Anti-MICA / B antibodies with enhanced effector functions and methods of use

Abstract

Antibodies or antigen-binding fragments thereof that specifically bind to MICA / B having a heavy chain, a light chain, a variable heavy chain domain (VH), a variable light chain domain (VL) and complementarity determining regions (CDRs) disclosed herein, as well as methods and uses thereof, are provided herein. In certain embodiments, the antibody or antigen-binding fragment thereof comprises one or more amino acid modifications for enhancing effector function as compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or lacks fucosylation or comprises reduced fucosylation.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 393,188, filed Jul. 28, 2022, the content of which is hereby incorporated by reference in its entirety into this disclosure.

[0002] Reference to a Sequence Listing in Electronic Form The content of the sequence listing in electronic form (67253WO01 Sequence Listing.xml; size: 42 kilobytes; created on Jul. 27, 2023) is hereby incorporated by reference in its entirety into this specification.

Summary of the Invention

Means for Solving the Problems

[0003] Overview Monoclonal antibodies that specifically bind to MICA / B and thereby modulate the immune response against diseased cells are disclosed herein.

[0004] In certain embodiments, monoclonal antibodies or antigen - binding fragments thereof are disclosed that comprise a light chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some embodiments, the monoclonal antibody or antigen - binding fragment thereof further comprises a heavy chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26, and the antibody or antigen - binding fragment thereof comprises: a) one or more amino acid modifications to enhance effector function compared to an unmodified monoclonal antibody or antigen - binding fragment thereof; and / or b) lacks fucosylation or has reduced fucosylation compared to the amount of fucose normally detected for similar antibodies produced by mammalian expression systems.

[0005] In certain embodiments, a monoclonal antibody or an antigen-binding fragment thereof is disclosed herein that comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown as SEQ ID NO:7, SEQ ID NO:15, or SEQ ID NO:19. In certain embodiments, a monoclonal antibody or an antigen-binding fragment thereof is disclosed herein that comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 90% identical to the amino acid sequence shown as SEQ ID NO:7, SEQ ID NO:15, or SEQ ID NO:19. In certain embodiments, a monoclonal antibody or an antigen-binding fragment thereof is disclosed herein that comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 95% identical to the amino acid sequence shown as SEQ ID NO:7, SEQ ID NO:15, or SEQ ID NO:19. In certain embodiments, a monoclonal antibody or an antigen-binding fragment thereof is disclosed herein that comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 99% identical to the amino acid sequence shown as SEQ ID NO:7, SEQ ID NO:15, or SEQ ID NO:19, wherein the antibody or an antigen-binding fragment thereof comprises: a) one or more amino acid modifications for enhancing effector function as compared to an unmodified monoclonal antibody or an antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation as compared to the amount of fucose normally detected for a similar antibody produced by a mammalian expression system.

[0006] In certain embodiments, a monoclonal antibody or an antigen-binding fragment thereof is disclosed herein that comprises a light chain variable domain (VL) comprising an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some cases, the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some cases, the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 90% identical to the amino acid sequence shown as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some cases, the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 95% identical to the amino acid sequence shown as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some cases, the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 99% identical to the amino acid sequence shown as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20, and the antibody or an antigen-binding fragment thereof comprises: a) one or more amino acid modifications for enhancing effector function as compared to the unmodified monoclonal antibody or an antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by mammalian expression systems.

[0007] In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) that comprises an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) that comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 7, and a heavy chain variable domain (VH) that comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 8. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) that comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 15, and a heavy chain variable domain (VH) that comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 16. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) that comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 19, and a heavy chain variable domain (VH) that comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 20. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain that comprises an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain that comprises an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some cases, the monoclonal antibody or its antigen-binding fragment specifically binds to MICA protein, MICB protein, or both MICA protein and MICB protein. In some cases, the monoclonal antibody or its antigen-binding fragment binds to the alpha-3 domain of MICA protein, MICB protein, or both MICA protein and MICB protein. In some cases, the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both. In some cases, the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both. In some cases, the monoclonal antibody or its antigen-binding fragment is selected from intact immunoglobulin, scFv, Fab, F(ab’)2, or disulfide-bonded Fv.In some cases, the monoclonal antibody or its antigen-binding fragment is IgG or IgM. In some cases, the monoclonal antibody or its antigen-binding fragment is humanized or chimeric.

