with NKG2D leads to the endocytosis and degradation of the receptor-ligand complex, and also inhibits NKG2D-mediated host cancer rejection.

[0049] The shedding of NKG2D ligands not only leads to reduced cell surface ligand density and decreased NK cell recognition, but sustained exposure to soluble ligands also results in downregulation of surface NKG2D expression and decreased NK cell and CD8+ T cell cytotoxicity. Furthermore, soluble MICA has been shown to negatively impact other activating receptors (such as T cell receptors, CD16, and NKp46) by inducing caspase-mediated CD3ζ degradation in T and NK cells, thereby inducing more generalized tolerance to cytotoxic cells. Additionally, NKG2D expression has been reported in some tumors, where soluble NKG2D ligands may stimulate pro-survival signaling and tumor cell proliferation.

[0050] The shedding of MICA / B is mediated by endoplasmic reticulum protein 5 (ERp5), which interacts with MICA and MICB. αThe conserved six-amino acid motif in the 3-domain binds and induces conformational changes, thereby allowing protease cleavage, for example, via ADAM10 or ADAM17. Regulation of NKG2D ligand expression has been reported at the transcriptional, post-transcriptional, and post-translational levels, but remains unclear. MicroRNAs can regulate MICA / B protein expression, while ubiquitination, palmitoylation, and glycosylation have been shown to regulate intracellular retention as well as cell surface expression and distribution. Furthermore, MICA / B does not always reach the cell surface but is released from the cell via exosomes. Most studies exploring MICA / B expression and localization have been conducted using cell lines typically engineered to overexpress MICA or MICB. Therefore, the expression of MICA / B in normal and tumor tissues, and especially its intracellular distribution, remains unclear.

[0051] In view of this, experiments were conducted to evaluate the ability of the anti-MICA antibody disclosed herein to attenuate NKG2D-mediated tumor cell immune escape, and thus provide a new therapeutic approach for treating cancer.

[0052] definition To facilitate understanding of this technology, several terms and phrases are defined below. Further definitions are set forth throughout the specific implementation.

[0053] Unless otherwise specified herein or obviously contradicted by the context, the use of the terms "a," "the," and "at least one," and similar indicators in the context of describing embodiments of this disclosure (particularly in the context of the following claims) shall be interpreted as covering both the singular and the plural. Unless otherwise specified herein or obviously contradicted by the context, the use of the term "at least one" followed by a list of one or more items (e.g., "at least one of A and B") shall be interpreted as meaning selected from one of the listed items (A or B) or any combination of two or more of the listed items (A and B). Unless otherwise specified, the terms "comprising," "having," "including," and "containing" shall be interpreted as open-ended terms (i.e., meaning "including but not limited to"). Unless otherwise specified herein, the enumeration of value ranges herein is intended only as a shorthand method of individually referring to each individual value falling within the said range, and each individual value is incorporated into this specification as individually enumerated herein. Unless otherwise specified herein or obviously contradicted by the context, all methods described herein may be performed in any suitable order. Unless otherwise required, the use of any and all instances or exemplary language (e.g., “such as”) provided herein is intended only to better illustrate the various embodiments of this disclosure and does not impose any limitation on the scope of these embodiments. The language in this specification should not be construed as indicating that any unclaimed element is necessary for practicing the various embodiments of this disclosure.

[0054] As used herein, unless the context clearly specifies otherwise, the term "or" is an inclusive "or" operator and is equivalent to the term "and / or". Unless the context clearly specifies otherwise, the term "based on" is not exclusive and allows for basing on additional factors not described. Furthermore, throughout the specification, the meanings of "an / a" and "described" include plural references. The meaning of "in" includes both "in" and "on".

[0055] The transitional phrase "consisting substantially of..." used in the claims of this application limits the scope of the claims to the specified materials or steps "and those materials or steps that do not substantially affect the basic and novel features of the claimed invention," as in... In re Herz As discussed in 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976). For example, a composition “consisting substantially of the listed elements” may contain a level of unlisted contaminants such that, although present, the contaminants do not alter the function of the listed composition compared to the pure composition (i.e., a composition “consisting of the listed components”).

[0056] As used herein, the term “one or more” refers to a number greater than one. For example, the term “one or more” covers any of the following: two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, thirteen or more, fourteen or more, fifteen or more, twenty or more, fifty or more, 100 or more, or even a larger number.

[0057] The terms "one or more but less than higher numbers", "two or more but less than higher numbers", "three or more but less than higher numbers", "four or more but less than higher numbers", "five or more but less than higher numbers", "six or more but less than higher numbers", "seven or more but less than higher numbers", "eight or more but less than higher numbers", "nine or more but less than higher numbers", "ten or more but less than higher numbers", "eleven or more but less than higher numbers", "twelve or more but less than higher numbers", "thirteen or more but less than higher numbers", "fourteen or more but less than higher numbers", or "fifteen or more but less than higher numbers" are not limited to higher numbers. For example, the higher number can be 10,000, 1,000, 100, 50, etc. For example, the higher number could be approximately 50 (e.g., 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 32, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, or 2).

[0058] As used herein, the terms "immunoglobulin" or "antibody" refer to proteins found in the blood or other bodily fluids of vertebrates that are used by the immune system to identify and neutralize foreign substances, such as bacteria and viruses. Typically, immunoglobulins or antibodies are proteins containing at least one complementarity-determining region (CDR). The CDR forms the "hypervariate region" of the antibody responsible for antigen binding (discussed further below). A complete antibody typically consists of four polypeptides: two identical copies of the heavy (H) chain polypeptide and two identical copies of the light (L) chain polypeptide. Each heavy chain contains an N-terminal variable (V) terminus. H ) region and three C-terminal constants (C H1 C H2 and C H3 The light chain contains an N-terminal variable (V) region, and each light chain contains an N-terminal variable (V) region. L ) region and a C-terminal constant (C L The light chains of an antibody can be designated as either κ (κ) or lambda (λ) based on the amino acid sequence of their constant domains. In a typical antibody, each light chain is linked to the heavy chain by a disulfide bond, and the two heavy chains are linked to each other by disulfide bonds. The variable regions of the light chains are aligned with the variable regions of the heavy chains, and the constant regions of the light chains are aligned with the first constant region of the heavy chains. The remaining constant regions of the heavy chains are aligned with each other.

[0059] The variable regions of each pair of light and heavy chains form the antigen-binding sites of the antibody.H and V L The regions have the same overall structure, and each region contains four frame (FW or FR) regions. As used herein, the term "frame region" refers to a relatively conserved amino acid sequence located between CDRs within a variable region. Each variable domain has four frame regions, which are designated as FR1, FR2, FR3, and FR4. The frame regions form β-sheets that provide the structural framework of the variable region (see, for example, CA Janeway et al. (edited)). Immunobiology , 5th ed., Garland Publishing, New York, NY (2001)).

[0060] The frame region is connected by three CDRs. As discussed above, the three CDRs (designated CDR1, CDR2, and CDR3) form the “hypervariant region” of the antibody responsible for antigen binding. The CDRs form loops that connect to the β-sheet structure formed by the frame region and, in some cases, constitute part of the β-sheet structure formed by the frame region. While the constant regions of the light and heavy chains do not directly participate in antibody-antigen binding, they can influence the orientation of the variable region. The constant regions also exhibit various effector functions, such as participating in antibody-dependent complement-mediated cleavage or antibody-dependent cytotoxicity via interactions with effector molecules and cells.

[0061] As used herein, when an antibody or other entity (e.g., an antigen-binding domain) “specifically recognizes” or “specifically binds” to an antigen or epitope, the antibody or other entity preferentially recognizes the antigen in a complex mixture of proteins and / or macromolecules and binds the antigen or epitope with a significantly higher affinity than other entities that do not exhibit the antigen or epitope. In this respect, “significantly higher affinity” means that the affinity is high enough to enable the detection of an antigen or epitope different from the entity using the desired assay or measurement device. Typically, this means a binding affinity of at least 10. 7 M -1 (For example, >10) 7 M -1 >10 8 M -1 >10 9 M -1 >10 10 M -1 >10 11 M -1 >10 12 M -1 >10 13 M -1 The binding constant (K) of (etc.) aIn some such embodiments, the antibody can bind to different antigens, as long as the different antigens contain the specific epitope. For example, in some cases, homologous proteins from different species may contain the same epitope.

[0062] The terms “fragment of antibody,” “antibody fragment,” and “antigen-binding fragment of antibody” are used interchangeably herein to refer to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (see generally Holliger et al.). Nat. Biotech ., 23 (9): 1126-1129 (2005)). Any antigen-binding fragment of the antibody described herein is within the scope of this disclosure. Antibody fragments are intended to include, for example, one or more CDRs, variable regions (or portions thereof), constant regions (or portions thereof), or combinations thereof. Examples of antibody fragments include, but are not limited to: (i) Fab fragments, which are formed by V L V H C L and C H1 (ii) The F(ab')2 fragment, which is a bivalent fragment consisting of two Fab fragments connected by a disulfide bridge at the hinge region, and (iii) the Fv fragment, which consists of the V of the antibody single arm. L and V H The domains consist of: (iv) the Fab' fragment, which is formed by breaking the disulfide bridge of the F(ab')2 fragment using mild reducing conditions; (v) the disulfide-stabilized Fv fragment (dsFv); and (vi) the domain antibody (dAb), which is an antibody monovariable domain (V) that specifically binds to the antigen. H or V L Polypeptide.

[0063] As used herein, the term "monoclonal antibody" refers to an antibody produced by a single clone of B lymphocytes that targets a single epitope on an antigen. Monoclonal antibodies are typically produced using hybridoma technology, as described by Köhler and Milstein. Eur. J. Immunol ., 5 First described in 511-519 (1976). Monoclonal antibodies can also be produced using recombinant DNA methods (see, for example, U.S. Patent 4,816,567) or isolated from phage display antibody libraries (see, for example, Clackson et al.). Nature , 352 : 624--628 (1991)); and Marks et al., J. Mol. Biol ., 222 :581--597 (1991)) or produced by transgenic mice carrying the fully human immunoglobulin system (see, for example, Lonberg, Nat. Biotechnol ., 23 (9): 1117-25 (2005), and Lonberg, Handb. Exp. Pharmacol ., 181 : 69-97 (2008)). In contrast, "polyclonal" antibodies are antibodies secreted by different B cell lineages in an animal. Polyclonal antibodies are a collection of immunoglobulin molecules that recognize multiple epitopes on the same antigen.

[0064] The terms “nucleic acid,” “polynucleotide,” “nucleotide sequence,” and “oligonucleotide” are used interchangeably herein and refer to polymers or oligomers of pyrimidine and / or purine bases (preferably cytosine, thymine, and uracil, and adenine and guanine, respectively) (see Albert L. Lehninger, Principles of Biochemistry (Pages 793-800 (Worth Pub. 1982)). The terminology encompasses any deoxyribonucleotide, ribonucleotide, or peptide nucleic acid component and any chemical variant thereof, such as methylated, hydroxymethylated, or glycosylated forms of these bases. Polymers or oligomers may be heterogeneous or homogeneous in composition, isolated from naturally occurring sources, or produced artificially or synthetically. Additionally, nucleic acids may be DNA or RNA or mixtures thereof, and may exist permanently or intermittently in single-stranded or double-stranded form (including homoduplexes, heteroduplexes, and hybrid states). In some embodiments, the nucleic acid or nucleic acid sequence comprises other types of nucleic acid structures, such as, for example, DNA / RNA helices, peptide nucleic acids (PNAs), morpholinonucleotides (see, for example, Braasch and Corey, ...). Biochemistry , 41 (14): 4503-4510 (2002) and US Patent 5,034,506), locked nucleic acid (LNA; see Wahllestedt et al., Proc. Natl. Acad. Sci. USA , 97 : 5633--5638 (2000)), cyclohexenyl nucleic acid (see Wang, J. Am. Chem. Soc ., 122 : 8595--8602 (2000)) and / or ribozymes. The terms “nucleic acid” and “nucleic acid sequence” may also cover chains containing non-natural nucleotides, modified nucleotides, and / or non-nucleotide building blocks (e.g., “nucleotide analogs”) that can exhibit the same function as natural nucleotides.

[0065] The terms “peptide,” “polypeptide,” and “protein” are used interchangeably herein and refer to a polymeric form of amino acids of any length, which may include coding and non-coding amino acids, chemically or biochemically modified or derived amino acids, and polypeptides having a modified peptide backbone.

[0066] As used herein, “nucleic acid” or “nucleic acid molecule” generally refers to any ribonucleic acid or deoxyribonucleic acid, which may be unmodified or modified DNA or RNA. “Nucleic acid” includes, but is not limited to, single-stranded and double-stranded nucleic acids. As used herein, the term “nucleic acid” also includes DNA containing one or more modified bases as described above. Therefore, DNA whose backbone is modified for stability or other reasons is a “nucleic acid.” As used herein, the term “nucleic acid” encompasses such chemically, enzymatically, or metabolically modified forms of nucleic acids, as well as DNA chemical forms specific to viruses and cells (including, for example, simple and complex cells).

[0067] The terms "oligonucleotide," "polynucleotide," "nucleotide," or "nucleic acid" refer to a molecule having two or more, preferably more than three, and usually more than ten deoxyribonucleotides or ribonucleotides. The exact size will depend on many factors, which in turn depend on the final function or use of the oligonucleotide. Oligonucleotides can be generated in any way, including chemical synthesis, DNA replication, reverse transcription, or a combination thereof. Typical deoxyribonucleotides of DNA are thymine, adenine, cytosine, and guanine. Typical ribonucleotides of RNA are uracil, adenine, cytosine, and guanine.

[0068] The terms "complementarity" and "complementarity" refer to nucleotides (e.g., a single nucleotide) or polynucleotides (e.g., a nucleotide sequence) that are related by base pairing rules. For example, sequence 5'-AGT-3' is complementary to sequence 3'-TCA-5'. Complementarity can be "partial," where only some bases of the nucleic acids match according to base pairing rules. Alternatively, there can be "complete" or "full" complementarity between nucleic acids. The degree of complementarity between nucleic acid chains affects the efficiency and strength of hybridization between nucleic acid chains. This is particularly important in amplification reactions and detection methods that depend on the binding between nucleic acids.

[0069] The term "gene" refers to a nucleic acid (e.g., DNA or RNA) sequence containing the coding sequence necessary for the production of RNA or a polypeptide or its precursor. A functional polypeptide may be encoded by the full-length coding sequence or by any portion of the coding sequence, as long as the desired activity or functional property of the polypeptide (e.g., enzyme activity, ligand binding, signal transduction, etc.) is preserved. When used to refer to a gene, the term "part" refers to a segment of the gene. The size of a segment can range from a few nucleotides to the entire gene sequence minus one nucleotide. Therefore, "nucleotides containing at least a portion of a gene" can include a gene segment or the entire gene.

[0070] The term "gene" also encompasses the coding region of a structural gene and includes sequences adjacent to the coding region at both the 5' and 3' ends, for example, a distance of approximately 1 kb at either end, such that a gene corresponds to the length of full-length mRNA (e.g., containing coding sequences, regulatory sequences, structural sequences, and other sequences). A sequence located at the 5' end of the coding region and present on the mRNA is called a 5' untranslated or untranslated sequence. A sequence located at or downstream of the coding region and present on the mRNA is called a 3' untranslated or 3' untranslated sequence. The term "gene" encompasses both the cDNA and genomic forms of a gene. In some organisms (e.g., eukaryotes), the genomic form or clone of a gene contains coding regions interrupted by non-coding sequences called "introns," "insertion regions," or "insertion sequences." Introns are segments of genes transcribed into nuclear RNA (hnRNA); introns may contain regulatory elements, such as enhancers. Introns are removed or "cut out" from nuclear transcripts or primary transcripts; therefore, introns are not present in messenger RNA (mRNA) transcripts. mRNA plays a role in translation, specifying the sequence or order of amino acids in the nascent polypeptide.

[0071] In addition to introns, the genomic form of a gene can also include sequences at the 5' and 3' ends of sequences present on the RNA transcript. These sequences are called "flanking" sequences or regions (these flanking sequences are located at the 5' or 3' end of untranslated sequences present on the mRNA transcript). 5' flanking regions can contain regulatory sequences, such as promoters and enhancers, which control or influence gene transcription. 3' flanking regions can contain sequences that guide transcription termination, post-transcriptional cleavage, and polyadenylation.

[0072] When referring to a gene, the term "wild-type" refers to a gene that possesses the characteristics of a gene isolated from a naturally occurring source. When referring to a gene product, the term "wild-type" refers to a gene product that possesses the characteristics of a gene product isolated from a naturally occurring source. When referring to a protein, the term "wild-type" refers to a protein that possesses the characteristics of a naturally occurring protein. As applied to an object, the term "naturally occurring" refers to the fact that the object can be found in nature. For example, polypeptide or polynucleotide sequences that are isolated from natural sources and have not been intentionally modified by laboratory personnel and are present in organisms (including viruses) are naturally occurring. Wild-type genes are usually the genes or alleles most frequently observed in a population and are therefore arbitrarily designated as the "normal" or "wild-type" form of a gene. In contrast, when referring to a gene or gene product, the terms "modified" or "mutated" refer to a gene or gene product that exhibits modifications in sequence and / or functional characteristics (e.g., altered traits) compared to a wild-type gene or gene product. Note that naturally occurring mutants can be isolated; these are identified by the fact that they are traitened compared to wild-type genes or gene products.

[0073] The term "allele" refers to a variation in a gene; such variation includes, but is not limited to, variants and mutants, polymorphic loci and single nucleotide polymorphic loci, frameshift and splicing mutations. Alleles may be naturally present in a population or may appear in the lifetime of any particular individual within the population.

[0074] Therefore, when used to refer to nucleotide sequences, the terms "variant" and "mutant" refer to nucleic acid sequences that differ from another normally related nucleotide sequence by one or more nucleotides. A "variation" is the difference between two different nucleotide sequences; typically, one sequence is a reference sequence.

[0075] The terms “immunogen” and “antigen” are used interchangeably herein and refer to any molecule, compound, or substance that induces an immune response in an animal (e.g., a mammal). An “immune response” can result in, for example, the production of antibodies and / or the activation of immune effector cells. In the context of this disclosure, an antigen may comprise any subunit, fragment, or epitope of any protein or non-protein (e.g., carbohydrate or lipid) molecule that elicits an immune response in a mammal. The term “epitaxe” refers to an antigenic sequence that is recognized by an antibody or antigen receptor. Epitopes are also referred to in the art as “antigenic determinants.” In some embodiments, an epitope is an antigenic region that an antibody specifically binds to. In some embodiments, an epitope may comprise a chemically active surface group of a molecule, such as an amino acid, a sugar side chain, a phosphoryl group, or a sulfonyl group. In some embodiments, an epitope may have specific three-dimensional structural features (e.g., a “conformational” epitope) and / or specific charge features. An antigen may be a virus, bacteria, parasite, fungus, protozoan, prion, cellular, or extracellular protein or peptide that elicits an immune response in a mammal, preferably resulting in protective immunity.

[0076] As used herein, "pharmaceuticalally acceptable carrier" refers to a component in a pharmaceutical preparation other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0077] As used herein, the term "pharmaceutical formulation" generally refers to a class of formulations that are in a form that allows the biological activity of the active ingredient contained therein (e.g., anti-MICA antibody, antibody conjugate, fusion protein, or polymer formulation) to be effective, and that do not contain any additional components that would have unacceptable toxicity to the subject to whom the formulation will be administered.

