Mhc class i chain-related protein a (MICA)-specific antibodies 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-Related Protein A (MICA) in a manner that reduces the ability of a tumor cell to escape immune clearance mediated by the natural killer group 2D (NKG2D) receptor.

Description

MHC CLASS I CHAIN-RELATED PROTEIN A (MICA)-SPECIFIC ANTIBODIES ANDUSES THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of 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.SEQUENCE LISTING

[0002] The text of the computer readable sequence listing filed herewith, titled “AKHA_41436_601_SequenceListing,” created June 13, 2024, having a file size of945,l 12 bytes, is hereby incorporated by reference in its entirety.FIELD

[0003] Embodiments of the present disclosure relate to the treatment of cancer. In particular, the present disclosure provides novel therapeutic antibodies that target MHC Class I Chain-Related Protein A (MICA) in a manner that reduces the ability of a tumor cell to escape immune clearance mediated by the natural killer group 2D (NKG2D) receptor.BACKGROUND

[0004] The immune system plays an important role in tumor development. For example, natural killer (NK) cells are important cytotoxic cells of the immune system, and the activated NKG2D receptor on the surface of NK cells can bind to NKG2DL expressed in tumor cells, thus enabling NK cells to activate and kill tumor cells. However, some tumors have developed the ability to escape immune clearance mediated by NKG2D receptor / NKG2DL through various mechanisms. The expression of NKG2D receptor on NK cells can be regulated by cells, molecules, and hypoxia in the tumor microenvironment. Tumor cells regulate the expression of NKG2DL at the level of transcription, translation, and post-translation and thereby escape recognition by NK cells. In particular, viruses and hormones have special mechanisms to affect the expression of NKG2D receptor and NKG2DL. Therefore, NKG2D\NKG2DL may have applications as targets for more effective antitumor therapy. Additionally, it is widely recognized that DNA damage,oncogene activation and excessive proliferation, chromatin modulations, or oxidative stress are all important hallmarks of cancer. Interestingly, all of these abnormalities also induce a cellular stress response. By upregulating stress-induced ligands, damaged or transformed cells (e.g., tumor cells) can be recognized by immune cells (e.g., NK cells) and cleared. Among the functional stress- induced ligands are 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 well-recognized as an important mediator of anti-tumor activity; however, patient data about the role of NKG2D ligands in immune surveillance and escape appears conflicting. As these ligands are often actively transcribed, tumor cells are urged to manipulate the expression of these ligands on post-transcriptional or post-translational level. Although knowledge on the regulation of NKG2D ligand expression remains fragmentary, recent research has revealed multiple cellular mechanisms that are adopted by tumor cells to reduce the expression of stress- induced ligands and therefore escape immune recognition. Therefore, there is a need for alternative therapeutic strategies to target NKG2D-mediated immune escape by tumor cells.SUMMARY

[0005] Embodiments of the present disclosure include an antibody, or antigen binding fragment thereof, that specifically binds MHC Class I Chain-Related Protein A (MICA), optionally wherein the MICA is human MICA, which is optionally a polypeptide comprising the amino acid sequence of any of SEQ ID NOs: 837-839.

[0006] In accordance with these embodiments, the antibody or fragment thereof exhibits any one or more the following functional characteristics: reduces and / or attenuates proteolytic cleavage of membrane -bound MICA into soluble MICA; and / or reduces and / or attenuates NKG2D-mediated escape by a tumor cell; enhances NK cell-mediated killing of a tumor cell; cross-reacts with at least one of Cynomolgus monkey MICA (cyMICA), human MICB, human MICA-alpha3, and / or human MICB-alpha3; and / or does not cross-react with at least one of Cynomolgus monkey MICA (cyMICA), human MICB, human MICA-alpha3; and / or human MICB-alpha3; and / or binds to human MICA with a KD of about 1.0 pM or lower; and / or binds to the same epitope on human MICA as an antibody comprising the VH and VL sequences of any one of the exemplary antibodies the sequences of which are provided in Table 6; and / or competesfor binding to human MICA with an antibody comprising the VH and VL sequences of any one of the exemplary antibodies the sequences of which are provided in Table 6.

[0007] In some embodiments, the antibody or antibody fragment of the present disclosure is monoclonal, optionally recombinant. In some embodiments, the antibody or antibody fragment of the present disclosure is human, humanized or chimeric. In some embodiments, the antibody or antibody fragment of the present disclosure 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), a Fab-C, a Fab’-SH, a (Fab’)2, a single-domain antibody (sdAb), a VHH antibody, a nanobody, a camelid-derived single-domain antibody, a shark IgNAR-derived single-domain antibody fragment (VNAR), a diabody, a triabody, an anticalin or an aptamer, optionally wherein the antibody is a full length antibody comprising an Fc region such as a human IgGl, IgG2, IgG3 or IgG4 region, and optionally wherein the antibody comprises a modified Fc region.

[0008] In some embodiments, the antibody or antibody fragment of the present disclosure is conjugated to at least one additional moiety, optionally selected from: an antigen binding moiety, such as an antibody or antigen-binding fragment thereof, which is capable of specific binding to a target which is not human MICA; and / or a therapeutic or cytotoxic moiety; and / or a detection moiety; and / or a purification moiety; and / or a half-life extension moiety.

[0009] In some embodiments, the antibody or antibody fragment of the present disclosure is a polypeptide comprising: one, two or all three HCDRs of any one of the exemplary antibodies the sequences of which are provided in Table 6, and optionally also one, two or all three of the corresponding LCDRs of the exemplary antibody; and / or a VH sequence having at least 90% identity to the VH sequence of any one of the exemplary antibodies the sequences of which are provided in Table 6, and optionally also a VL sequence having at least 90% identity to the corresponding VL sequence of the exemplary antibody, preferably wherein variation is not permitted in the HCDRs or LCDRs; and / or all six CDRs of any one of the exemplary antibodies the sequences of which are provided in Table 6; and / or the VH and VL sequences of any one of the exemplary antibodies the sequences of which are provided in Table 6; and / or the full length heavy chain (VH + constant) sequence of any one 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.

[0010] Embodiments of the present disclosure also include a polynucleotide encoding an antibody or antibody fragment of the present disclosure, optionally wherein the polynucleotide comprises or consists of a nucleic acid sequence having at least 70, 80, 90 or 100% identity to a nucleic acid sequence of any one of the exemplary antibodies the sequences of which are provided in Table 6.

[0011] Embodiments of the present disclosure also include an expression vector comprising any of the polynucleotides of the present disclosure, which is optionally an adeno-associated virus (AAV) vector, a lentiviral (LV) vector, a herpes simplex virus (HSV) vector, or a retrovirus vector.

[0012] Embodiments of the present disclosure also include a pharmaceutical composition comprising an antibody or antibody fragment, a polynucleotide, or an 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 for ocular, oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration.

[0013] Embodiments of the present disclosure also include a polynucleotide, an expression vector, or a composition of the present disclosure, for use as a medicament, optionally for use in a method of treating cancer in a subject. In some embodiments, the antibody, antibody fragment, polynucleotide, expression vector, or composition of the present disclosure is used as part of a method of treating cancer in a subject, wherein the cancer is characterized as exhibiting the ability to escape immune clearance mediated by the natural killer group 2D (NKG2D) receptor. In some embodiments, the antibody, antibody fragment, polynucleotide, expression vector, or composition of the present disclosure is used as part of a method of treating cancer in a subject, wherein the method comprises intravenous administration of the antibody, antibody fragment, polynucleotide, expression vector, or composition, and wherein the intravenous administration relieves at least one symptom in the subject. In accordance with these embodiments, the cancer is lung cancer, pancreatic cancer, ovarian cancer, colon cancer, and prostate cancer.

[0014] Embodiments of the present disclosure include antibodies directed against MHC Class 1 Chain-Related Protein A (MICA) peptides, or antigen-binding fragments thereof. In accordance with these embodiments, the present disclosure provides a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and alight chain variable region (VL) comprising complementarity determining regions (CDRs) LCDR1 , LCDR2, and LCDR3. In some embodiments, the HCDR1 comprises one of the following amino acid sequences: (a) X1YX2MX3 (SEQ ID NO: 1), wherein Xi is R, S, or T; X2 is S or A; and X3is N or S; (b) X1X2X3MH (SEQ ID NO: 64), wherein Xi is N, D, or S; X2is H, Y, or S; X3is A or G; (c) X1X2X3X4X5 (SEQ ID NO: 85), wherein Xi is G, S, V, A, N, or T; X2is N or Y; X3is Y, D, L, or G; X4is I, M, or L; and X5is H, N, E, or S; (d) X1YDX2N (SEQ ID NO: 145), wherein Xi is S, H, or N; X2 is I or V; or (e) X1X2X3X4X5 (SEQ ID NO: 172), wherein Xi is D, N, S, or A; X2 is N, Y, or Q; X3 is Y, N, or A; X4is I, W, or M; and X5 is S, H, Y, or N; wherein the HCDR2 comprises one of the following amino acid sequences: (a) X1IX2X3X4X5X6X7X8X9YADSVKG (SEQ ID NO: 22), wherein Xi is Y, F, S, or V; X2is N, S or T; X3 is S, T, Y, or G; X4is R or S; X5 is S, G, or E; Xe is N, S, T, G, or D; X7 is T, R, or N; Xs is I or T; and X9is Y or D; (b) X1IX2X3X4GX5X6X7X8YX9DSVKG (SEQ ID NO: 71), wherein Xi is L, I, G, or V; X2 is W or S; X3 is Y or W; X4is D or S; X5 is S, G, or N; Xe is N or S; X7 is K or I; X8is Y, G, or F; X9is A or E; (c) X1IX2X3X4X5GX6TX7X8X9X10X11FX12X13 (SEQ ID NO: 105), wherein Xi is W or A; X2 is N, D, or S; X3 is P or S; X4is N, D, G, or Y; and X5 is S or N; Xe is A, G, or N; X7 is N or H; Xs is S or Y; X9 is A or N; X10 is Q or E; Xu is N, K, or E; X12 is Q or K; and X13 is G or D; (d) WNMPX1SX2NTGX3AQKFQG (SEQ ID NO: 154) wherein Xi is N or D; X2is G or S; and X3is Y or F; or (e) X1IX2X3X4X5X6X7X8X9X10X11X12X13X14X15 (SEQ ID NO: 178), wherein Xi is W, T, Y, or F; X2is Y, N, E, or F; X3is A, P, N, or T; X4is G, S, Y, T or H; X5is T, G, or N; X6is G, V, or I; X7is G, S, V, T, or D; X8is S, T, P, or N; X9is S, M, Y, or T; X10 is Y or N; Xu is N, A, or P; X12 is Q, P, S, or D; X13 is K, R, L, or D; X14 is F or K; and X15 is R, Q, K, or S; and wherein the HCDR3 comprises one of the following amino acid sequences: (a) X1X2X3X4X5X6X7 (SEQ ID NO: 43), wherein Xi is Xi is V, A, or G; X2 is S, M, or G; X3is D, S, A, V, I or Y; X4is I, V, R, Q or W; X5is T, G, L, or F; X6is G, S, T, W or D; and X7is N, G, S, P or N; (b) X1X2X3X4 (SEQ ID NO: 78), wherein Xi is Xi is E or S; X2is R or Y; X3is D, F, L, or V; X4is Y, P, or V; (c) X1X2X3X4X5X6X7X8 (SEQ ID NO: 125), wherein Xi is D, S, A, F, or E; X2is T, A, S, N, or L; X3is F, A, W, Y, or G; X4is K, R, A, G, P, or N; and X5is P, G, A, Y, or W; X6is Y, F, S, or N; X7is Y, F, or D; and X8is Y, S, or N; (d) X1X2X3X4X5X6DX7 (SEQ ID NO: 163) wherein Xi is S or G; X2is A or S; X3is A or I; X4is S, A, or R; X5is G or A; X6is F, V, or S; and X7is Y, N, S, or I; or (e) X1X2X3X4X5X6X7X8 (SEQ ID NO: 184), wherein Xi is H, Y, S, G, or T; X2is D, S, G, M, or Y; X3is Y, W, S, A, or G; X4isY, G, S, A, or N; X5is G, P, N, R, or Y; X6is T, G, F, P, or A; X7is S, A, D, Y, or M; X8is G, F, Y, or D.

[0015] In accordance with the above embodiments, the LCDR1 of the anti-MICA antibodies of the present disclosure includes an amino acid sequence of any of SEQ ID NOs: 191-213, SEQ ID NOs: 263-284, or SEQ ID NOs: 332-344; the LCDR2 comprises an amino acid sequence of any of SEQ ID NOs: 215-237, SEQ ID NOs: 286-306, or SEQ ID NOs: 346-358; and the LCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 239-261, SEQ ID NOs: 309-330, or SEQ ID NOs: 360-372.

[0016] In some embodiments, the present disclosure provides antibodies directed against MICA peptides, or antigen-binding fragments thereof, that include a VH comprising complementarity determining regions HCDR1, HCDR2, and HCDR3, and a VL comprising complementarity determining regions LCDR1, LCDR2, and LCDR3, wherein the LCDR1 comprises one of the following amino acid sequences: (a) X1X2SX3X4IX5X6X7X8X9 (SEQ ID NO: 190), wherein Xi 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; X6is N, S, Y, I, or D; X7is Y, F, D, or H; X8is L, F, or Y; and X9 is N, G, A, or L; (b) XiX2SX3X4X5X6X7X8X9Xio (SEQ ID NO: 262), wherein Xi is R, S, or K; X2is T, A, or S; X3is Q or G; X4is G, A, V, N, D, H, S, or R; X5is V or I; X6is N, G, S, H, R, V, or L; X7is S, N, H, or Y; X8is W, Y, or S; X9is L, N, or S; and X10 is A, N, or E; or (c) RXISQSX2X3X4X5X6X7(SEQ ID NO: 331), wherein Xi is A or T; X2is V or I; X3is I, S, or N; X4is I, T, or S; X5is N, K, S, W, or Y; Xe is Q, Y, H, or L; and X7is L or A; wherein the LCDR2 comprises one of the following amino acid sequences: (a) X1X2X3X4LX5S (SEQ ID NO: 214), wherein Xi is A, S, G, or R; X2 is A or T; X3is S or F; X4is S, T, G, or N; and X5is Q or A; (b) XiX2X3X4X5X6X7(SEQ ID NO: 285), wherein Xi 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; X6is Q, A, H, L, F, or E; and X7is S, D, or L; or (c) XiX2SX3X4X5X6X7(SEQ ID NO: 345), wherein Xi 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 Xe is T or S; and wherein the LCDR3 comprises one of the following amino acid sequences: (a) XiX2X3X4X5X6X7X8(SEQ ID NO: 238), wherein Xi is Q or L; X2is Q or E; X3is S, H, L, or G; X4is Y, N, H, or S; and X5is N, S, T, or I; (b) XIQX2X3X4X5PX6X7(SEQ ID NO: 308), wherein Xi is F or Q; X2is A, F, Y, G, or S; X3 is N, W, S, or Y; X4is I, S, T, K, or H; X5is F, V, T, or Y; X6is L, I, Y, R, or W; and X7is S or T; or (c) QQX1X2X3X4PX5X6 (SEQ ID NO: 359), whereinXi 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; Xe is T or S.

[0017] In accordance with the above embodiments, the HCDR1 of the anti-MICA antibodies of the present disclosure includes an amino acid sequence of any of SEQ ID NOs: 2-21, SEQ ID NOs: 65-70, SEQ ID NOs: 86-104, SEQ ID NOs: 147-153 or SEQ ID NOs: 173-177; the HCDR2 comprises an amino acid sequence of any of SEQ ID NOs: 23-42, SEQ ID NOs: 72-77, SEQ ID NOs: 106-124, SEQ ID NOs: 153-162, or SEQ ID NOs: 179-183; and the HCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 44-63, SEQ ID NOs: 79-84, SEQ ID NOs: 126-143, SEQ ID NOs: 163-171, or SEQ ID NOs: 185-189.

[0018] In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 2; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 23; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 24; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 45. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 4; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 25; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 46. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 5; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 26; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 6; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 27; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 48. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 7; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 28; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 49. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 8; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 29; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 50. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 9; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 30; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 51. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 10; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 31 ; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 52. In some embodiments,the HCDR1 comprises the amino acid sequence of SEQ ID NO: 11; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 32; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 53. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 12; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 33; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 54. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 34; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 55. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 14; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 35; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 56. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 15; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 36; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 57. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 16; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 37; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 58. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 17; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 38; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 59. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 18; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 39; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 60. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 19; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 40; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 61. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 20; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 41 ; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 62. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 21; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 42; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 63. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 65; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 72; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 79. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 66; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 73; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:80. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 67; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 74; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 80. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 68; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 75; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 81. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 69; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 76; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 82. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 70; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 77; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 84. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 86; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 106; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 126. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 87; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 107; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 127. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 88; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 108; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 128. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 89; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 109; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 129. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 90; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 110; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 130. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 91; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 111; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 131. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 92; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 112; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 132. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 93; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 113; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 133. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 94; the HCDR2 comprises the amino acidsequence of SEQ ID NO: 114; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 134. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 95; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 115; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 135. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 96; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 116; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 136. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 97; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 117; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 137. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 98; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 118; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 138. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 99; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 119; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 139. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 100; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 120; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 140. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 101; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 121; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 141. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 102; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 122; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 142. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 103; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 123; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 143. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 104; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 124; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 144. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 146; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 155; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 164. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 147; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 156; and the HCDR3 comprises the amino acid sequence of SEQ IDNO: 165. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 148; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 157; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 166. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 149; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 158; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 167. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 150; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 159; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 168. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 151; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 160; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 169. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 152; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 161; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 170. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 153; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 162; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 171. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 173; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 179; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 185. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 174; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 180; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 186. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 175; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 181; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 187. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 176; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 182; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 189. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 acidsequence of SEQ ID NO: 253. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the LCDR1 comprises the amino acidsequence 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In someembodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0019] In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to any of SEQ ID NOs: 373-430. In some embodiments, the VL comprises an amino acid sequence that is at least 90% identical to any of SEQ ID NOs: 489-546.

[0020] In some embodiments, the heavy chain Fc domain of the antibody comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 845, and comprises at least one amino acid substitution selected from S239D, A330L, and / or I332E. In some embodiments, the antibody comprises at least two amino acid substitutions selected from S239D, A330L, and / or I332E. In some embodiments, the antibody comprises all three amino acid substitutions selected from S239D, A330L, and / or I332E. In some embodiments, the antibody comprises at least one additional amino acid substitution with reference to SEQ ID NO: 845.

[0021] In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 373 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 489. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 374 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 490. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 375 and the VL comprises anamino acid sequence that is at least 90% identical to SEQ ID NO: 491. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 376 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 492. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 377 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 493. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 378 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 494. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 379 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 495. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 380 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 496. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 381 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 497. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 382 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 498. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 383 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 499. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 384 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 500. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 385 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 501. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 386 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 502. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 387 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 503. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 388 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 504. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 389 and the VL comprises an amino acid sequencethat is at least 90% identical to SEQ ID NO: 505. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 390 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 506. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 391 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 507. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 392 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 508. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 393 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 509. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 394 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 510. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 395 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 511. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 396 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 512. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 397 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 513. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 398 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 514. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 399 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 515. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 400 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 516. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 401 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 517. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 402 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 518. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 403 and the VL comprises an amino acid sequence that is at least 90%identical to SEQ ID NO: 519. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 404 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 520. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 405 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 521. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 406 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 522. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 407 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 523. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 408 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 524. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 409 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 525. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 410 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 526. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 411 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 527. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 412 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 528. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 413 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 529. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 414 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 530. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 415 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 531. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 416 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 532. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 417 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ IDNO: 533. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 418 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 534. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 419 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 535. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 420 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 536. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 421 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 537. In some embodiments, 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. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 423 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 539. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 424 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 540. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 425 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 541. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 426 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 542. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 427 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 543. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 428 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 544. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 429 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 545. In some embodiments, the VH comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 430 and the VL comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 546.