[0008] In certain embodiments, a monoclonal antibody or its antigen-binding fragment comprising a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20, and comprising: a) one or more amino acid modifications for enhancing effector function compared to the unmodified monoclonal antibody or its antigen-binding fragment; and / or b) lacking fucosylation or having reduced fucosylation compared to the amount of fucose normally detected for similar antibodies produced by a mammalian expression system, is disclosed herein.

[0009] In certain embodiments, a monoclonal antibody or its antigen-binding fragment comprising a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 90% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20, and comprising: a) one or more amino acid modifications for enhancing effector function compared to the unmodified monoclonal antibody or its antigen-binding fragment; and / or b) lacking fucosylation or having reduced fucosylation compared to the amount of fucose normally detected for similar antibodies produced by a mammalian expression system, is disclosed herein.

[0010] In certain embodiments, a monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 95% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20, wherein the monoclonal antibody or antigen-binding fragment thereof comprises: a) one or more amino acid modifications for enhancing effector function as compared to the unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by mammalian expression systems, is disclosed herein.

[0011] In certain embodiments, a monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 99% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20, wherein the monoclonal antibody or antigen-binding fragment thereof comprises: a) one or more amino acid modifications for enhancing effector function as compared to the unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by mammalian expression systems, is disclosed herein.

[0012] In certain embodiments, a monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 100% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20, wherein the monoclonal antibody or antigen-binding fragment thereof comprises: a) one or more amino acid modifications for enhancing effector function as compared to the unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by mammalian expression systems, is disclosed herein.

[0013] In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 90% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 95% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 99% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 100% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 8, and a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 7. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 16, and a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 15. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 20, and a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 19. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some cases, the monoclonal antibody or antigen-binding fragment thereof specifically binds to the MICA protein, the MICB protein, or both the MICA protein and the MICB protein. In some cases, the monoclonal antibody or antigen-binding fragment thereof binds to the alpha-3 domain of the MICA protein, the MICB protein, or both the MICA protein and the MICB protein. In some cases, the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both. In some cases, the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both. In some cases, the monoclonal antibody or antigen-binding fragment thereof is selected from whole immunoglobulins, scFv, Fab, F(ab’)2, or disulfide-bonded Fv. In some cases, the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM. In some cases, the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric.

[0014] In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody does not have at least one CDR selected from the list comprising SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; and the antibody or antigen-binding fragment thereof comprises a) one or more amino acid modifications to enhance effector function as compared to the unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by mammalian expression systems, is disclosed herein.

[0015] In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody does not have at least one CDR selected from the list comprising SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; and the antibody or antigen-binding fragment thereof comprises a) one or more amino acid modifications to enhance effector function as compared to the unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by mammalian expression systems, is disclosed herein.

[0016] In certain embodiments, a monoclonal antibody or an antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody does not have at least one CDR selected from the list comprising SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; and the antibody or antigen-binding fragment thereof comprises a) one or more amino acid modifications to enhance effector function as compared to the unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation as compared to the amount of fucose normally detected for a similar antibody produced by a mammalian expression system, is disclosed herein.

[0017] In certain embodiments, a monoclonal antibody or an antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody does not have at least one CDR selected from the list comprising SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; and the antibody or antigen-binding fragment thereof comprises a) one or more amino acid modifications to enhance effector function as compared to the unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation as compared to the amount of fucose normally detected for a similar antibody produced by a mammalian expression system, is disclosed herein.

[0018] In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 100% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody does not have at least one CDR selected from the list comprising SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; the antibody or antigen-binding fragment thereof comprises: a) one or more amino acid modifications for enhancing effector function as compared to the unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by a mammalian expression system, is disclosed herein.