[0078] As used herein, “treatment” (and its grammatical variations such as “treat” or “treating”) generally refers to a clinical intervention that attempts to alter the natural course of the disease in an individual being treated, and may be used for prevention or in the course of clinicopathology. Desired therapeutic effects include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, improving or alleviating the disease state, and mitigating or improving prognosis. In some embodiments, the anti-MICA antibody of this disclosure or other compositions comprising the anti-MICA antibody of this disclosure (e.g., antibody conjugates, fusion proteins, or polymer formulations) are used to delay the development of the disease or slow its progression.

[0079] As used herein, the term "half-life" generally refers to the time required for the concentration of a substance (e.g., anti-MICA antibody, antibody conjugate, fusion protein (e.g., Fab fusion protein), or polymer formulation) to decrease by half in vivo or in vitro.

[0080] The “effective amount” of an agent (e.g., a pharmaceutical preparation) as used herein generally refers to the amount that effectively achieves the desired therapeutic or preventative outcome at the required dosage and time period.

[0081] "Individual" or "subject" is a mammal. Mammals include, but are not limited to: domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., human and non-human primates, such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the individual or subject is a human. "Subject" can be a "patient".

[0082] Anti-MICA antibody As further described herein, embodiments of this disclosure relate to the treatment and / or prevention of cancer. In particular, this disclosure provides novel therapeutic antibodies that target MHC class I chain-associated protein A (MICA) in a manner that reduces the ability of tumor cells to escape immune clearance mediated by the natural killer cell group 2D (NKG2D) receptor.

[0083] As further described herein, anti-MICA antibodies were generated, and their structural and functional properties were elucidated. Based on these data, embodiments of this disclosure include anti-MICA antibodies or antigen-binding fragments thereof, said antibodies or antigen-binding fragments thereof comprising a heavy chain variable region (VH) containing complementarity-determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) containing complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3. In some embodiments, HCDR1 comprises one of the following amino acid sequences: (a) X1YX2MX3 (SEQ ID NO: 1), wherein X1 is R, S, or T; X2 is S or A; and X3 is N or S; (b) X1X2X3MH (SEQ ID NO: 64), wherein X1 is N, D, or S; X2 is H, Y, or S; and X3 is A or G; (c) X1X2X3X4X5 (SEQ ID NO: 85), wherein X1 is G, S, V, A, N, or T; X2 is N or Y; X3 is Y, D, L, or G; X4 is I, M, or L; and X5 is H, N, E, or S; (d) X1YDX2N (SEQ ID NO: 145), wherein X1 is S, H, or N; X2 is I or V; or (e) X1X2X3X4X5 (SEQ ID NO: 145) 172), wherein X1 is D, N, S or A; X2 is N, Y or Q; X3 is Y, N or A; X4 is I, W or M; and X5 is S, H, Y or N; wherein HCDR2 contains one of the following amino acid sequences: (a) X1IX2X3X4X5X6X7X8X9YADSVKG (SEQ ID NO:22), wherein X1 is Y, F, S or V; X2 is N, S or T; X3 is S, T, Y or G; X4 is R or S; X5 is S, G or E; X6 is N, S, T, G or D; X7 is T, R or N; X8 is I or T; and X9 is Y or D; (b) X1IX2X3X4GX5X6X7X8YX9DSVKG (SEQ ID NO:22) NO:71), where X1 is L, I, G or V; X2 is W or S; X3 is Y or W; X4 is D or S; X5 is S, G or N; X6 is N or S; X7 is K or I; X8 is Y, G or F; X9 is A or E; (c) X1IX2X3X4X5GX6TX7X8X9X 10 X 11 FX 12 X 13 (SEQ ID NO: 105), wherein X1 is W or A; X2 is N, D or S; X3 is P or S; X4 is N, D, G or Y; and X5 is S or N; X6 is A, G or N; X7 is N or H; X8 is S or Y; X9 is A or N; X 10 For Q or E; X 11For N, K, or E; X 12 For Q or K; and X 13 (d) WNMPX1SX2NTGX3AQKFQG (SEQ ID NO: 154), where X1 is N or D; X2 is G or S; and X3 is Y or F; or (e) X1IX2X3X4X5X6X7X8X9X10X 11 X 12 X 13 X 14 X 15 (SEQ ID NO: 178), wherein X1 is W, T, Y, or F; X2 is Y, N, E, or F; X3 is A, P, N, or T; X4 is G, S, Y, T, or H; X5 is T, G, or N; X6 is G, V, or I; X7 is G, S, V, T, or D; X8 is S, T, P, or N; X9 is S, M, Y, or T; X 10 For Y or N; X 11 For N, A, or P; X 12 For Q, P, S, or D; X 13 For K, R, L, or D; X 14 For F or K; and X 15The amino acid sequence is R, Q, K, or S; and HCDR3 contains one of the following amino acid sequences: (a) X1X2X3X4X5X6X7 (SEQ ID NO: 43), wherein X1 is V, A, or G; X2 is S, M, or G; X3 is D, S, A, V, I, or Y; X4 is I, V, R, Q, or W; X5 is T, G, L, or F; X6 is G, S, T, W, or D; and X7 is N, G, S, P, or N; (b) X1X2X3X4 (SEQ ID NO: 78), wherein X1 is E or S; X2 is R or Y; X3 is D, F, L, or V; X4 is Y, P, or V; (c) X1X2X3X4X5X6X7X8 (SEQ ID NO: 78) 125), wherein X1 is D, S, A, F or E; X2 is T, A, S, N or L; X3 is F, A, W, Y or G; X4 is K, R, A, G, P or N; and X5 is P, G, A, Y or W; X6 is Y, F, S or N; X7 is Y, F or D; and X8 is Y, S or N; (d) X1X2X3X4X5X6DX7 (SEQ ID NO: 163), wherein X1 is S or G; X2 is A or S; X3 is A or I; X4 is S, A or R; X5 is G or A; X6 is F, V or S; and X7 is Y, N, S or I; or (e) X1X2X3X4X5X6X7X8 (SEQ ID NO: 163) NO:184), where X1 is H, Y, S, G or T; X2 is D, S, G, M or Y; X3 is Y, W, S, A or G; X4 is Y, G, S, A or N; X5 is G, P, N, R or Y; X6 is T, G, F, P or A; X7 is S, A, D, Y or M; X8 is G, F, Y or D.

[0084] In addition to the HCDR1, HCDR2, and HCDR3 sequences described above, the anti-MICA antibody disclosed herein also comprises: LCDR1 containing any one of the amino acid sequences of SEQ ID NO: 191-213, SEQ ID NO: 263-284, or SEQ ID NO: 332-344; LCDR2 containing any one of the amino acid sequences of SEQ ID NO: 215-237, SEQ ID NO: 286-306, or SEQ ID NO: 346-358; and LCDR3 containing any one of the amino acid sequences of SEQ ID NO: 239-261, SEQ ID NO: 309-330, or SEQ ID NO: 360-372.

[0085] In some embodiments, this disclosure provides an anti-MICA antibody or an antigen-binding fragment thereof comprising VH and VL, wherein the VH comprises complementarity-determining regions HCDR1, HCDR2, and HCDR3, and the VL comprises complementarity-determining regions LCDR1, LCDR2, and LCDR3. In some embodiments, LCDR1 comprises one of the following amino acid sequences: (a) X1X2X3X4X5X6X7X8X9 (SEQ ID NO: 190), wherein X1 is R or S; X2 is A or S; X3 is Q or S; X4 is S, T, R, or G; X5 is H, S, N, T, or R; X6 is N, S, Y, I, or D; X7 is Y, F, D, or H; X8 is L, F, or Y; and X9 is N, G, A, or L; (b) X1X2X3X4X5X6X7X8X9X 10 (SEQ ID NO: 262), wherein X1 is R, S, or K; X2 is T, A, or S; X3 is Q or G; X4 is G, A, V, N, D, H, S, or R; X5 is V or I; X6 is N, G, S, H, R, V, or L; X7 is S, N, H, or Y; X8 is W, Y, or S; X9 is L, N, or S; and X 10(a) X1X2X3X4LX5S (SEQ ID NO: 214), wherein X1 is A or T; X2 is V or I; X3 is I, S or N; X4 is I, T or S; X5 is N, K, S, W or Y; X6 is Q, Y, H or L; and X7 is L or A; wherein LCDR2 contains one of the following amino acid sequences: (a) X1X2X3X4LX5S (SEQ ID NO: 214), wherein X1 is A, S, G or R; X2 is A or T; X3 is S or F; X4 is S, T, G or N; and X5 is Q or A; (b) X1X2X3X4X5X6X7 (SEQ ID NO: 214) 285), wherein X1 is A, Y, D, T, K or W; X2 is A, T or V; X3 is S or E; X4 is S, T, I or N; X5 is L or R; X6 is Q, A, H, L, F or E; and X7 is S, D or L; or (c) X1X2SX3X4X5X6X7 (SEQ ID NO: 345), wherein X1 is G, K or D; X2 is A or T; X3 is S, T or N; X4 is R or L; X5 is A, E, V or Q; and X6 is T or S; and wherein LCDR3 contains one of the following amino acid sequences: (a) X1X2X3X4X5X6X7X8 (SEQ ID NO: (b) X1QX2X3X4X5PX6X7 (SEQ ID NO: 308), wherein X1 is F or Q; X2 is A, F, Y, G or S; X3 is N, W, S or Y; X4 is I, S, T, K or H; X5 is F, V, T or Y; X6 is L, I, Y, R or W; and X7 is S or T; or (c) QQX1X2X3X4PX5X6 (SEQ ID NO: 359), wherein X1 is Y, A or R; X2 is G, N or S; X3 is S, V, N or I; X4 is S, F or W; X5 is R, L or I; and X6 is T or S.

[0086] In addition to the LCDR1, LCDR2, and LCDR3 sequences described above, the anti-MICA antibody disclosed herein also comprises: HCDR1 containing an amino acid sequence of any one of SEQ ID NO: 2-21, SEQ ID NO: 65-70, SEQ ID NO: 86-104, SEQ ID NO: 147-153, or SEQ ID NO: 173-177; HCDR2 containing an amino acid sequence of any one of SEQ ID NO: 23-42, SEQ ID NO: 72-77, SEQ ID NO: 106-124, SEQ ID NO: 153-162, or SEQ ID NO: 179-183; and HCDR3 containing an amino acid sequence of any one of SEQ ID NO: 44-63, SEQ ID NO: 79-84, SEQ ID NO: 126-143, SEQ ID NO: 163-171, or SEQ ID NO: 185-189.

[0087] In some embodiments, the anti-MICA antibody comprises HCDR1 of SEQ ID NO: 2, HCDR2 comprising the amino acid sequence of SEQ ID NO: 23, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 44. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 24; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 45. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 4; HCDR2 comprises the amino acid sequence of SEQ ID NO: 25; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 46. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 5; HCDR2 comprises the amino acid sequence of SEQ ID NO: 26; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 6; HCDR2 comprises the amino acid sequence of SEQ ID NO: 27; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 48. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 7; HCDR2 comprises the amino acid sequence of SEQ ID NO: 28; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 49. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 8; HCDR2 comprises the amino acid sequence of SEQ ID NO: 29; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 50. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 9; HCDR2 comprises the amino acid sequence of SEQ ID NO: 30; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 51. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 10; HCDR2 comprises the amino acid sequence of SEQ ID NO: 31; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 52. In some embodiments, HCDR1 contains the amino acid sequence of SEQ ID NO: 11; HCDR2 contains the amino acid sequence of SEQ ID NO: 32; and HCDR3 contains the amino acid sequence of SEQ ID NO: 53.In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 12; HCDR2 comprises the amino acid sequence of SEQ ID NO: 33; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 54. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; HCDR2 comprises the amino acid sequence of SEQ ID NO: 34; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 55. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 14; HCDR2 comprises the amino acid sequence of SEQ ID NO: 35; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 56. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 15; HCDR2 comprises the amino acid sequence of SEQ ID NO: 36; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 57. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 16; HCDR2 comprises the amino acid sequence of SEQ ID NO: 37; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 58. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 17; HCDR2 comprises the amino acid sequence of SEQ ID NO: 38; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 59. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 18; HCDR2 comprises the amino acid sequence of SEQ ID NO: 39; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 60. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 19; HCDR2 comprises the amino acid sequence of SEQ ID NO: 40; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 61. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 20; HCDR2 comprises the amino acid sequence of SEQ ID NO: 41; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 62. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 21; HCDR2 comprises the amino acid sequence of SEQ ID NO: 42; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 63.In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 65; HCDR2 comprises the amino acid sequence of SEQ ID NO: 72; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 79. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 66; HCDR2 comprises the amino acid sequence of SEQ ID NO: 73; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 80. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 67; HCDR2 comprises the amino acid sequence of SEQ ID NO: 74; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 80. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 68; HCDR2 comprises the amino acid sequence of SEQ ID NO: 75; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 81. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 69; HCDR2 comprises the amino acid sequence of SEQ ID NO: 76; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 82. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 70; HCDR2 comprises the amino acid sequence of SEQ ID NO: 77; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 84. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 86; HCDR2 comprises the amino acid sequence of SEQ ID NO: 106; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 126. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 87; HCDR2 comprises the amino acid sequence of SEQ ID NO: 107; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 127. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 88; HCDR2 comprises the amino acid sequence of SEQ ID NO: 108; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 128. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 89; HCDR2 comprises the amino acid sequence of SEQ ID NO: 109; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 129.In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 90; HCDR2 comprises the amino acid sequence of SEQ ID NO: 110; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 130. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 91; HCDR2 comprises the amino acid sequence of SEQ ID NO: 111; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 131. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 92; HCDR2 comprises the amino acid sequence of SEQ ID NO: 112; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 132. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 93; HCDR2 comprises the amino acid sequence of SEQ ID NO: 113; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 133. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 94; HCDR2 comprises the amino acid sequence of SEQ ID NO: 114; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 134. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 95; HCDR2 comprises the amino acid sequence of SEQ ID NO: 115; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 135. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 96; HCDR2 comprises the amino acid sequence of SEQ ID NO: 116; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 136. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 97; HCDR2 comprises the amino acid sequence of SEQ ID NO: 117; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 137. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 98; HCDR2 comprises the amino acid sequence of SEQ ID NO: 118; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 138. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 99; HCDR2 comprises the amino acid sequence of SEQ ID NO: 119; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 139.In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 100; HCDR2 comprises the amino acid sequence of SEQ ID NO: 120; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 140. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 101; HCDR2 comprises the amino acid sequence of SEQ ID NO: 121; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 141. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 102; HCDR2 comprises the amino acid sequence of SEQ ID NO: 122; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 142. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 103; HCDR2 comprises the amino acid sequence of SEQ ID NO: 123; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 143. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 104; HCDR2 comprises the amino acid sequence of SEQ ID NO: 124; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 144. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 146; HCDR2 comprises the amino acid sequence of SEQ ID NO: 155; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 164. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 147; HCDR2 comprises the amino acid sequence of SEQ ID NO: 156; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 165. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 148; HCDR2 comprises the amino acid sequence of SEQ ID NO: 157; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 166. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 149; HCDR2 comprises the amino acid sequence of SEQ ID NO: 158; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 167. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 150; HCDR2 comprises the amino acid sequence of SEQ ID NO: 159; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 168.In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 151; HCDR2 comprises the amino acid sequence of SEQ ID NO: 160; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 169. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 152; HCDR2 comprises the amino acid sequence of SEQ ID NO: 161; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 170. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 153; HCDR2 comprises the amino acid sequence of SEQ ID NO: 162; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 171. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 173; HCDR2 comprises the amino acid sequence of SEQ ID NO: 179; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 185. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 174; HCDR2 comprises the amino acid sequence of SEQ ID NO: 180; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 186. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 175; HCDR2 comprises the amino acid sequence of SEQ ID NO: 181; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 187. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 176; HCDR2 comprises the amino acid sequence of SEQ ID NO: 182; and HCDR3 comprises the amino acid sequence of SEQ ID NO: 189.

[0088] In some embodiments, the anti-MICA antibody comprises LCDR1 of SEQ ID NO: 191, LCDR2 comprising the amino acid sequence of SEQ ID NO: 215, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 239. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 192; LCDR2 comprises the amino acid sequence of SEQ ID NO: 216; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 240. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 193; LCDR2 comprises the amino acid sequence of SEQ ID NO: 217; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 241. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 194; LCDR2 comprises the amino acid sequence of SEQ ID NO: 218; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 242. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 195; LCDR2 comprises the amino acid sequence of SEQ ID NO: 219; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 243. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 196; LCDR2 comprises the amino acid sequence of SEQ ID NO: 220; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 244. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 197; LCDR2 comprises the amino acid sequence of SEQ ID NO: 221; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 245. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 198; LCDR2 comprises the amino acid sequence of SEQ ID NO: 222; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 246. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 199; LCDR2 comprises the amino acid sequence of SEQ ID NO: 223; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 247. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 200; LCDR2 comprises the amino acid sequence of SEQ ID NO: 224; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 248.In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 201; LCDR2 comprises the amino acid sequence of SEQ ID NO: 225; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 249. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 202; LCDR2 comprises the amino acid sequence of SEQ ID NO: 226; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 250. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 203; LCDR2 comprises the amino acid sequence of SEQ ID NO: 227; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 251. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 204; LCDR2 comprises the amino acid sequence of SEQ ID NO: 228; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 252. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 205; LCDR2 comprises the amino acid sequence of SEQ ID NO: 229; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 253. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 206; LCDR2 comprises the amino acid sequence of SEQ ID NO: 230; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 254. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 207; LCDR2 comprises the amino acid sequence of SEQ ID NO: 231; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 255. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 208; LCDR2 comprises the amino acid sequence of SEQ ID NO: 232; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 256. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 209; LCDR2 comprises the amino acid sequence of SEQ ID NO: 233; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 257. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 210; LCDR2 comprises the amino acid sequence of SEQ ID NO: 234; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 258.In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 211; LCDR2 comprises the amino acid sequence of SEQ ID NO: 235; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 259. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 212; LCDR2 comprises the amino acid sequence of SEQ ID NO: 236; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 260. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 213; LCDR2 comprises the amino acid sequence of SEQ ID NO: 237; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 261. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 263; LCDR2 comprises the amino acid sequence of SEQ ID NO: 286; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 309. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 264; LCDR2 comprises the amino acid sequence of SEQ ID NO: 287; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 310. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 265; LCDR2 comprises the amino acid sequence of SEQ ID NO: 288; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 311. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 266; LCDR2 comprises the amino acid sequence of SEQ ID NO: 289; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 312. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 267; LCDR2 comprises the amino acid sequence of SEQ ID NO: 290; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 313. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 268; LCDR2 comprises the amino acid sequence of SEQ ID NO: 291; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 314. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 269; LCDR2 comprises the amino acid sequence of SEQ ID NO: 292; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 315.In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 270; LCDR2 comprises the amino acid sequence of SEQ ID NO: 293; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 316. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 271; LCDR2 comprises the amino acid sequence of SEQ ID NO: 294; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 317. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 272; LCDR2 comprises the amino acid sequence of SEQ ID NO: 295; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 318. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 273; LCDR2 comprises the amino acid sequence of SEQ ID NO: 296; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 319. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 274; LCDR2 comprises the amino acid sequence of SEQ ID NO: 297; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 320. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 275; LCDR2 comprises the amino acid sequence of SEQ ID NO: 298; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 321. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 276; LCDR2 comprises the amino acid sequence of SEQ ID NO: 299; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 322. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 277; LCDR2 comprises the amino acid sequence of SEQ ID NO: 300; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 323. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 278; LCDR2 comprises the amino acid sequence of SEQ ID NO: 301; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 324. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 279; LCDR2 comprises the amino acid sequence of SEQ ID NO: 302; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 325.In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 280; LCDR2 comprises the amino acid sequence of SEQ ID NO: 303; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 326. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 281; LCDR2 comprises the amino acid sequence of SEQ ID NO: 304; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 327. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 282; LCDR2 comprises the amino acid sequence of SEQ ID NO: 305; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 328. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 283; LCDR2 comprises the amino acid sequence of SEQ ID NO: 306; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 329. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 284; LCDR2 comprises the amino acid sequence of SEQ ID NO: 307; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 330. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 332; LCDR2 comprises the amino acid sequence of SEQ ID NO: 346; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 360. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 333; LCDR2 comprises the amino acid sequence of SEQ ID NO: 347; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 361. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 334; LCDR2 comprises the amino acid sequence of SEQ ID NO: 348; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 362. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 335; LCDR2 comprises the amino acid sequence of SEQ ID NO: 349; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 363. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 336; LCDR2 comprises the amino acid sequence of SEQ ID NO: 350; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 364.In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 337; LCDR2 comprises the amino acid sequence of SEQ ID NO: 351; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 365. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 338; LCDR2 comprises the amino acid sequence of SEQ ID NO: 352; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 366. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 339; LCDR2 comprises the amino acid sequence of SEQ ID NO: 353; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 367. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 340; LCDR2 comprises the amino acid sequence of SEQ ID NO: 354; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 368. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 341; LCDR2 comprises the amino acid sequence of SEQ ID NO: 355; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 369. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 342; LCDR2 comprises the amino acid sequence of SEQ ID NO: 356; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 370. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 343; LCDR2 comprises the amino acid sequence of SEQ ID NO: 357; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 371. In some embodiments, LCDR1 comprises the amino acid sequence of SEQ ID NO: 344; LCDR2 comprises the amino acid sequence of SEQ ID NO: 358; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 372.