[0022] In some embodiments, the heavy chain Fc domain of the antibody comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 845, and comprises at least one aminoacid substitution selected from S239D, A330L, and / or I332E. In some embodiments, the antibody comprises at least two amino acid substitutions selected from S239D, A330L, and / or I332E. In some embodiments, the antibody comprises all three amino acid substitutions selected from S239D, A330L, and / or I332E. In some embodiments, the antibody comprises at least one additional amino acid substitution with reference to SEQ ID NO: 845.

[0023] In accordance with the above embodiments, the present disclosure provides anti-MICA antibodies comprising various functional characteristics. In some embodiments, the anti-MICA antibodies described herein bind an antigen on MICA or a variant or isoform thereof (e.g., SEQ ID NOs: 837-844), via interaction with its antigenic determinants (epitopes). In some embodiments, binding of an anti-MICA antibody to MICA reduces proteolytic cleavage of MICA (e.g., inhibits MICA shedding). In some embodiments, binding of an anti-MICA antibody to MICA attenuates NKG2D-mediated escape by a tumor cell. In some embodiments, the anti-MICA antibody binds human MICA with a KD of about 1.0 pM or lower (FIG. 4).

[0024] In some embodiments, the anti-MICA antibody cross-reacts with one or more of Cynomolgus monkey MICA (cyMICA), human MICA-alpha3, and human MICB-alpha3. In some embodiments, the anti-MICA antibody does not cross-react with one or more of cyMICA, human MICA-alpha3, and human MICB-alpha3. In some embodiments, the anti-MICA antibody comprises a VH region and a VL region that are at least 90% identical to a VH region and a 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, 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-1832, ATX-P-1833, ATX-P-1835, 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.

[0025] In accordance with the above embodiments, the anti-MICA antibodies of the present 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 groupconsisting 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 antibody, a trivalent antibody, or a tetravalent antibody that recognizes different epitopes on the same or different antigens.

[0026] In some embodiments, the antibody comprises a detection moiety. In some embodiments, the antibody comprises a purification moiety. In some embodiments, the antibody comprises a half-life extension moiety.

[0027] The anti-MICA antibodies of the present disclosure can be administered as part of a pharmaceutical composition in a therapeutically effective amount to treat a tumor or a disease or condition associated with a tumor (e.g., cancer). In some embodiments, the composition is suitable for delivery by a single bolus administration of the composition, by multiple bolus administrations of the composition, or by continuous infusion administration of the composition. The composition comprising an anti-MICA antibody, or antigen-binding fragment thereof, can be administered to a mammal using standard administration techniques, including ocular, oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration. In some embodiments, administration comprises delivering an anti-MICA antibody using a needle, a gel, a nanoparticle, a mucoadhesive polymer, an ointment, a solution, a suspension, drops, and / or an implant. In some embodiments, the pharmaceutical composition comprising a therapeutically effective amount of an anti-MICA antibody of the present 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 from about 0.0001 mg / ml to about 100 mg / ml.

[0028] Embodiments of the present disclosure also include a polynucleotide encoding any of the anti-MICA antibodies of the present disclosure. In some embodiments, the polynucleotide comprises a sequence that is at least 70% identical to any of SEQ ID NOs: 431-488 or SEQ ID NOs: 547-604. In some embodiments, the polynucleotide comprises a sequence that is at least 80% identical to any of SEQ ID NOs: 431-488 or SEQ ID NOs: 547-604. In some embodiments, the polynucleotide comprises a sequence that is at least 90% identical to any of SEQ ID NOs: 431- 488 or SEQ ID NOs: 547-604. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 70% identical to any one of SEQ ID NOs: 431-488; and a nucleic acidsequence that is at least 70% identical to any one of SEQ ID NOs: 547-604. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 80% identical to any one of SEQ ID NOs: 431-488; and a nucleic acid sequence that is at least 80% identical to any one of SEQ ID NOs: 547-604. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 90% identical to any one of SEQ ID NOs: 431-488; and a nucleic acid sequence that is at least 90% identical to any one of SEQ ID NOs: 547-604.

[0029] In some embodiments, the polynucleotide comprises a nucleic acid sequence having at least 70% identity to any of: (a) SEQ ID NOs: 663-720; (b) SEQ ID NOs: 779-836; (c) SEQ ID NOs: 663-720; (d) SEQ ID NOs: 779-836; (e) SEQ ID NOs: 663-720; or (f) SEQ ID NOs: 779- 836.

[0030] In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 70% identical to any one of SEQ ID NOs: 663-720; and a nucleic acid sequence that is at least 70% identical to any one of SEQ ID NOs: 779-836. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 80% identical to any one of SEQ ID NOs: 663- 720; and a nucleic acid sequence that is at least 80% identical to any one of SEQ ID NOs: 779- 836. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 90% identical to any one of SEQ ID NOs: 663-720; and a nucleic acid sequence that is at least 90% identical to any one of SEQ ID NOs: 779-836.

[0031] In accordance with these embodiments, the present disclosure includes an expression vector comprising any of the polynucleotides encoding an anti-MICA antibody of the present disclosure. In some embodiments, the expression vector is suitable for manufacturing an anti- MICA antibody of the present disclosure for delivery of the antibody to a subject. In some embodiments, the expression vector is suitable for use in gene therapy (e.g., an expression vector for delivering a polynucleotide encoding an anti-MICA antibody of the present disclosure to a subject). In some embodiments, the expression vector is an adeno-associated virus (AAV) vector, or comprises an AAV backbone. In some embodiments, the expression vector is a lentiviral vector (LV), or comprises an LV backbone. In some embodiments, the expression vector is a herpes simplex virus (HSV) vector, or a retrovirus vector.

[0032] In accordance with these embodiments, the present disclosure also provides a method of administering gene therapy to a subject in need thereof comprising injecting a pharmaceutical composition comprising an effective amount of an expression vector described herein (e.g., anexpression vector comprising a polynucleotides encoding an anti-MICA antibody of the present disclosure). In accordance with these embodiments, the present disclosure also provides a method of treating cancer comprising administering a pharmaceutical composition comprising an effective amount of an expression vector described herein (e.g., an expression vector comprising a polynucleotides encoding an anti-MICA antibody of the present disclosure). In some embodiments, administering the pharmaceutical composition treats at least one symptom present in a subject that has cancer.BRIEF DESCRIPTION OF THE DRAWING(S)

[0033] FIG. 1 : Representative ELISA results used to determine antigen positive serum titers of mice immunized with human MICA, according to different immunization protocols / cohorts.

[0034] FIG. 2: Representative results of cell binding assays using Raji cells expressing the anti-MICA antibodies of the present disclosure.

[0035] FIG. 3: Representative thermal stabilities of the anti-MICA antibodies of the present disclosure, assessed via differential scanning fluorimetry (DSF) utilizing the Protein Thermal Shift (PTS) assay.

[0036] FIG. 4: Representative tables that include various anti-MICA antibody characteristics, including epitope binning analysis, binding affinity, and cross-reactivity.

[0037] FIGS. 5A-5C: Representative results of anti-MICA antibody cross-blocking experiments, including data, which progressively groups antibodies with similar competition profiles. FIG. 5A includes a representative granular binning network map (comparator antibodies are highlighted with blue stars), FIG. 5B includes a representative community binning network map, and FIG. 5C includes a representative combined binary dendrogram (color indicates bins in the network maps).

[0038] FIGS. 6A-6C: Representative functional data for the anti-MICA antibodies of the present disclosure, including comparisons to benchmark antibodies (i.e., 791, 792, 793, 794, 3F9, C16F10, C619 are control MICA antibodies). FIG. 6A includes results demonstrating the ability of anti-MICA antibodies to stabilize MICA on the surface of cancer cells. FIG. 6B includes results demonstrating the ability of anti-MICA antibodies to inhibit MICA shedding. FIG. 6C includes data comparing cell surface MICA stabilization and shedding inhibition at various concentrations of anti-MICA antibodies.

[0039] FIGS. 7A-7D: Representative functional data for four anti-MICA antibodies of the present disclosure, including comparisons to benchmark antibodies (i.e., 7C6, 1D5, and CLN-619 antibodies). FIG. 7A includes results demonstrating the ability of the four anti-MICA antibodies to stabilize MICA on the surface of cancer cells. FIG. 7B includes results demonstrating the ability of the four anti-MICA antibodies to inhibit MICA shedding. FIG. 7C includes data demonstrating the ability of the four anti-MICA antibodies to enhance A375 melanoma target cell killing by primary human NK cells at different effector to target cells ratio. FIG. 7D includes data demonstrating the ability of the four anti-MICA antibodies to enhance A375 melanoma target cell killing by primary human NK cells in the presence of varying concentrations of MICA antibodies.

[0040] FIG. 8: Representative results of binding kinetics of fully humanized anti-MICA antibody (ATX-P-1826) binding tested against human MICA, human MICB, and Cynomolgus MICA. Similar binding affinities were demonstrated for MICA, MICB, and cyno MICA.

[0041] FIGS. 9A-9B: Representative results of an FcyRIIIa activation assay (FIG. 9A) and an ADCC assay (FIG. 9B) for testing the efficacy of AHA-P-1031, ATX-P-1826 and ATX-P-1826 (Afucosylated) antibodies for killing cancer cells.

[0042] FIG. 10: Representative results of in vivo experiments testing the anti-tumor efficacy of AHA-P-1031 (Fc enhanced) in human xenografts (A375 melanoma cell line).

[0043] FIGS. 11A-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; FIG. 11A); pancreatic cancer cell lines (PANCI and Capan-2; FIG. 1 IB); ovarian cancer cell lines (OVCAR3; FIG. 1 IB); colon cancer cell lines (HCT116; FIG. 1 IB); and prostate cancer cell lines (22Rvl, PC3, and LNCaP; FIG. 11C).

[0044] FIG. 12: Representative results of a cytokine release assay testing the safety profile of AHA-P-1031.DETAILED DESCRIPTION

[0045] Embodiments of the present disclosure relate to the treatment of cancer. In particular, the present disclosure provides novel therapeutic antibodies that target MHC Class I Chain-Related Protein A (MICA) in a manner that reduces the ability of a tumor cell to escape immune clearance mediated by the natural killer group 2D (NKG2D) receptor.

[0046] The MHC class I chain related-protein A (MICA) and B (MICB) are cancer cell-surface molecules that reflect both cancer cell-centric biological behavior and host immune status. The major histocompatibility complex (MHC) class I chain related (MIC) gene family, which lies 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, which are frequently expressed by carcinomas of the breast, lung, colon, ovary, kidney, prostate, as well as in melanomas, gliomas, and leukemia. MICA and MICB, as signals of cellular stress, engage with natural killer group 2D (NKG2D). This engagement actives the cytolytic responses of y8 T cells and NK cells against epithelial tumor cells.

[0047] In addition to the membrane-bound form, a soluble isoform of MICA / B (sMICA / B) is present in the serum. This serum-soluble form is derived from the proteolytic shedding of the membrane bound molecule. MICA present on the surface forms a complex with a disulfide isomerase / chaperone (ERp5). This complex induces a conformational change, enabling proteolytic cleavage of MICA by disintegrin and metalloproteinase (ADAM) proteins. Then, the interaction of sMICA / B with NKG2D results in the endocytosis and degradation of receptor-ligand complexes and also suppresses NKG2D-mediated host cancer rejection.

[0048] Shedding of NKG2D ligands leads not only to reduced cell surface ligand density and reduced NK cell recognition but also continual exposure to soluble ligands also results in downregulation of surface NKG2D expression and subsequent reduction of NK and CD8+ T-cell cytotoxicity. Moreover, by inducing caspase-mediated CD3£ degradation in T and NK cells, soluble MICA has also been shown to negatively affect other activating receptors, such as the T- cell receptor, CD 16 and NKp46, thereby inducing a more general tolerization of cytotoxic cells. In addition, NKG2D expression has been reported on some tumors, where soluble NKG2D ligands may stimulate pro-survival signals and stimulate tumor cell proliferation.

[0049] Shedding of MICA / B is mediated by endoplasmic reticulum protein 5 (ERp5), which binds to a conserved six amino acid motif in the a3 -domain of MICA and MICB and induces a conformational change that allows protease cleavage, for example, by ADAM 10 or ADAM 17. Regulation of NKG2D ligand expression has been reported to occur at the transcriptional, post- transcriptional and post-translational levels, but is still not well understood. MicroRNAs can regulate MICA / B protein expression, while ubiquitination, palmitoylation and glycosylation have been shown to regulate intracellular retention and cell surface expression and distribution.Moreover, MICA / B does not always reach the cell surface and can instead be released from cells through exosomes. Most studies investigating expression and localization of MICA / B have been performed using cell lines, often ones that were engineered to over-express MICA or MICB. Therefore, expression and, in particular, intracellular distribution of MICA / B in normal and tumor tissue is not well understood.

[0050] In light of this, experiments were performed to assess the ability of the anti-MICA antibodies of the present disclosure to attenuate NKG2D-mediated immune escape by tumor cells, and thus provide a new therapeutic approach for the treatment of cancer.Definitions

[0051] To facilitate an understanding of the present technology, a number of terms and phrases are defined below. Additional definitions are set forth throughout the detailed description.

[0052] The use of the terms “a” and “an” and “the” and “at least one” and similar referents in the context of describing the embodiments of the present disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the various embodiments of the present disclosure, and does not pose a limitation on the scope of these embodiment unless otherwise claimed. No language in the specification should be construed as indicating any nonclaimed element as essential to the practice of the various embodiments of the present disclosure.

[0053] As used herein, the term “or” is an inclusive “or” operator and is equivalent to the term “and / or” unless the context clearly dictates otherwise. The term “based on” is not exclusive andallows for being based on additional factors not described, unless the context clearly dictates otherwise. In addition, throughout the specification, the meaning of “a,” “an,” and “the” include plural references. The meaning of “in” includes “in” and “on.”

[0054] The transitional phrase “consisting essentially of’ as used in claims in the present application limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention, as discussed in In re Herz, 537 F.2d 549, 551-52, 190 USPQ 461, 463 (CCPA 1976). For example, a composition “consisting essentially of’ recited elements may contain an unrecited contaminant at a level such that, though present, the contaminant does not alter the function of the recited composition as compared to a pure composition, i.e., a composition “consisting of’ the recited components.

[0055] The term “one or more,” as used herein, refers to a number higher than one. For example, the term “one or more” encompasses 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 an even greater number.

[0056] The term “one or more but less than a higher number,” “two or more but less than a higher number,” “three or more but less than a higher number,” “four or more but less than a higher number,” “five or more but less than a higher number,” “six or more but less than a higher number,” “seven or more but less than a higher number,” “eight or more but less than a higher number,” “nine or more but less than a higher number,” “ten or more but less than a higher number,” “eleven or more but less than a higher number,” “twelve or more but less than a higher number,” “thirteen or more but less than a higher number,” “fourteen or more but less than a higher number,” or “fifteen or more but less than a higher number” is not limited to a higher number. For example, the higher number can be 10,000, 1,000, 100, 50, etc. For example, the higher number can 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).

[0057] The term “immunoglobulin” or “antibody,” as used herein, refers to a protein that is found in blood or other bodily fluids of vertebrates, which is used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses. Typically, an immunoglobulin or antibody is a protein that comprises at least one complementarity determining region (CDR). TheCDRs form the “hypervariable region” of an antibody, which is responsible for antigen binding (discussed further below). A whole antibody typically consists of four polypeptides: two identical copies of a heavy (H) chain polypeptide and two identical copies of a light (L) chain polypeptide. Each of the heavy chains contains one N-terminal variable (VH) region and three C-terminal constant (CHI, CH2, and Cm) regions, and each light chain contains one N-terminal variable (VL) region and one C-terminal constant (CL) region. The light chains of antibodies can be assigned to one of two distinct types, either kappa (K) or lambda (A.), based upon the amino acid sequences of their constant domains. In a typical antibody, each light chain is linked to a heavy chain by disulfide bonds, and the two heavy chains are linked to each other by disulfide bonds. The light chain variable region is aligned with the variable region of the heavy chain, and the light chain constant region is aligned with the first constant region of the heavy chain. The remaining constant regions of the heavy chains are aligned with each other.

[0058] The variable regions of each pair of light and heavy chains form the antigen binding site of an antibody. The VH and VL regions have the same general structure, with each region comprising four framework (FW or FR) regions. The term “framework region,” as used herein, refers to the relatively conserved amino acid sequences within the variable region which are located between the CDRs. There are four framework regions in each variable domain, which are designated FR1, FR2, FR3, and FR4. The framework regions form the sheets that provide the structural framework of the variable region (see, e.g., C. A. Janeway et al. (eds.), Immunobiology, 5th Ed., Garland Publishing, New York, N.Y. (2001)).

[0059] The framework regions are connected by three CDRs. As discussed above, the three CDRs, known as CDR1, CDR2, and CDR3, form the “hypervariable region” of an antibody, which is responsible for antigen binding. The CDRs form loops connecting, and in some cases comprising part of, the beta-sheet structure formed by the framework regions. While the constant regions of the light and heavy chains are not directly involved in binding of the antibody to an antigen, the constant regions can influence the orientation of the variable regions. The constant regions also exhibit various effector functions, such as participation in antibody-dependent complement- mediated lysis or antibody-dependent cellular toxicity via interactions with effector molecules and cells.

[0060] As used herein, when an antibody or other entity (e.g., antigen binding domain) “specifically recognizes” or “specifically binds” an antigen or epitope, it preferentially recognizesthe antigen in a complex mixture of proteins and / or macromolecules, and binds the antigen or epitope with affinity which is substantially higher than to other entities not displaying the antigen or epitope. In this regard, “affinity which is substantially higher” means affinity that is high enough to enable detection of an antigen or epitope which is distinguished from entities using a desired assay or measurement apparatus. Typically, it means binding affinity having a binding constant (Ka) of at least 107M-1(e.g., >107M’1, >108M’1, >109M’1, >1O10M’1, >10nM’1, >1012M’1, >1013M’1, etc.). In certain such embodiments, an antibody is capable of binding different antigens so long as the different antigens comprise that particular epitope. In certain instances, for example, homologous proteins from different species may comprise the same epitope.

[0061] The terms “fragment of an antibody,” “antibody fragment,” and “antigen-binding fragment” of an 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 the present disclosure. The antibody fragment desirably comprises, for example, one or more CDRs, the variable region (or portions thereof), the constant region (or portions thereof), or combinations thereof. Examples of antibody fragments include, but are not limited to, (i) a Fab fragment, which is a monovalent fragment consisting of the VL, VH, CL, and CHI domains, (ii) a F(ab’)2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, (iii) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (iv) a Fab’ fragment, which results from breaking the disulfide bridge of an F(ab’)2 fragment using mild reducing conditions, (v) a disulfide-stabilized Fv fragment (dsFv), and (vi) a domain antibody (dAb), which is an antibody single variable region domain (VH or VL) polypeptide that specifically binds antigen.

[0062] The term “monoclonal antibody,” as used herein, refers to an antibody produced by a single clone of B lymphocytes that is directed against a single epitope on an antigen. Monoclonal antibodies typically are produced using hybridoma technology, as first described in Kohler and Milstein, Eur. J. Immunol., 5: 511-519 (1976). Monoclonal antibodies may also be produced using recombinant DNA methods (see, e.g., U.S. Patent 4,816,567), isolated from phage display antibody libraries (see, e.g., Clackson et al. Nature, 352: 624-628 (1991)); and Marks et al., J. Mol. Biol., 222: 581-597 (1991)), or produced from transgenic mice carrying a fully human immunoglobulin system (see, e.g., Lonberg, Nat. Biotechnol., 23(9): 1117-25 (2005), and Lonberg,Handb. Exp. Pharmacol., 181: 69-97 (2008)). In contrast, “polyclonal” antibodies are antibodies that are secreted by different B cell lineages within an animal. Polyclonal antibodies are a collection of immunoglobulin molecules that recognize multiple epitopes on the same antigen.