[0019] In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to one of SEQ ID NO: 6 or SEQ ID NO: 14.In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 3. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 9, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 10, and a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 11. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 17, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 3. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 6. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 12, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 13, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 14.In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 18, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 6. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15 or SEQ ID NO: 19. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16 or SEQ ID NO: 20. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7 or SEQ ID NO: 15, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8 or SEQ ID NO: 16. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8 or SEQ ID NO: 16, and a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7 or SEQ ID NO: 15. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 7, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 8. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 15, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 16.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 19, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 20. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some cases, the monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA protein and MICB protein. In some cases, the monoclonal antibody or antigen-binding fragment thereof binds to the alpha-3 domain of MICA protein, MICB protein, or both MICA protein and MICB protein. In some cases, the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both. In some cases, the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both. In some cases, the monoclonal antibody or antigen-binding fragment thereof is selected from whole immunoglobulin, scFv, Fab, F(ab’)2, or disulfide-bonded Fv. In some cases, the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM. In some cases, the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric.

[0020] In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody does not have at least one CDR selected from the list comprising SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; and the antibody or antigen-binding fragment thereof comprises a) one or more amino acid modifications for enhancing effector function as compared to the unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by a mammalian expression system, is disclosed herein.

[0021] In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody does not have at least one CDR selected from the list comprising SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; and the antibody or antigen-binding fragment thereof comprises a) one or more amino acid modifications for enhancing effector function as compared to the unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by a mammalian expression system, is disclosed herein.

[0022] In certain embodiments, a monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody does not have at least one CDR selected from the list comprising SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; and the antibody or antigen-binding fragment thereof comprises: a) one or more amino acid modifications to enhance effector function as compared to the unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by mammalian expression systems, is disclosed herein.

[0023] In certain embodiments, a monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody does not have at least one CDR selected from the list comprising SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; and the antibody or antigen-binding fragment thereof comprises: a) one or more amino acid modifications to enhance effector function as compared to the unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by mammalian expression systems, is disclosed herein.

[0024] In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 100% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody does not have at least one CDR selected from the list comprising SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; the antibody or antigen-binding fragment thereof comprises a) one or more amino acid modifications for enhancing effector function as compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by a mammalian expression system, is disclosed herein.

[0025] In some cases, the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity-determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 1-3, 9-11, and 17. In some cases, the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity-determining region (CDR) having an amino acid sequence that is at least 90% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 1-3, 9-11, and 17. In some cases, the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity-determining region (CDR) having an amino acid sequence that is at least 95% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 1-3, 9-11, and 17. In some cases, the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity-determining region (CDR) having an amino acid sequence that is at least 99% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 1-3, 9-11, and 17. In some cases, the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity-determining region (CDR) having an amino acid sequence that is at least 100% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 1-3, 9-11, and 17. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18, a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to one of SEQ ID NO: 6 or SEQ ID NO: 14, a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, and a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11.In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 6. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 18, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 6. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 3. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 3. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 9, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 10, and a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 11.In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 17, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 3. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16 or SEQ ID NO: 20. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15 or SEQ ID NO: 19. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16 or SEQ ID NO: 20, and a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7 or SEQ ID NO: 15. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7 or SEQ ID NO: 15, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8 or SEQ ID NO: 16. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8, and a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 16, and a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 15.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown as SEQ ID NO: 20, and a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown as SEQ ID NO: 19. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some cases, the monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA protein and MICB protein. In some cases, the monoclonal antibody or antigen-binding fragment thereof binds to the alpha-3 domain of MICA protein, MICB protein, or both MICA protein and MICB protein. In some cases, the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both. In some cases, the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both. In some cases, the monoclonal antibody or antigen-binding fragment thereof is selected from whole immunoglobulin, scFv, Fab, F(ab’)2, or disulfide-bonded Fv. In some cases, the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM. In some cases, the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric.