[0089] In some embodiments, the VH of the anti-MICA antibody of this disclosure comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to any one of SEQ ID NO: 373-430. In some embodiments, the VL of the anti-MICA antibody of this disclosure comprises an amino acid sequence that is at least 90% identical (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to any one of SEQ ID NO: 489-546.

[0090] In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 373 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 489 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 374 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 490 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 375 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 491 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 376 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 492 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical).In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 377 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 493 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 378 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 494 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 379 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 495 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 380, and VL contains an amino acid sequence that is at least 90% identical to (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 496.In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 381 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 497 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 382 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 498 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 383 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 499 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 384 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 500 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical).In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 385 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 501 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 386 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 502 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 387 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 503 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 388 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 504 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical).In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 389 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 505 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 390 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 506 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 391 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 507 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 392 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 508 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical).In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 393 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 509 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 394 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 510 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 395 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 511 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 396 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 512 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical).In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 397 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 513 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 398 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 514 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 399 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 515 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 400 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 516 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical).In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 401 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 517 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 402 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 518 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 403 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 519 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 404 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 520 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical).In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 405 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 521 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 406 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 522 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 407 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 523 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 408 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 524 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical).In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 409 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 525 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 410 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 526 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 411 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 527 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 412 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 528 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical).In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 413 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 529 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 414 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 530 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 415 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 531 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 416 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 532 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical).In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 417 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 533 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 418 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 534 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 419 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 535 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 420, and VL contains an amino acid sequence that is at least 90% identical to (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical) to SEQ ID NO: 536.In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 421 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 537 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 422 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 538 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 423 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 539 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 424 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 540 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical).In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 425 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 541 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 426 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 542 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 427 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 543 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 428 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 544 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical).In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 429 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 545 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical). In some embodiments, VH contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 430 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical), and VL contains an amino acid sequence that is at least 90% identical to SEQ ID NO: 546 (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical).

[0091] As described herein, the “identity” of a nucleic acid or amino acid sequence can be determined by comparing the nucleic acid or amino acid sequence of interest with a reference nucleic acid or amino acid sequence. Many mathematical algorithms for obtaining optimal alignment and calculating the identity between two or more sequences are known and incorporated into numerous available software programs. Examples of such programs include CLUSTAL-W, T-Coffee, and ALIGN (for nucleic acid and amino acid sequence alignment), BLAST programs (e.g., BLAST2.1, BL2SEQ, and subsequent versions), and FASTA programs (e.g., FASTA3x, FAS™, and SSEARCH) (for sequence alignment and sequence similarity search). Sequence alignment algorithms are also disclosed, for example, by Altschul et al. J. Molecular Biol ., 215 (3): 403-410 (1990); Beigert et al., Proc. Natl. Acad. Sci. USA , 106 (10): 3770-3775 (2009); edited by Durbin et al. Biological Sequence Analysis: Probabilistic Models of Proteins and Nucleic Acids , Cambridge University Press, Cambridge, UK(2009), Soding, Bioinformatics , 21 (7): 951-960 (2005); Altschul et al., Nucleic Acids Res .,25 (17): 3389-3402 (1997); and Gusfield, Algorithms on Strings, Trees and Sequences , Cambridge University Press, Cambridge UK (1997)).

[0092] As those skilled in the art will recognize based on this disclosure, one or more amino acids of the aforementioned anti-MICA antibody or its antigen fragment may be replaced or substituted with different amino acids. An amino acid "replacement" or "substitution" means that one amino acid at a given position or residue within a polypeptide sequence is replaced by another amino acid at the same position or residue. Amino acids are broadly classified as "aromatic" or "aliphatic." Aromatic amino acids include aromatic rings. Examples of "aromatic" amino acids include histidine (H or His), phenylalanine (F or Phe), tyrosine (Y or Tyr), and tryptophan (W or Trp). Non-aromatic amino acids are broadly classified as "aliphatic." Examples of aliphatic amino acids include glycine (G or Gly), alanine (A or Ala), valine (V or Val), leucine (L or Leu), isoleucine (I or Ile), methionine (M or Met), serine (S or Ser), threonine (T or Thr), cysteine ​​(C or Cys), proline (P or Pro), glutamic acid (E or Glu), aspartic acid (A or Asp), asparagine (N or Asn), glutamine (Q or Gln), lysine (K or Lys), and arginine (R or Arg). Aliphatic amino acids can be further subdivided into four subgroups. The "large aliphatic nonpolar subgroup" consists of valine, leucine, and isoleucine. The "aliphatic weakly polar subgroup" consists of methionine, serine, threonine, and cysteine. The "aliphatic polar / charged subgroup" consists of glutamic acid, aspartic acid, asparagine, glutamine, lysine, and arginine. The "small residue subgroup" consists of glycine and alanine. The charged / polar amino acid group can be further subdivided into three subgroups: the "positively charged subgroup" composed of lysine and arginine, the "negatively charged subgroup" composed of glutamic acid and aspartic acid, and the "polar subgroup" composed of asparagine and glutamine. Aromatic amino acids can be further subdivided into two subgroups: the "nitrogen-cyclic subgroup" composed of histidine and tryptophan, and the "phenyl subgroup" composed of phenylalanine and tyrosine.

[0093] Amino acid substitutions or replacements can be conserved, semi-conserved, or non-conserved. The phrase "conserved amino acid substitution" or "conserved mutation" refers to the replacement of one amino acid with another that shares a common characteristic. One functional way to define the common characteristic between individual amino acids is to analyze the normalized frequency of amino acid changes between corresponding proteins in homologous organisms (Schulz and Schirmer, Principles of Protein Structure(Springer-Verlag, New York (1979)). Based on this type of analysis, amino acid groups can be defined where amino acids within a group preferentially exchange with each other, thus having the most similar effects on the overall protein structure. Examples of conserved amino acid substitutions include amino acid substitutions within the aforementioned subgroups, such as lysine replacing arginine and vice versa, to maintain a positive charge; glutamic acid replacing aspartic acid and vice versa, to maintain a negative charge; serine replacing threonine, to maintain a free -OH group; and glutamine replacing asparagine, to maintain a free -NH2 group. "Semi-conserved mutations" include amino acid substitutions within the same group but not within the same subgroup listed above. For example, substitutions of aspartic acid replacing asparagine or asparagine replacing lysine involve amino acids within the same group but different subgroups. "Non-conserved mutations" involve amino acid substitutions between different groups (e.g., lysine replacing tryptophan or phenylalanine replacing serine, etc.).

[0094] Additionally, one or more amino acids may be inserted into the anti-MICA antibody or its antigen-binding fragment (e.g., into the amino acid sequence of the heavy chain and / or light chain variable region). Any number of suitable amino acids may be inserted into the amino acid sequence of the antibody or its antigen-binding fragment. In this regard, at least one amino acid (e.g., two or more, five or more, or ten or more amino acids) but no more than 20 amino acids (e.g., 18 or fewer, 15 or fewer, or 12 or fewer amino acids) may be inserted into the amino acid sequence of the antibody or its antigen-binding fragment. For example, one to ten amino acids (e.g., one, two, three, four, five, six, seven, eight, nine, or ten amino acids) may be inserted into the amino acid sequence of the monoclonal antibody or its antigen-binding fragment. In this regard, amino acids may be inserted at any suitable position on the antibody or its antigen-binding fragment. Preferably, one or more amino acids are inserted into the CDR (e.g., CDR1, CDR2, or CDR3) of the antibody or its antigen-binding fragment.

[0095] The amino acid sequence of an anti-MICA antibody or its antigen-binding fragment is not limited to the specific amino acid sequence described herein. In fact, an anti-MICA antibody or its antigen-binding fragment may comprise any heavy-chain or light-chain polypeptide that competes with the anti-MICA antibody or its antigen-binding fragment for binding to the MICA conformation. Antibody competition can be determined using conventional peptide competition assays, such as ELISA, Western blotting, or immunohistochemical methods (see, for example, U.S. Patents 4,828,981 and 8,568,992; and Braitbard et al., Proteome Sci ., 4 : 12 (2006)).

[0096] The anti-MICA antibody disclosed herein may be a complete antibody or an antigen-binding fragment of a complete antibody. As defined herein, the antigen-binding antibody fragments covered by this disclosure include, but are not limited to: F(ab')2, Fab', Fab, Fv, scFv, dsFv, dAb, and single-chain binding peptides. Antibody fragments and their therapeutic efficacy are further described, for example, in Nelson, AL, MAbs. Jan-Feb 2010;2(1): 77-83; Joosten et al., Microbial Cell Factories Vol. 2, Article No.: 1 (2003); and Bates A, Power CA., Antibodies (Basel). 2019;8(2):28; doi:10.3390 / antib8020028). In some embodiments, the anti-MICA antigen-binding fragment is a single-chain variable fragment (scFv) engineered antibody generated by fusing the heavy chain (VH) and light chain (VL) of an immunoglobulin through a short peptide linker. Single-chain variable domain (Fv) fragments (scFv) are used in the field for a variety of clinical and therapeutic applications, primarily due to their improved pharmacokinetic properties compared to parental monoclonal antibodies, and their relative ease of mass production at low cost (Monnier et al., Antibodies 2013, 2(2), 193-208; doi.org / 10.3390 / antib2020193; Safdari et al., Mol Med. 2016; 22: 258-270; and Lu, R., Hwang, Y., Liu, I. et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci 27, 1 (2020). https: / / doi.org / 10.1186 / s12929-019-0592-z).

[0097] The anti-MICA antibody disclosed herein may be a biantibody. A biantibody is an antibody fragment that may be bivalent or bispecific and has two antigen-binding sites. See, for example, EP 404,097; WO 1993 / 01161; Hudson et al. Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444--6448 (1993). Tri-antibodies and tetra-antibodies were also described by Hudson et al. Nat. Med.9:129-134 (2003). The anti-MICA antibody disclosed herein may be a single-domain antibody (also known as a nanobody). A single-domain antibody is an antibody fragment comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of the antibody. In some embodiments, the single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, Mass.; see, for example, U.S. Patent No. 6,248,516 B1). The antibody fragment may be prepared by a variety of techniques, including but not limited to the proteolytic digestion of intact antibodies as described herein and by recombinant host cells (e.g., *Escherichia coli*). E. coli (or bacteriophage) produced.

[0098] In other embodiments, the anti-MICA antibody is a complete antibody. As defined herein, a complete antibody comprises two identical copies of the heavy (H) chain polypeptide and two identical copies of the light (L) chain polypeptide. Each heavy chain contains an N-terminal variable (V) H ) region and three C-terminal constants (C H1 C H2 and C H3 The light chain contains an N-terminal variable (V) region, and each light chain contains an N-terminal variable (V) region. L ) region and a C-terminal constant (C L The C-terminal constant region of the heavy chain contains a crystallizable fragment (Fc) domain, which determines the antibody class and is responsible for humoral and cellular effector functions. Antibodies are classified into five major classes (or "isotypes"): IgG, IgM, IgA, IgD, and IgE, which have different functions in the immune system. IgG is the most abundant immunoglobulin in the blood, accounting for 60% of total antibodies in human serum. IgG antibodies can be further subdivided into IgG1, IgG2, IgG3, and IgG4, named in order of their abundance in serum (IgG1 is the most abundant) (Vidarsson et al., Frontiers in Immunology. 5: 520 (2014)). The intact anti-MICA monoclonal antibody described herein may belong to any suitable class and / or subclass. In some embodiments, the monoclonal antibody belongs to the IgG class (e.g., IgG1, IgG2, IgG3, or IgG4). For example, the monoclonal antibody may be an IgG1 antibody.

[0099] As discussed above, the Fc domain mediates several effector functions of antibodies, such as binding to receptors on target cells and complement fixation (which triggers the elimination of antigens). In some embodiments, the Fc domain can be modified or engineered to alter its effector function. For example, the Fc domain can be modified to enhance antibody-dependent cytotoxicity (ADCC) and antibody-dependent phagocytosis (ADCP) and to control serum half-life. In some embodiments, the Fc domain of anti-MICA antibodies can be engineered to modulate affinity for Fc receptors such as the Fcγ receptor (FcγR) and the neonatal Fc receptor (FcRn). In fact, optimizing the interaction between antibodies and FcγR has become a promising approach for enhancing the activity of therapeutic antibodies in treating various diseases (Mimoto et al., Curr. Pharm. Biotechnol. 17, 1298-1314 (2016); Lazar et al., Proc. Natl Acad. Sci. USA 103, 4005-4010 (2006); Richards et al., Mol. Cancer Ther. 7, 2517-2527 (2008); Nordstrom et al., Breast Cancer Res. 13, R123 (2011); and Kang, TH, Jung, ST, Exp Mol Med 51, 1-9 (2019)). The Fc domain can also be modified to improve serum half-life, for example, by engineering IgG Fc to obtain higher FcRn binding (Zalevsky et al., Nat. Biotechnol. 28, 157-159 (2010); and Dall'Acqua et al., J. Immunol. 169, 5171-5180 (2002)). In other embodiments, the Fc domain can be modified to produce monovalent or antibody bispecificity, thereby improving therapeutic efficacy. For example, an Fc domain mFc that does not form a homodimer but remains a soluble monomer can be generated, which exhibits high affinity for FcγRI but has no detectable binding to FcγRIIIa. In other embodiments, a heterodimeric Fc domain can be generated to obtain bispecific antigen binding properties, thereby avoiding the formation of homodimers.Engineered Fc domains can be generated by inducing point mutations or by modifying the glycosylation of the Fc domain (Saunders, KO, Front Immunol. 2019;10:1296; Kelley, RF, Meng, YG, Liu et al., J Biol Chem. 2014;289:3571-90; Monnet et al., MAbs. 2014;6:422-36; Li et al., Proc Natl Acad Sci US A. 2017;114:3485-90; and Lin et al., Proc Natl Acad Sci US A. 2015;112:10611-6; Kang and Jung,). Same as above ).

[0100] Based on the above, embodiments of this disclosure include an antibody or an antigen-binding fragment thereof that specifically binds to MHCI-type chain-associated protein A (MICA), optionally wherein the MICA is human MICA, optionally being a polypeptide comprising an amino acid sequence of any one of SEQ ID NO: 837-839.

[0101] In some embodiments, the antibody or fragment thereof exhibits any one or more of the following functional characteristics: reducing and / or attenuating the hydrolysis of membrane-bound MICA proteins into soluble MICA; and / or reducing and / or attenuating NKG2D-mediated tumor cell escape; enhancing NK cell-mediated tumor cell killing; cross-reactivity with at least one of cynomolgus monkey MICA (cyMICA), human MICB, human MICA-α3 and / or human MICB-α3; and / or no cross-reactivity with at least one of cynomolgus monkey MICA (cyMICA), human MICB, human MICA-α3 and / or human MICB-α3 and / or human MICB-α3; and / or at about 1.0 μM or lower K D Binds to human MICA; and / or binds to the same epitope on human MICA as an antibody containing the VH and VL sequences of any of the exemplary antibodies (sequences provided in Table 6); and / or competes with an antibody containing the VH and VL sequences of any of the exemplary antibodies (sequences provided in Table 6) for binding to human MICA.

[0102] In some embodiments, the antibodies or antibody fragments of this disclosure are monoclonal, optionally recombinant. In some embodiments, the antibodies or antibody fragments of this disclosure are human, humanized, or chimeric. In some embodiments, the antibodies or antibody fragments of this disclosure are full-length antibodies, single-chain antibodies, single-chain variable fragments (scFv), variable fragments (Fv), fragment antigen-binding regions (Fab), Fab-C, Fab'-SH, (Fab')2, single-domain antibodies (sdAb), VHH antibodies, nanobodies, camel-derived single-domain antibodies, shark IgNAR-derived single-domain antibody fragments (VNAR), biantibodies, triantibodies, anticarrier proteins, or aptamers, optionally wherein said antibody is a full-length antibody containing an Fc region (such as human IgG1, IgG2, IgG3, or IgG4 regions), and optionally wherein said antibody contains modified Fc regions.

[0103] In some embodiments, the antibody or antibody fragment of this disclosure is conjugated to at least one additional portion, said additional portion optionally selected from: an antigen-binding portion, such as an antibody or an antigen-binding fragment thereof, which is capable of specifically binding to a non-human MICA target; and / or a therapeutic or cytotoxic portion; and / or a detection portion; and / or a purification portion; and / or a half-life extension portion.

[0104] In some embodiments, the antibodies or antibody fragments of this disclosure are polypeptides comprising: one, two, or all three HCDRs of any of the exemplary antibodies (sequences provided in Table 6), and optionally also comprising one, two, or all three corresponding LCDRs of the exemplary antibody; and / or a VH sequence having at least 90% identity with the VH sequence of any of the exemplary antibodies (sequences provided in Table 6), and optionally also comprising a VL sequence having at least 90% identity with the corresponding VL sequence of the exemplary antibody, preferably wherein variation in the HCDRs or LCDRs is not permitted; and / or all six CDRs of any of the exemplary antibodies (sequences provided in Table 6); and / or the VH and VL sequences of any of the exemplary antibodies (sequences provided in Table 6); and / or the full-length heavy chain (VH + constant) sequence of any of the exemplary antibodies (sequences provided in Table 6), and optionally comprising the corresponding full-length light chain (VL + constant) sequence of the exemplary antibody.

[0105] Embodiments of this disclosure also include polynucleotides encoding antibodies or antibody fragments of this disclosure, optionally said polynucleotides comprising or consisting of a nucleic acid sequence having at least 70%, 80%, 90%, or 100% identity with a nucleic acid sequence of any of the exemplary antibodies (whose sequences are provided in Table 6).

[0106] Embodiments of this disclosure also include an expression vector comprising any of the polynucleotides disclosed herein, said expression vector optionally being an adeno-associated virus (AAV) vector, a lentiviral (LV) vector, a herpes simplex virus (HSV) vector, or a retroviral vector.

[0107] Embodiments of this disclosure also include a pharmaceutical composition comprising an antibody or antibody fragment, polynucleotide, or expression vector of the present disclosure, and optionally: at least one pharmaceutically acceptable carrier, diluent, or preservative; and / or at least one additional active ingredient. In some embodiments, the pharmaceutical composition is suitable for administration to a subject, optionally via ocular, oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration.