[0063] The terms “nucleic acid,” “polynucleotide,” “nucleotide sequence,” and “oligonucleotide” are used interchangeably herein and refer to a polymer or oligomer of pyrimidine and / or purine bases, preferably cytosine, thymine, and uracil, and adenine and guanine, respectively (See Albert L. Lehninger, Principles of Biochemistry, at 793-800 (Worth Pub. 1982)). The terms encompass any deoxyribonucleotide, ribonucleotide, or peptide nucleic acid component, and any chemical variants thereof, such as methylated, hydroxymethylated, or glycosylated forms of these bases. The polymers or oligomers may be heterogenous or homogenous in composition, may be isolated from naturally occurring sources, or may be artificially or synthetically produced. In addition, the nucleic acids may be DNA or RNA, or a mixture thereof, and may exist permanently or transitionally in single-stranded or double-stranded form, including homoduplex, heteroduplex, and hybrid states. In some embodiments, a nucleic acid or nucleic acid sequence comprises other kinds of nucleic acid structures such as, for instance, a DNA / RNA helix, peptide nucleic acid (PNA), morpholino nucleic acid (see, e.g., Braasch and Corey, Biochemistry, 41( f. 4503-4510 (2002) and U.S. Patent 5,034,506), locked nucleic acid (LNA; see Wahlestedt et al., Proc. Natl. Acad. Sci. U.S.A., 97: 5633-5638 (2000)), cyclohexenyl nucleic acids (see Wang, J. Am. Chem. Soc., 122: 8595-8602 (2000)), and / or a ribozyme. The terms “nucleic acid” and “nucleic acid sequence” may also encompass a chain comprising nonnatural nucleotides, modified nucleotides, and / or non-nucleotide building blocks that can exhibit the same function as natural nucleotides (e.g., “nucleotide analogs”).

[0064] The terms “peptide,” “polypeptide,” and “protein” are used interchangeably herein and refer to a polymeric form of amino acids of any length, which can include coded and non-coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified peptide backbones.

[0065] As used herein, a “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 acids” include, without limitation, single- and double-stranded nucleic acids. As used herein, the term “nucleic acid” also includes DNA as described above that contains one or more modified bases. Thus, DNA with a backbone modified for stability or for other reasons is a “nucleicacid.” The term “nucleic acid” as it is used herein embraces such chemically, enzymatically, or metabolically modified forms of nucleic acids, as well as the chemical forms of DNA characteristic of viruses and cells, including for example, simple and complex cells.

[0066] The terms “oligonucleotide” or “polynucleotide” or “nucleotide” or “nucleic acid” refer to a molecule having two or more deoxyribonucleotides or ribonucleotides, preferably more than three, and usually more than ten. The exact size will depend on many factors, which in turn depends on the ultimate function or use of the oligonucleotide. The oligonucleotide may be generated in any manner, including chemical synthesis, DNA replication, reverse transcription, or a combination thereof. Typical deoxyribonucleotides for DNA are thymine, adenine, cytosine, and guanine. Typical ribonucleotides for RNA are uracil, adenine, cytosine, and guanine.

[0067] The terms “complementary” and “complementarity” refer to nucleotides (e.g., 1 nucleotide) or polynucleotides (e.g., a sequence of nucleotides) related by the base-pairing rules. For example, the sequence 5’-A-G-T-3’ is complementary to the sequence 3'-T-C-A-5'. Complementarity may be “partial,” in which only some of the nucleic acids’ bases are matched according to the base pairing rules. Or, there may be “complete” or “total” complementarity between the nucleic acids. The degree of complementarity between nucleic acid strands affects the efficiency and strength of hybridization between nucleic acid strands. This is of particular importance in amplification reactions and in detection methods that depend upon binding between nucleic acids.

[0068] The term “gene” refers to a nucleic acid (e.g., DNA or RNA) sequence that comprises coding sequences necessary for the production of an RNA, or of a polypeptide or its precursor. A functional polypeptide can be encoded by a full-length coding sequence or by any portion of the coding sequence as long as the desired activity or functional properties (e.g., enzymatic activity, ligand binding, signal transduction, etc.) of the polypeptide are retained. The term “portion” when used in reference to a gene refers to fragments of that gene. The fragments may range in size from a few nucleotides to the entire gene sequence minus one nucleotide. Thus, “a nucleotide comprising at least a portion of a “gene” may comprise fragments of the gene or the entire gene.

[0069] The term “gene” also encompasses the coding regions of a structural gene and includes sequences located adjacent to the coding region on both the 5' and 3' ends, e.g., for a distance of about 1 kb on either end, such that the gene corresponds to the length of the full-length mRNA (e.g., comprising coding, regulatory, structural and other sequences). The sequences that arelocated 5' of the coding region and that are present on the mRNA are referred to as 5' non-translated or untranslated sequences. The sequences that are located 3' or downstream of the coding region and that are present on the mRNA are referred to as 3' non-translated or 3' untranslated sequences. The term “gene” encompasses both cDNA and genomic forms of a gene. In some organisms (e.g., eukaryotes), a genomic form or clone of a gene contains the coding region interrupted with noncoding sequences termed “introns” or “intervening regions” or “intervening sequences.” Introns are segments of a gene that are transcribed into nuclear RNA (hnRNA); introns may contain regulatory elements such as enhancers. Introns are removed or “spliced out” from the nuclear or primary transcript; introns therefore are absent in the messenger RNA (mRNA) transcript. The mRNA functions during translation to specify the sequence or order of amino acids in a nascent polypeptide.

[0070] In addition to containing introns, genomic forms of a gene may also include sequences located on both the 5' and 3' ends of the sequences that are present on the RNA transcript. These sequences are referred to as “flanking” sequences or regions (these flanking sequences are located 5' or 3' to the non-translated sequences present on the mRNA transcript). The 5' flanking region may contain regulatory sequences such as promoters and enhancers that control or influence the transcription of the gene. The 3' flanking region may contain sequences that direct the termination of transcription, posttranscriptional cleavage, and polyadenylation.

[0071] The term “wild-type” when made in reference to a gene refers to a gene that has the characteristics of a gene isolated from a naturally occurring source. The term “wild-type” when made in reference to a gene product refers to a gene product that has the characteristics of a gene product isolated from a naturally occurring source. The term “wild-type” when made in reference to a protein refers to a protein that has the characteristics of a naturally occurring protein. The term “naturally-occurring” as applied to an object refers to the fact that an object can be found in nature. For example, a polypeptide or polynucleotide sequence that is present in an organism (including viruses) that can be isolated from a source in nature, and which has not been intentionally modified by the hand of a person in the laboratory is naturally-occurring. A wild-type gene is often that gene or allele that is most frequently observed in a population and is thus arbitrarily designated the “normal” or “wild-type” form of the gene. In contrast, the term “modified” or “mutant” when made in reference to a gene or to a gene product refers, respectively, to a gene or to a gene product that displays modifications in sequence and / or functional properties (e.g., altered characteristics) whencompared to the wild-type gene or gene product. It is noted that naturally-occurring mutants can be isolated; these are identified by the fact that they have altered characteristics when compared to the wild-type gene or gene product.

[0072] The term “allele” refers to a variation of a gene; the variations include but are not limited to variants and mutants, polymorphic loci, and single nucleotide polymorphic loci, frameshift, and splice mutations. An allele may occur naturally in a population, or it might arise during the lifetime of any particular individual of the population.

[0073] Thus, the terms “variant” and “mutant” when used in reference to a nucleotide sequence refer to a nucleic acid sequence that differs by one or more nucleotides from another, usually related, nucleotide acid sequence. A “variation” is a difference between two different nucleotide sequences; typically, one sequence is a reference sequence.

[0074] 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 entail, for example, antibody production and / or the activation of immune effector cells. An antigen in the context of the disclosure can comprise any subunit, fragment, or epitope of any proteinaceous or non-proteinaceous (e.g., carbohydrate or lipid) molecule that provokes an immune response in a mammal. The term “epitope” refers to a sequence of an antigen that is recognized by an antibody or an antigen receptor. Epitopes also are referred to in the art as “antigenic determinants.” In certain embodiments, an epitope is a region of an antigen that is specifically bound by an antibody. In certain embodiments, an epitope may include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl groups. In certain embodiments, an epitope may have specific three- dimensional structural characteristics (e.g., a “conformational” epitope) and / or specific charge characteristics. The antigen can be a protein or peptide of viral, bacterial, parasitic, fungal, protozoan, prion, cellular, or extracellular origin, which provokes an immune response in a mammal, preferably leading to protective immunity.

[0075] A “pharmaceutically acceptable carrier” as used herein generally refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.

[0076] The term “pharmaceutical formulation” as used herein generally refers to a preparation which is in such form as to permit the biological activity of an active ingredient (e.g., an anti- MICA antibody, an antibody conjugate, a fusion protein, or a polymeric formulation) contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.

[0077] As used herein, “treatment” (and grammatical variations thereof such as “treat” or “treating”) generally refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some embodiments, anti-MICA antibodies of the present disclosure or other compositions that include an anti-MICA antibody of the present disclosure (e.g., an antibody conjugate, a fusion protein, or a polymeric formulation) are used to delay development of a disease or to slow the progression of a disease.

[0078] The term “half-life” as used herein generally refers to the time required for the concentration of a substance (e.g., an anti-MICA antibody, an antibody conjugate, a fusion protein (e.g., a Fab fusion protein), or a polymeric formulation) to decrease by one-half in vivo or in vitro.

[0079] An “effective amount” of an agent, e.g., a pharmaceutical formulation, as used herein generally refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result.

[0080] An “individual” or “subject” is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and nonhuman primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual or subject is a human. A “subject” may be a “patient.”Anti-MICA Antibodies

[0081] As described further herein, embodiments of the present disclosure relate to the treatment and / or prevention of cancer. In particular, the present disclosure provides novel therapeutic antibodies that target MHC Class I Chain-Related Protein A (MICA) in a manner thatreduces the ability of a tumor cell to escape immune clearance mediated by the natural killer group 2D (NKG2D) receptor.

[0082] As described further herein, anti-MICA antibodies were generated, and their structural and functional properties were elucidated. Based on these data, embodiments of the present disclosure include anti-MICA antibodies, or antigen-binding fragments thereof, that are comprised of a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) comprising complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3. In some embodiments, the HCDR1 comprises one of the following amino acid sequences: (a) X1YX2MX3 (SEQ ID NO: 1), wherein Xi is R, S, or T; X2is S or A; and X3 is N or S; (b) X1X2X3MH (SEQ ID NO: 64), wherein Xi is N, D, or S; X2is H, Y, or S; X3is A or G; (c) X1X2X3X4X5 (SEQ ID NO: 85), wherein Xi is G, S, V, A, N, or T; X2is N or Y; X3 is Y, D, L, or G; X4 is I, M, or L; and X5is H, N, E, or S; (d) X1YDX2N (SEQ ID NO: 145), wherein Xi is S, H, or N; X2is I or V; or (e) X1X2X3X4X5 (SEQ ID NO: 172), wherein Xi is D, N, S, or A; X2is N, Y, or Q; X3is Y, N, or A; X4 is I, W, or M; and X5 is S, H, Y, or N; wherein the HCDR2 comprises one of the following amino acid sequences: (a) X1IX2X3X4X5X6X7X8X9YADSVKG (SEQ ID NO: 22), wherein Xi is Y, F, S, or V; X2is N, S or T; X3is S, T, Y, or G; X4is R or S; X5is S, G, or E; X6is N, S, T, G, or D; X7is T, R, or N; X8is I or T; and X9is Y or D; (b) XIIX2X3X4GX5X6X7X8YX9DSVKG (SEQ ID NO: 71), wherein Xi is L, I, G, or V; X2is W or S; X3is Y or W; X4is D or S; X5is S, G, or N; Xe is N or S; X7 is K or I; X8is Y, G, or F; X9 is A or E; (c) XiIX2X3X4X5GX6TX7X8X9XioXiiFXi2Xi3 (SEQ ID NO: 105), wherein Xi is W or A; X2is N, D, or S; X3 is P or S; X4 is N, D, G, or Y; and X5 is S or N; Xe is A, G, or N; X7 is N or H; X8is S or Y; X9 is A or N; X10 is Q or E; Xu is N, K, or E; X12 is Q or K; and X13 is G or D; (d) WNMPX1SX2NTGX3AQKFQG (SEQ ID NO: 154) wherein Xi is N or D; X2is G or S; and X3is Y or F; or (e) XiIX2X3X4X5X6X7X8X9XioXi 1X12X13X14X15 (SEQ ID NO: 178), wherein Xi is W, T, Y, or F; X2is Y, N, E, or F; X3is A, P, N, or T; X4is G, S, Y, T or H; X5is T, G, or N; X6is G, V, or I; X7is G, S, V, T, or D; X8is S, T, P, or N; X9is S, M, Y, or T; X10 is Y or N; Xu is N, A, or P; X12 is Q, P, S, or D; X13 is K, R, L, or D; X14 is F or K; and X15 is R, Q, K, or S; and wherein the HCDR3 comprises one of the following amino acid sequences: (a) X1X2X3X4X5X6X7 (SEQ ID NO: 43), wherein Xi is Xi is V, A, or G; X2is S, M, or G; X3 is D, S, A, V, I or Y; X4 is I, V, R, Q or W; X5is T, G, L, or F; X6is G, S, T, W or D; and X7is N, G, S, P or N; (b) X1X2X3X4 (SEQID NO: 78), wherein Xi is Xi 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: 125), wherein Xi is D, S, A, F, or E; X2is T, A, S, N, or L; X3 is F, A, W, Y, or G; X4is K, R, A, G, P, or N; and X5is P, G, A, Y, or W; X6is Y, F, S, or N; X7 is Y, F, or D; and X8is Y, S, or N; (d) X1X2X3X4X5X6DX7 (SEQ ID NO: 163) wherein Xi 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; Xe is F, V, or S; and X7 is Y, N, S, or I; or (e) XiX2X3X4X5X6X7X8(SEQ ID NO: 184), wherein Xi is H, Y, S, G, or T; X2is D, S, G, M, or Y; X3is Y, W, S, A, or G; X4is Y, G, S, A, or N; X5is G, P, N, R, or Y; X6is T, G, F, P, or A; X7is S, A, D, Y, or M; X8is G, F, Y, or D.

[0083] In addition to the above HCDR1, HCDR2, and HCDR3 sequences, anti-MICA antibodies of the present disclosure include an LCDR1 comprising an amino acid sequence of any of SEQ ID NOs: 191-213, SEQ ID NOs: 263-284, or SEQ ID NOs: 332-344; the LCDR2 comprises an amino acid sequence of any of SEQ ID NOs: 215-237, SEQ ID NOs: 286-306, or SEQ ID NOs: 346-358; and the LCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 239-261, SEQ ID NOs: 309-330, or SEQ ID NOs: 360-372.

[0084] In some embodiments, the present disclosure provides anti-MICA antibodies, or antigen-binding fragments thereof, that include a VH comprising complementarity determining regions HCDR1, HCDR2, and HCDR3, and a VL comprising complementarity determining regions LCDR1, LCDR2, and LCDR3. In some embodiments, the LCDR1 comprises one of the following amino acid sequences: (a) XiX2SX3X4lXsX6X7X8X9 (SEQ ID NO: 190), wherein Xi is R or S; X2is A or S; X3is Q or S; X4is S, T, R, or G; X5is H, S, N, T, or R; X6is N, S, Y, I, or D; X7 is Y, F, D, or H; X8is L, F, or Y; and X9 is N, G, A, or L; (b) XiX2SX3X4X5X6X7X8X9Xio (SEQ ID NO: 262), wherein Xi is R, S, or K; X2is T, A, or S; X3is Q or G; X4is G, A, V, N, D, H, S, or R; X5is V or I; X6is N, G, S, H, R, V, or L; X7is S, N, H, or Y; X8is W, Y, or S; X9is L, N, or S; and X10 is A, N, or E; or (c) RX1SQSX2X3X4X5X6X7 (SEQ ID NO: 331), wherein Xi is A or T; X2is V or I; X3is I, S, or N; X4is I, T, or S; X5is N, K, S, W, or Y; X6is Q, Y, H, or L; and X7 is L or A; wherein the LCDR2 comprises one of the following amino acid sequences: (a) X1X2X3X4LX5S (SEQ ID NO: 214), wherein Xi is A, S, G, or R; X2is A or T; X3is S or F; X4is S, T, G, or N; and X5is Q or A; (b) X1X2X3X4X5X6X7 (SEQ ID NO: 285), wherein Xi 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; Xe is Q, A, H, L, F, or E; and X7is S, D, or L; or (c) X1X2SX3X4X5X6X7 (SEQ ID NO: 345), wherein Xi 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 Xe is T or S; and whereinthe LCDR3 comprises one of the following amino acid sequences: (a) X1X2X3X4X5X6X7X8 (SEQ ID NO: 238), wherein Xi 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) Xi QX2X3X4X5PX6X7 (SEQ ID NO: 308), wherein Xi is F or Q; X2is A, F, Y, G, or S; X3is N, W, S, or Y; X4is I, S, T, K, or H; X5is F, V, T, or Y; X6is L, I, Y, R, or W; and X7is S or T; or (c) QQX1X2X3X4PX5X6 (SEQ ID NO: 359), wherein Xi is Y, A, or R; X2is G, N, or S; X3is S, V, N, or I; X4is S, F, or W; X5is R, L, or I; X6is T or S.

[0085] In addition to the above LCDR1, LCDR2, and LCDR3 sequences, anti-MICA antibodies of the present disclosure include an HCDR1 comprising an amino acid sequence of any of SEQ ID NOs: 2-21, SEQ ID NOs: 65-70, SEQ ID NOs: 86-104, SEQ ID NOs: 147-153 or SEQ ID NOs: 173-177; the HCDR2 comprises an amino acid sequence of any of SEQ ID NOs: 23-42, SEQ ID NOs: 72-77, SEQ ID NOs: 106-124, SEQ ID NOs: 153-162, or SEQ ID NOs: 179-183; and the HCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 44-63, SEQ ID NOs: 79-84, SEQ ID NOs: 126-143, SEQ ID NOs: 163-171, or SEQ ID NOs: 185-189.

[0086] In some embodiments, an anti-MICA antibody comprises the HCDR1 of SEQ ID NO: 2; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 23; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 24; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 45. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 4; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 25; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 46. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 5; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 26; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 47. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 6; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 27; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 48. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 7; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 28; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 49. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 8; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 29; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 50. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 9; theHCDR2 comprises the amino acid sequence of SEQ ID NO: 30; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 51. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 10; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 31 ; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 52. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 11; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 32; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 53. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 12; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 33; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 54. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 34; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 55. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 14; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 35; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 56. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 15; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 36; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 57. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 16; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 37; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 58. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 17; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 38; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 59. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 18; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 39; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 60. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 19; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 40; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 61. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 20; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 41 ; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 62. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 21; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 42; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 63. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQID NO: 65; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 72; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 79. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 66; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 73; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 80. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 67; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 74; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 80. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 68; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 75; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 81. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 69; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 76; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 82. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 70; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 77; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 84. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 86; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 106; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 126. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 87; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 107; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 127. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 88; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 108; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 128. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 89; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 109; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 129. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 90; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 110; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 130. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 91; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 111; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 131. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 92; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 112; and the HCDR3 comprises the amino acid sequence of SEQ IDNO: 132. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 93; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 113; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 133. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 94; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 114; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 134. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 95; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 115; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 135. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 96; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 116; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 136. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 97; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 117; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 137. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 98; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 118; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 138. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 99; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 119; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 139. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 100; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 120; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 140. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 101; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 121; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 141. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 102; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 122; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 142. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 103; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 123; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 143. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 104; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 124; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 144. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO:146; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 155; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 164. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 147; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 156; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 165. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 148; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 157; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 166. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 149; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 158; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 167. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 150; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 159; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 168. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 151; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 160; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 169. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 152; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 161; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 170. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 153; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 162; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 171. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 173; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 179; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 185. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 174; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 180; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 186. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 175; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 181; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 187. In some embodiments, the HCDR1 comprises the amino acid sequence of SEQ ID NO: 176; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 182; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 189.

[0087] In some embodiments, an anti-MICA antibody comprises the LCDR1 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 203; the LCDR2comprises the amino acid sequence of SEQ ID NO: 227; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 251. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 acidsequence of SEQ ID NO: 310. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the LCDR1 comprises the amino acidsequence 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0088] In some embodiments, the VH of the anti-MICA antibodies of the present disclosure includes 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 of SEQ ID NOs: 373-430. In some embodiments, the VL of the anti-MICA antibodies of the present disclosure includes 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 of SEQ ID NOs: 489-546.