[0108] Embodiments of this disclosure also include methods of using the polynucleotides, expression vectors, or compositions of this disclosure as medicaments, optionally for treating a subject's cancer. In some embodiments, the antibodies, antibody fragments, polynucleotides, expression vectors, or compositions of this disclosure are used as part of a method of treating a subject's cancer, wherein the cancer is characterized by exhibiting the ability to evade immune clearance mediated by natural killer cell group 2D (NKG2D) receptors. In some embodiments, the antibodies, antibody fragments, polynucleotides, expression vectors, or compositions of this disclosure are used as part of a method of treating a subject's cancer, wherein the method includes intravenous administration of the antibody, antibody fragment, polynucleotide, expression vector, or composition, and wherein intravenous administration relieves at least one symptom in the subject. According to these embodiments, the cancers are lung cancer, pancreatic cancer, ovarian cancer, colon cancer, and prostate cancer.

[0109] Multispecific anti-MICA antibody As described above, the anti-MICA antibody of this disclosure can be a monoclonal antibody, a human antibody, a humanized antibody, and / or a chimeric antibody. In some embodiments, the antibody is a fragment selected from the group consisting of: Fab, Fab-C, Fab'-SH, Fv, scFv, and (Fab')2 fragments. In some embodiments, the anti-MICA antibody is a monospecific antibody. In some embodiments, the anti-MICA antibody is a bispecific antibody. In some embodiments, the anti-MICA antibody comprises two or more single-domain antibodies that form a bivalent, trivalent, or quadrivalent antibody that recognizes different epitopes on the same or different antigens.

[0110] In some embodiments, the anti-MICA antibodies provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567; and in Morrison et al. Proc. Natl. Acad. Sci. USA.In 81:6851-6855 (1984), a chimeric antibody comprises a non-human variable region (e.g., a variable domain derived from a mouse, rat, hamster, rabbit, or non-human primate such as a monkey) and a human constant domain. In a further example, a chimeric antibody is a "class-switched" antibody, wherein the class or subclass has been changed from that of the parent antibody. A chimeric antibody includes its antigen-binding fragment.

[0111] In some embodiments, the chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce its immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibody. Typically, a humanized antibody contains one or more variable domains in which the HVR, such as the CDR (or a portion thereof), is derived from the non-human antibody, and the FR (or a portion thereof) is derived from the human antibody sequence. The humanized antibody may optionally also contain at least a portion of a human constant region. In some embodiments, some FR residues in the humanized antibody are substituted with corresponding residues from the non-human antibody (e.g., an antibody derived from HVR residues) to, for example, restore or enhance antibody specificity or affinity.

[0112] A review of humanized antibodies and their preparation methods can be found, for example, by Almagro and Fransson. Front. Biosci. 13:1619-1633 (2008), and further described, for example, by Riechmann et al. Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321 and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (Description of Specific Determinant Region (SDR) transplantation); Padlan, Mol. Immunol. 28:489-498 (1991) (Description of “resurfacing”); Dall'Acqua et al., Methods 36:43-60 (2005) (describing "FR shuffling"); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer 83:252-260 (2000) (Describes the “guided selection” approach to FR reorganization).

[0113] According to the above embodiments, the anti-MICA antibody disclosed herein can be prepared in bivalent, trivalent, or quadrivalent forms. For example, the anti-MICA antibody disclosed herein can be a bivalent, bispecific antibody with heteropolymer heavy chains (e.g., Triomab, knobs-into-holes (KIH), Duobody, etc.). The anti-MICA antibody disclosed herein can be a tetravalent multispecific antibody composed of IgG and other binding domains fused to the N-terminus or C-terminus of a heavy or light chain (e.g., dual variable domain [DVD], IgG-scFv fusion, Mabtyrin (IgG with a non-antibody binding scaffold fused to the C-terminus of the heavy chain, "centyrin"). The anti-MICA antibody of this disclosure can also be composed of IgG with additional antigen binding sites added to its structure (e.g., a two-in-one antibody, the MAT "modular antibody technology" platform from F-Star). The anti-MICA antibody of this disclosure can be an engineered antibody fragment linked by a short peptide linker, which can be prepared in a bivalent, trivalent, or tetravalent form targeting two to three targets (e.g., a bispecific T-cell adaptor (BiTE), a nanobody platform, a dual-affinity retargeting (DART) antibody, a "tandem antibody" structure (TandAbs)). Furthermore, the anti-MICA antibody of this disclosure can be composed of chemically conjugated IgG.

[0114] In some embodiments, the anti-MICA antibody of this disclosure is a multispecific antibody, such as a bispecific antibody, which has binding specificity to at least two different antigens. In some embodiments, the anti-MICA antibody of this disclosure or its antigen-binding fragment can be used to form one arm (e.g., the antigen-binding portion) of a bispecific antibody, while the other arm of the bispecific antibody may be specific to a different antigen.

[0115] Functional characteristics of anti-MICA antibodies Based on the above embodiments, this disclosure provides anti-MICA antibodies including various functional characteristics. In some embodiments, the anti-MICA antibodies described herein bind to the antigen or a variant or isotype of MICA (SEQ ID NO: 837-844) (via interaction with its antigenic determinant (epitope). In some embodiments, the binding of the anti-MICA antibody to MICA (or fragments thereof) reduces the proteolytic cleavage of MICA (e.g., inhibits MICA shedding) (Figures 6 and 7). In some embodiments, the binding of the anti-MICA antibody to MICA attenuates NKG2D-mediated tumor cell escape (Figures 6 and 7). In some embodiments, the anti-MICA antibody is administered at about 1.0 μM or lower K+. D Combined with human MICA ( Figure 4 ).

[0116] In some embodiments, the anti-MICA antibody cross-reacts with one or more of cynomolgus monkey MICA (cyMICA), human MICA-α3, and human MICB-α3. In some embodiments, the anti-MICA antibody does not cross-react with one or more of cyMICA, human MICA-α3, and human MICB-α3. In some embodiments, the anti-MICA antibody comprises a VH region and a VL region, said VH region and VL region being at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to the VH and VL regions of an antibody selected from the group consisting of: AHA-P-1, AHA-P-2, AHA-P-3, AHA-P-4, AHA-P-5, AHA-P-6, AHA-P-7, AHA-P-8, ... ATX-P-1550, ATX-P-1551, ATX-P-1552, ATX-P-1553, ATX-P-1554, ATX-P-1555, ATX-P-1556, ATX-P-1563, ATX -P-1564, ATX-P-1565, ATX-P-1568, ATX-P-1569, ATX-P-1572, ATX-P-1678, ATX-P-1680, ATX-P-1684, ATX-P- 1820, ATX-P-1822, ATX-P-1825, ATX-P-1826, ATX-P-1827, ATX-P-1828, ATX-P-1829, ATX-P-1831, ATX-P-183 2. ATX-P-1833, ATX-P-1835, ATX-P-1838, ATX-P-1839, ATX-P-1840, ATX-P-1841, ATX-P-1842, ATX-P-1843, A TX-P-1844, ATX-P-1845, ATX-P-1846, ATX-P-1847, ATX-P-1848, ATX-P-1850, ATX-P-1852, ATX-P-1853, ATX- P-1856, ATX-P-1857, ATX-P-1858, ATX-P-1860, ATX-P-1861, ATX-P-791, ATX-P-792, ATX-P-793 and ATX-P-794.

[0117] peptides and expression vectors Embodiments of this disclosure also include a polynucleotide encoding any anti-MICA antibody of this disclosure. In some embodiments, the polynucleotide comprises a sequence that is at least 70% identical to any one of SEQ ID NO: 431-488 or SEQ ID NO: 547-604. In some embodiments, the polynucleotide comprises a sequence that is at least 75% identical to any one of SEQ ID NO: 431-488 or SEQ ID NO: 547-604. In some embodiments, the polynucleotide comprises a sequence that is at least 80% identical to any one of SEQ ID NO: 431-488 or SEQ ID NO: 547-604. In some embodiments, the polynucleotide comprises a sequence that is at least 85% identical to any one of SEQ ID NO: 431-488 or SEQ ID NO: 547-604. In some embodiments, the polynucleotide comprises a sequence that is at least 90% identical to any one of SEQ ID NO: 431-488 or SEQ ID NO: 547-604. In some implementations, the polynucleotide comprises a sequence that is at least 95% identical to any one of SEQ ID NO: 431-488 or SEQ ID NO: 547-604.

[0118] In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 70% identical to any one of SEQ ID NO: 431-488; and a nucleic acid sequence that is at least 70% identical to any one of SEQ ID NO: 547-604. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 75% identical to any one of SEQ ID NO: 431-488; and a nucleic acid sequence that is at least 75% identical to any one of SEQ ID NO: 547-604. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 80% identical to any one of SEQ ID NO: 431-488; and a nucleic acid sequence that is at least 80% identical to any one of SEQ ID NO: 547-604. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 85% identical to any one of SEQ ID NO: 431-488; and a nucleic acid sequence that is at least 85% identical to any one of SEQ ID NO: 547-604. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 90% identical to any one of SEQ ID NO: 431-488; and a nucleic acid sequence that is at least 90% identical to any one of SEQ ID NO: 547-604. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 95% identical to any one of SEQ ID NO: 431-488; and a nucleic acid sequence that is at least 95% identical to any one of SEQ ID NO: 547-604.

[0119] In some implementations, the polynucleotide comprises a nucleic acid sequence having at least 70% identity with any of the following: (a) SEQ ID NO: 663-720; (b) SEQ ID NO: 779-836; (c) SEQ ID NO: 663-720; (d) SEQ ID NO: 779-836; (e) SEQ ID NO: 663-720; or (f) SEQ ID NO: 779-836. In some implementations, the polynucleotide comprises a nucleic acid sequence having at least 75% identity with any of the following: (a) SEQ ID NO: 663-720; (b) SEQ ID NO: 779-836; (c) SEQ ID NO: 663-720; (d) SEQ ID NO: 779-836; (e) SEQ ID NO: 663-720; or (f) SEQ ID NO: 779-836. In some implementations, the polynucleotide comprises a nucleic acid sequence having at least 80% identity with any of the following: (a) SEQ ID NO: 663-720; (b) SEQ ID NO: 779-836; (c) SEQ ID NO: 663-720; (d) SEQ ID NO: 779-836; (e) SEQ ID NO: 663-720; or (f) SEQ ID NO: 779-836. In some implementations, the polynucleotide comprises a nucleic acid sequence having at least 85% identity with any of the following: (a) SEQ ID NO: 663-720; (b) SEQ ID NO: 779-836; (c) SEQ ID NO: 663-720; (d) SEQ ID NO: 779-836; (e) SEQ ID NO: 663-720; or (f) SEQ ID NO: 779-836. In some implementations, the polynucleotide comprises a nucleic acid sequence having at least 90% identity with any of the following: (a) SEQ ID NO: 663-720; (b) SEQ ID NO: 779-836; (c) SEQ ID NO: 663-720; (d) SEQ ID NO: 779-836; (e) SEQ ID NO: 663-720; or (f) SEQ ID NO: 779-836.In some implementations, the polynucleotide comprises a nucleic acid sequence having at least 95% identity with any of the following: (a) SEQ ID NO: 663-720; (b) SEQ ID NO: 779-836; (c) SEQ ID NO: 663-720; (d) SEQ ID NO: 779-836; (e) SEQ ID NO: 663-720; or (f) SEQ ID NO: 779-836.

[0120] In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to any one of SEQ ID NO: 663-720; and a nucleic acid sequence that is at least 70% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to any one of SEQ ID NO: 779-836. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 80% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to any one of SEQ ID NO: 663-720; and a nucleic acid sequence that is at least 80% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to any one of SEQ ID NO: 779-836. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 90% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to any one of SEQ ID NO: 663-720; and a nucleic acid sequence that is at least 90% identical (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% identical) to any one of SEQ ID NO: 779-836.

[0121] According to these embodiments, this disclosure includes an expression vector comprising any polynucleotide encoding an anti-MICA antibody of this disclosure. In some embodiments, the expression vector is adapted to manufacture the anti-MICA antibody of this disclosure for delivery to a subject. In some embodiments, the nucleic acid sequence is in the form of a vector. The vector may be, for example, a plasmid, episome, granule, viral vector (e.g., retrovirus or adenovirus), or bacteriophage. Suitable vectors and methods of vector preparation are well known in the art (see, for example, Sambrook et al.). Molecular Cloning, a Laboratory Manual4th edition, Cold Spring Harbor Press, Cold Spring Harbor, NY (2012), and Ausubel et al. Current Protocols in Molecular Biology , Greene Publishing Associates and John Wiley & Sons, New York, NY (1994)).

[0122] In addition to the nucleic acid encoding an anti-MICA antibody or its antigen-binding fragment, the vector desirously contains expression control sequences, such as promoters, enhancers, polyadenylation signals, transcription terminators, internal ribosome entry sites (IRES), etc., which provide for the expression of the antibody-encoded nucleic acid sequence in the host cell. Exemplary expression control sequences are known in the art and described, for example, in Goeddel. Gene Expression Technology: Methods in Enzymology Volume 185, Academic Press, San Diego, California (1990).

[0123] A vector containing a nucleic acid sequence encoding an anti-MICA antibody or its antigen-binding fragment can be introduced into a host cell capable of expressing the encoded polypeptide, including any suitable prokaryotic or eukaryotic cell. Examples of suitable prokaryotic cells include, but are not limited to, those from the genus Bacillus (…). Bacillus (such as Bacillus subtilis) Bacillus subtilis ) and Bacillus brevis ( Bacillus brevis Escherichia coli spp. Escherichia (such as Escherichia coli), Pseudomonas spp. Pseudomonas Streptomyces ( Streptomyces Salmonella ( Salmonella ) and Erwinia spp. Erwinia Cells of which are particularly useful. Prokaryotic cells include... Escherichia coli Various strains (e.g., K12, HB101 (ATCC No. 33694), DH5α, DH10, MC1061 (ATCC No. 53338), and CC102). Suitable eukaryotic cells are known in the art and include, for example, yeast cells, insect cells, and mammalian cells. Examples of suitable yeast cells include *Hansenula polymorpha* (…). Hansenula ), Kluyveromyces ( Kluyveromyces ), Pichia pastoris ( Pichia ), Nasal spores ( Rhinosporidium ), Saccharomyces cerevisiae ( Saccharomyces ) and yeasts of the genus *Schizosaccharomyces* ( SchizosaccharomycesSuitable insect cells include Sf-9 cells and HIS cells (Invitrogen, Carlsbad, Calif.) and are described, for example, by Kitts et al. Biotechniques , 14 : 810-817 (1993); Lucklow, Curr. Opin. Biotechnol ., 4 : 564-572 (1993); and Lucklow et al., J. Virol ., 67 : 4566-4579 (1993). Examples of suitable mammalian cells include, but are not limited to: Chinese hamster ovary cells (CHO) (ATCC No. CCL61), CHO DHFR cells (Urlaub et al., Proc. Natl. Acad. Sci. USA , 97 :4216-4220 (1980)), human embryonic kidney (HEK) 293 cells or 293T cells (ATCC CRL1573) and 3T3 cells (ATCC CCL92). Other suitable mammalian cell lines are monkey COS-1 cell line (ATCC CRL1650) and COS-7 cell line (ATCC CRL1651) and CV-1 cell line (ATCC CCL70). Further exemplary mammalian host cells include primate cell lines and rodent cell lines, including transformed cell lines. Normal diploid cells, derived from primary tissues in vitro Cultured cell lines and primary explants are also suitable. Other suitable mammalian cell lines include, but are not limited to, mouse neuroblastoma N2A cells, HeLa cells, mouse L-929 cells, and BHK or HaK hamster cell lines, all of which are available from ATCC. Methods for selecting suitable mammalian host cells and for transforming, culturing, expanding, screening, and purifying such cells are well known in the art (see, for example, Ausubel et al., edited). Short Protocols in Molecular Biology (5th edition, John Wiley & Sons, Inc., Hoboken, NJ (2002)). Preferably, the mammalian cell is a human cell.

[0124] In some embodiments, the vector may include a manner for attaching a detection portion to the anti-MICA antibody of this disclosure. In some embodiments, the vector may include a manner for attaching a purified portion to the anti-MICA antibody of this disclosure. Exemplary detection and / or purified portions / tags that may be conjugated to the anti-MICA antibody of this disclosure include, but are not limited to: hemagglutinin (HA), c-Myc, V5, DYKDDDDK, His tag (e.g., 6x-HIS), glutathione S-transferase (GST), maltose-binding protein (MBP), fluorophores (e.g., green fluorescent protein (GFP), red fluorescent protein (RFP), mCherry), chromophores, and / or luminescent peptides (e.g., luciferase).

[0125] In some embodiments, the expression vector is suitable for gene therapy (e.g., an expression vector for delivering a polynucleotide encoding an anti-MICA antibody disclosed herein to a subject). In some embodiments, the expression vector is a herpes simplex virus (HSV) vector or a retroviral vector. In some embodiments, the expression vector is an adeno-associated virus (AAV) vector or contains an AAV backbone. For example, AAV vectors have been designed, manufactured, and used to mediate gene delivery to human subjects, including for therapeutic purposes. Typically, AAV vectors used for gene transfer contain a replication-deficient AAV genome that lacks functional Rep and Cap encoding viral sequences. Such replication-deficient AAV vectors more preferably lack most or all of the Rep and Cap encoding sequences and substantially retain one or two AAV ITR sequences and packaging sequences. The defective genome is packaged in viral particles to form a defective recombinant AAV virus, also referred to as an "AAV vector". Methods for producing such AAV vectors have been disclosed in the literature, including the use of packaging cells, helper viruses or plasmids and / or baculovirus systems (Samulski et al., (1989) J. Virology 63, 3822; Xiao et al., (1998) J. Virology 72, 2224; Inoue et al., (1998) J. Virol. 72, 7024; WO98 / 22607; WO2005 / 072364). Methods for producing pseudotyped AAV vectors have also been reported (e.g., WO00 / 28004), as well as various modifications or formulations of AAV vectors to reduce their immunogenicity when administered in vivo (see, for example, WO001 / 23001; WO00 / 73316; WO04 / 112727; WO005 / 005610; WO99 / 06562). AAV vectors can be prepared from or derived from various serotypes of AAV, and can even be mixed together or with other types of viruses to produce chimeric (e.g., pseudotyped) AAV viruses. Examples of tAAVs are human AAV4 vectors, human AAV7 vectors, human AAV9 vectors, human AAV10 vectors, or bovine AAV vectors. AAV vectors can be derived from a single AAV serotype or contain sequences or components derived from at least two different AAV serotypes (pseudotyped AAV vectors), for example, an AAV vector containing an AAV genome derived from one AAV serotype (e.g., AAV9) and a capsid at least partially derived from different AAV serotypes. As used herein, an AAV vector is a vector containing at least one component that can be derived from adeno-associated virus (AAV). Preferably, this component is involved in the biological mechanism by which the vector infects or transduces target cells and expresses the anti-MICA antibody of this disclosure.

[0126] In other implementations, the expression vector is a lentiviral vector (LV) or contains an LV backbone. Lentivirals are part of a large class of retroviruses. A detailed list of lentiviruses can be found in Coffin et al. (1997) “Retroviruses”, Cold Spring Harbour Laboratory Press, eds. JM Coffin, SM Hughes, HE Varmus, pp. 758-763. For example, lentiviruses can be divided into primate and non-primate groups. Examples of primate lentiviruses include, but are not limited to, human immunodeficiency virus (HIV), the pathogen of human autoimmune syndrome (AIDS), and simian immunodeficiency virus (SIV). The non-primate lentivirus group includes the prototype “slow virus” visna / maedi virus (VMV), and related caprine arthritis-encephalitis virus (CAEV), equine infectious anemia virus (EIAV), feline immunodeficiency virus (FIV), maedi-visna virus (MVV), and bovine immunodeficiency virus (BIV). In one embodiment, the lentiviral vector is derived from HIV-1, HIV-2, SIV, FIV, BIV, EIAV, CAEV, or Vesna lentivirus. The lentiviral family differs from retroviruses in that lentiviruses can infect both dividing and non-dividing cells (Lewis et al. (1992) EMBO J 11 (8): 3053-3058 and Lewis and Emerman (1994) J Virol 68 (1): 510-516). In contrast, other retroviruses, such as MLV, cannot infect non-dividing or slowly dividing cells, such as those constituting tissues like muscle, brain, lung, and liver. As used herein, a lentiviral vector is a vector containing at least one component that may be derived from a lentivirus. Preferably, this component is involved in the biological mechanism by which the vector infects or transduces target cells and expresses the anti-MICA antibody of this disclosure.

[0127] According to these embodiments, this disclosure also provides a method of administering gene therapy to a subject in need, the method comprising injecting a pharmaceutical composition comprising an effective amount of the expression vector described herein (e.g., an expression vector comprising a polynucleotide encoding an anti-MICA antibody of this disclosure). As further described below, this disclosure also provides a method of treating cancer by administering a pharmaceutical composition comprising an effective amount of the expression vector described herein (e.g., an expression vector comprising a polynucleotide encoding an anti-MICA antibody of this disclosure). In some embodiments, the pharmaceutical composition is administered to treat at least one symptom present in a subject suffering from cancer.

[0128] Compositions and methods of treatment The anti-MICA antibody of this disclosure can be administered as part of a pharmaceutical composition in a therapeutically effective amount to treat cancer. In some embodiments, the composition is suitable for intravenous, subcutaneous, intraperitoneal, or intramuscular administration. In some embodiments, administration includes delivery of the anti-MICA antibody using needles, gels, nanoparticles, mucosal adhesion polymers, ointments, solutions, suspensions, drops, and / or implants. In some embodiments, the pharmaceutical composition comprising a therapeutically effective amount of the anti-MICA antibody of this disclosure is administered at a dose ranging from about 0.0001 mg / dose to about 100 mg / dose. In some embodiments, the pharmaceutical composition is administered at a dose ranging from about 0.0001 mg / ml to about 100 mg / ml.

[0129] According to these embodiments, the method includes administering a pharmaceutical composition comprising a therapeutically effective amount of the anti-MICA antibody of this disclosure. In some embodiments, the pharmaceutical composition is administered to a subject and used to treat at least one cancer symptom. In some embodiments, the pharmaceutical composition is administered to stabilize MICA on tumor cells and / or inhibit MICA shedding from tumor cells, which reduces the ability of tumor cells to escape immune clearance mediated by natural killer cell group 2D (NKG2D) receptors.

[0130] In some embodiments, the pharmaceutical composition comprising a therapeutically effective amount of the anti-MICA antibody of this disclosure is administered at a dose ranging from about 0.0001 mg / dose to about 100 mg / dose. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.001 mg / dose to about 100 mg / dose. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.01 mg / dose to about 100 mg / dose. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.1 mg / dose to about 100 mg / dose. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 1.0 mg / dose to about 100 mg / dose. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 10 mg / dose to about 100 mg / dose. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.0001 mg / dose to about 1.0 mg / dose. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.0001 mg / dose to about 0.1 mg / dose. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.0001 mg / dose to about 0.001 mg / dose. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.01 mg / dose to about 10 mg / dose. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.001 mg / dose to about 1.0 mg / dose.

[0131] In some embodiments, the pharmaceutical composition comprising a therapeutically effective amount of the anti-MICA antibody of this disclosure is administered at a dose ranging from about 0.0001 mg / ml to about 100 mg / ml. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.001 mg / ml to about 100 mg / ml. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.01 mg / ml to about 100 mg / ml. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.1 mg / ml to about 100 mg / ml. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 1.0 mg / ml to about 100 mg / ml. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 10 mg / ml to about 100 mg / ml. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.0001 mg / ml to about 10 mg / ml. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.0001 mg / ml to about 1.0 mg / ml. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.0001 mg / ml to about 0.1 mg / ml. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.0001 mg / ml to about 0.01 mg / ml. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.0001 mg / ml to about 0.001 mg / ml. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.01 mg / ml to about 10 mg / ml. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.001 mg / ml to about 1.0 mg / ml. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.1 mg / ml to about 10 mg / ml.

[0132] As used herein, the terms "treatment," "treating," etc., refer to achieving a desired pharmacological and / or physiological effect. In some embodiments, the effect is therapeutic, meaning that the effect partially or completely cures the disease and / or adverse symptoms attributable to the disease. To this end, the methods of this disclosure include administering a "therapeuticly effective amount" of an anti-MICA antibody or a composition containing an anti-MICA antibody. A "therapeuticly effective amount" refers to an amount that effectively achieves the desired therapeutic outcome at the necessary dose and time period. Therapeuticly effective amounts can vary depending on factors such as an individual's disease state, age, sex, and weight, and the ability of the monoclonal antibody to elicit a desired response in the individual. For example, a therapeutically effective amount of the anti-MICA antibody of this disclosure is an amount that treats at least one cancer-related symptom in a subject. In some embodiments, the pharmacological and / or physiological effect can be prophylactic, meaning that the effect completely or partially prevents the disease or its symptoms. In this regard, the methods of this disclosure include administering a "prophylacticly effective amount" of an anti-MICA antibody or a composition containing an anti-MICA antibody. "Preventive effective dose" refers to the amount that effectively achieves the desired preventive outcome at the necessary dose and time period.

[0133] Typical therapeutically effective doses of the anti-MICA antibodies of this disclosure range from, for example, about 0.0001 mg / dose to about 100 mg / dose. In some embodiments, the therapeutically effective doses of the anti-MICA antibodies of this disclosure range from about 0.001 mg / dose to about 100 mg / dose, about 0.01 mg / dose to about 100 mg / dose, about 0.05 mg / dose to about 50 mg / dose, about 0.1 mg / dose to about 10 mg / dose, about 0.5 mg / dose to about 5 mg / dose, and about 1 mg / dose to about 10 mg / dose. In some embodiments, the therapeutically effective concentrations of the anti-MICA antibodies of this disclosure range from, for example, about 0.0001 mg to about 100 mg of antibody per milliliter of solution. In some embodiments, the therapeutically effective concentration of the anti-MICA antibody disclosed herein may range from about 0.001 mg / ml to about 100 mg / ml, about 0.01 mg / ml to about 100 mg / ml, about 0.1 mg / ml to about 100 mg / ml, about 1.0 mg / ml to about 100 mg / ml, about 0.001 mg / ml to about 50 mg / ml, about 0.01 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 50 mg / ml, about 0.1 mg / ml to about 25 mg / ml, about 0.1 mg / ml to about 10 mg / ml, and about 1.0 mg / ml to about 10 mg / ml. In some embodiments, the therapeutically effective dose of the anti-MICA antibody of this disclosure may be precisely or approximately 0.1 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, or 25.0 mg, or may fall within the range defined by any two of the foregoing values.For example, in some embodiments, the sustained-release formulation may be precisely or approximately 0.1 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 10.0 mg, 15.0 mg, 20.0 mg, or 25.0 mg of anti-MICA antibody, or an amount falling within the range defined by any two of the foregoing values.

[0134] Therapeutic or prophylactic efficacy can be monitored through regular assessment of treated patients. For repeated administration over several days or longer, treatment may be repeated as needed until the desired suppression of disease symptoms occurs. However, other dosing regimens may also be useful and are within the scope of this disclosure. The desired dose can be delivered by a single bolus injection, by multiple bolus injections, or by continuous infusion. Compositions containing anti-MICA antibodies or their antigen-binding fragments can be administered to mammals using standard administration techniques, including ocular, oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration.

[0135] This disclosure also provides compositions comprising any anti-MICA antibody or antigen-binding fragment thereof described herein. The compositions are preferably pharmaceutically acceptable (e.g., physiologically acceptable) compositions comprising a carrier, preferably a pharmaceutically acceptable (e.g., physiologically acceptable) carrier, and an anti-MICA antibody or antigen-binding fragment thereof. Any suitable carrier may be used in the context of this disclosure, and such carriers are well known in the art. For example, the compositions may contain preservatives such as methylparaben, propylparaben, sodium benzoate, and benzalkonium chloride. A mixture of two or more preservatives may optionally be used. Additionally, the compositions may contain buffers. Suitable buffers include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts. A mixture of two or more buffers may optionally be used. Methods for preparing compositions for pharmaceutical use are known to those skilled in the art and are described, for example, Remington: The Science and Practice of Pharmacy Lippincott Williams & Wilkins; 21st edition (May 1, 2005).

[0136] Once administered to mammals (e.g., humans), the biological activity of an anti-MICA antibody or its antigen-binding fragment can be measured by any suitable method known in the art. For example, biological activity can be assessed by determining the stability of the anti-MICA antibody. The biological activity of an anti-MICA antibody can also be assessed by determining its binding affinity to MICA peptides and / or by evaluating its binding affinity to peptides that may cross-react with it. The term "affinity" refers to the equilibrium constant for the reversible binding of two agents and is expressed as the dissociation constant (K0). D The affinity of the binder for the ligand, such as the affinity of the antibody for the epitope, can be, for example, from about 1 femtomolar (fM) to about 1 millimole (mM) (e.g., from about 1 picomolar (pM) to about 1 nanomolar (nM) or from about 1 nM to about 1 micromolar (μM)). In some embodiments, the affinity of the anti-MICA antibody can be from about 1 nm to about 20 nm, and preferably from about 5 nm to about 10 nm. The antibody affinity for the antigen or epitope of interest can be measured using any assay recognized in the art. Such methods include, for example, fluorescence-activated cell sorting (FACS), separable beads (e.g., magnetic beads), antigen panning, and / or ELISA (see, for example, Janeway et al. (eds.), Immunobiology, 5th edition, Garland Publishing, New York, NY, 2001).

[0137] In some embodiments, anti-MICA antibodies or compositions containing anti-MICA antibodies may be administered alone or in combination with other drugs. For example, anti-MICA antibodies may be administered in combination with other agents disclosed herein for the treatment or prevention of cancer. For example, the anti-MICA antibodies of this disclosure or their antibody conjugates, fusion proteins, or polymer formulations may be used alone or in combination with other agents in a therapy. For example, anti-MICA antibodies may be co-administered with at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is another antibody, chemotherapeutic agent, cytotoxic agent, anti-angiogenic agent, immunosuppressant, prodrug, cytokine, cytokine antagonist, cytotoxic radiotherapy, corticosteroid, antiemetic, cancer vaccine, analgesic, growth inhibitor, or combination thereof. For example, in some embodiments, any of the foregoing methods further includes administering one or more additional compounds. In some embodiments, anti-MICA antibodies, antibody conjugates, fusion proteins, or polymer formulations are administered simultaneously with one or more additional compounds. In some embodiments, anti-MICA antibodies, antibody conjugates, fusion proteins, or polymer formulations are administered before or after one or more additional compounds.

[0138] In addition to therapeutic uses, the anti-MICA antibodies or antigen-binding fragments described herein can also be used for diagnostic or research applications. Research applications include, for example, methods using anti-MICA antibodies and tags to detect MICA in samples, such as human fluids or cell or tissue extracts. Anti-MICA antibodies or their antigen-binding fragments can be used in any suitable assay to measure MICA in a sample for diagnostic and / or research purposes. Such assays include, but are not limited to, sandwich immunoassays, enzyme immunoassays (EIA), enzyme-linked immunosorbent assays (ELISA), lateral flow assays, competitive inhibition immunoassays (e.g., forward and reverse), competitive binding assays, Forster resonance energy transfer (FRET), one-step antibody assays, single-molecule assays, radioimmunoassays (RIA), and FACS. Such methods are disclosed, for example, in U.S. Patents 6,143,576; 6,113,855; 6,019,944; 5,985,579; 5,947,124; 5,939,272; 5,922,615; 5,885,527; 5,851,776; 5,824,799; 5,679,526; 5,525,524 and 5,480,792; and in Adamczyk et al. Anal. Chim. Acta , 579 (1): 61-67 (2006).

[0139] Anti-MICA antibodies or their antigen-binding fragments are available in a kit, for example, a packaged combination of a predetermined amount of reagent and instructions for use in an assay (e.g., an assay for detecting MICA). Therefore, this disclosure provides kits comprising the antibodies or antigen-binding fragments described herein and their instructions for use. The instructions may be in paper or computer-readable form, such as a disk, CD, DVD, etc. Alternatively or additionally, the kit may contain a calibrator or control, and / or at least one container (e.g., tube, microtiter plate, or test strip) for performing the assay, and / or buffers, such as assay buffers or wash buffers. Ideally, the kit contains all the components necessary to perform the assay, i.e., reagents, standards, buffers, diluents, etc. Other additives may be included in the kit, such as stabilizers, buffers (e.g., blocking buffers or lysis buffers), etc. The relative amounts of various reagents can be varied to provide concentrations in the reagent solution, thereby significantly optimizing the sensitivity of the assay. Reagents may be provided in the form of dry powder (typically lyophilized powder), including excipients that, upon dissolution, will provide a reagent solution with an appropriate concentration.

[0140] The following examples further illustrate various embodiments of this disclosure, but should not be construed as limiting its scope in any way.

[0141] Example It will be apparent to those skilled in the art that other suitable modifications and adaptations to the methods of this disclosure described herein are readily applicable and understandable, and that suitable equivalents may be used without departing from the scope of this disclosure or the aspects and embodiments disclosed herein. Having now been described in detail, this disclosure will be more clearly understood by referring to the following examples, which are intended only to illustrate some aspects and embodiments of this disclosure and should not be considered as limiting the scope of this disclosure. All journal references, U.S. patents, and published disclosures cited herein are hereby incorporated in their entirety by reference.

[0142] This disclosure has several aspects, which are illustrated by the following non-limiting embodiments.

[0143] Example 1 The MICA antibody sequence was recovered from immunized mice. MICA / B immunization: Alloy Therapeutic transgenic humanized mice (ATX-GK) in three cohorts were immunized with human MICA / B using the following 5-week protocol. All cohorts followed the standard 35-day multisite repeat immunization (RIMMS) protocol. The cohorts were as follows: Cohort 1: Human MICA-HIS α-3 domain (P-796); Cohort 2: Human MICA-Fc α-3 domain (P-1001); Cohort 3: Human MICB-His α-3 domain (P-798); Cohort 4: Injected with cynomolgus monkey MICA-His α-3 domain on days 0 and 7 (P-797), human MICA-HIS α-3 domain on day 14 (P-796), and human MICB His α-3 domain on day 21 (P-798); Cohort 5: Human MICA-His (Acro MIA-5221). Cohorts 3 and 4 did not produce a sufficiently high immune response and were terminated. All cohorts had N = 6 female ATX-GK Mix mice.

[0144] As described above, Cohort 1 included GK Mix mice administered the human MICA-HIS α-3 domain (P-796). On day 20, ELISA plates were coated with 1 μg / mL of human MICA-His, human MICB His, cynomolgus monkey MICA-His, or a His control (P-114) (data not shown but available upon request). HRP goat anti-mouse secondary antibody was used at a 1:5000 dilution, with a development time of 12:30. Absorbance was measured at 450 nm using an ELISA microplate reader. Following the day 20 ELISA and considering the low titers obtained with P-796, Cohort 1 was boosted with α-3-MICA-ATX-Fc (P-1001). Representative ELISA results used to determine the antigen-positive serum titers of the mice immunized as described above are shown in [the table / incomplete]. Figure 1 As shown in the diagram. In short, the ELISA plate was coated with 1 μg / mL human MICA-his-α3 (top left), His control (top right), human MICA-ATX-Fc-α3 (bottom left), or ATX-Fc control (bottom right). The secondary antibodies used were HRP goat anti-mouse (P-796 and P-114), HRP goat anti-rat (P-1001 and P-199), or HRP goat anti-human (positive control), diluted 1:5000. The positive control used was ATX-P-794 (human IgG1), starting at 5 μg / mL. The color development time was 4:05. The absorbance signal at 450 nm was measured using an ELISA microplate reader.

[0145] Additionally, immune tissues from high-titer mice were harvested and preserved for antibody discovery. Hybridoma cell lines producing MICA antibodies were generated by fusing single B cells from the spleen and lymph nodes of titer-positive mice with myeloma cells. Hybridomas expressing MICA-specific antibodies were detected by antigen binding via ELISA. The affinity of antibodies in the hybridoma supernatant was measured by SPR using an Octet instrument. MICA antibodies from the hybridoma supernatant were loaded onto a biosensor. The reaction was measured as a nm shift in the interference pattern and was proportional to the amount of antibody bound to the biosensor surface. The binding interaction of MICA with the immobilized antibody was measured as association (kon). After analyte association, the biosensor was immersed in MICA-free PBS, allowing the bound antigen to dissociate from the antibody (kdis). KD (M), or antibody affinity for MICA, was measured as kdis / kon. Heavy and light chains from validated hybridomas were sequenced. RNA was isolated from hybridomas secreting MICA antibodies and cloned from both the heavy and light chain variable regions by reverse transcription using gene-specific primers followed by PCR amplification using variable strand gene-specific primers. The PCR products were sequenced using standard Sanger sequencing methods.

[0146] Variable heavy and light chains were amplified from the spleens of high-titer immunized mice using reverse transcription with gene-specific primers followed by PCR amplification with variable chain gene-specific primers. The variable regions were cloned into a phage display vector designed to express Fab on the phage g3p protein. A phage library expressing unique Fab was amplified and purified. Phages were allowed to bind to biotinylated MICA antigens captured on streptavidin beads. Phages still bound to the antigen beads after several rigorous washes were eluted with alkaline triethylamine solution and neutralized with Tris buffer (pH 8.0). The eluted phages were re-infected into TG1 bacterial cells, amplified by co-infection with M13 helper phages, and purified by PEG precipitation. Purified phages expressing Fab were selected for antigen binding as described. A second round of phage dilution and infection was performed into TG1 cells. The resulting phage polyclonal pools from the two rounds of panning were tested by ELISA to confirm the presence of MICA-specific phages. The variable heavy and light chain regions from a single infected bacterial colony were sequenced using rolling circle amplification and standard Sanger sequencing.

[0147] Unique variable heavy and light chain pairs derived from hybridoma and phage display activities were cloned into a vector designed to express full-length antibodies as IgG in HEK293 cells under the control of a CMV promoter. The antibody expression vector was conjugated with polyethyleneimine and transfected into HEK293 cultures. After 5 days of shaking at 37°C in HEK293 cell culture medium, the antibody was captured on agarose-based protein A resin. Following several rigorous washes, the antibody was eluted in glycine solution (pH 3), neutralized with Hepes (pH 9), and the buffer was exchanged for PBS.

[0148] In addition, cell binding was performed using the anti-MICA antibody disclosed herein. Briefly, Raji cells expressing MICA or parental Raji cells were tested in a binding assay on ice at concentrations ranging from 100 nM to 0.6 pM (serial 3-fold dilutions). Cells were then incubated with the secondary antibody R-phycoerythrin AffiniPure goat anti-human IgG (Jackson Immunoresearch 109-115-098). Data were acquired on a FACS Canto II. Median fluorescence intensity (MFI) was plotted against antibody concentration. EC50 was derived from the fitted 4-parameter dose-response curve. Figure 2 ).