[0089] In some embodiments, the VH 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 SEQ ID NO: 373 and the VL comprisesan 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 SEQ ID NO: 489. In some embodiments, the VH 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 SEQ ID NO: 374 and the VL 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 SEQ ID NO: 490. In some embodiments, the VH 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 SEQ ID NO: 375 and the VL 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 SEQ ID NO: 491. In some embodiments, the VH 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 SEQ ID NO: 376 and the VL 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 SEQ ID NO: 492. In some embodiments, the VH 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 SEQ ID NO: 377 and the VL 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 SEQ ID NO: 493. In some embodiments, the VH 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 SEQ ID NO: 378 and the VL 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 SEQ ID NO: 494. In some embodiments, the VH 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 SEQ ID NO: 379 and the VL comprises an aminoacid 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 SEQ ID NO: 495. In some embodiments, the VH 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 SEQ ID NO: 380 and the VL 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 SEQ ID NO: 496. In some embodiments, the VH 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 SEQ ID NO: 381 and the VL 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 SEQ ID NO: 497. In some embodiments, the VH 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 SEQ ID NO: 382 and the VL 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 SEQ ID NO: 498. In some embodiments, the VH 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 SEQ ID NO: 383 and the VL 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 SEQ ID NO: 499. In some embodiments, the VH 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 SEQ ID NO: 384 and the VL 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 SEQ ID NO: 500. In some embodiments, the VH 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 SEQ ID NO: 385 and the VL comprises an aminoacid 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 SEQ ID NO: 501 . In some embodiments, the VH 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 SEQ ID NO: 386 and the VL 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 SEQ ID NO: 502. In some embodiments, the VH 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 SEQ ID NO: 387 and the VL 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 SEQ ID NO: 503. In some embodiments, the VH 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 SEQ ID NO: 388 and the VL 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 SEQ ID NO: 504. In some embodiments, the VH 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 SEQ ID NO: 389 and the VL 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 SEQ ID NO: 505. In some embodiments, the VH 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 SEQ ID NO: 390 and the VL 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 SEQ ID NO: 506. In some embodiments, the VH 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 SEQ ID NO: 391 and the VL comprises an aminoacid 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 SEQ ID NO: 507. In some embodiments, the VH 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 SEQ ID NO: 392 and the VL 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 SEQ ID NO: 508. In some embodiments, the VH 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 SEQ ID NO: 393 and the VL 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 SEQ ID NO: 509. In some embodiments, the VH 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 SEQ ID NO: 394 and the VL 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 SEQ ID NO: 510. In some embodiments, the VH 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 SEQ ID NO: 395 and the VL 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 SEQ ID NO: 511. In some embodiments, the VH 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 SEQ ID NO: 396 and the VL 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 SEQ ID NO: 512. In some embodiments, the VH 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 SEQ ID NO: 397 and the VL comprises an aminoacid 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 SEQ ID NO: 513. In some embodiments, the VH 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 SEQ ID NO: 398 and the VL 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 SEQ ID NO: 514. In some embodiments, the VH 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 SEQ ID NO: 399 and the VL 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 SEQ ID NO: 515. In some embodiments, the VH 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 SEQ ID NO: 400 and the VL 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 SEQ ID NO: 516. In some embodiments, the VH 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 SEQ ID NO: 401 and the VL 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 SEQ ID NO: 517. In some embodiments, the VH 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 SEQ ID NO: 402 and the VL 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 SEQ ID NO: 518. In some embodiments, the VH 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 SEQ ID NO: 403 and the VL comprises an aminoacid 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 SEQ ID NO: 519. In some embodiments, the VH 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 SEQ ID NO: 404 and the VL 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 SEQ ID NO: 520. In some embodiments, the VH 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 SEQ ID NO: 405 and the VL 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 SEQ ID NO: 521. In some embodiments, the VH 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 SEQ ID NO: 406 and the VL 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 SEQ ID NO: 522. In some embodiments, the VH 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 SEQ ID NO: 407 and the VL 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 SEQ ID NO: 523. In some embodiments, the VH 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 SEQ ID NO: 408 and the VL 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 SEQ ID NO: 524. In some embodiments, the VH 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 SEQ ID NO: 409 and the VL comprises an aminoacid 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 SEQ ID NO: 525. In some embodiments, the VH 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 SEQ ID NO: 410 and the VL 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 SEQ ID NO: 526. In some embodiments, the VH 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 SEQ ID NO: 411 and the VL 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 SEQ ID NO: 527. In some embodiments, the VH 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 SEQ ID NO: 412 and the VL 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 SEQ ID NO: 528. In some embodiments, the VH 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 SEQ ID NO: 413 and the VL 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 SEQ ID NO: 529. In some embodiments, the VH 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 SEQ ID NO: 414 and the VL 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 SEQ ID NO: 530. In some embodiments, the VH 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 SEQ ID NO: 415 and the VL comprises an aminoacid 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 SEQ ID NO: 531 . In some embodiments, the VH 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 SEQ ID NO: 416 and the VL 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 SEQ ID NO: 532. In some embodiments, the VH 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 SEQ ID NO: 417 and the VL 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 SEQ ID NO: 533. In some embodiments, the VH 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 SEQ ID NO: 418 and the VL 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 SEQ ID NO: 534. In some embodiments, the VH 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 SEQ ID NO: 419 and the VL 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 SEQ ID NO: 535. In some embodiments, the VH 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 SEQ ID NO: 420 and the VL 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 SEQ ID NO: 536. In some embodiments, the VH 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 SEQ ID NO: 421 and the VL comprises an aminoacid 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 SEQ ID NO: 537. In some embodiments, the VH 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 SEQ ID NO: 422 and the VL 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 SEQ ID NO: 538. In some embodiments, the VH 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 SEQ ID NO: 423 and the VL 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 SEQ ID NO: 539. In some embodiments, the VH 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 SEQ ID NO: 424 and the VL 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 SEQ ID NO: 540. In some embodiments, the VH 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 SEQ ID NO: 425 and the VL 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 SEQ ID NO: 541. In some embodiments, the VH 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 SEQ ID NO: 426 and the VL 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 SEQ ID NO: 542. In some embodiments, the VH 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 SEQ ID NO: 427 and the VL comprises an aminoacid 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 SEQ ID NO: 543. In some embodiments, the VH 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 SEQ ID NO: 428 and the VL 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 SEQ ID NO: 544. In some embodiments, the VH 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 SEQ ID NO: 429 and the VL 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 SEQ ID NO: 545. In some embodiments, the VH 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 SEQ ID NO: 430 and the VL 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 SEQ ID NO: 546.

[0090] Nucleic acid or amino acid sequence “identity,” as described herein, can be determined by comparing a nucleic acid or amino acid sequence of interest to a reference nucleic acid or amino acid sequence. A number of mathematical algorithms for obtaining the optimal alignment and calculating identity between two or more sequences are known and incorporated into a number of available software programs. Examples of such programs include CLUSTAL-W, T-Coffee, and ALIGN (for alignment of nucleic acid and amino acid sequences), BLAST programs (e.g., BLAST 2.1, BL2SEQ, and later versions thereof) and FASTA programs (e.g., FASTA3x, FAS™, and SSEARCH) (for sequence alignment and sequence similarity searches). Sequence alignment algorithms also are disclosed in, for example, Altschul et al., J. Molecular Biol., 215(3): 403-410 (1990), Beigert et al., Proc. Natl. Acad. Sci. USA, 106(10): 3770-3775 (2009), Durbin et al., eds., Biological Sequence Analysis: Probabilistic Models of Proteins and Nucleic Acids, Cambridge University Press, Cambridge, UK (2009), Soding, Bioinformatics, 21(1): 951 -960 (2005), Altschulet al., Nucleic Acids Res., 25(17): 3389-3402 (1997), and Gusfield, Algorithms on Strings, Trees and Sequences, Cambridge University Press, Cambridge UK (1997)).

[0091] As would be recognized by one of ordinary skill in the art based on the present disclosure, one or more amino acids of the aforementioned anti-MICA antibodies, or antigen fragments thereof, can be replaced or substituted with a different amino acid. An amino acid “replacement” or “substitution” refers to the replacement of one amino acid at a given position or residue by another amino acid at the same position or residue within a polypeptide sequence. Amino acids are broadly grouped as “aromatic” or “aliphatic.” An aromatic amino acid includes an aromatic ring. 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 grouped as “aliphatic.” Examples of “aliphatic” amino acids include glycine (G or Gly), alanine (A or Ala), valine (V or Vai), leucine (L or Leu), isoleucine (I or He), 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 Gin), lysine (K or Lys), and arginine (R or Arg). Aliphatic amino acids may be sub-divided into four sub-groups. The “large aliphatic non-polar sub-group” consists of valine, leucine, and isoleucine. The “aliphatic slightly- polar sub-group” consists of methionine, serine, threonine, and cysteine. The “aliphatic polar / charged sub-group” consists of glutamic acid, aspartic acid, asparagine, glutamine, lysine, and arginine. The “small-residue sub-group” consists of glycine and alanine. The group of charged / polar amino acids may be sub-divided into three sub-groups: the “positively-charged subgroup” consisting of lysine and arginine, the “negatively-charged sub-group” consisting of glutamic acid and aspartic acid, and the “polar sub-group” consisting of asparagine and glutamine. Aromatic amino acids may be sub-divided into two sub-groups: the “nitrogen ring sub-group” consisting of histidine and tryptophan and the “phenyl sub-group” consisting of phenylalanine and tyrosine.

[0092] The amino acid replacement or substitution can be conservative, semi-conservative, or non-conservative. The phrase “conservative amino acid substitution” or “conservative mutation” refers to the replacement of one amino acid by another amino acid with a common property. A functional way to define common properties between individual amino acids is to analyze the normalized frequencies of amino acid changes between corresponding proteins of homologous organisms (Schulz and Schirmer, Principles of Protein Structure, Spring er- Verlag, New York(1979)). According to such analyses, groups of amino acids may be defined where amino acids within a group exchange preferentially with each other, and therefore resemble each other most in their impact on the overall protein structure. Examples of conservative amino acid substitutions include substitutions of amino acids within the sub-groups described above, for example, lysine for arginine and vice versa such that a positive charge may be maintained, glutamic acid for aspartic acid and vice versa such that a negative charge may be maintained, serine for threonine such that a free -OH can be maintained, and glutamine for asparagine such that a free -NH2 can be maintained. “Semi-conservative mutations” include amino acid substitutions of amino acids within the same groups listed above, but not within the same sub-group. For example, the substitution of aspartic acid for asparagine, or asparagine for lysine, involves amino acids within the same group, but different sub-groups. “Non-conservative mutations” involve amino acid substitutions between different groups, for example, lysine for tryptophan, or phenylalanine for serine, etc.

[0093] In addition, one or more amino acids can be inserted into the anti-MICA antibodies, or antigen-binding fragments thereof (e.g., insertion into the heavy and / or light chain variable region amino acid sequence). Any number of suitable amino acids can be inserted into the amino acid sequence of the antibody or antigen-binding fragment thereof. In this respect, at least one amino acid (e.g., 2 or more, 5 or more, or 10 or more amino acids), but not more than 20 amino acids (e.g., 18 or less, 15 or less, or 12 or less amino acids), can be inserted into the amino acid sequence of the antibody or antigen-binding fragment thereof. For example, 1-10 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids) may be inserted into the amino acid sequence of the monoclonal antibody or antigen-binding fragment thereof. In this respect, the amino acid(s) can be inserted into an antibody or antigen-binding fragment thereof in any suitable location. Preferably, the amino acid(s) are inserted into a CDR (e.g., CDR1, CDR2, or CDR3) of the antibody or antigen-binding fragment thereof.

[0094] The amino acid sequences of the anti-MICA antibodies, or antigen-binding fragments thereof, are not limited to the specific amino acid sequences described herein. Indeed, an anti- MICA antibody or antigen-binding fragment thereof can comprise any heavy chain polypeptide or light chain polypeptide that competes with the anti-MICA antibodies or antigen-binding fragments thereof for conformational binding to MICA. Antibody competition can be assayed using routine peptide competition assays such as, for example, ELISA, Western blot, or immunohistochemistrymethods (see, e.g., U.S. Patents 4,828,981 and 8,568,992; and Braitbard et al., Proteome Sci., 4: 12 (2006)).

[0095] An anti-MICA antibody of the present disclosure may be a whole antibody, or an antigen-binding fragment of a whole antibody. As defined herein, antigen-binding antibody fragments encompassed by the present disclosure include, but are not limited to, F(ab’)2, Fab’, Fab, Fv, scFv, dsFv, dAb, and single chain binding polypeptides. Antibody fragments and their therapeutic utility are further described in, e.g., Nelson, A.L., MAbs. 2010 Jan-Feb; 2(1): 77-83; Joosten et al., Microbial Cell Factories volume 2, Article number: 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), which is an engineered antibody generated by the fusion of the heavy (VH) and light chains (VL) of immunoglobulins through a short polypeptide linker. Single chain variable domain (Fv) fragments (scFv) are used in the art in a variety of clinical and therapeutic applications, primarily due to their improved pharmacokinetic properties as compared to the parent monoclonal antibodies and the relative ease of producing them in large quantities 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 / sl2929-019-0592-z).

[0096] An anti-MICA antibody of the present disclosure may be a diabody. Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. 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). Triabodies and tetrabodies are also described in Hudson et al., Mat. Med. 9:129-134 (2003). An anti-MICA antibody of the present disclosure may be a single-domain antibody (also referred to as a nanobody). Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, Mass.; see, e.g., U.S. Pat. No. 6,248,516 Bl). Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g., E. coli or phage), as described herein.

[0097] In other embodiments, the anti-MICA antibody is a whole antibody. As defined herein, a whole antibody comprises two identical copies of a heavy (H) chain polypeptide and two identical copies of a light (L) chain polypeptide. Each of the heavy chains contains one N-terminal variable (VH) region and three C-terminal constant (CHI, CH2, and Cm) regions, and each light chain contains one N-terminal variable (VL) region and one C-terminal constant (CL). The heavy chain C-terminal constant region contains the fragment crystallizable (Fc) domain, which determines antibody class and is responsible for humoral and cellular effector functions. Antibodies are divided into five major classes (or “isotypes”), IgG, IgM, IgA, IgD and IgE, which differ in their function in the immune system. IgGs are the most abundant immunoglobulins in the blood, representing 60% of total serum antibodies in humans. IgG antibodies may be subclassified as IgGl , IgG2, IgG3, and IgG4, named in order of their abundance in serum (IgGl being the most abundant) (Vidarsson et al., Frontiers in Immunology. 5: 520 (2014)). A whole anti-MICA monoclonal antibody described herein may be of any suitable class and / or subclass. In some embodiments, the monoclonal antibody is of class IgG (e.g., IgGl, IgG2, IgG3, or IgG4). For example, the monoclonal antibody may be an IgGl antibody.

[0098] As discussed above, the Fc domain mediates several effector functions of antibodies, such as binding to receptors on target cells and complement fixation (triggering effector functions that eliminate the antigen). In some embodiments, the Fc domain may be modified or engineered to alter its effector functions. For example, Fc domains may be modified to improve antibodydependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), and to control serum half-life. In some embodiments, the Fc domain of the anti-MICA antibody may be engineered to modulate affinity for an Fc receptor, such as Fey receptors (FcyRs) and the neonatal Fc receptor (FcRn). Indeed, optimization of the interactions between antibodies and FcyRs has emerged as a promising approach for enhancing the activity of therapeutic antibodies for the treatment of 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, T.H., Jung, S.T., Exp Mol Med 51, 1-9 (2019)). The Fc domain also may be modified to improve serum half-life, e.g., by engineering IgG Fc for 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 may be modified to create monovalency or antibodybispecificity for improving therapeutic potency. For example, an Fc domain may be generated that does not form a homodimer but remains as a soluble monomer, mFc, that exhibits high affinity for FcyRI but no detectable binding to FcyRIIIa. In other embodiments, a heterodimeric Fc domain may be generated to obtain bispecific properties for antigen binding to circumvent homodimer formation. Engineered Fc domains may be generated by inducing point mutations or by modifying glycosylation of the Fc domain (Saunders, K.O., Front Immunol. 2019; 10: 1296; Kelley, R.F., Meng, Y.G., 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 U S A. 2017; 114:3485-90; and Lin et al., Proc Natl Acad Sci U S A. 2015; 112: 10611-6; Kang and Jung, supra).

[0099] In accordance with the above, embodiments of the present disclosure include an antibody, or antigen binding fragment thereof, that specifically binds MHC Class I Chain-Related Protein A (MICA), optionally wherein the MICA is human MICA, which is optionally a polypeptide comprising the amino acid sequence of any of SEQ ID NOs: 837-839.

[0100] In some embodiments, the antibody or fragment thereof exhibits any one or more the following functional characteristics: reduces and / or attenuates proteolytic cleavage of membranebound MICA into soluble MICA; and / or reduces and / or attenuates NKG2D-mediated escape by a tumor cell; enhanced NK cell-mediated killing of a tumor cell; cross-reacts with at least one of Cynomolgus monkey MICA (cyMICA), human MICB, human MICA-alpha3, and / or human MICB-alpha3; and / or does not cross-react with at least one of Cynomolgus monkey MICA (cyMICA), human MICB, human MICA-alpha3, and / or human MICB-alpha3; and / or human MICB-alpha3; and / or binds to human MICA with a KD of about 1.0 pM or lower; and / or binds to the same epitope on human MICA as an antibody comprising the VH and VL sequences of any one of the exemplary antibodies the sequences of which are provided in Table 6; and / or competes for binding to human MICA with an antibody comprising the VH and VL sequences of any one of the exemplary antibodies the sequences of which are provided in Table 6.

[0101] In some embodiments, the antibody or antibody fragment of the present disclosure is monoclonal, optionally recombinant. In some embodiments, the antibody or antibody fragment of the present disclosure is human, humanized or chimeric. In some embodiments, the antibody or antibody fragment of the present disclosure 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), a Fab-C, a Fab’-SH, a (Fab’)2, a single-domain antibody (sdAb), a VHH antibody, ananobody, a camelid-derived single-domain antibody, a shark IgNAR-derived single-domain antibody fragment (VNAR), a diabody, a triabody, an anticalin or an aptamer, optionally wherein the antibody is a full length antibody comprising an Fc region such as a human IgGl, IgG2, IgG3 or IgG4 region, and optionally wherein the antibody comprises a modified Fc region.

[0102] In some embodiments, the antibody or antibody fragment of the present disclosure is conjugated to at least one additional moiety, optionally selected from: an antigen binding moiety, such as an antibody or antigen-binding fragment thereof, which is capable of specific binding to a target which is not human MICA; and / or a therapeutic or cytotoxic moiety; and / or a detection moiety; and / or a purification moiety; and / or a half-life extension moiety.

[0103] In some embodiments, the antibody or antibody fragment of the present disclosure is a polypeptide comprising: one, two or all three HCDRs of any one of the exemplary antibodies the sequences of which are provided in Table 6, and optionally also one, two or all three of the corresponding LCDRs of the exemplary antibody; and / or a VH sequence having at least 90% identity to the VH sequence of any one of the exemplary antibodies the sequences of which are provided in Table 6, and optionally also a VL sequence having at least 90% identity to the corresponding VL sequence of the exemplary antibody, preferably wherein variation is not permitted in the HCDRs or LCDRs; and / or all six CDRs of any one of the exemplary antibodies the sequences of which are provided in Table 6; and / or the VH and VL sequences of any one of the exemplary antibodies the sequences of which are provided in Table 6; and / or the full length heavy chain (VH + constant) sequence of any one 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.

[0104] Embodiments of the present disclosure also include a polynucleotide encoding an antibody or antibody fragment of the present disclosure, optionally wherein the polynucleotide comprises or consists of a nucleic acid sequence having at least 70, 80, 90 or 100% identity to a nucleic acid sequence of any one of the exemplary antibodies the sequences of which are provided in Table 6.

[0105] Embodiments of the present disclosure also include an expression vector comprising any of the polynucleotides of the present disclosure, which is optionally an adeno-associated virus (AAV) vector, a lentiviral (LV) vector, a herpes simplex virus (HSV) vector, or a retrovirus vector.