[0149] Example 2 Biophysical properties of human MICA monoclonal antibodies. The development of effective monoclonal antibodies depends not only on their biological activity but also on their physicochemical properties, such as purity, homogeneity, and stability. Briefly, size exclusion chromatography (SEC) was performed on an Agilent 1200 series HPLC instrument using a YMC Diol-200 8 x 300 mm column (catalog number DL20S05-3008WT). The run buffer was 20 mM sodium phosphate, 400 mM NaCl (pH 7.0), and the flow rate was 0.3 mL / min. For freeze-thaw stability, the sample was frozen at -80°C for 20 min and then thawed at room temperature for approximately 20 min. Furthermore, capillary electrophoresis of sodium dodecyl sulfate (CE-SDS) was performed on a LapChip GX II instrument using ProteinExpress 200 (Perkin Elmer, #760499) and the Protein Express assay kit (Perkin Elmer, #CLS960008). Reagents and chips were prepared according to the manufacturer's instructions. In short, the reducing sample buffer was prepared by mixing 1 M dichlorodiphenyltrichloroethane with Protein Express sample buffer, while the non-reducing buffer consisted solely of Protein Express sample buffer. Samples were mixed with either the reducing or non-reducing buffer and denatured at 80°C for 10 min. Samples were centrifuged at 2,000 g for 1 min to remove air bubbles and then analyzed using a LapChip GXII instrument.

[0150] Antibody stability can be affected by its formulation. Among the many techniques used to study mAb stability, differential scanning fluorescence (DSF) offers excellent throughput and minimal material consumption. DSF measures the temperature (Tm) of protein unfolding transition based on changes in fluorescence intensity of an environmentally sensitive dye. Experiments were performed to assess the thermal stability of the human MICA monoclonal antibody (“ATX” antibody) of this disclosure by determining the melting temperature (Table 1). Briefly, thermal stability was assessed via nano-differential scanning fluorescence (nanoDSF) on a Prometheus Panta. Measurements were repeated twice for each sample. The melting temperature of the antibody was detected during linear heating (0.5 °C / min, 25–95 °C). Data were analyzed using Panta analysis software. The unfolding transition point was determined by changes in emission wavelengths of tryptophan fluorescence at 350 and 330 nm. Data were analyzed using protein thermal transfer software and from the melt curve ( Figure 3 Calculate the melting temperature (Tm).

[0151] Table 1: DSF analysis of human anti-MICA monoclonal antibody.

[0152]

[0153]

[0154] Affinity-capture self-interacting nanoparticle spectrometry (AC-SINS) was performed. This assay tests the potential for antibody-to-self interaction. It uses gold nanoparticles coated with anti-Fc antibodies. When a diluted antibody solution is added, the antibodies rapidly immobilize on the gold beads. If these antibodies subsequently attract each other, this results in a shorter interatomic distance and a longer absorption wavelength, which can be detected by spectrometry. Briefly, the gold nanoparticles (Ted Pella, 15705-20) were washed with water. An 80 / 20 (v / v) antibody mixture (Jackson Immuno Research Labs) buffer was exchanged for 20 mM sodium acetate (pH 4.5) to a concentration of 500 μg / ml. To prepare 1 ml of coated particles, 900 μL of gold nanoparticles were incubated with 100 μL of antibody mixture overnight at room temperature for 90 min. After antibody coating, the beads were quenched using thiolized PEG (MW: 2000 Da). The beads were then concentrated 10-fold in PBS. 10 μL of a 10-fold concentrated particle solution was incubated with 100 μL of a 40 μg / mL antibody sample on a 384-well polypropylene plate at room temperature for 2 hours. The plate was then rapidly deflected at 3000 rpm and scanned in 2 nm increments from 510 to 580 nm on a Synergy Neo2 multimode plate reader (BioTek). The reported values ​​are the average of the replicate wells and are the sample redshift wavelength at maximum absorbance minus the blank reference (PBS only). A larger redshift indicates stronger self-interactions.

[0155] In addition, baculovirus particle (BVP) ELISA assays were performed. Empty BVP (empty viral capsids without the genome) was used to measure the multispecificity of therapeutic antibody candidates in in vitro assays. These assays evaluated antibody activity. Briefly, similar to that reported by Hötzel et al. (2012), baculovirus particles (BVP, Lake Pharma) were diluted 1:100 in 50 mM sodium bicarbonate (pH 9.5). After incubating 50 μL of BVP overnight at 4 °C on an ELISA plate (3369; Corning), unbound BVP was aspirated from the wells. All remaining steps were performed at room temperature. The plate was blocked with 100 μL of blocking buffer (PBS with 1% BSA) for 1 h, followed by washing three times with 100 μL of PBS. Next, 50 μL of 2.5 ug / mL test antibody was added to the wells and incubated for 1 h, followed by washing with 100 μL of PBS. A 1:1000 dilution of HRP-conjugated goat anti-human IgG antibody (Jackson ImmunoResearch) was used as the secondary antibody and incubated for 1 h, followed by washing as before. Finally, 100 μL of TMB substrate (34021; Fisher Scientific) was added to each well and incubated for 6 min. The reaction was stopped by adding 50 μL of 2 M sulfuric acid to each well. Absorbance was read at 450 nm, and the BVP fraction was determined by normalizing the absorbance of the control wells without the test antibody. Folding background was determined using the average of the buffer-only wells. All measurements were repeated three times.

[0156] Example 3 MICA antibody binding kinetics. Kinetic experiments were performed on a Carterra LSA using running buffer HBSTE, 10 mM HEPES (pH 7.4), 150 mM NaCl, 3 mM EDTA, and 0.05% Tween 20. Goat anti-human IgG capture antibody (Jackson ImmunoResearch) was immobilized on an HC30M sensor using a standard amine conjugation program. The sensor chip was activated with 0.2 M EDC / 0.05 M sulfo-NHS. Subsequently, the capture antibody was immobilized at 15 μg / ml in 10 mM sodium acetate (pH 4.5) and then quenched with 0.5 M ethanolamine. The test antibody was captured on the prepared anti-human Fc capture chip. For kinetic analysis, human MICA-His, human MICA-α3-His, human MICB-α3-His, and cynomolgus monkey MICA-α3-His were sequentially injected from Acro or internally prepared at concentrations ranging from 0.076 nM to 1500 nM (serial 3-fold dilutions). For each concentration, association was performed for 5 min, followed by dissociation for 15 min. Results were processed and analyzed in Carterra LSA kinetic software. Kinetic data were referenced to an interstitial reference point, and a double-reference buffer cycle was performed, followed by a 1:1 binding model to determine the apparent association and dissociation kinetic rate constants (ka and kd values). The ratio kd / ka was used to derive the KD value for each antigen / mAb interaction, i.e., KD = kd / ka ( Figure 4 ).

[0157] MICA antibody cross-reactivity. Experiments were performed to determine the reactivity of the MICA / B antibody of this disclosure (developed using the MICA / B antigen; see Example 3) with various other MICA / B proteins. The binding of 54 purified antibodies to the full-length human MICA (FL), the human MICA α3 domain, the human MICB α3 domain, and the cynomolgus monkey MICA α3 domain was examined. Figure 4As shown, experiments were performed to determine the reactivity of the antibody with cynomolgus monkey protein. Binding experiments were conducted on a Carterra LSA using run buffer of PBS (pH 7.40), 1% BSA, and 0.05% Tween 20. The antibody was covalently printed onto an HC30M chip. The chip was activated for 7 min with 33 mM s-NHS and 133 mM EDC in 100 mM MME S (pH 5.5). Printing was then performed for 10 min with 10 mg / ml antibody in acetate buffer (pH 4.5). The printed chip was then quenched for 7 min with 1 M ethanolamine (pH 8.5). The results were processed and analyzed in Carterra LSA kinetic software. Data were referenced using a mesenchymal reference point, and double reference buffer cycles were performed before reporting the post-association reaction (nm). An isotype control was used to determine the cutoff reaction for positive binding.

[0158] Example 4 MICA antibody cross-blocking. High-throughput epitope binning experiments were performed on a real-time label-free biosensor (Carterra LSA) to sort a large number of mAbs into bins based on their ability to block each other's binding to antigens. In pairwise epitope binning analysis, human MICA and antibody 2 (analyte antibody) were sequentially applied to a sensor chip (HC200M) covalently preloaded with antibody 1 (ligand antibody). An increased response after exposure to the analyte antibody indicated no competition between the two antibodies, while a lack of signal change indicated competition. Antibodies in the test set with the same blocking characteristics as other antibodies were grouped into bins. Clustering of mAbs sharing similar but not necessarily identical competitive characteristics was explored using a network graph. Figure 5A This includes representative granularity binning network diagrams (antibodies are highlighted with a blue asterisk), and Figure 5B Includes a representative group binning network diagram. Figure 5C This includes representative combined binary tree diagrams (color indicates the boxes in the network diagram).

[0159] Example 5 MICA antibody function. Experiments were performed to evaluate the ability of the anti-MICA antibodies of this disclosure to stabilize MICA on cancer cells and inhibit MICA shedding, including comparisons with baseline antibodies (i.e., 791, 792, 793, 794, 3F9, C16F10, and C619 as control MICA antibodies). A375, A549, HCT116, H2030, and OVACAR 3 cell lines were incubated with anti-MICA antibodies and control baseline antibodies (including Hu allotype IgG1 and antibody-free groups) in 96-well plates treated with cell culture for 24 to 72 hours. All antibodies were titrated from 20 nM to subpicomolar concentrations. After incubation, the supernatant was collected and stored at -80°C, and cells were separated from the plates using Versene and analyzed immediately. The amount of soluble MICA (sMICA) in the supernatant was then estimated by sandwich ELISA (R&D Biosystems). The amount of MICA stabilized on the cell surface was quantified using flow cytometry. MICA on cell surfaces was detected via a PE-conjugated anti-MICA antibody (6D4, Biolegend). MICA surface stability and sMICA showed an indirect correlation.

[0160] Figure 6A This includes results demonstrating the ability of anti-MICA antibodies to effectively stabilize MICA on the surface of cancer cells, and Figure 6B This includes results demonstrating the ability of anti-MICA antibodies to effectively inhibit MICA shedding. Figure 6C This includes data demonstrating a strong correlation between MICA stability and shedding inhibition on the cell surface at various concentrations of anti-MICA antibodies. Additionally, four anti-MICA antibodies were further tested and compared with benchmark antibodies (i.e., 7C6, 1D5, and CLN-619 antibodies).

[0161] Figure 7A This includes results demonstrating the ability of four anti-MICA antibodies to effectively stabilize MICA on the surface of cancer cells, and Figure 7B This includes results demonstrating the ability of four anti-MICA antibodies to effectively inhibit MICA shedding. Figure 7C This includes data demonstrating that four anti-MICA antibodies enhance the killing ability of A375 melanoma target cells via primary human NK cells at different effector cell to target cell ratios, and Figure 7D This includes data demonstrating that four anti-MICA antibodies enhance the ability of different concentrations of MICA antibodies to kill A375 melanoma target cells via primary human NK cells.

[0162] Example 6 like Figure 8As shown, experiments were conducted to determine the binding kinetics of the fully humanized anti-MICA antibody ATX-P-1826 with human MICA, human MICB, and cynomolgus monkey MICA. The binding affinity of ATX-P-1826 was evaluated monovalently using a label-free biolayer interferometry (BLI) system (Gator Bio, California, USA). ATX-P-1826 and control antibodies were loaded onto an anti-Fc biosensor for 120 seconds, followed by equilibration in K buffer for 60 seconds to establish a baseline. The antibody-loaded sensor was then immersed in a 200 nM solution of 6XHis-labeled MICA / MICB for 120 seconds to record the association phase in real time. The sensor was then returned to the running buffer for 120 seconds to record the dissociation phase and calculate the dissociation constant (typically measured for 120–240 seconds or until equilibration). Data were analyzed using BLI software to determine the KD values ​​of the binding pairs. As shown in the figure, ATX-P-1826 exhibits similar binding affinity to MICA, MICB, and cynomolgus monkey MICA (with slightly better predictability and reliability of cynomolgus monkey toxicity profiles).

[0163] Example 7 like Figures 9A to 9BAs shown, experiments were conducted to evaluate the efficacy of the anti-MICA antibody of this disclosure in killing cancer cells. Briefly, an FcγRIIIa activation assay was performed as an alternative to the ADCC assay. The target cells used were A375 cells, and the effector cells were Jurkat / FcγRIIIa / NFAT-Luc cells. AHA-P-1031, an Fc-enhanced version of ATX-P-1826 (see, for example, PCT Patent Application No. PCT / US2004 / 009298 and the corresponding U.S. Patent Application Serial No. 10 / 672,280, both of which are incorporated herein by reference in their entirety and for all purposes), has been developed and tested in conjunction with ATX-P-1826 and ATX-P-1826 (defucosylated) and Hu isotype IgG1 antibody. These antibodies were used at a starting concentration of 20 nM and serially diluted to 0.005 nM levels in serum-free medium, followed by incubation at 37°C for 30 min. A375 and Jurkat / FcγRIIIa / NFAT-Luc cells suspended in Opti-MEM were seeded at 90 μL / well in 96-well plates at an effector cell to target cell ratio of 10:1. Subsequently, the pre-incubated antibody mixture was... A volume of μL / well was added to each well, and the plate was incubated at 37°C for 5 hours. Luciferase activity was measured using the ONE-Glo Luciferase Assay Reagent (Promega) and a Synergy 2 (BioTek plate reader). Luciferase activity was normalized to a negative control, and the percentage of activity against MICA mAb concentration was plotted. The IC50 value of AHA-P-1031 was determined using 4-parameter logistic regression.

[0164] about Figure 9B In this study, peripheral blood mononuclear cells (PBMCs) were separated by Ficoll-Paque gradient centrifugation using products from Amersham Pharmacia Biotech (Uppsala, Sweden) and erythrocyte sedimentation rate (ESR) amber layer obtained from Carter BloodCare (Bedford, Texas). Subsequently, primary human NK cells were isolated from the PBMCs using an NK cell isolation kit (Miltenyi Biotec 130-092-657). Non-NK cells were magnetically labeled using a mixture of biotin-conjugated antibody and NK cell microbeads. High-purity NK cells were isolated from the depleted magnetically labeled cells. NK cell viability and cell density were examined using 1% trypan blue dye.

[0165] The antibody-dependent cytotoxicity (ADCC) activity of human primary NK cells was evaluated using two-color flow cytometry. Target tumor cells A375 (1 × 10⁻⁶) were used. 6Incubate with 1 mL of CFSE dye. (A working stock solution was prepared by adding 1 μl of 0.5 mM carboxyfluorescein diacetate succinimide (CFSE; Invitrogen, Eugene, Oregon, USA) to 10 mL of 1X PBS phosphate-buffered saline (PBS) at 37°C for 10 min.) Cells were then washed three times with ice-cold RPMI 1640 medium. Effector NK cells and target cells were mixed at an effector cell to target cell (E / T) ratio of 10:1 (5.0 × 10⁻⁶ cells / ... 6 / ml effector cells, 5 × 10 5 / ml target cells; final volume: 200 μl), incubated with or without 20 nM antibodies (AHA-P-1031 and ATX-P-1826), titrated to sub-picomolar levels, and incubated overnight at 37°C in a humidified atmosphere containing 5% CO2. After incubation, cells were washed twice with 1X PBS and stained with 7-aminoactinomycin D (7-AAD; eBioscience, A1310, San Diego, CA, USA) for subsequent analysis via two-color flow cytometry performed on an Attune™ device (Thermo Scientific). Double-positive CFSE and 7AAD cells indicated tumor target cells lysed via ADCC. The ADCC activity levels of different antibodies were compared, and EC50 was calculated using nonlinear regression analysis performed with GraphPad Prism.

[0166] In summary, these results demonstrate that, compared to other Fc variants, ADCC-engineered Fc regions of AHA-P-1031 improve NK cell-mediated cancer cell killing. Figure 9A Furthermore, compared to ATX-P-1826, the anti-MICA Fc enhancing antibody AHA-P-1031 is significantly more effective in NK cell-mediated killing of cancer cells.

[0167] Example 8 like Figure 10 As shown, in vivo experiments were conducted to test the antitumor efficacy of AHA-P-1031 (Fc enhanced version) in human xenografts (A375 melanoma cell line). Briefly, female athymic nude mice (NU / J strain: 002019, homozygous Foxn1) were used. <nu>; purchased from Jackson Laboratory), 6-10 weeks of age, were housed at the ARC located at UTSW Medical Center according to IACUC guidelines. Mice were housed under specific pathogen-free conditions at 20 °C and 40-60% relative humidity with a 12-hour light / dark cycle. Prior to injection, A375 cells were maintained in exponential growth phase, prepared by trypsinization, and checked for viability using trypan blue exclusion method (requiring 98% viability). A375 tumor cells (5 x 105 6 suspended in PBS and Matrigel, 100 μL injection volume) were injected subcutaneously into the back of mice to form xenografts. The injection site was palpated three times per week until tumors were established. Tumor growth was measured using a digital caliper. When tumors reached 80-100 mm 3 in volume, mice were grouped (10 mice per group) and administered 10 mg / kg purified mAb AHA-P-1031 intraperitoneally three times per week for 3-4 weeks, or an equal volume of phosphate-buffered saline (PBS) as a control. Tumor size was measured three times per week, and tumor volume was calculated using the following formula: Tumor size = (width 2 ) / 2 x length. At the end of the experiment or when a predetermined size limit of 2,000 mm 3 was reached, mice were humanely euthanized using CO2 asphyxiation followed by cervical dislocation in accordance with the Institutional Animal Care and Use Committee (IACUC) approved guidelines for the care and use of laboratory animals at UTSW Medical Center. Tumors were excised, weighed, and subjected to ex vivo volume measurement and experimentation. Necropsy was performed, and specific tissues were collected for downstream analysis. Tumors and tissues were stabilized in RNA-later reagent, snap-frozen in liquid nitrogen, or prepared for histology. All in vivo experiments were approved by the IACUC committee at UTSW Medical Center in Dallas, TX (Approval Protocol Number 2022-103216-EXT; Discovery of Novel Antibodies for Cancer Immunotherapy, expiration date: April 2025).

[0168] Example 9 As Figures 11A to 11C , experiments were performed to test the ability of AHA-P-1031 to inhibit MICA shedding in different tumor cell lines: lung cancer cell lines (A549, H2030, NCI-H226, and Calu-3; Figure 11A ); pancreatic cancer cell lines (PANC1 and Capan-2; Figure 11B ); ovarian cancer cell line (OVCAR3; Figure 11B ); colon cancer cell line (HCT116; Figure 11B ); and prostate cancer cell lines (22Rv1, PC3, and LNCaP; Figure 11C In short, cell lines A375, A549, H2030, NCI-H226, Calu3, PANC1, Capan2, OVACAR3, HCT116, 22Rv1, PC3, and LNCap were cultured for 24 to 72 hours in 96-well plates treated with cell culture treatment, containing α3 domain-specific anti-MICA antibodies and control baseline antibodies (including Hu allotype IgG1 and antibody-free groups). 200 nM of AHA-P-1031 monoclonal antibody was titrated down to a subpicomolar concentration. After incubation, cells were isolated using Versene for MICA stabilization of the cell surface. The isolated cells were decanted, washed with 1X PBS, and stained with fixed live / dead cell staining (Invitrogen eBioscience, 65-0865-14) for 15 minutes at room temperature. Cells were washed and stained on ice for 20 min with PE-conjugated anti-MICA antibody (clone 6D4, Biolegend, 320902) in FACS buffer (2% FBS in PBS and 2 mMEDTA). Samples were analyzed using a Thermo Scientific Attune NxT flow cytometer, and data were analyzed using FlowJo.

[0169] For the above experiments, the human melanoma cell lines A375 (CRL-1619), lung cancer A549 (CCL-185), non-small cell lung cancer H2030 (CRL-5914), squamous cell carcinoma NCI-H226 (CRL-5826), lung adenocarcinoma Calu3 (HTB-55), pancreatic cancer PANC1 (CRL-1469), pancreatic adenocarcinoma Capan2 (HTB-80), ovarian cancer OVACAR3 (HTB-161), colon cancer HCT116, prostate cancer 22Rv1 (CRL-2505), grade IV adenocarcinoma PC3 (CRL-1435), and LNCaP (CRL-1740) were all obtained from the American Type Culture Collection (ATCC, USA). All cell lines were cultured in the recommended medium containing a 1% antibiotic mixture (penicillin / streptomycin-Pen / Strep, 10,000 IU / mL; Sigma-Aldrich) and 10% fetal bovine serum (FBS; Gibco, Thermo Fisher Scientific). Cells were maintained at 37°C in a humidified atmosphere containing 5% carbon dioxide (CO2).

[0170] Example 10 like Figure 12 As shown, experiments were performed using a cytokine release assay to evaluate the safety profile of AHA-P-1031. In summary, AHA-P-1031 exhibits a favorable safety profile, similar to other NK cell-based therapies, and is significantly safer than T cell-guided therapies. Cytokine release assays were performed using human PBMCs from multiple donors. PBMCs from multiple donors were incubated with AHA-P-1031 (150 ug / ml and 750 ug / ml) or Hu isotype IgG1 (750 ug / ml) and anti-CD3 and anti-CD28 (as positive controls). After overnight incubation with AHA-1031 and control antibodies, the release of multiple cytokines from the cell supernatant was measured using the Biolegend Multiple Cytokine Assay Kit. AHA-P-1031 did not result in a significant increase in the levels of pro-inflammatory cytokines IFNγ, IL-2, IL-4, and IL-17A. Figure 12 These data demonstrate the low toxicity risk of AHA-P-1031.

[0171] In addition, physicochemical characterization was performed, a biophysical characterization technique used to assess the conformational stability of biological samples. AHA-P-1031 was generated in CHOK1 cells using a two-plasmid system (heavy and light chains), with transient transfection in 200 ml. The expressed recombinant antibody was purified using a Protein A column and characterized by size exclusion chromatography. The stability of AHA-P-1031 mAb was examined at room temperature, under stress at 37°C, and under stress at pH 3.5 for 2 hours. All samples were run on an SEC column and SDS-PAGE to assess aggregation or fragmentation. The results demonstrated that AHA-P-1031 exhibited excellent transient expression characteristics, with high titers (>1.4 gm / L) and purity, indicating stable cell line production without significant fragment aggregation.

[0172] sequence The following section provides the various amino acid and nucleic acid sequences cited in this article.

[0173] Table 2: Anti-MICA antibody (CDR sequence)

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184] Table 3: Anti-MICA antibody (VH and VL sequences)

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215] Table 4: Anti-MICA antibodies (HC IgG1 Fc and LCκ sequences)

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303] Human MHC class I chain-associated protein A (MICA) (see e.g. UniProt accession number B0FYL7): PHSLRYNLTVLSWDGSVQSGFLAEVHLDGQPFLRYDRQKCRAKPQGQWAEDVLGNKTWDRETRDLTGN GKDLRMTLAHIKDQKEGLHSLQEIRVCEIHEDNSTRSSQHFYYDGELFLSQNVETEEWTVPQSSRAQTLAMNVRNFLKEDAMKTKTHYHAMHADCLQEL RRYLESSVVLRRTVPPMVNVTRSEASEGNITVTCRASSFYPRNITLTWRQDGVSLSHDTQQWGDVLPDGNGTYQTWVATRICQGEEQRFTCYMEHSGNHSTHPVPSGKVLVLQSHWQTFHVSAVAAAAAAAAAIFVIIIFYVCCCKKKTSAAEGPELVSLQVLDQHPVGTSDHRDATQLGFQPLMSDLGSTGSTEGA (SEQ ID NO: 837).

[0304] Human MHC class I chain-associated protein A (MICA), with the α3 domain underlined (see, for example, UniProt accession number B0FYL7): MEPHSLRYNLTVLSWDGSVQSGFLTEVHLDGQPFLRCDRQKCRAKPQGQWAEDVLGNKTWDRETRDLTGNGKDLRMTLAHIKDQKEGLHSLQEIRVCEIHEDNSTRSSQHFYYDGELFLSQNLETKEWTMPQSSRAQTLAMNVRNFLKEDAMKTKTHYHAMHADCLQELRRYLKSGVVLRR TVPPMVNVTRSEASEGNITVTCRASGFYPWNITLSWRQD GVSLSHDTQQWGDVLPDGNGTYQTWVATRICQGEEQRFTCYMEHSGNHSTHPVPS (SEQ ID NO: 838). (See, for example, MABS 2019, Vol. 11, No. 1, pp. 75-93, Spiess et al.) Extracellular domain (ECD) of human MICA (see, for example, UniProt accession number Q29983): EPHSLRYNLTVLSWDGSVQSGFLTEVHLDGQPFLRCDRQKCRAKPQGQWAEDVLGNKTWDRETRDLTGNGKDLRMTLAHIKDQKEGLHSLQEIRVCEIHEDNSTRSSQHFYYDGELFLSQNLETKEWTMPQSSRAQTLAMNVRNFLKEDAMKTKTHYHAMHADCLQELRRYLKSGVVLRRTVPPMVNVTRSEASEGNITVTCRASGFYPWNITLSWRQDGVSLSHDTQQWGDVLPDGNGTYQTWVATRICQGEEQRFTCYMEHSGNHSTHPVPSGKVLVLQSHW (SEQ ID NO:839).

[0305] The extracellular domain (ECD) of human MICB (see, for example, UniProt accession number Q29980): AEPHSLRYNLMVLSQDGSVQSGFLAEGHLDGQPFLRYDRQKRRAKPQGQWAENVLGAKTWDTETEDLTENGQDLRRTLTHIKDQKGGLHSLQEIRVCEIHEDSSTRGSRHFYYDGELFLSQNLETQESTVPQSSRAQTLAMNVTNFWKEDAMKTKTHYRAMQADCLQKLQRYLKSGVAIRRTVPPMVNVTCSEVSEGNITVTCRASSFYPRNITLTWRQDGVSLSHNTQQWGDVLPDGNGTYQTWVATRIRQGEEQRFTCYMEHSGNHGTHPVPSGKALVLQSQRTD (SEQ IDNO: 840).

[0306] MICA ( Crab-eating macaques ) ECD (see, for example, GenBank: AAO24115.1 (Chinese biological sequence)): ELHSLRYNVTVLSRDGSVQSEFLAEGHLDGQLFVRYDRETRRARPQGQWAEDVLGAKTWDTETGDLTENGKDLRMTLAHIKGQKGGLHSLQEIKVCEIHEDNSTGGLRHFYYDGELFLSQNLETQEWTELQSSRAQTLALNIRNFWKEDTMKTKTHYRAVQADCLKKLQRYLESGVAVRRTAPPMVNVTHSEASEGNITVTCRASGFYPRNIALTWRQDGVSLNHNAQQWGGILPDQNGTYQTWVATRIRQGEEQRFACYMEHSGNHSTHPVPSGKVLVFQSQW (SEQ ID NO:841).

[0307] ECD of cynomolgus macaque MICA (see, for example, US 2019 / 0315870A1): ELHSLRYNVTVLSRDGSVQSGFLAEGHLDGQLFLLYDRQKCRARPQGEWSEDVLGAKTWDTETGDLTENGKDLRMTLAHIKGQKGGLHSLQEIKVCEIHEDNSTGGLRHFYYDGELFLSQNLETQEWTELQSSRAQTLALNIRNFWKEDTMKTKTHYRAVQADCLKKLQQYLESGVAVRRTAPPMVNVTHSEASEGNITVTCRASGFYPRNIALTWRQDGVSLNHNAQQWGGILPDQNGTYQTWVATRIRQGEEQRFACYMEHSGNHSTHPVPS (SEQ ID NO: 842).

[0308] α3 domain of human MICA (amino acids 183 to 274): VPPMVNVTRSEASEGNITVTCRASGFYPWNITLSWRQDGVSLSHDTQQWGDVLPDGNGTYQTWVATRICQGEEQRFTCYMEHSGNHSTHPVPSGKVLVLQSHW (SEQ ID NO: 843).

[0309] α3 domain of human MICA-008 (Genentech): TVPPMVNVTRSEASEGNITVTCRASSFYPRNIILTWRQDGVSLSHDTQQWGDVLPDGNGTYQTWVATRICRGEEQRFTCYMEHSGNHSTHPVPS (SEQ ID NO: 844).

[0310] ATX-P-1826 (fully humanized anti-MICA antibody, as described herein; see, for example, SEQ ID NO: 93, 113, 133, 272, 295, 318, 400, 458, 516, 574, 632, 690, 748, and 806) was used to generate an Fc-enhancing antibody, named AHA-P-1031. The amino acid sequences of the light chains of ATX-P-1826 and AHA-P-1031 are identical (Table 5). The amino acid sequences of the variable region (VH) of the heavy chain of ATX-P-1826 and AHA-P-1031 are also identical (Table 5). However, the Fc region of the heavy chain of AHA-P-1031 is modified to include the following three amino acids in substitution: S239D, A330L, and I332E (SEQ ID NO: 845). Therefore, AHA-P-1031 comprises the sequence shown in Table 5 below.

[0311] Table 5: Amino acid and polynucleotide sequences of AHA-P-1031.

[0312]

[0313]

[0314] Table 6: Summary of SEQ ID NOs of individual exemplary antibodies of this disclosure.

[0315]

[0316]

[0317]

[0318]

[0319]

[0320] Symbol explanation: aa = amino acid; HCDR 1, 2, 3 = heavy chain CDR 1, 2, and 3 (in numerical order); LCDR 1, 2, 3 = light chain CDR 1, 2, and 3 (in numerical order); VH = heavy chain variable region; VL = light chain variable region; VH + constant = heavy chain variable region sequence and exemplary human heavy chain constant region sequence (typically IgG1); VL + constant = light chain variable region sequence and exemplary human light chain constant region sequence (typically κ). All numbers except those in "Antibody Name" correspond to SEQ ID NO in the sequence listing and Tables 2, 3, 4, and 5.

[0321] This document describes various embodiments of the present disclosure. Variations of those embodiments will become apparent to those skilled in the art upon reading the foregoing description. The inventors intend that those skilled in the art adopt such variations as appropriate, and the inventors intend to practice the various embodiments of the present disclosure in ways different from those specifically described herein. Therefore, embodiments of the present disclosure include all modifications and equivalents of the subject matter listed in the appended claims as permitted by applicable law. Furthermore, unless otherwise indicated herein or obviously contradicted by the context, the various embodiments of the present disclosure cover any combination of the foregoing elements in all possible variations.< / nu>

Claims

1. An antibody or an antigen-binding fragment thereof that specifically binds to MHC class I chain-associated protein A (MICA), optionally wherein said MICA is human MICA, optionally being a polypeptide comprising an amino acid sequence comprising any one of SEQ ID NO: 837-839.

2. The antibody or fragment of claim 1, exhibiting any one or more of the following functional characteristics: a. Reduce and / or weaken the hydrolysis of membrane-bound MICA proteins into soluble MICA; and / or b. Reduce and / or attenuate NKG2D-mediated tumor cell escape; c. Enhance NK cell-mediated tumor cell killing; d. Cross-reactive with at least one of cynomolgus monkey MICA (cyMICA), human MICB, human MICA-α3 and / or human MICB-α3; and / or e. No cross-reactivity with at least one of cynomolgus monkey MICA (cyMICA), human MICB, human MICA-α3 and / or human MICB-α3; and / or f. At approximately 1.0 μM or lower K D Combining with human MICA; and / or g. An antibody comprising the VH and VL sequences of any of the exemplary antibodies binds to the same epitope on the human MICA, the sequences of which are provided in Table 6; and / or h. Compete with an antibody containing the VH and VL sequences of any of the exemplary antibodies, the sequences of which are provided in Table 6, for binding to human MICA.

3. The antibody or fragment according to any one of the preceding claims is monoclonal, optionally recombinant.

4. The antibody or fragment according to any one of the preceding claims is human, humanized, or chimeric.

5. The antibody or fragment according to any one of the preceding claims is a full-length antibody, a single-chain antibody, a single-chain variable fragment (scFv), a variable fragment (Fv), a fragment antigen-binding region (Fab), Fab-C, Fab'-SH, (Fab')2, a single-domain antibody (sdAb), a VHH antibody, a nanobody, a camel-derived single-domain antibody, a shark IgNAR-derived single-domain antibody fragment (VNAR), a biantibody, a triantibody, an anti-carrier protein, or an aptamer, optionally wherein the antibody is a full-length antibody comprising an Fc region (such as a human IgG1, IgG2, IgG3, or IgG4 region), and optionally wherein the antibody comprises a modified Fc region.

6. An antibody or fragment according to any one of the preceding claims, conjugated to at least one additional portion, said additional portion optionally selected from: a. An antigen-binding moiety, such as an antibody or its antigen-binding fragment, said antigen-binding moiety being capable of specifically binding to a non-human MICA target; and / or b. Therapeutic or cytotoxic components; and / or c. Detection section; and / or d. Purified portion; and / or e. The portion with extended half-life.

7. The antibody or fragment according to any one of the preceding claims, comprising a polypeptide comprising: a. One, two, or all three HCDRs of any one of the exemplary antibodies, the sequences of which are provided in Table 6, and optionally one, two, or all three corresponding LCDRs of the exemplary antibodies; and / or b. A VH sequence having at least 90% identity with the VH sequence of any of the exemplary antibodies, the sequences of which are provided in Table 6, and optionally a VL sequence having at least 90% identity with the corresponding VL sequence of the exemplary antibody, preferably wherein variation in the HCDR or LCDR is not permitted; and / or c. All six CDRs of any one of the exemplary antibodies, the sequences of which are provided in Table 6; and / or d. The VH and VL sequences of any of the exemplary antibodies, the sequences of which are provided in Table 6; and / or e. The full-length heavy chain (VH+ constant) sequence of any of the exemplary antibodies, the sequences of which are provided in Table 6, and optionally the corresponding full-length light chain (VL+ constant) sequence of the exemplary antibody.

8. A polynucleotide encoding an antibody or fragment according to any one of the preceding claims, optionally wherein the polynucleotide comprises or is composed of a nucleic acid sequence having at least 70%, 80%, 90%, or 100% identity with a nucleic acid sequence of any of the exemplary antibodies, the sequences of which are provided in Table 6.

9. An expression vector comprising the polynucleotide of claim 8, optionally an adeno-associated virus (AAV) vector, a lentiviral (LV) vector, a herpes simplex virus (HSV) vector, or a retroviral vector.

10. A pharmaceutical composition comprising an antibody or fragment, a polynucleotide or a carrier according to any one of the preceding claims, and optionally: a. At least one pharmaceutically acceptable carrier, diluent, or preservative; and / or b. At least one other active ingredient.

11. The pharmaceutical composition of claim 10, suitable for administration to a subject, optionally by ocular, oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual or suppository administration.

12. An antibody or fragment according to any one of claims 1 to 7, a polynucleotide according to claim 8, a carrier according to claim 9, or a composition according to claim 10 or 11, used as a medicament, optionally for treating a subject with cancer.

13. The antibody, fragment, polynucleotide, carrier, or composition used in claim 12, wherein the cancer is characterized by exhibiting the ability to evade immune clearance mediated by the natural killer cell group 2D (NKG2D) receptor.

14. The antibody, fragment, polynucleotide, vector, or composition used according to claim 12 or 13, wherein the method comprises intravenous administration of the antibody, and wherein the intravenous administration relieves at least one symptom of the subject.

15. The antibody, fragment, polynucleotide, carrier, or composition used according to any one of claims 12 to 14, wherein the cancer is lung cancer, pancreatic cancer, ovarian cancer, colon cancer, and prostate cancer.

16. An antibody or antigen-binding fragment thereof targeting an MHC class I chain-associated protein A (MICA) peptide, said antibody or antigen-binding fragment comprising a heavy chain variable region (VH) and a light chain variable region (VL), said heavy chain variable region comprising complementarity-determining regions (CDRs) HCDR1, HCDR2, and HCDR3, said light chain variable region comprising complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3, wherein: The HCDR1 contains one of the following amino acid sequences: (a) X1YX2MX3 (SEQ ID NO: 1), wherein X1 is R, S or T; X2 is S or A; and X3 is N or S; (b) X1X2X3MH (SEQ ID NO: 64), wherein X1 is N, D or S; X2 is H, Y or S; and X3 is A or G; (c) X1X2X3X4X5 (SEQ ID NO: 85), wherein X1 is G, S, V, A, N or T; X2 is N or Y; X3 is Y, D, L or G; X4 is I, M or L; and X5 is H, N, E or S; (d) X1YDX2N (SEQ ID NO: 145), where X1 is S, H, or N; X2 is I or V; or (e) X1X2X3X4X5 (SEQ ID NO: 172), wherein X1 is D, N, S or A; X2 is N, Y or Q; X3 is Y, N or A; X4 is I, W or M; and X5 is S, H, Y or N; The HCDR2 contains one of the following amino acid sequences: (a) X1IX2X3X4X5X6X7X8X9YADSVKG (SEQ ID NO: 22), wherein X1 is Y, F, S or V; X2 is N, S or T; X3 is S, T, Y or G; X4 is R or S; X5 is S, G or E; X6 is N, S, T, G or D; X7 is T, R or N; X8 is I or T; and X9 is Y or D; (b) X1IX2X3X4GX5X6X7X8YX9DSVKG (SEQ ID NO: 71), wherein X1 is L, I, G or V; X2 is W or S; X3 is Y or W; X4 is D or S; X5 is S, G or N; X6 is N or S; X7 is K or I; X8 is Y, G or F; X9 is A or E; (c) X1IX2X3X4X5GX6TX7X8X9X 10 X 11 FX 12 X 13 (SEQ ID NO: 105), wherein X1 is W or A; X2 is N, D or S; X3 is P or S; X4 is N, D, G or Y; and X5 is S or N; X6 is A, G or N; X7 is N or H; X8 is S or Y; X9 is A or N; X 10 For Q or E; X 11 For N, K, or E; X 12 For Q or K; and X 13 For G or D; (d) WNMPX1SX2NTGX3AQKFQG (SEQ ID NO: 154), where X1 is N or D; X2 is G or S; and X3 is Y or F; or (e) X1IX2X3X4X5X6X7X8X9X 10 X 11 X 12 X 13 X 14 X 15 (SEQ ID NO: 178), wherein X1 is W, T, Y, or F; X2 is Y, N, E, or F; X3 is A, P, N, or T; X4 is G, S, Y, T, or H; X5 is T, G, or N; X6 is G, V, or I; X7 is G, S, V, T, or D; X8 is S, T, P, or N; X9 is S, M, Y, or T; X 10 For Y or N; X 11 For N, A, or P; X 12 For Q, P, S, or D; X 13 For K, R, L, or D; X 14 For F or K; and X 15 For R, Q, K, or S; The HCDR3 contains one of the following amino acid sequences: (a) X1X2X3X4X5X6X7 (SEQ ID NO: 43), wherein X1 is V, A or G; X2 is S, M or G; X3 is D, S, A, V, I or Y; X4 is I, V, R, Q or W; X5 is T, G, L or F; X6 is G, S, T, W or D; and X7 is N, G, S, P or N; (b) X1X2X3X4 (SEQ ID NO: 78), wherein X1 is E or S; X2 is R or Y; X3 is D, F, L or V; and X4 is Y, P or V; (c) X1X2X3X4X5X6X7X8 (SEQ ID NO: 125), wherein X1 is D, S, A, F or E; X2 is T, A, S, N or L; X3 is F, A, W, Y or G; X4 is K, R, A, G, P or N; and X5 is P, G, A, Y or W; X6 is Y, F, S or N; X7 is Y, F or D; and X8 is Y, S or N; (d) X1X2X3X4X5X6DX7 (SEQ ID NO: 163), wherein X1 is S or G; X2 is A or S; X3 is A or I; X4 is S, A, or R; X5 is G or A; X6 is F, V, or S; and X7 is Y, N, S, or I; or (e) X1X2X3X4X5X6X7X8 (SEQ ID NO: 184), wherein X1 is H, Y, S, G, or T; X2 is D, S, G, M, or Y; X3 is Y, W, S, A, or G; X4 is Y, G, S, A, or N; X5 is G, P, N, R, or Y; X6 is T, G, F, P, or A; X7 is S, A, D, Y, or M; X8 is G, F, Y, or D; and The LCDR1 comprises an amino acid sequence of any one of SEQ ID NO: 191-213, SEQ ID NO: 263-284, or SEQ ID NO: 332-344; the LCDR2 comprises an amino acid sequence of any one of SEQ ID NO: 215-237, SEQ ID NO: 286-306, or SEQ ID NO: 346-358; and the LCDR3 comprises an amino acid sequence of any one of SEQ ID NO: 239-261, SEQ ID NO: 309-330, or SEQ ID NO: 360-372.