[0106] Embodiments of the present disclosure also include a pharmaceutical composition comprising an antibody or antibody fragment, a polynucleotide, or an 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 for ocular, oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration.

[0107] Embodiments of the present disclosure also include a polynucleotide, an expression vector, or a composition of the present disclosure, for use as a medicament, optionally for use in a method of treating cancer in a subject. In some embodiments, the antibody, antibody fragment, polynucleotide, expression vector, or composition of the present disclosure is used as part of a method of treating cancer in a subject, wherein the cancer is characterized as exhibiting the ability to escape immune clearance mediated by the natural killer group 2D (NKG2D) receptor. In some embodiments, the antibody, antibody fragment, polynucleotide, expression vector, or composition of the present disclosure is used as part of a method of treating cancer in a subject, wherein the method comprises intravenous administration of the antibody, antibody fragment, polynucleotide, expression vector, or composition, and wherein the intravenous administration relieves at least one symptom in the subject. In accordance with these embodiments, the cancer is lung cancer, pancreatic cancer, ovarian cancer, colon cancer, and prostate cancer.Multispecific Anti-MICA Antibodies

[0108] As described above, the anti-MICA antibodies of the present 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 antibody, a trivalent antibody, or a tetravalent antibody that recognizes different epitopes on the same or different antigens.

[0109] In some embodiments, an anti-MICA antibody provided herein is a chimeric antibody. Certain chimeric antibodies are described, for example, in U.S. Pat. No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA. 81:6851-6855 (1984). In one example, a chimeric antibodycomprises 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 in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

[0110] In certain embodiments, a chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which HVRs, for example, CDRs, (or portions thereof) are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody optionally will also comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.

[0111] Humanized antibodies and methods of making them are reviewed, for example, in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and are further described, for example, in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86: 10029-10033 (1989); U.S. Pat. Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing “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., Sr. J. Cancer, 83:252-260 (2000) (describing the “guided selection” approach to FR shuffling).

[0112] In accordance with the above embodiments, an anti-MICA antibody of the present disclosure can be made into bivalent, trivalent, or tetravalent formats. For example, an anti-MICA antibody of the present disclosure can be a bivalent, bispecific antibody with heteromeric heavy chains (e.g., Triomab, knobs-into-holes (KIH), Duobody, etc). An anti-MICA antibody of the present disclosure can be a tetraval ent multispecific antibody comprised of IgGs with other binding domains fused to either the N- or C-termini of either the heavy or light chains (e.g., dual variable domain [DVD], IgG-scFv fusion, Mabtyrin (IgG with non-antibody binding scaffold “centyrin” fused to C-terminal end of heavy chains). An anti-MICA antibody of the present disclosure can becomprised of IgGs to which additional antigen combining sites have been added within the structure (e.g., two-in-one antibodies, MAT “Modular Antibody Technology” platform from F- Star). An anti-MICA antibody of the present disclosure can be an engineered antibody fragment linked by short peptide linkers which can be made into bivalent, trivalent, or tetravalent formats addressing two to three targets (e.g., bispecific T-cell engager (BiTE), Nanobody platform, dualaffinity re -targeting (DART) antibodies, “tandem antibody” structures (TandAbs)). And an anti- MICA antibody of the present disclosure can be comprised of chemically coupled IgGs.

[0113] In some embodiments, an anti-MICA antibody of the present disclosure is a multispecific antibody, such as a bispecific antibody, which have binding specificities for at least two different antigens. In some embodiments, the anti-MICA antibodies of the present disclosure, or antigen-binding fragments thereof, can be used to form one arm (e.g., antigen-binding portion) of a bispecific antibody, whereas the other arm of the bispecific antibody can be specific for a different antigen.Functional Characteristics of Anti-MICA Antibodies

[0114] In accordance with the above embodiments, the present disclosure provides anti-MICA antibodies comprising various functional characteristics. In some embodiments, the anti-MICA antibodies described herein bind an antigen on MICA (SEQ ID NOs: 837-844), or a variant or isoform thereof, via interaction with its antigenic determinants (epitopes). In some embodiments, binding of an anti-MICA antibody to MICA (or a fragment thereof) reduces proteolytic cleavage of MICA (e.g., inhibits MICA shedding) (FIGS. 6 and 7). In some embodiments, binding of an anti-MICA antibody to MICA attenuates NKG2D-mediated escape by a tumor cell (FIGS. 6 and 7). In some embodiments, the anti-MICA antibody binds human MICA with a KD of about 1.0 pM or lower (FIG. 4).

[0115] In some embodiments, the anti-MICA antibody cross-reacts with one or more of Cynomolgus monkey MICA (cyMICA), human MICA-alpha3, and human MICB-alpha3. In some embodiments, the anti-MICA antibody does not cross-react with one or more of cyMICA, human MICA-alpha3, and human MICB-alpha3. In some embodiments, the anti-MICA antibody comprises a VH region and a VL region that are at least 90% identical (e.g., at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical) to a VH region and a 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, 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-1832, ATX-P-1833, ATX-P-1835, 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.Polypeptides and Expression Vectors

[0116] Embodiments of the present disclosure also include a polynucleotide encoding any of the anti-MICA antibodies of the present disclosure. In some embodiments, the polynucleotide comprises a sequence that is at least 70% identical to any of SEQ ID NOs: 431-488 or SEQ ID NOs: 547-604. In some embodiments, the polynucleotide comprises a sequence that is at least 75% identical to any of SEQ ID NOs: 431-488 or SEQ ID NOs: 547-604. In some embodiments, the polynucleotide comprises a sequence that is at least 80% identical to any of SEQ ID NOs: 431- 488 or SEQ ID NOs: 547-604. In some embodiments, the polynucleotide comprises a sequence that is at least 85% identical to any of SEQ ID NOs: 431-488 or SEQ ID NOs: 547-604. In some embodiments, the polynucleotide comprises a sequence that is at least 90% identical to any of SEQ ID NOs: 431-488 or SEQ ID NOs: 547-604. In some embodiments, the polynucleotide comprises a sequence that is at least 95% identical to any of SEQ ID NOs: 431-488 or SEQ ID NOs: 547- 604.

[0117] In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 70% identical to any one of SEQ ID NOs: 431-488; and a nucleic acid sequence that is at least 70% identical to any one of SEQ ID NOs: 547-604. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 75% identical to any one of SEQ ID NOs: 431- 488; and a nucleic acid sequence that is at least 75% identical to any one of SEQ ID NOs: 547- 604. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 80% identical to any one of SEQ ID NOs: 431-488; and a nucleic acid sequence that is at least 80% identical to any one of SEQ ID NOs: 547-604. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 85% identical to any one of SEQ ID NOs: 431- 488; and a nucleic acid sequence that is at least 85% identical to any one of SEQ ID NOs: 547-604. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 90% identical to any one of SEQ ID NOs: 431-488; and a nucleic acid sequence that is at least 90% identical to any one of SEQ ID NOs: 547-604. In some embodiments, the polynucleotide comprises a nucleic acid sequence that is at least 95% identical to any one of SEQ ID NOs: 431- 488; and a nucleic acid sequence that is at least 95% identical to any one of SEQ ID NOs: 547- 604.

[0118] In some embodiments, the polynucleotide comprises a nucleic acid sequence having at least 70% identity to any of: (a) SEQ ID NOs: 663-720; (b) SEQ ID NOs: 779-836; (c) SEQ ID NOs: 663-720; (d) SEQ ID NOs: 779-836; (e) SEQ ID NOs: 663-720; or (f) SEQ ID NOs: 779- 836. In some embodiments, the polynucleotide comprises a nucleic acid sequence having at least 75% identity to any of: (a) SEQ ID NOs: 663-720; (b) SEQ ID NOs: 779-836; (c) SEQ ID NOs: 663-720; (d) SEQ ID NOs: 779-836; (e) SEQ ID NOs: 663-720; or (f) SEQ ID NOs: 779-836. In some embodiments, the polynucleotide comprises a nucleic acid sequence having at least 80% identity to any of: (a) SEQ ID NOs: 663-720; (b) SEQ ID NOs: 779-836; (c) SEQ ID NOs: 663- 720; (d) SEQ ID NOs: 779-836; (e) SEQ ID NOs: 663-720; or (f) SEQ ID NOs: 779-836. In some embodiments, the polynucleotide comprises a nucleic acid sequence having at least 85% identity to any of: (a) SEQ ID NOs: 663-720; (b) SEQ ID NOs: 779-836; (c) SEQ ID NOs: 663-720; (d) SEQ ID NOs: 779-836; (e) SEQ ID NOs: 663-720; or (f) SEQ ID NOs: 779-836. In some embodiments, the polynucleotide comprises a nucleic acid sequence having at least 90% identity to any of: (a) SEQ ID NOs: 663-720; (b) SEQ ID NOs: 779-836; (c) SEQ ID NOs: 663-720; (d) SEQ ID NOs: 779-836; (e) SEQ ID NOs: 663-720; or (f) SEQ ID NOs: 779-836. In some embodiments, the polynucleotide comprises a nucleic acid sequence having at least 95% identity to any of: (a) SEQ ID NOs: 663-720; (b) SEQ ID NOs: 779-836; (c) SEQ ID NOs: 663-720; (d) SEQ ID NOs: 779-836; (e) SEQ ID NOs: 663-720; or (f) SEQ ID NOs: 779-836.

[0119] 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 NOs: 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 NOs: 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 anyone of SEQ ID NOs: 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 NOs: 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 NOs: 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 NOs: 779- 836.

[0120] In accordance with these embodiments, the present disclosure includes an expression vector comprising any of the polynucleotides encoding an anti-MICA antibody of the present disclosure. In some embodiments, the expression vector is suitable for manufacturing an anti- MICA antibody of the present disclosure for delivery of the antibody to a subject. In certain embodiments, the nucleic acid sequence is in the form of a vector. The vector can be, for example, a plasmid, episome, cosmid, viral vector (e.g., retroviral or adenoviral), or phage. Suitable vectors and methods of vector preparation are well known in the art (see, e.g., Sambrook et aL, Molecular Cloning, a Laboratory Manual, 4th edition, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. (2012), and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates and John Wiley & Sons, New York, N.Y. (1994)).

[0121] In addition to the nucleic acid encoding an anti-MICA antibody or antigen-binding fragment thereof, the vector desirably comprises expression control sequences, such as promoters, enhancers, polyadenylation signals, transcription terminators, internal ribosome entry sites (IRES), and the like, that provide for the expression of the antibody-encoding nucleic sequence in a host cell. Exemplary expression control sequences are known in the art and described in, for example, Goeddel, Gene Expression Technology: Methods in Enzymology, Vol. 185, Academic Press, San Diego, Calif. (1990).

[0122] A vector comprising a nucleic acid sequence encoding an anti-MICA antibody or antigen-binding fragment thereof may be introduced into a host cell that is capable of expressing the polypeptides encoded thereby, including any suitable prokaryotic or eukaryotic cell. Examples of suitable prokaryotic cells include, but are not limited to, cells from the genera Bacillus (such as Bacillus subtilis and Bacillus brevis), Escherichia (such as E. coli), Pseudomonas, Streptomyces , Salmonella, and Erwinia. Particularly useful prokaryotic cells include the various strains ofEscherichia coli (e.g., K12, HB101 (ATCC No. 33694), DH5a, 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 those from the genera Hansenula, Kluyveromyces, Pichia, Rhinosporidium, Saccharomyces , and Schizosaccharomyces. Suitable insect cells include Sf-9 and HIS cells (Invitrogen, Carlsbad, Calif.) and are described in, for example, 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 or 293T cells (ATCC No. CRL1573), and 3T3 cells (ATCC No. CCL92). Other suitable mammalian cell lines are the monkey COS-1 (ATCC No. CRL1650) and COS-7 cell lines (ATCC No. CRL1651), as well as the CV-1 cell line (ATCC No. CCL70). Further exemplary mammalian host cells include primate cell lines and rodent cell lines, including transformed cell lines. Normal diploid cells, cell strains derived from in vitro culture of primary tissue, as well as primary explants also are suitable. Other suitable mammalian cell lines include, but are not limited to, mouse neuroblastoma N2A cells, HeLa, mouse L-929 cells, and BHK or HaK hamster cell lines, all of which are available from the ATCC. Methods for selecting suitable mammalian host cells and methods for transformation, culture, amplification, screening, and purification of such cells are well known in the art (see, e.g., Ausubel et al., eds., Short Protocols in Molecular Biology , 5th ed., John Wiley & Sons, Inc., Hoboken, N.J. (2002)). Preferably, the mammalian cell is a human cell.

[0123] In some embodiments, the vector can include means for attaching a detection moiety to an anti-MICA antibody of the present disclosure. In some embodiments, the vector can include means for attaching a purification moiety to an anti-MICA antibody of the present disclosure. Exemplary detection and / or purification moieties / tags that can be coupled to an anti-MICA antibody of the present disclosure includes, but is not limited to, hemagglutinin (HA), c-Myc, V5, DYKDDDDK, His tag (e.g., 6x-HIS), Glutathione S-Transferase (GST), Maltose Binding Protein (MBP), a fluorophore (e.g., Green Fluorescent Protein (GFP), Red Fluorescent Protein (RFP), mCherry, a chromophore, and / or a luminescent peptide (e.g., luciferase).

[0124] In some embodiments, the expression vector is suitable for use in gene therapy (e.g., an expression vector for delivering a polynucleotide encoding an anti-MICA antibody of thepresent disclosure to a subject). In some embodiments, the expression vector is a herpes simplex virus (HSV) vector, or a retrovirus vector. In some embodiments, the expression vector is an adeno-associated virus (AAV) vector, or comprises an AAV backbone. For example, AAV vectors have been designed, produced and used to mediate gene delivery in human subjects, including for therapeutic purposes. Typically, AAV vectors for use in gene transfer comprise a replication defective AAV genome lacking functional Rep and Cap coding viral sequences. Such replication defective AAV vectors more preferably lack most or all of the Rep and Cap coding sequences, and essentially retain one or two AAV ITR sequences and a packaging sequence. The defective genome is packaged in a viral particle, to form a defective, recombined AAV virus, also termed “AAV vector”. Methods of producing such AAV vectors have been disclosed in the literature, including using packaging cells, auxiliary 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; W02005 / 072364). Methods of 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 upon in vivo administration (see e.g., W001 / 23001; WOOO / 73316; WO04 / 112727; W005 / 005610; WO99 / 06562). AAV vectors may be prepared or derived from various serotypes of AAVs, which may be even 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. The AAV vector may be derived from a single AAV serotype or comprise sequences or components originating from at least two distinct AAV serotypes (pseudotyped AAV vector), e.g., an AAV vector comprising an AAV genome derived from one AAV serotype (for example AAV9), and a capsid derived at least in part from a distinct AAV serotype. An AAV vector, as used herein, is a vector which comprises at least one component part derivable from an adeno-associated virus. Preferably, that component part is involved in the biological mechanisms by which the vector infects or transduces target cells and expresses an anti-MICA antibody of the present disclosure.

[0125] In other embodiments, the expression vector is a lentiviral vector (LV), or comprises an LV backbone. Lentiviruses are part of a larger group of retroviruses. A detailed list of lentiviruses may 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 bedivided into primate and non-primate groups. Examples of primate lentiviruses include but are not limited to: the human immunodeficiency virus (HIV), the causative agent of human auto immunodeficiency syndrome (AIDS), and the simian immunodeficiency virus (SIV). The non- primate lentiviral group includes the prototype “slow virus” visna / maedi virus (VMV), as well as the related caprine arthritis-encephalitis virus (CAEV), equine infectious anaemia 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 Visna lentivirus. The lentivirus family differs from retroviruses in that lentiviruses have the capability to infect both dividing and non-dividing cells (Lewis et al (1992) EM BO J 11 (8): 3053-3058 and Lewis and Emerman (1994) J Virol 68 (l):510-516). In contrast, other retroviruses, such as MLV, are unable to infect non-dividing or slowly dividing cells such as those that make up, for example, muscle, brain, lung and liver tissue. A lentiviral vector, as used herein, is a vector which comprises at least one component part derivable from a lentivirus. Preferably, that component part is involved in the biological mechanisms by which the vector infects or transduces target cells and expresses an anti-MICA antibody of the present disclosure.

[0126] In accordance with these embodiments, the present disclosure also provides a method of administering gene therapy to a subject in need thereof comprising injecting a pharmaceutical composition comprising an effective amount of an expression vector described herein (e.g., an expression vector comprising a polynucleotides encoding an anti-MICA antibody of the present disclosure). As described further below, the present disclosure also provides a method of treating cancer by administering a pharmaceutical composition comprising an effective amount of an expression vector described herein (e.g., an expression vector comprising a polynucleotides encoding an anti-MICA antibody of the present disclosure). In some embodiments, administering the pharmaceutical composition treats at least one symptom present in a subject that has cancer.Compositions and Methods of Treatment

[0127] The anti-MICA antibodies of the present 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 comprises delivering an anti- MICA antibody using a needle, a gel, a nanoparticle, a mucoadhesive polymer, an ointment, a solution, a suspension, drops, and / or an implant. In some embodiments, the pharmaceuticalcomposition comprising a therapeutically effective amount of an anti-MICA antibody of the present 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 from about 0.0001 mg / ml to about 100 mg / ml.

[0128] In accordance with these embodiments, the methods include administering a pharmaceutical composition comprising a therapeutically effective amount of an anti-MICA antibody of the present disclosure. In some embodiments, the pharmaceutical composition is administered to a subject and treats at least one cancer symptom. In some embodiments, administering the pharmaceutical composition stabilizes MICA on a tumor cell, and / or inhibits MICA shedding from a tumor cell, which reduces the ability of the tumor cell to escape immune clearance mediated by the natural killer group 2D (NKG2D) receptor.

[0129] In some embodiments, the pharmaceutical composition comprising a therapeutically effective amount of an anti-MICA antibody of the present 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 10 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. In some embodiments, the anti-MICA antibody is administered at a dose ranging from about 0.1 mg / dose to about 10 mg / dose.

[0130] In some embodiments, the pharmaceutical composition comprising a therapeutically effective amount of an anti-MICA antibody of the present 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.

[0131] As used herein, the terms “treatment,” “treating,” and the like refer to obtaining a desired pharmacologic and / or physiologic effect. In some embodiments, the effect is therapeutic, i.e., the effect partially or completely cures a disease and / or adverse symptom attributable to the disease. To this end, the methods of the present disclosure comprise administering a “therapeutically effective amount” of an anti-MICA antibody, or composition comprising an anti- MICA antibody. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. The therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the monoclonal antibody to elicit a desired response in the individual. For example, a therapeutically effective amount of an anti-MICA antibody of the present disclosure is an amount which treats at least one symptom associated with cancer in thesubject. In some embodiments, the pharmacologic and / or physiologic effect may be prophylactic, i.e., the effect completely or partially prevents a disease or symptom thereof. In this respect, the methods of the present disclosure comprise administering a “prophylactically effective amount” of an anti-MICA antibody or composition comprising an anti-MICA antibody. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired prophylactic result.

[0132] A typical dose of a therapeutically effective amount of an anti-MICA antibody of the present disclosure can range from, for example, about 0.0001 mg / dose to about 100 mg / dose. In some embodiments, a therapeutically effective amount of an anti-MICA antibody of the present disclosure can range from about 0.001 mg / dose to about 100 mg / dose, from about 0.01 mg / dose to about 100 mg / dose, from about 0.05 mg / dose to about 50 mg / dose, from about 0.1 mg / dose to about 10 mg / dose, from about 0.5 mg / dose to about 5 mg / dose, and from about 1 mg / dose to about 10 mg / dose. In some embodiments, a therapeutically effective concentration of an anti-MICA antibody of the present disclosure can range from, for example, about 0.0001 mg to about 100 mg of the antibody per milliliter of solution. In some embodiments, a therapeutically effective concentration of an anti-MICA antibody of the present disclosure can range from about 0.001 mg / ml to about 100 mg / ml, from about 0.01 mg / ml to about 100 mg / ml, from about 0.1 mg / ml to about 100 mg / ml, from about 1.0 mg / ml and about 100 mg / ml, from about 0.001 mg / ml and about 50 mg / ml, from about 0.01 mg / ml and about 50 mg / ml, from about 0.1 mg / ml and about 50 mg / ml, from about 0.1 mg / ml and about 25 mg / ml, from about 0.1 mg / ml and about 10 mg / ml, and from about 1.0 mg / ml and about 10 mg / ml. In some embodiments, a therapeutically effective dose of an anti-MICA antibody of the present disclosure can be, exactly 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 can fall within a range delimited by any two of the foregoing values. For example, in certain embodiments, a sustained release formulation can be, exactly 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 an anti-MICA antibody, or an amount that falls within a range delimited by any two of the foregoing values.

[0133] Therapeutic or prophylactic efficacy can be monitored by periodic assessment of treated patients. For repeated administrations over several days or longer, depending on the condition, the treatment is repeated until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful and are within the scope of the present disclosure. The desired dosage can be delivered by a single bolus administration of the composition, by multiple bolus administrations of the composition, or by continuous infusion administration of the composition. The composition comprising an anti-MICA antibody, or antigen-binding fragment thereof, can be administered to a mammal using standard administration techniques, including ocular, oral, intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal, sublingual, or suppository administration.

[0134] The present disclosure also provides a composition comprising any of the anti-MICA antibodies or antigen-binding fragments thereof described herein. The composition desirably is a pharmaceutically acceptable (e.g., physiologically acceptable) composition, which comprises a carrier, preferably a pharmaceutically acceptable (e.g., physiologically acceptable) carrier, and the anti-MICA antibody or antigen-binding fragment thereof. Any suitable carrier can be used within the context of the present disclosure, and such carriers are well known in the art. For example, the composition may contain preservatives, such as, for example, methylparaben, propylparaben, sodium benzoate, and benzalkonium chloride. A mixture of two or more preservatives optionally may be used. In addition, buffering agents may be included in the composition. Suitable buffering agents include, for example, citric acid, sodium citrate, phosphoric acid, potassium phosphate, and various other acids and salts. A mixture of two or more buffering agents optionally may be used. Methods for preparing compositions for pharmaceutical use are known to those skilled in the art and are described in, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins; 21st ed. (May 1, 2005).

[0135] Once administered to a mammal (e.g., a human), the biological activity of the anti- MICA antibody, or antigen-binding fragment thereof, can be measured by any suitable method known in the art. For example, the biological activity can be assessed by determining the stability of the anti-MICA antibody. The biological activity of the anti-MICA antibody also can be assessed by determining its binding affinity to MICA peptides and / or by assessing its binding affinity to peptides with which it may cross-react. The term “affinity” refers to the equilibrium constant for the reversible binding of two agents and is expressed as the dissociation constant (KD). Affinity ofa binding agent to a ligand, such as affinity of an antibody for an epitope, can be, for example, from about 1 femtomolar (fM) to about 1 millimolar (mM) (e.g., from about 1 picomolar (pM) to about 1 nanomolar (nM), or from about 1 nM to about 1 micromolar (pM)). In some embodiments, the affinity of an anti-MICA antibody may be from about 1 nm to about 20 nm, and desirably from about 5 nm to about 10 nm. Antibody affinity for an antigen or epitope of interest can be measured using any art-recognized assay. Such methods include, for example, fluorescence activated cell sorting (FACS), separable beads (e.g., magnetic beads), antigen panning, and / or ELISA (see, e.g., Janeway et al. (eds.), Immunobiology, 5th ed., Garland Publishing, New York, N.Y., 2001).

[0136] In some embodiments, an anti-MICA antibody, or composition comprising an anti- MICA antibody, may be administered alone or in combination with other drugs. For example, the anti-MICA antibody can be administered in combination with other agents for the treatment or prevention of cancer, as disclosed herein. For example, anti-MICA antibodies of the present disclosure, or antibody conjugates, fusion proteins, or polymeric formulations thereof, can be used either alone or in combination with other agents in a therapy. For instance, an anti-MICA antibody may be co-administered with at least one additional therapeutic agent. In certain embodiments, an additional therapeutic agent is another antibody, a chemotherapeutic agent, a cytotoxic agent, an anti-angiogenic agent, an immunosuppressive agent, a prodrug, a cytokine, a cytokine antagonist, cytotoxic radiotherapy, a corticosteroid, an anti-emetic, a cancer vaccine, an analgesic, a growth- inhibitory agent, or combinations thereof. For example, in certain embodiments, any of the preceding methods further comprises administering one or more additional compounds. In certain embodiments, the anti-MICA antibody, antibody conjugate, fusion protein, or polymeric formulation is administered simultaneously with the additional compound(s). In certain embodiments, the anti-MICA antibody, antibody conjugate, fusion protein, or polymeric formulation is administered before or after the additional compound(s).

[0137] In addition to therapeutic uses, an anti-MICA antibody or antigen-binding fragment, described herein can be used in diagnostic or research applications. Research applications include, for example, methods that utilize the anti-MICA antibody and a label to detect MICA in a sample, e.g., in a human body fluid or in a cell or tissue extract. The anti-MICA antibody or antigen-binding fragment thereof may be employed in any suitable assay for measuring 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 detection assays, single molecule detection assays, radioimmunoassays (RIA), and FACS. Such methods are disclosed in, for example, 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 Adamczyk et al., Anal. Chim. Acta, 579(1): 61-67 (2006).

[0138] The anti-MICA antibody or antigen-binding fragment thereof can be provided in a kit, e.g., a packaged combination of reagents in predetermined amounts with instructions for performing an assay using the antibody (e.g., an assay that detects MICA). As such, the disclosure provides a kit comprising the antibody or antigen-binding fragment described herein and instructions for use thereof. The instructions can be in paper form or computer-readable form, such as a disk, CD, DVD, etc. Alternatively or additionally, the kit can comprise a calibrator or control, and / or at least one container (e.g., tube, microtiter plates, or strips) for conducting an assay, and / or a buffer, such as an assay buffer or a wash buffer. Ideally, the kit comprises all components, i.e., reagents, standards, buffers, diluents, etc., which are necessary to perform the assay. Other additives may be included in the kit, such as stabilizers, buffers (e.g., a blocking buffer or lysis buffer), and the like. The relative amounts of the various reagents can be varied to provide for concentrations in solution of the reagents which substantially optimize the sensitivity of the assay. The reagents may be provided as dry powders (typically lyophilized), including excipients which on dissolution will provide a reagent solution having the appropriate concentration.

[0139] The following examples further illustrate the various embodiments of the present disclosure but should not be construed as in any way limiting its scope.EXAMPLES

[0140] It will be readily apparent to those skilled in the art that other suitable modifications and adaptations of the methods of the present disclosure described herein are readily applicable and appreciable, and may be made using suitable equivalents without departing from the scope of the present disclosure or the aspects and embodiments disclosed herein. Having now described the present disclosure in detail, the same will be more clearly understood by reference to the following examples, which are merely intended only to illustrate some aspects and embodiments of the disclosure, and should not be viewed as limiting to the scope of the disclosure. Thedisclosures of all journal references, U.S. patents, and publications referred to herein are hereby incorporated by reference in their entireties.

[0141] The present disclosure has multiple aspects, illustrated by the following non-limiting examples.EXAMPLE 1

[0142] Recovery of MICA antibody sequences from immunized mice. MICA / B Immunization: Three cohorts of Alloy Therapeutic transgenic humanized mice (ATX-GK) were immunized with human MICA / B using the following 5-week protocols. All cohorts followed a standard 35 day repetitive immunization at multiple sites (RIMMS) protocol. The cohorts were as follows: Cohort 1 : Human MICA-HIS alpha-3 domain (P-796); Cohort 2: Human MICA-Fc alpha- 3 domain (P-1001); Cohort 3: Human MICB-His alpha-3 domain (P-798); Cohort 4: Cyno MICA- His alpha-3 domain (P-797) was injected on day 0 & 7), Human MICA-HIS alpha-3 domain (P- 796) on day 14), and Human MICB His alpha-3 domain (P-798) on day 21); Cohort 5: Human MICA-His (Aero MIA-5221). Cohort 3 and 4 did not produce high enough immune response and were discontinued. All Cohorts had N = 6 Female ATX-GK Mix mice.

[0143] As described above, Cohort 1 included GK Mix Mice dosed with Human MICA-HIS alpha-3 domain (P-796). At Day 20, ELISA plates were coated with 1 ug / mL of Human MICA- His, Human MICB His, Cyno MICA-His, or His Control (P-114) (data not shown but can be provided upon request). The secondary antibody HRP Goat anti-Mouse was used at 1:5000 dilution, with a development time of 12:30. The absorbance signal at 450 nm was measured with an ELISA microplate reader. After Day 20 ELISA and considering the weak titers obtained with P-796 immunization, it was decided to continue boosting Cohort 1 with alpha-3 -MICA-ATX-Fc (P-1001). Representative ELISA results used to determine antigen positive serum titers of mice immunized as described above are shown in FIG. 1. Briefly, ELISA plates were coated with 1 ug / mL of Human MICA-his-alpha 3 (Top Left), His Control (Top Right), Human MICA-ATX-Fc -alpha 3 (Bottom Left), or ATX-Fc Control (Bottom Right). The secondary antibodies used were HRP Goat anti-Mouse (P-796 & P-114), HRP Goat anti-Rat (P-1001 & P-199), or HRP Goat antiHuman (Pos Control) at 1 :5000 dilution. The positive control used was ATX-P-794 (Human IgGl) starting at 5 ug / mL. The development time was 4:05. The absorbance signal at 450 nm was measured with an ELISA microplate reader.

[0144] Additionally, immune tissues from high titer mice were harvested and preserved for antibody discovery. Hybridoma cell lines producing MICA antibodies were produced by fusion of single B Cells from spleen and lymph nodes of titer positive mice with myeloma cells. Hybridomas expressing MICA specific antibodies were detected by antigen binding by ELISA. Affinity of antibodies in the hybridoma supernatants were measured by SPR using the Octet instrument. MICA antibodies in hybridoma supernatant were loaded on a biosensor. Response was measured as a nm shift in the interference pattern and was proportional to the number of antibodies bound to the surface of the biosensor. The binding interaction of MICA to the immobilized antibodies was measured as association (kon). Following analyte association, the biosensor was dipped into PBS without MICA, and the bound antigen was allowed to dissociate from the antibody (kdis). KD (M), or affinity of the antibodies for MICA was measured as kdis / kon. Heavy and light chains from validated hybridomas were sequenced. RNA was isolated from MICA antibody secreting hybridomas and heavy and light chain variable regions were cloned by reverse transcription using gene specific primers followed by PCR amplification with variable chain gene specific primers. PCR products were sequenced by standard Sanger sequencing methods.

[0145] Variable heavy and light chains were amplified from the spleen of high titer immunized mice by reverse transcription using gene specific primers followed by PCR amplification with variable chain gene specific primers. Variable regions were cloned into a phage display vector designed to express Fabs on phage g3p protein. Libraries of phage expressing unique Fabs were amplified and purified. Phage were allowed to bind to biotinylated MICA antigens captured on streptavidin magnetic beads. Phage remaining bound to antigen beads after several stringent washes was eluted using a basic triethylamine solution and neutralized with Tris buffer pH 8.0. Eluted phages were reinfected into TGI bacterial cells, amplified by co-infection with M13 helper phage, and purified by PEG precipitation. Purified phages expressing Fabs were selected for antigen binding as described. Phage from the second round were diluted and infected into TGI cells. Polyclonal pools of phage output from two rounds of panning were tested by ELISA to confirm that the pools contained MICA-specific phage. Variable heavy and light chain regions were sequenced from single infected bacterial colonies using a rolling circle amplification and standard Sanger sequencing.

[0146] Unique variable heavy and light chain pairs from hybridoma and phage display campaigns were cloned into vectors designed to express full length antibodies as IgGs in HEK293cells under the control of a CMV promoter. Antibody expression vectors were complexed with polyethylenimine and transfected into HEK293 cultures. After 5 days of shaking at 37 °C in 293 cell culture media, antibodies were captured on agarose-based protein A resin. After several stringent washes, antibodies were eluted in glycine solution, pH 3, neutralized with Hepes, pH 9, and buffer exchanged into PBS.

[0147] Additionally, cell binding were conducted with the anti-MICA antibodies of the present disclosure. Briefly, Raji cells expressing MICA or parental Raji cells were tested in binding assay with anti-MICA antibodies at concentrations from 100 nM to 0.6 pM (a serial 3-fold dilution) for 45 min on ice. Cells were then incubated with the secondary antibody R- Phycoerythrin AffiniPure Goat Anti-Human IgG (Jackson Immunoresearch 109-115-098). The data was acquired on FACSCanto II. Median fluorescence intensities (MFI) were plotted against the concentrations of the antibodies. EC50 was derived from fitting to 4 parameter dose-response curve (FIG. 2).EXAMPLE 2

[0148] Human MICA Monoclonal Antibody Biophysical Properties. 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 with a YMC Diol-200 8 x 300 mm column (Cat.no # DL20S05-3008WT) on an Agilent 1200 series HPLC instrument. The running buffer was 20mM sodium phosphate, 400mM NaCl pH 7.0 at a flow rate of 0.3 mL / min. For freeze-thaw stability, samples were frozen at -80C for 20 minutes, then thawed at room temperature for approximately 20 minutes. Additionally, capillary electrophoresis sodium dodecyl sulfate (CE-SDS) was performed on a LapChip GX II instrument using Protein Express 200 (Perkin Elmer, #760499) and Protein Express Assay Reagent Kit (Perkin Elmer, # CLS960008). The reagents and chips were prepared according to the manufacturer’s instruction. Briefly, the reducing sample buffer was prepared by mixing 1 M dichlorodiphenyltri chloroethane with Protein Express Sample Buffer, while the nonreducing buffer consisted of only Protein Express Sample Buffer. Samples were mixed with reducing or non-reducing buffer and denatured at 80 °C for 10 min. Samples were centrifuged at 2,000 g for Imin to remove air bubbles before placing in the LapChip GXII instrument for analysis.

[0149] Antibody stability can be affected by their formulation. Among the many techniques used to study the stability of mAbs, differential scanning fluorimetry (DSF) offers both excellent throughput and minimal material consumption. DSF measures the temperature of the protein unfolding transition (Tm) based on the change in fluorescence intensity of an environmentally sensitive dye. Experiments were conducted to assess the thermal stability of the human MICA monoclonal antibodies (“ATX” antibodies) of the present disclosure by determining the melting temperature (Table 1). Briefly, thermal stability was assessed via nano differential scanning fluorimetry (nanoDSF) on Prometheus Panta. Each sample was measured in duplicate. Melting temperatures of the antibodies were detected during heating in a linear thermal ramp (0.5 °C / min, 25-95 °C). Data was analyzed using the Panta Analysis software. The unfolding transition points were determined from changes in the emission wavelengths of tryptophan fluorescence at 350 and 330 nm. Data was analyzed by using Protein Thermal Shift Software and the melting temperature (Tm) was calculated from the melt curve (FIG. 3).

[0150] Table 1: DSF analysis of human anti-MICA monoclonal antibodies.

[0151] Affinity-capture Self-interaction Nanoparticle Spectroscopy (AC-SINS) assays were conducted. This assay tests how likely an antibody is to interact with itself. It uses gold nanoparticles that are coated with anti-Fc antibodies. When a dilute solution of antibodies is added, they rapidly become immobilized on the gold beads. If these antibodies subsequently attract one another, it leads to shorter interatomic distances and longer absorption wavelengths that can bedetected by spectroscopy. Briefly, gold nanoparticles (Ted Pella, 15705-20) were washed with water. Antibody mixture of 80 / 20 (v / v) capture antibody / non-capture antibodies (Jackson Immuno Research Labs) was buffer exchanges into 20 mM Sodium Acetate pH 4.5 to a concentration of 500 ug / ml. To prepare 1 ml coated particles, 900 pL of gold nanoparticles were incubated overnight with 100 pL of antibody mixture for 90 min at RT. After antibody coating, thiolated PEG (MW: 2000 Da) were used to quench the beads. The beads were then concentrated 10 fold in PBS. 10 pL lOx concentrated particles solution was incubated with 100 pL of 40 pg / mL of antibody samples on a 384-well polypropylene plate for 2 hrs RT. The plate was then quickly spun down at 3000 rpm and scanned from 510 to 580 nm in increments of 2 nm on Synergy Neo2 MultiMode Plate Reader (BioTek). Values reported are averages of duplicate wells and are sample red shift wavelengths at maximum absorbance subtracting the blank reference (PBS only). Greater red shifts indicate increased self-interaction.

[0152] Additionally, baculovirus particle (BVP) ELISA experiments were conducted. Empty BVPs (empty viral capsids without genomes) can be used to measure polyspecificity of therapeutic antibody candidates in in vitro assays. These assays assess the viability of an antibody. Briefly, similar to what was reported by Hbtzel et al. (2012), baculovirus particles (BVP, Lake Pharma) were diluted 1: 100 in 50 mM sodium bicarbonate (pH 9.5). After overnight incubation of 50 pL of BVP on ELISA plates (3369; Coming) at 4 °C overnight, unbound BVPs were aspirated from the wells. All remaining steps were performed at RT. The plate was blocked with 100 pL of blocking buffer (PBS with 1% BSA) for 1 h before three washes with 100 pL of PBS. Next, 50 pL of 2.5 ug / mL testing antibodies was added to the wells and incubated for 1 h followed by washes with 100 pL of PBS. HRP-conjugated goat anti-human IgG antibody at 1: 1000 (Jackson ImmunoResearch) was used as the secondary antibody, and incubated for 1 h followed by washes as before. Finally, 100 pL ofTMB substrate (34021; Fisher Scientific) was added to each well and incubated for 6 min. The reactions were stopped by adding 50 pL of 2 M sulfuric acid to each well. The absorbance was read at 450 nm and BVP score determined by normalizing absorbance by control wells with no test antibody. Fold-over background was determined using an average of buffer-only wells. All measurements were performed in triplicate.EXAMPLE 3

[0153] MICA Antibody Binding Kinetics. Kinetic experiments were performed on Carterra LSA with a running buffer HBSTE, lOmM HEPES pH7.4, 150mM NaCl, 3mM EDTA, 0.05% Tween 20. Immobilization of goat anti-human IgG capture antibodies (Jackson ImmunoResearch) onto a HC30M sensor was performed using a standard amine-coupling procedure. The sensor chip was activated by 0.2 M EDC / 0.05 M sulfo-NHS. Subsequently, the capture antibodies were immobilized at 15 pg / ml in 10 mM sodium acetate pH 4.5, followed by quenching with 0.5 M ethanolamine. Test antibodies were captured on this anti -human Fc capture chip prepared. For kinetics analysis, human MICA-His, human MICA-alpha3-His, human MICB-alpha3-His, cyno MICA-alpha3-His from Aero or prepared internally at a concentration from 0.076 nM to 1500 nM (a serial 3 -fold dilution) was injected sequentially. For each concentration, there was 5 Min association followed by 15 Min dissociation. Results were processed and analyzed in Carterra LSA Kinetics Software. The kinetic data was referenced with the interstitial reference spots and doublereferenced to a buffer cycle, and then fit globally to a 1 : 1 binding model to determine their apparent association and dissociation kinetic rate constants (ka and kd values). The ratio kd / ka was used to derive the KD value of each antigen / mAb interaction, i.e., KD=kd / ka (FIG. 4).