17. An antibody or antigen-binding fragment thereof targeting an MHC class I chain-associated protein A (MICA) peptide, said antibody or antigen-binding fragment comprising a heavy chain variable region (VH) and a light chain variable region (VL), said heavy chain variable region comprising complementarity-determining regions (CDRs) HCDR1, HCDR2, and HCDR3, said light chain variable region comprising complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3, wherein: The LCDR1 contains one of the following amino acid sequences: (a) X1X2SX3X4IX5X6X7X8X9 (SEQ ID NO: 190), wherein X1 is R or S; X2 is A or S; X3 is Q or S; X4 is S, T, R or G; X5 is H, S, N, T or R; X6 is N, S, Y, I or D; X7 is Y, F, D or H; X8 is L, F or Y; and X9 is N, G, A or L; (b) X1X2SX3X4X5X6X7X8X9X 10 (SEQ ID NO: 262), wherein X1 is R, S, or K; X2 is T, A, or S; X3 is Q or G; X4 is G, A, V, N, D, H, S, or R; X5 is V or I; X6 is N, G, S, H, R, V, or L; X7 is S, N, H, or Y; X8 is W, Y, or S; X9 is L, N, or S; and X 10 It can be A, N, or E; or (c) RX1SQSX2X3X4X5X6X7 (SEQ ID NO: 331), wherein X1 is A or T; X2 is V or I; X3 is I, S or N; X4 is I, T or S; X5 is N, K, S, W or Y; X6 is Q, Y, H or L; and X7 is L or A; The LCDR2 contains one of the following amino acid sequences: (a) X1X2X3X4LX5S (SEQ ID NO: 214), wherein X1 is A, S, G or R; X2 is A or T; X3 is S or F; X4 is S, T, G or N; and X5 is Q or A; (b) X1X2X3X4X5X6X7 (SEQ ID NO: 285), wherein X1 is A, Y, D, T, K, or W; X2 is A, T, or V; X3 is S or E; X4 is S, T, I, or N; X5 is L or R; X6 is Q, A, H, L, F, or E; and X7 is S, D, or L; or (c) X1X2SX3X4X5X6X7 (SEQ ID NO: 345), wherein X1 is G, K or D; X2 is A or T; X3 is S, T or N; X4 is R or L; X5 is A, E, V or Q; and X6 is T or S; The LCDR3 contains one of the following amino acid sequences: (a) X1X2X3X4X5X6X7X8 (SEQ ID NO: 238), wherein X1 is Q or L; X2 is Q or E; X3 is S, H, L or G; X4 is Y, N, H or S; and X5 is N, S, T or I; (b) X1QX2X3X4X5PX6X7 (SEQ ID NO: 308), wherein X1 is F or Q; X2 is A, F, Y, G or S; X3 is N, W, S or Y; X4 is I, S, T, K or H; X5 is F, V, T or Y; X6 is L, I, Y, R or W; and X7 is S or T; or (c) QQX1X2X3X4PX5X6 (SEQ ID NO: 359), wherein X1 is Y, A, or R; X2 is G, N, or S; X3 is S, V, N, or I; X4 is S, F, or W; X5 is R, L, or I; X6 is T or S; and The HCDR1 comprises the amino acid sequence of any one of SEQ ID NO: 2-21, SEQ ID NO: 65-70, SEQ ID NO: 86-104, SEQ ID NO: 147-153, or SEQ ID NO: 173-177; the HCDR2 comprises the amino acid sequence of any one of SEQ ID NO: 23-42, SEQ ID NO: 72-77, SEQ ID NO: 106-124, SEQ ID NO: 153-162, or SEQ ID NO: 179-183; and the HCDR3 comprises the amino acid sequence of any one of SEQ ID NO: 44-63, SEQ ID NO: 79-84, SEQ ID NO: 126-143, SEQ ID NO: 163-171, or SEQ ID NO: 185-189.

18. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 2; HCDR2 comprises the amino acid sequence of SEQ ID NO: 23; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

44.

19. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 24; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

45.

20. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 4; HCDR2 comprises the amino acid sequence of SEQ ID NO: 25; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

46.

21. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 5; HCDR2 comprises the amino acid sequence of SEQ ID NO: 26; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

47.

22. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 6; HCDR2 comprises the amino acid sequence of SEQ ID NO: 27; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

48.

23. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 7; HCDR2 comprises the amino acid sequence of SEQ ID NO: 28; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

49.

24. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 8; HCDR2 comprises the amino acid sequence of SEQ ID NO: 29; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

50.

25. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 9; HCDR2 comprises the amino acid sequence of SEQ ID NO: 30; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

51.

26. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 10; HCDR2 comprises the amino acid sequence of SEQ ID NO: 31; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

52.

27. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 11; HCDR2 comprises the amino acid sequence of SEQ ID NO: 32; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

53.

28. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 12; HCDR2 comprises the amino acid sequence of SEQ ID NO: 33; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

54.

29. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; HCDR2 comprises the amino acid sequence of SEQ ID NO: 34; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

55.

30. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 14; HCDR2 comprises the amino acid sequence of SEQ ID NO: 35; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

56.

31. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 15; HCDR2 comprises the amino acid sequence of SEQ ID NO: 36; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

57.

32. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 16; HCDR2 comprises the amino acid sequence of SEQ ID NO: 37; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

58.

33. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 17; HCDR2 comprises the amino acid sequence of SEQ ID NO: 38; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

59.

34. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 18; HCDR2 comprises the amino acid sequence of SEQ ID NO: 39; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

60.

35. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 19; HCDR2 comprises the amino acid sequence of SEQ ID NO: 40; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

61.

36. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 20; HCDR2 comprises the amino acid sequence of SEQ ID NO: 41; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

62.

37. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 21; HCDR2 comprises the amino acid sequence of SEQ ID NO: 42; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

63.

38. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 65; HCDR2 comprises the amino acid sequence of SEQ ID NO: 72; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

79.

39. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 66; HCDR2 comprises the amino acid sequence of SEQ ID NO: 73; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

80.

40. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 67; HCDR2 comprises the amino acid sequence of SEQ ID NO: 74; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

80.

41. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 68; HCDR2 comprises the amino acid sequence of SEQ ID NO: 75; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

81.

42. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 69; HCDR2 comprises the amino acid sequence of SEQ ID NO: 76; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

82.

43. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 70; HCDR2 comprises the amino acid sequence of SEQ ID NO: 77; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

84.

44. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 86; HCDR2 comprises the amino acid sequence of SEQ ID NO: 106; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

126.

45. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 87; HCDR2 comprises the amino acid sequence of SEQ ID NO: 107; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

127.

46. ​​The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 88; HCDR2 comprises the amino acid sequence of SEQ ID NO: 108; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

128.

47. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 89; HCDR2 comprises the amino acid sequence of SEQ ID NO: 109; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

129.

48. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 90; HCDR2 comprises the amino acid sequence of SEQ ID NO: 110; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

130.

49. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 91; HCDR2 comprises the amino acid sequence of SEQ ID NO: 111; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

131.

50. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 92; HCDR2 comprises the amino acid sequence of SEQ ID NO: 112; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

132.

51. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 93; HCDR2 comprises the amino acid sequence of SEQ ID NO: 113; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

133.

52. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 94; HCDR2 comprises the amino acid sequence of SEQ ID NO: 114; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

134.

53. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 95; HCDR2 comprises the amino acid sequence of SEQ ID NO: 115; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

135.

54. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 96; HCDR2 comprises the amino acid sequence of SEQ ID NO: 116; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

136.

55. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 97; HCDR2 comprises the amino acid sequence of SEQ ID NO: 117; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

137.

56. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 98; HCDR2 comprises the amino acid sequence of SEQ ID NO: 118; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

138.

57. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 99; HCDR2 comprises the amino acid sequence of SEQ ID NO: 119; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

139.

58. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 100; HCDR2 comprises the amino acid sequence of SEQ ID NO: 120; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

140.

59. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 101; HCDR2 comprises the amino acid sequence of SEQ ID NO: 121; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

141.

60. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 102; HCDR2 comprises the amino acid sequence of SEQ ID NO: 122; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

142.

61. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 103; HCDR2 comprises the amino acid sequence of SEQ ID NO: 123; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

143.

62. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 104; HCDR2 comprises the amino acid sequence of SEQ ID NO: 124; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

144.

63. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 146; HCDR2 comprises the amino acid sequence of SEQ ID NO: 155; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

164.

64. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 147; HCDR2 comprises the amino acid sequence of SEQ ID NO: 156; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

165.

65. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 148; HCDR2 comprises the amino acid sequence of SEQ ID NO: 157; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

166.

66. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 149; HCDR2 comprises the amino acid sequence of SEQ ID NO: 158; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

167.

67. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 150; HCDR2 comprises the amino acid sequence of SEQ ID NO: 159; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

168.

68. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 151; HCDR2 comprises the amino acid sequence of SEQ ID NO: 160; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

169.

69. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 152; HCDR2 comprises the amino acid sequence of SEQ ID NO: 161; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

170.

70. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 153; HCDR2 comprises the amino acid sequence of SEQ ID NO: 162; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

171.

71. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 173; HCDR2 comprises the amino acid sequence of SEQ ID NO: 179; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

185.

72. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 174; HCDR2 comprises the amino acid sequence of SEQ ID NO: 180; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

186.

73. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 175; HCDR2 comprises the amino acid sequence of SEQ ID NO: 181; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

187.

74. The antibody of claim 16 or claim 17, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 176; HCDR2 comprises the amino acid sequence of SEQ ID NO: 182; and HCDR3 comprises the amino acid sequence of SEQ ID NO:

189.

75. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 191; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 215; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

239.

76. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 192; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 216; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

240.

77. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 193; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 217; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

241.

78. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 194; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 218; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

242.

79. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 195; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 219; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

243.

80. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 196; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 220; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

244.

81. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 197; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 221; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

245.

82. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 198; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 222; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

246.

83. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 199; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 223; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

247.

84. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 200; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 224; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

248.

85. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 201; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 225; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

249.

86. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 202; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 226; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

250.

87. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 203; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 227; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

251.

88. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 204; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 228; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

252.

89. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 205; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 229; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

253.

90. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 206; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 230; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

254.

91. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 207; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 231; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

255.

92. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 208; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 232; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

256.

93. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 209; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 233; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

257.

94. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 210; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 234; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

258.

95. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 211; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 235; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

259.

96. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 212; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 236; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

260.

97. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 213; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 237; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

261.

98. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 263; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 286; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

309.

99. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 264; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 287; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

310.

100. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 265; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 288; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

311.

101. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 266; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 289; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

312.

102. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 267; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 290; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

313.

103. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 268; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 291; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

314.

104. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 269; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 292; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

315.

105. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 270; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 293; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

316.

106. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 271; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 294; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

317.

107. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 272; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 295; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

318.

108. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 273; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 296; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

319.

109. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 274; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 297; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

320.

110. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 275; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 298; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

321.

111. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 276; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 299; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

322.

112. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 277; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 300; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

323.

113. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 278; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 301; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

324.

114. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 279; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 302; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

325.

115. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 280; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 303; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

326.

116. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 281; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 304; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

327.

117. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 282; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 305; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

328.

118. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 283; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 306; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

329.

119. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 284; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 307; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

330.

120. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 332; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 346; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

360.

121. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 333; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 347; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

361.

122. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 334; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 348; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

362.

123. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 335; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 349; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

363.

124. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 336; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 350; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

364.

125. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 337; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 351; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

365.

126. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 338; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 352; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

366.

127. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 339; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 353; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

367.

128. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 340; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 354; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

368.

129. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 341; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 355; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

369.

130. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 342; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 356; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

370.

131. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 343; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 357; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

371.

132. The antibody of claim 16 or claim 17, wherein the LCDR1 comprises the amino acid sequence of SEQ ID NO: 344; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 358; and the LCDR3 comprises the amino acid sequence of SEQ ID NO:

372.

133. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NO: 373-430.

134. The antibody of claim 16 or claim 17, wherein the VL comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NO: 489-546.

135. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 373, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

489.

136. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 374, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

490.

137. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 375, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

491.

138. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 376, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

492.

139. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 377, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

493.

140. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 378, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

494.

141. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 379, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

495.

142. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 380, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

496.

143. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 381, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

497.

144. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 382, ​​and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

498.

145. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 383, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

499.

146. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 384, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

500.

147. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 385, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

501.

148. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 386, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

502.

149. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 387, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

503.

150. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 388, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

504.

151. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 389, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

505.

152. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 390, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

506.

153. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 391, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

507.

154. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 392, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

508.

155. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 393, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

509.

156. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 394, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

510.

157. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 395, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

511.

158. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 396, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

512.

159. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 397, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

513.

160. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 398, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

514.

161. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 399, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

515.

162. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 400, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

516.

163. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 401, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

517.

164. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 402, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

518.

165. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 403, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

519.

166. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 404, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

520.

167. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 405, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

521.

168. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 406, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

522.

169. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 407, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

523.

170. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 408, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

524.

171. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 409, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

525.

172. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 410, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

526.

173. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 411, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

527.

174. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 412, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

528.

175. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 413, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

529.

176. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 414, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

530.

177. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 415, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

531.

178. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 416, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

532.

179. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 417, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

533.

180. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 418, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

534.

181. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 419, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

535.

182. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 420, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

536.

183. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 421, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

537.

184. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 422, and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:

538.

185. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 423, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

539.

186. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 424, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

540.

187. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 425, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

541.

188. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 426, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

542.

189. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 427, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

543.

190. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 428, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

544.

191. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 429, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

545.

192. The antibody of claim 16 or claim 17, wherein the VH comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 430, and the VL comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO:

546.

193. The antibody of claim 16 or claim 17, wherein the heavy chain Fc domain of the antibody comprises an amino acid sequence that is at least 90% identical to that of SEQ ID NO: 845, and comprises at least one amino acid substitution selected from S239D, A330L and / or I332E.

194. The antibody of claim 16 or claim 17, wherein the antibody binds to MICA and reduces the proteolytic cleavage of MICA.

195. The antibody of claim 16 or claim 17, wherein the antibody attenuates NKG2D-mediated tumor cell escape.

196. The antibody of claim 16 or claim 17, wherein the antibody is at about 1.0 μM or lower K D Combined with human MICA.

197. The antibody of claim 16 or claim 17, wherein the antibody cross-reacts with one or more of cynomolgus monkey MICA (cyMICA), human MICA-α3, and human MICB-α3.

198. The antibody of claim 16 or claim 17, wherein the antibody does not cross-react with one or more of cynomolgus monkey MICA (cyMICA), human MICA-α3, and human MICB-α3.

199. The antibody of claim 16 or claim 17, wherein the antibody is a monoclonal antibody, a human antibody, a humanized antibody, and / or a chimeric antibody.

200. The antibody of claim 16 or claim 17, wherein the antibody is a fragment selected from the group consisting of: Fab, Fab-C, Fab'-SH, Fv, scFv and (Fab')2 fragments.

201. The antibody of claim 16 or claim 17, wherein the antibody is a monospecific antibody.

202. The antibody of claim 16 or claim 17, wherein the antibody is a bispecific antibody.

203. The antibody of claim 16 or claim 17, wherein the antibody comprises a detection portion.

204. The antibody of claim 16 or claim 17, wherein the antibody comprises a purified portion.

205. A pharmaceutical composition comprising any one of the antibodies of claims 1 to 204.

206. A method of treating cancer, the method comprising administering to a subject in need a pharmaceutical composition comprising an effective amount of the antibody of claim 16 or claim 17.

207. A polynucleotide having at least 70% identity with the polynucleotide encoding the antibody of claim 16 or claim 17.

208. A polynucleotide having at least 70% identity with any one of SEQ ID NO: 431-488.

209. A polynucleotide having at least 70% identity with any one of SEQ ID NO: 547-604.

210. A polynucleotide having at least 80% identity with any one of SEQ ID NO: 431-488.

211. A polynucleotide having at least 80% identity with any one of SEQ ID NO: 547-604.

212. A polynucleotide having at least 90% identity with any one of SEQ ID NO: 431-488.

213. A polynucleotide having at least 90% identity with any one of SEQ ID NO: 547-604.

214. A polynucleotide comprising: (a) A nucleic acid sequence that is at least 70% identical to any one of SEQ ID NO: 431-488; and (b) A nucleic acid sequence that is at least 70% identical to any one of SEQ ID NO: 547-604.

215. A polynucleotide comprising: (a) A nucleic acid sequence that is at least 80% identical to any one of SEQ ID NO: 431-488; and (b) A nucleic acid sequence that is at least 80% identical to any one of SEQ ID NO: 547-604.

216. A polynucleotide comprising: (a) A nucleic acid sequence that is at least 90% identical to any one of SEQ ID NO: 431-488; and (b) A nucleic acid sequence that is at least 90% identical to any one of SEQ ID NO: 547-604.

217. A polynucleotide comprising a nucleic acid sequence having at least 70% identity with any of the following: (a) SEQ ID NO: 663-720; (b) SEQ ID NO: 779-836; (c) SEQ ID NO: 663-720; (d) SEQ ID NO: 779-836; (e) SEQ ID NO: 663-720; or (f) SEQ ID NO: 779-836.

218. A polynucleotide comprising: (a) A nucleic acid sequence that is at least 70% identical to any one of SEQ ID NO: 663-720; and (b) A nucleic acid sequence that is at least 70% identical to any one of SEQ ID NO: 779-836.

219. A polynucleotide comprising: (a) A nucleic acid sequence that is at least 80% identical to any one of SEQ ID NO: 663-720; and (b) A nucleic acid sequence that is at least 80% identical to any one of SEQ ID NO: 779-836.

220. A polynucleotide comprising: (a) A nucleic acid sequence that is at least 90% identical to any one of SEQ ID NO: 663-720; and (b) A nucleic acid sequence that is at least 90% identical to any one of SEQ ID NO: 779-836.

221. An expression vector comprising any one of the polynucleotides of claims 207-219.

222. The expression vector of claim 220, wherein the expression vector is at least one of the following: adeno-associated virus (AAV) vector, lentiviral (LV) vector, herpes simplex virus (HSV) vector, and retroviral vector.

223. A method of administering gene therapy to a subject in need, the method comprising injecting a pharmaceutical composition comprising an effective amount of the expression vector of claim 220.

224. The antibody of claim 16 or claim 17, wherein the antibody binds to an epitope of a MICA polypeptide having an amino acid sequence having any one of SEQ ID NO: 837-844.

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