[0154] MICA Antibody Cross Reactivity. Experiments were conducted to determine the reactivity of the MICA / B antibodies of the present disclosure (developed using MICA / B antigen; see Example 3) with various other MICA / B proteins. The binding of the 54 purified antibodies was checked against human MICA full length (FL), human MICA alpha 3 domain, human MICB alpha3 domain, and cyno MICA alpha3 domain. As shown in FIG. 4, experiments were conducted to determine the reactivity of the antibodies with the Cynomolgus monkey protein. The binding experiments were performed on Carterra LSA with a running buffer of PBS pH 7.40, 1% BSA, 0.05% Tween20. Antibodies were covalently printed on an HC30M chip. Chip was activated with 33 mM s-NHS and 133 mM EDC in 100 mM MES pH 5.5 for 7 Min . Antibodies at 10 mg / ml in acetic acid buffer pH 4.5 were used for printing for 10 min. The printed chip was then quenched with 1 M ethanolamine pH 8.5 for 7 min. Results were processed and analyzed in Carterra LSA Kinetics Software. The data was referenced with the interstitial reference spots and doublereferenced to a buffer cycle, and then the responses (nm) after association were reported. Isotype control was used to determine the cutoff response for positive binding.EXAMPLE 4

[0155] MICA Antibody Cross-Blocking. High-throughput epitope binning experiment was done on real-time label-free biosensors (Carterra LSA) to sort large panels of mAbs into bins based on their ability to block one another for binding to the antigen. In a pairwise epitope binning analysis, human MICA and antibody 2 (analyte antibody) are sequentially applied to the sensor chip (HC200M) covalently pre-loaded with antibody 1 (ligand antibody). An increase in response upon exposure to the analyte antibody indicates non-competition between the two antibodies, whereas a lack of change in the signal indicates competition. Antibodies having the same blocking profiles as others in the test set are grouped into one bin. Network plots are used to explore clustering of mAbs that share similar but not necessarily identical competition profiles. FIG. 5A includes a representative granular binning network map (comparator antibodies are highlighted with blue stars), and FIG. 5B includes a representative community binning network map. FIG. 5C includes a representative combined binary dendrogram (color indicates bins in the network maps).EXAMPLE 5

[0156] MICA Antibody Functions. Experiments were conducted to assess the ability of the anti-MICA antibodies of the present disclosure to both stabilize MICA on cancer cells and to inhibit MICA shedding, including comparisons to benchmark antibodies (i.e., 791, 792, 793, 794, 3F9, C16F10, C619 are control MICA antibodies). A375, A549, HCT116, H2030, OVACAR 3 cell lines were incubated with the anti-MICA and control benchmark antibodies (including Hu Isotype IgGl and no antibody groups) for 24 to 72 hours in cell-culture treated 96 well plates. All antibodies were titrated from 20 nM to sub-picomolar concentration. After incubation, supernatants were collected and stored at -80 °C, and the cells were dislodged from the plates using Versene and immediately analyzed. The amount of soluble MICA (sMICA) in the supernatant was then estimated via sandwich ELISA(R&D Biosystems). The amount of MICA stabilized on the surface of the cells was quantified using flow cytometry. MICA on the surface of the cells was detected via a PE conjugated anti-MICA antibody (6D4, Biolegend). MICA surface stabilization and sMICA showed an indirect correlation.

[0157] FIG. 6A includes results demonstrating the ability of anti-MICA antibodies to effectively stabilize MICA on the surface of cancer cells, and FIG. 6B includes results demonstrating the ability of anti-MICA antibodies to effectively inhibit MICA shedding. FIG. 6Cincludes data demonstrating a strong correlation between cell surface MICA stabilization and shedding inhibition at various concentrations of anti-MICA antibodies. Additionally, four anti- MICA antibodies were further tested and compared to benchmark antibodies (i.e., 7C6, 1D5, and CLN-619 antibodies).

[0158] FIG. 7A includes results demonstrating the ability of the four anti-MICA antibodies to effectively stabilize MICA on the surface of cancer cells, and FIG. 7B includes results demonstrating the ability of the four anti-MICA antibodies to effectively inhibit MICA shedding. FIG. 7C includes data demonstrating the ability of the four anti-MICA antibodies to enhance A375 melanoma target cell killing by primary human NK cells at different effector to target cells ratio, and FIG. 7D includes data demonstrating the ability of the four anti-MICA antibodies to enhance A375 melanoma target cell killing by primary human NK cells in the presence of varying concentrations of MICA antibodies.EXAMPLE 6

[0159] As shown in FIG. 8, experiments were conducted to determine the binding kinetics of ATX-P-1826, a fully humanized anti-MICA antibody, against human MICA, human MICB, and Cynomolgus MICA. The binding affinities of ATX-P- 1826 were evaluated using a label-free BioLayer Interferometry (BLI) system (Gator Bio, California, USA) in monovalent format. ATX-P- 1826 and control antibodies were loaded onto anti-Fc biosensors for 120 seconds, followed by equilibration in K buffer for 60 seconds to establish a baseline. The antibody-loaded sensors were then immersed in a 200 nM solution of 6XHis tagged MICA / MICB for 120 seconds to record the association phase in real-time. The sensors were 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 equilibrium). Data were analyzed using BLI software to determine the KD values for the binding pairs. As shown, ATX-P-1826 exhibited similar binding affinity for MICA, MICB, and cyno MICA tested (with somewhat better predictability and reliability of cyno tox profile).EXAMPLE 7

[0160] As shown in FIGS. 9A-9B, experiments were conducted to assess the efficacy of anti- MICA antibodies of the present disclosure for killing cancer cells. Briefly, an FcyRIIIa activationassay was conducted as a surrogate for the ADCC assay. The target cells used were A375 cells, and the effector cells were Jurkat / FcyRIIIa / NFAT-Luc cells. AHA-P-1031, an Fc-enhanced version of ATX-P-1826, was developed (see, e.g., PCT Patent Application No. PCT / US2004 / 009298 and corresponding U.S. Patent Appln. Serial No. 10 / 672,280, both of which are incorporated herein by reference in their entireties and for all purposes) and tested alongside ATX-P-1826 and ATX-P-1826 (Afucosylated) and Hu Isotype IgGl antibodies. These antibodies were used at a starting concentration of 20 nM and serially diluted 0.005 nM levels in serum free media, followed by a 30-minute incubation at 37°C. A375 and Jurkat / FcyRIIIa / NFAT-Luc cells, suspended in Opti-MEM, were seeded into a 96-well plate at a volume of 90 pL per well, with an effector-to-target ratio of 10: 1. Subsequently, the pre-incubated antibody mixtures were added to each well at a volume of 10 pL per 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 Synergy 2, a BioTek plate reader. The luciferase activity was normalized to the negative control, and the percentage of activity was plotted against the concentration of anti-MICA mAbs. The IC50 value of AHA-P- 1031 was determined using a 4-parameter logistic regression.

[0161] With respect to the results in FIG. 9B, peripheral blood mononuclear cells (PBMCs) were isolated via Ficoll-Paque gradient centrifugation, employing products from Amersham Pharmacia Biotech (Uppsala, Sweden), using huffy coat obtained from Carter BloodCare (Bedford, TX. Subsequently, human primary NK cells were isolated from the PBMCs utilizing the NK Cell Isolation Kit (Miltenyi Biotec 130-092-657). Non-NK cells were magnetically labeled using a cocktail of biotin-conjugated antibodies and the NK Cell Microbead Cocktail. Highly pure NK cells were isolated via depletion of magnetically labeled cells. NK cells viability and cell density checked using 1% trypan blue dye.

[0162] The antibody-dependent cellular cytotoxicity (ADCC) activity of human primary NK cells was evaluated using a two-color flow cytometric assay. Target tumor cells A375 (1 x 106) were incubated with 1 mL of CFSE dye. (Working stock prepare by adding 1 pl of 0.5 mM carboxyfluorescein diacetate succinimidyl ester (CFSE; Invitrogen, Eugene, OR, USA) in phosphate-buffered saline (PBS) in 10 mL of IX PBS) for 10 min at 37°C. Subsequently, the cells were washed thrice with ice-cold RPMI 1640 medium. Effector NK cells were mixed with the target cells at an effector-to-target (E / T) ratio of 10:1 (5.0 x 106 / ml effector cells, 5 x 105 / ml target cells; final volume: 200 pl) and incubated with or without antibodies (AHA-P-1031 and ATX-P-1826) at a concentration of 20 nM, titrated down to sub-picomolar levels, for overnight incubation at 37°C in a humidified atmosphere containing 5% CO2. Following incubation, the cells were washed twice with 1X PBS and stained with 7-aminoactinomycin D (7-AAD; eBioscience, Al 310, San Diego, CA, USA) for subsequent analysis via two-color flow cytometry, conducted on an Attune™ device (Thermo Scientific). CFSE and 7AAD double-positive cells were indicative of tumor target cells lysed via ADCC. The degree of ADCC activity was compared among different antibodies, and the EC50 was calculated using nonlinear regression analysis performed with GraphPad Prism.

[0163] Taken together, these results demonstrate that ADCC engineered Fc region of AHA-P- 1031 improves NK cell-mediated cancer cell killing compared to other Fc variants (FIG. 9A), and that the anti-MICA Fc enhanced antibody, AHA-P-1031, was significantly more effective at NK cell-mediated cancer cell killing compared to ATX-P-1826.EXAMPLE 8

[0164] As shown in FIG. 10, in vivo experiments were conducted to test the anti -tumor efficacy of AHA-P-1031 (Fc enhanced) in human xenografts (A375 melanoma cell line). Briefly, female athymic nude mice (NU / J Strain: 002019, homozygous for Foxnl<nu>; purchased from the Jackson Laboratory), aged 6-10 weeks, were maintained in accordance with LACUC guidelines at the ARC situated at UTSW Medical Center. The mice were housed under specific pathogen- free conditions at 20°C with 40-60% relative humidity and a 12-hour light / dark cycle. A375 cells were kept in the exponential growth phase before injection, prepared by trypsinization, and checked for viability using the trypan blue exclusion method (requiring 98% viability). Xenografts were created by injecting A375 tumor cells (5* 106resuspended in PBS and Matrigel, 100 pL injecting volume) subcutaneously into the backs of the mice. Injection sites were palpated thrice weekly until tumors were established. Tumor growth was measured using digital calipers. When tumors reached a volume of 80-100 mm3, mice were grouped (10 mice per group) and administered intraperitoneally with 10 mg / kg of purified mAb AHA-P-1031 thrice weekly for 3-4 weeks, or with an equivalent volume of phosphate-buffered saline (PBS) as a control. Tumor size was measured thrice weekly, and tumor volume was calculated using the formula: tumor size = (width2) / 2xlength. At experimental endpoints or when the predetermined size limit of 2,000 mm3was reached, mice were euthanized humanely using CO2 asphyxiation followed by cervicaldislocation in compliance with the Guide for the Care and Use of Laboratory Animals, approved by UTSW Medical Center IACUC. Tumors were excised, weighed, and processed for ex-vivo volume measurement and experiments. Gross necropsies were performed, and specified 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 of the UTSW Medical Center, Dallas, Texas (Approved Protocol # 2022-103216-EXT; Discovery of Novel Antibodies for Cancer Immunotherapy, Expiration date: APR-2025).EXAMPLE 9

[0165] As shown in FIGS. 11A-11C, experiments were conducted 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; FIG. 11A); pancreatic cancer cell lines (PANCI and Capan-2; FIG. 1 IB); ovarian cancer cell lines (OVCAR3; FIG. 1 IB); colon cancer cell lines (HCT116; FIG. 11B); and prostate cancer cell lines (22Rvl, PC3, and LNCaP; FIG. 11C). Briefly, the cell lines A375, A549, H2030, NCI-H226, Calu3, PANCI, Capan2, OVACAR3, HCT116, 22Rvl, PC3, and LNCap were cultured with the a3 domain-specific anti-MICA antibodies and control benchmark antibodies (including Hu Isotype IgGl and a no antibody group) for 24 to 72 hours in cell-culture -treated 96-well plates. The AHA-P-1031 monoclonal antibody was used at 200 nM and titrated down to sub-picomolar concentrations. After incubation, cells were detached using Versene for cell surface MICA stabilization. Detached cells were spun down, washed with IX PBS, and stained with fixative live / dead cell stain (Invitrogen eBioscience, 65-0865-14) for 15 minutes at room temperature. Cells were washed and stained with a PE-conjugated anti-MICA antibody (Clone 6D4, Biolegend, 320902) in FACS buffer (2% FBS in PBS and 2 mM EDTA) for 20 minutes on ice. Samples were analyzed using the Thermo Scientific Attune NxT Flow Cytometer, and data were analyzed with FlowJo.

[0166] For the above-described experiments, the human melanoma cell line A375 (CRL- 1619), lung carcinoma A549 (CCL-185), non-small cell lung cancer H2030 (CRL-5914), squamous cell carcinoma NCI-H226 (CRL-5826), lung adenocarcinoma Calu3 (HTB-55), pancreatic carcinoma PANCI (CRL-1469), pancreatic adenocarcinoma Capan2 (HTB-80), ovarian cancer OVACAR3 (HTB-161), colon carcinoma HCT116, prostate carcinoma 22Rvl(CRL-2505), adenocarcinoma Grade IV PC3 (CRL-1435), and LNCaP (CRL-1740) were obtained from the American Type Culture Collection (ATCC, USA). All cell lines were cultured in their recommended media with 1% antibiotic mixture (Penicillin / Streptomycin - Pen / Strep, 10,000 lU / mL; Sigma-Aldrich) and 10% Fetal Bovine Serum (FBS; Gibco, Thermo Fisher Scientific). The cells were maintained at 37°C in a humidified atmosphere containing 5% carbon dioxide (CO2).EXAMPLE 10

[0167] As shown in FIG. 12, experiments were conducted to assess the safety profile of AHA- P-1031 using a cytokine release assay. Briefly, AHA-P-1031 demonstrated a favorable safety profile, similar to other NK cell-based therapies, which are considerably safer than T cell-directing therapies. A cytokine release assay was 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 IgGl 750 ug / ml and anti CD3 & anti CD28 as a positive control. After overnight incubation with AHA- 1031 and control antibodies, cell supernatant were assayed for multiple cytokine release using Biolegend Multiplex Cytokine estimation kit. AHA-P-1031 did not result in a significant increase in the levels of the pro-inflammatory cytokines IFNy, IL-2, IL-4, and IL- 17A (FIG. 12). These data demonstrate a low toxicity risk for AHA-P-1031.

[0168] Additionally, physicochemical properties analysis, a biophysical characterization technique used for assessing the conformational stability of a biological sample, was performed. AHA-P-1031 was produced in CHOK1 cells using two plasmids (Heavy chain and Light chain) system, 200 ml transient transfection. Expressed recombinant antibodies were purified using protein A column and run on the size exclusion chromatography for characterization. AHA-P- 1031 mAbs stability checked at room temperature, stressed at 37C and stressed at pH 3.5 for 2 hours. All samples run on SEC column and SDS PAGE to assess aggregation or fragmentation. Results demonstrated that AHA-P- 1031 has an excellent transient expression profile with a high titer (>1.4 gm / L) and purity, indicative of stable cell line production, without significant aggregates of fragmentation.Sequences

[0169] The various amino acid sequences and nucleic acid sequences referenced herein are provided below.

[0170] Table 2: Anti-MICA Antibodies (CDR sequences)

[0171] Table 3: Anti-MICA Antibodies (VH and VL sequences)Ill

[0172] Table 4: Anti-MICA Antibodies (HC IgGl Fc and LC Kappa sequences)

[0173] Human MHC Class I Chain-Related Protein A (MICA) (see, e.g., UniProt AccessionNo. B0FYL7):PHSLRYNLTVLSWDGSVQSGFLAEVHLDGQPFLRYDRQKCRAKPQGQWAEDVLGNKTWDRETRDLTGNGKDLRMTLAHIKDQKEGLHSLQEIRVCEIHEDNSTRSSQHFYYDGELFLSQNVETEEWTVPQSSRAQTLAMNVRNFLKEDAMKTKTHYHAMHADCLQELRRYLESSVVLRRTVPPMVNVTRSEASEGNITVTCRASSFYPRNITLTWRQDGVSLSHDTQQWGDVLPDGNGTYQTWVATRICQGEEQRFTCYMEHSGNHSTHPVPSGKVLVLQSHWQTFHVSAVAAAAAAAAAIFVIIIFYVCCCKKKTSAAEGPELVSLQVLDQHPVGTSDHRDATQLGFQPLMSDLGSTGSTEGA (SEQ ID NO: 837).

[0174] Human MHC Class I Chain-Related Protein A (MICA) with Alpha 3 Domain underlined (see, e.g., UniProt Accession No. B0FYL7):

[0175] MEPHSLRYNLTVLSWDGSVQSGFLTEVHLDGQPFLRCDRQKCRAKPQGQWAEDVLGNKTWDRETRDLTGNGKDLRMTLAHIKDQKEGLHSLQEIRVCEIHEDNSTRSSQHFYYDGELFLSQNLETKEWTMPQSSRAQTLAMNVRNFLKEDAMKTKTHYHAMHADCLQELRRYLKSGVVLRRTVPPMVNVTRSEASEGNITVTCRASGFYPWNITLSWRODGVSLSHDTOOWGDVLPDGNGTYOTWVATRICOGEEQRFTCYMEHSGNHSTHPVPS (SEQ ID NO: 838). (See, e.g., MABS 2019, VOL. 11, NO. 1, 75-93, Spiess et.al.)

[0176] Extracellular Domain (ECD) of Human MICA (see, e.g., UniProt Accession No.Q29983):

[0177] EPHSLRYNLTVLSWDGSVQSGFLTEVHLDGQPFLRCDRQKCRAKPQGQWAEDVLGNKTWDRETRDLTGNGKDLRMTLAHIKDQKEGLHSLQEIRVCEIHEDNSTRSSQHFYYDGELFLSQNLETKEWTMPQSSRAQTLAMNVRNFLKEDAMKTKTHYHAMHADCLQELRRYLKSGVVLRRTVPPMVNVTRSEASEGNITVTCRASGFYPWNITLSWRQDGVSLSHDTQQWGDVLPDGNGTYQTWVATRICQGEEQRFTCYMEHSGNHSTHPVPSGKVLVLQS HW (SEQ ID NO: 839).

[0178] Extracellular Domain (ECD) of Human MICB (see, e.g., UniProt Accession No.Q29980):

[0179] AEPHSLRYNLMVLSQDGSVQSGFLAEGHLDGQPFLRYDRQKRRAKPQGQWAENVLGAKTWDTETEDLTENGQDLRRTLTHIKDQKGGLHSLQEIRVCEIHEDSSTRGSRHFYYDGELFLSQNLETQESTVPQSSRAQTLAMNVTNFWKEDAMKTKTHYRAMQADCLQKLQRYLKSGVAIRRTVPPMVNVTCSEVSEGNITVTCRASSFYPRNITLTWRQDGVSLSHNTQQWGDVLPDGNGTYQTWVATRIRQGEEQRFTCYMEHSGNHGTHPVPSGKALVLQS QRTD (SEQ ID NO: 840).

[0180] ECD of MICA (Macaca fascicularis) (see, e.g., GenBank: AAO24115.1 (sino biological sequence)):

[0181] ELHSLRYNVTVLSRDGSVQSEFLAEGHLDGQLFVRYDRETRRARPQGQWAE DVLGAKTWDTETGDLTENGKDLRMTLAHIKGQKGGLHSLQEIKVCEIHEDNSTGGLRH FYYDGELFLSQNLETQEWTELQSSRAQTLALNIRNFWKEDTMKTKTHYRAVQADCLKK LQRYLESGVAVRRTAPPMVNVTHSEASEGNITVTCRASGFYPRNIALTWRQDGVSLNH NAQQWGGILPDQNGTYQTWVATRIRQGEEQRFACYMEHSGNHSTHPVPSGKVLVFQS QW (SEQ ID NO: 841).

[0182] ECD of cyno MICA (see, e.g., US 2019 / 0315870A1):

[0183] ELHSLRYNVTVLSRDGSVQSGFLAEGHLDGQLFLLYDRQKCRARPQGEWSE DVLGAKTWDTETGDLTENGKDLRMTLAHIKGQKGGLHSLQEIKVCEIHEDNSTGGLRH FYYDGELFLSQNLETQEWTELQSSRAQTLALNIRNFWKEDTMKTKTHYRAVQADCLKK LQQYLESGVAVRRTAPPMVNVTHSEASEGNITVTCRASGFYPRNIALTWRQDGVSLNH NAQQWGGILPDQNGTYQTWVATRIRQGEEQRFACYMEHSGNHSTHPVPS (SEQ ID NO: 842).

[0184] Alpha 3 domain of human MICA (amino acids 183 to 274):

[0185] VPPMVNVTRSEASEGNITVTCRASGFYPWNITLSWRQDGVSLSHDTQQWGD VLPDGNGTYQTWVATRICQGEEQRFTCYMEHSGNHSTHPVPSGKVLVLQSHW (SEQ ID NO: 843).

[0186] Alpha 3 domain of human MICA-008 (Genentech):

[0187] TVPPMVNVTRSEASEGNITVTCRASSFYPRNIILTWRQDGVSLSHDTQQWGD VLPDGNGTYQTWVATRICRGEEQRFTCYMEHSGNHSTHPVPS (SEQ ID NO: 844).

[0188] ATX-P-1826 (fully humanized anti-MICA antibody, as described herein; see, e.g.,SEQ ID NOs: 93, 113, 133, 272, 295, 318, 400, 458, 516, 574, 632, 690, 748, and 806) was used to generate the Fc-enhanced antibody, termed 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 heavy chain variable region (VH) 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 was modified to include the following three amino acid substitutions: S239D, A330L, I332E (SEQ ID NO: 845). Thus, AHA- P-1031 comprises the sequences shown below in Table 5.

[0189] Table 5: Amino acid and polynucleotide sequences for AHA-P- 1031.AKHA-41436.601

[0190] Table 6: Summary of SEQ ID NOs for individual exemplary antibodies of the present disclosure.AKHA-41436.601AKHA-41436.601KEY : aa = amino acid; HCDR 1, 2, 3 = heavy chain CDRs 1, 2, and 3 (in numerical order); LCDRs 1, 2, 3 = light chain CDRs 1, 2, and 3 (in numerical order); VH = heavy chain variable region; VL = light chain variable region; VH + constant = heavy chain variable region sequence with an exemplary human heavy chain constant region sequence (typically IgGl); VL + constant = light chain variable region sequence with an exemplary human light chain constant region sequence (typically kappa). All numbers except in “Antibody Name” correspond to SEQ ID NOs in the sequence listing and Tables 2, 3, 4, and 5.

[0191] Various embodiments of the present disclosure are described herein. Variations of those embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the various embodiments of the present disclosure to be practiced otherwise than as specifically described herein. Accordingly, embodiments of the present disclosure include all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the abovedescribed elements in all possible variations thereof is encompassed by the various embodiments of the present disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIMSWhat is claimed is:

1. An antibody, or antigen binding fragment thereof, which specifically binds MHC Class 1 Chain-Related Protein A (MICA), optionally wherein the MICA is human MICA, which is optionally a polypeptide comprising the amino acid sequence of any of SEQ ID NOs: 837-839.

2. The antibody or fragment of claim 1, which exhibits any one or more the following functional characteristics: a. reduces and / or attenuates proteolytic cleavage of membrane -bound MICA into soluble MICA; and / or b. reduces and / or attenuates NKG2D-mediated escape by a tumor cell; c. enhances NK cell-mediated killing of a tumor cell; d. cross-reacts with at least one of Cynomolgus monkey MICA (cyMICA), human M1CB, human MlCA-alpha3, and / or human MlCB-alpha3; and / or e. does not cross-react with at least one of Cynomolgus monkey MICA (cyMICA), human M1CB, human MlCA-alpha3, and / or human MlCB-alpha3; and / or f. binds to human MICA with a KD of about 1.0 pM or lower; and / or g. binds to the same epitope on human MICA as an antibody comprising the VH and VL sequences of any one of the exemplary antibodies the sequences of which are provided in Table 6; and / or h. competes for binding to human MICA with an antibody comprising the VH and VL sequences of any one of the exemplary antibodies the sequences of which are provided in Table 6.

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

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

5. The antibody or fragment according to any one of the preceding claims, which 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), a Fab-C, a Fab’-SH, a (Fab’)2, a singledomain antibody (sdAb), a VHH antibody, a nanobody, a camelid-derived single-domain antibody, a shark IgNAR-derived single-domain antibody fragment (VNAR), a diabody, a triabody, an anticalin or an aptamer, optionally wherein the antibody is a full length antibody comprising an Fc region such as a human IgGl, IgG2, IgG3 or IgG4 region, and optionally wherein the antibody comprises a modified Fc region.

6. The antibody or fragment according to any one of the preceding claims, which is conjugated to at least one additional moiety, optionally selected from: a. an antigen binding moiety, such as an antibody or antigen-binding fragment thereof, which is capable of specific binding to a target which is not human MICA; and / or b. a therapeutic or cytotoxic moiety; and / or c. a detection moiety; and / or d. a purification moiety; and / or e. a half-life extension moiety.

7. The antibody or fragment according to any one of the preceding claims, which is 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 also one, two or all three of the corresponding LCDRs of the exemplary antibody; and / or b. a VH sequence having at least 90% identity to the VH sequence of any one of the exemplary antibodies the sequences of which are provided in Table 6, and optionally also a VL sequence having at least 90% identity to the corresponding VL sequence of the exemplary antibody, preferably wherein variation is not permitted in the HCDRs or LCDRs; and / or c. all six CDRs of any one of the exemplary antibodies the sequences of which are provided in Table 6; and / ord. the VH and VL sequences of any one 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 one 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 consists of a nucleic acid sequence having at least 70, 80, 90 or 100% identity to a nucleic acid sequence of any one of the exemplary antibodies the sequences of which are provided in Table 6.

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

10. A pharmaceutical composition comprising an antibody or fragment, a polynucleotide, or a vector 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 additional active ingredient.

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

12. The antibody or fragment according to any one of claims 1 to 7, the polynucleotide of claim 8, the vector of claim 9, or the composition of claims 10 or 11, for use as a medicament, optionally for use in a method of treating cancer in a subject.

13. The antibody, fragment, polynucleotide, vector, or composition for use according to claim 12, wherein the cancer is characterized as exhibiting the ability to escape immune clearance mediated by the natural killer group 2D (NKG2D) receptor.

14. The antibody, fragment, polynucleotide, vector or composition for use 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 in the subject.

15. The antibody, fragment, polynucleotide, vector or composition for use according to any one of claims 12 to 14, where the cancer is lung cancer, pancreatic cancer, ovarian cancer, colon cancer, and prostate cancer.

16. An antibody directed against MHC Class I Chain-Related Protein A (MICA) peptides, or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) comprising complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3, wherein: the HCDR1 comprises one of the following amino acid sequences:(a) X1YX2MX3 (SEQ ID NO: 1), wherein Xi is R, S, or T; X2is S or A; and X3is N or S;(b) X1X2X3MH (SEQ ID NO: 64), wherein Xi is N, D, or S; X2is H, Y, or S; X3is A or G;(c) X1X2X3X4X5 (SEQ ID NO: 85), wherein Xi is G, S, V, A, N, or T; X2is N or Y; X3is 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 Xi is S, H, or N; X2is I or V; or(e) X1X2X3X4X5 (SEQ ID NO: 172), wherein Xi is D, N, S, or A; X2is N, Y, or Q; X3is Y, N, or A; X4is I, W, or M; and X5is S, H, Y, or N; wherein the HCDR2 comprises one of the following amino acid sequences:(a) XIIX2X3X4X5X6X7X8X9YADSVKG (SEQ ID NO: 22), wherein Xi is Y, F, S, or V; X2is N, S or T; X3is S, T, Y, or G; X4is R or S; X5is S, G, or E; X6is N, S, T, G, or D; X7is T,R, or N; X8is I or T; and X9 is Y or D;(b) XIIX2X3X4GX5X6X7X8YX9DSVKG (SEQ ID NO: 71), wherein Xi is L, I, G, or V; X2is W or S; X3 is Y or W; X4is D or S; X5 is S, G, or N; Xe is N or S; X7 is K or I; X8is Y, G, or F; X9 is A or E;(c) XiIX2X3X4X5GX6TX7X8X9XioXiiFXi2Xi3 (SEQ ID NO: 105), wherein Xi is W or A; X2is N, D, or S; X3 is P or S; X4is N, D, G, or Y; and X5 is S or N; Xe is A, G, or N; X7 is N or H; X8is S or Y; X9 is A or N; X10 is Q or E; Xu is N, K, or E; X12 is Q or K; and X13 is G or D;(d) WNMPXISX2NTGX3AQKFQG (SEQ ID NO: 154) wherein Xi is N or D; X2is G or S; and X3 is Y or F; or(e) XiIX2X3X4X5X6X7X8X9XioXiiXi2Xi3Xi4Xi5 (SEQ ID NO: 178), wherein Xi is W, T, Y, or F; X2is Y, N, E, or F; X3is A, P, N, or T; X4is G, S, Y, T or H; X5is T, G, or N; X6is G, V, or I; X7is G, S, V, T, or D; X8is S, T, P, or N; X9is S, M, Y, or T; X10 is Y or N; Xu is N, A, or P; Xi2is Q, P, S, or D; X13 is K, R, L, or D; X14 is F or K; and X15 is R, Q, K, or S; wherein the HCDR3 comprises one of the following amino acid sequences:(a) XiX2X3X4X5X6X7 (SEQ ID NO: 43), wherein Xi is Xi is V, A, or G; X2is S, M, or G; X3is D, S, A, V, I or Y; X4is I, V, R, Q or W; X5is T, G, L, or F; X6is G, S, T, W or D; and X7is N, G, S, P or N;(b) XiX2X3X4(SEQ ID NO: 78), wherein Xi is Xi is E or S; X2is R or Y; X3 is D, F, L, or V; X4is Y, P, or V;(c) XiX2X3X4X5X6X7X8(SEQ ID NO: 125), wherein Xi is D, S, A, F, or E; X2is T, A, S, N, or L; X3is F, A, W, Y, or G; X4is K, R, A, G, P, or N; and X5is P, G, A, Y, or W; X6is Y, F,S, or N; X7 is Y, F, or D; and X8is Y, S, or N;(d) XIX2X3X4X5X6DX7 (SEQ ID NO: 163) wherein Xi is S or G; X2is A or S; X3is A or I; X4is S, A, or R; X5 is G or A; Xe is F, V, or S; and X7 is Y, N, S, or I; or(e) XiX2X3X4X5X6X7X8(SEQ ID NO: 184), wherein Xi is H, Y, S, G, or T; X2is D, S, G, M, or Y; X3 is Y, W, S, A, or G; X4is Y, G, S, A, or N; X5is G, P, N, R, or Y; X6is T, G, F, P, or A; X7 is S, A, D, Y, or M; X8is G, F, Y, or D; andwherein the LCDR1 comprises an amino acid sequence of any of SEQ ID NOs: 191-213, SEQ ID NOs: 263-284, or SEQ ID NOs: 332-344; the LCDR2 comprises an amino acid sequence of any of SEQ ID NOs: 215-237, SEQ ID NOs: 286-306, or SEQ ID NOs: 346-358; and the LCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 239-261, SEQ ID NOs: 309-330, or SEQ ID NOs: 360-372.

17. An antibody directed against MHC Class I Chain-Related Protein A (MICA) peptides, or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) comprising complementarity determining regions (CDRs) LCDR1, LCDR2, and LCDR3, wherein: the LCDR1 comprises one of the following amino acid sequences:(a) XiX2SX3X4lX5X6X7X8X9 (SEQ ID NO: 190), wherein Xi is R or S; X2is A or S; X3is Q or S; X4is S, T, R, or G; X5is H, S, N, T, or R; X6is N, S, Y, I, or D; X7is Y, F, D, or H; X8is L, F, or Y; and X9 is N, G, A, or L;(b) XiX2SX3X4X5X6X7X8X9Xio (SEQ ID NO: 262), wherein Xi is R, S, or K; X2is T, A, or S; X3is Q or G; X4is G, A, V, N, D, H, S, or R; X5is V or I; X6is N, G, S, H, R, V, or L; X7is S, N, H, or Y; X8is W, Y, or S; X9is L, N, or S; and Xio is A, N, or E; or(c) RXISQSX2X3X4X5X6X7 (SEQ ID NO: 331), wherein Xi is A or T; X2is V or I; X3is I, S, or N; X4is I, T, or S; X5is N, K, S, W, or Y; X6is Q, Y, H, or L; and X7is L or A; wherein the LCDR2 comprises one of the following amino acid sequences:(a) XIX2X3X4LX5S (SEQ ID NO: 214), wherein Xi is A, S, G, or R; X2is A or T; X3is S or F; X4is S, T, G, or N; and X5 is Q or A;(b) XiX2X3X4X5X6X7 (SEQ ID NO: 285), wherein Xi is A, Y, D, T, K, or W; X2is A, T, or V; X3 is S or E; X4is S, T, I, or N; X5 is L or R; Xe is Q, A, H, L, F, or E; and X7 is S, D, or L; or(c) XiX2SX3X4X5X6X7 (SEQ ID NO: 345), wherein Xi is G, K, or D; X2is A or T; X3 is S, T, or N; X4is R or L; X5 is A, E, V, or Q; and Xe is T or S;wherein the LCDR3 comprises one of the following amino acid sequences:(a) X1X2X3X4X5X6X7X8 (SEQ ID NO: 238), wherein Xi is Q or L; X2is Q or E; X3 is S, H, L, or G; X4is Y, N, H, or S; and X5is N, S, T, or I;(b) X1QX2X3X4X5PX6X7 (SEQ ID NO: 308), wherein Xi is F or Q; X2is A, F, Y, G, or S; X3is N, W, S, or Y; X4is I, S, T, K, or H; X5is F, V, T, or Y; X6is L, I, Y, R, or W; and X7is S or T; or(c) QQX1X2X3X4PX5X6 (SEQ ID NO: 359), wherein Xi is Y, A, or R; X2is G, N, or S; X3 is S, V, N, or I; X4is S, F, or W; X5 is R, L, or I; Xe is T or S; and wherein the HCDR1 comprises an amino acid sequence of any of SEQ ID NOs: 2-21, SEQ ID NOs: 65-70, SEQ ID NOs: 86-104, SEQ ID NOs: 147-153 or SEQ ID NOs: 173-177; the HCDR2 comprises an amino acid sequence of any of SEQ ID NOs: 23-42, SEQ ID NOs: 72- 77, SEQ ID NOs: 106-124, SEQ ID NOs: 153-162, or SEQ ID NOs: 179-183; and the HCDR3 comprises an amino acid sequence of any of SEQ ID NOs: 44-63, SEQ ID NOs: 79-84, SEQ ID NOs: 126-143, SEQ ID NOs: 163-171, or SEQ ID NOs: 185-189.

18. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 2; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 23; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 44.

19. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 24; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 45.

20. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 4; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 25; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 46.

21. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 5; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 26; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 47.

22. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 6; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 27; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 48.

23. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 7; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 28; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 49.

24. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 8; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 29; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 50.

25. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 9; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 30; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 51.

26. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 10; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 31 ; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 52.

27. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 11; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 32; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 53.

28. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 12; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 33; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 54.

29. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 13; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 34; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 55.

30. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 14; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 35; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 56.

31. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 15; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 36; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 57.

32. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 16; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 37; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 58.

33. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 17; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 38; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 59.

34. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 18; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 39; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 60.

35. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 19; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 40; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 61.

36. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 20; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 41; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 62.

37. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 21; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 42; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 63.

38. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 65; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 72; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 79.

39. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 66; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 73; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 80.

40. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 67; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 74; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 80.

41. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 68; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 75; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 81.

42. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 69; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 76; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 82.

43. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 70; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 77; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 84.

44. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 86; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 106; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 126.

45. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 87; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 107; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 127.

46. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 88; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 108; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 128.

47. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 89; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 109; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 129.

48. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 90; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 110; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 130.

49. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 91; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 111; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 131.

50. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 92; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 112; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 132.

51. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 93; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 113; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 133.

52. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 94; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 114; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 134.

53. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 95; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 115; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 135.

54. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 96; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 116; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 136.

55. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 97; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 117; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 137.

56. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 98; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 118; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 138.

57. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 99; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 119; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 139.

58. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 100; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 120; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 140.

59. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 101 ; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 121; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 141.

60. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 102; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 122; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 142.

61. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 103; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 123; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 143.

62. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 104; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 124; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 144.

63. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 146; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 155; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 164.

64. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 147; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 156; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 165.

65. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 148; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 157; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 166.

66. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 149; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 158; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 167.

67. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 150; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 159; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 168.

68. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 151 ; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 160; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 169.

69. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 152; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 161; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 170.

70. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 153; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 162; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 171.

71. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 173; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 179; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 185.

72. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 174; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 180; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 186.

73. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 175; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 181; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 187.

74. The antibody of claim 16 or claim 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 176; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 182; and the 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 of SEQ ID NOs: 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 of SEQ ID NOs: 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 SEQ ID NO: 373 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 374 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 375 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 376 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 377 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 378 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 379 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 380 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 381 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 382 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 383 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 384 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 385 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 386 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 387 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 388 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 389 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 390 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 391 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 392 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 393 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 394 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 395 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 396 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 397 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 398 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 399 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 400 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 401 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 402 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 403 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 404 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 405 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 406 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 407 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 408 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 409 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 410 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 411 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 412 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 413 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 414 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 415 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 416 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 417 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 418 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 419 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 420 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 421 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 423 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 424 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 425 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 426 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 427 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 428 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 429 and the VL comprises an amino acid sequence that is at least 90% identical to 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 SEQ ID NO: 430 and the VL comprises an amino acid sequence that is at least 90% identical to 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 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 MICA and reduces proteolytic cleavage of MICA.

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

196. The antibody of claim 16 or claim 17, wherein the antibody binds human MICA with a KD of about 1.0 pM or lower.

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-alpha3, and human MICB-alpha3.

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-alpha3, and human MICB- alpha3.

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 moiety.

204. The antibody of claim 16 or claim 17, wherein the antibody comprises a purification moiety.

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

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

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

208. A polynucleotide having at least 70% identity to any of SEQ ID NOs: 431 -488.

209. A polynucleotide having at least 70% identity to any of SEQ ID NOs: 547-604.

210. A polynucleotide having at least 80% identity to any of SEQ ID NOs: 431-488.

211. A polynucleotide having at least 80% identity to any of SEQ ID NOs: 547-604.

212. A polynucleotide having at least 90% identity to any of SEQ ID NOs: 431-488.

213. A polynucleotide having at least 90% identity to any of SEQ ID NOs: 547-604.

214. A polynucleotide comprising:(a) a nucleic acid sequence that is at least 70% identical to any one of SEQ ID NOs: 431- 488; and(b) a nucleic acid sequence that is at least 70% identical to any one of SEQ ID NOs: 547- 604.

215. A polynucleotide comprising:(a) a nucleic acid sequence that is at least 80% identical to any one of SEQ ID NOs: 431- 488; and(b) a nucleic acid sequence that is at least 80% identical to any one of SEQ ID NOs: 547- 604.

216. A polynucleotide comprising:(a) a nucleic acid sequence that is at least 90% identical to any one of SEQ ID NOs: 431- 488; and(b) a nucleic acid sequence that is at least 90% identical to any one of SEQ ID NOs: 547-604.

217. A polynucleotide comprising a nucleic acid sequence having at least 70% identity to any of:(a) SEQ ID NOs: 663-720;(b) SEQ ID NOs: 779-836;(c) SEQ ID NOs: 663-720;(d) SEQ ID NOs: 779-836;(e) SEQ ID NOs: 663-720; or(f) SEQ ID NOs: 779-836.

218. A polynucleotide comprising:(a) a nucleic acid sequence that is at least 70% identical to any one of SEQ ID NOs: 663- 720; and(b) a nucleic acid sequence that is at least 70% identical to any one of SEQ ID NOs: 779- 836.

203. A polynucleotide comprising:(a) a nucleic acid sequence that is at least 80% identical to any one of SEQ ID NOs: 663- 720; and(b) a nucleic acid sequence that is at least 80% identical to any one of SEQ ID NOs: 779- 836.

219. A polynucleotide comprising:(a) a nucleic acid sequence that is at least 90% identical to any one of SEQ ID NOs: 663- 720; and(b) a nucleic acid sequence that is at least 90% identical to any one of SEQ ID NOs: 779- 836.

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

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

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

223. The antibody of claim 16 or claim 17, wherein the antibody binds an epitope from a MICA polypeptide having an amino acid sequence of any one of SEQ ID NOs: 837-844.

Images