[0026] In certain embodiments, a pharmaceutical composition comprising a monoclonal antibody or antigen-binding fragment thereof according to any one of the disclosures herein and a pharmaceutically acceptable carrier or additive, wherein the antibody or antigen-binding fragment thereof comprises: a) one or more amino acid modifications to enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or has reduced fucosylation compared to the amount of fucose normally detected for a similar antibody produced by a mammalian expression system, is disclosed herein.

[0027] In certain embodiments, a method of treating cancer in an individual in need thereof, the method comprising administering to the individual an effective amount of a monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody does not have at least one CDR selected from the list consisting of SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; and the antibody or antigen-binding fragment thereof comprises: a) one or more amino acid modifications to enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or has reduced fucosylation compared to the amount of fucose normally detected for a similar antibody produced by a mammalian expression system, is disclosed herein.

[0028] In certain embodiments, a method of treating cancer in an individual in need thereof, the method comprising administering to the individual an effective amount of a monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody does not have at least one CDR selected from the list consisting of SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; and the antibody or antigen-binding fragment thereof comprises: a) one or more amino acid modifications for enhancing effector function as compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or has reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by mammalian expression systems, is disclosed herein.

[0029] In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity-determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity-determining region (CDR) having an amino acid sequence that is at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity-determining region (CDR) having an amino acid sequence that is at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity-determining region (CDR) having an amino acid sequence that is at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18.In some cases, the monoclonal antibody or its antigen-binding fragment comprises (a) a light chain complementarity-determining region (CDR) having an amino acid sequence that is at least 100% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 100% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 2 or SEQ ID NO: 10, a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 3 or SEQ ID NO: 11, a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 4 or SEQ ID NO: 12, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 6 or SEQ ID NO: 14. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 3. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 9, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 10, and a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 11.In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 3. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 6. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 12, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 13, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 14. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 18, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 6. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20.In some cases, the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some cases, the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 7, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 8. In some cases, the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 15, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 16. In some cases, the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 19, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 20. In some cases, the monoclonal antibody or an antigen-binding fragment thereof comprises a light chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some cases, the monoclonal antibody or an antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some cases, the monoclonal antibody or an antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA protein and MICB protein. In some cases, the monoclonal antibody or an antigen-binding fragment thereof binds to the alpha-3 domain of MICA protein, MICB protein, or both MICA protein and MICB protein. In some cases, the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both. In some cases, the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both.In some cases, the monoclonal antibody or antigen-binding fragment thereof is selected from whole immunoglobulins, scFv, Fab, F(ab’)2, or disulfide-bonded Fv. In some cases, the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM. In some cases, the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric. In some cases, the monoclonal antibody or antigen-binding fragment thereof reduces the level of soluble MICA protein, soluble MICB protein, or both. In some cases, the monoclonal antibody or antigen-binding fragment thereof reduces shedding of soluble MICA protein, soluble MICB protein, or both. In some cases, the monoclonal antibody or antigen-binding fragment thereof inhibits shedding of soluble MICA protein, soluble MICB protein, or both.

[0030] In certain embodiments, a method of treating cancer in an individual in need thereof, comprising administering to the individual an effective amount of a monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody does not have at least one CDR selected from the list consisting of SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; and the antibody or antigen-binding fragment thereof comprises: a) one or more amino acid modifications to enhance effector function as compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or has reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by a mammalian expression system, is disclosed herein.

[0031] In certain embodiments, a method of treating cancer in an individual in need thereof, the method comprising administering to the individual an effective amount of a monoclonal antibody or an antigen-binding fragment thereof that comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody does not have at least one CDR selected from the list consisting of SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; and the antibody or antigen-binding fragment thereof comprises: a) one or more amino acid modifications for enhancing effector function as compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by a mammalian expression system, is disclosed herein.

[0032] In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity-determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity-determining region (CDR) having an amino acid sequence that is at least 90% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 90% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity-determining region (CDR) having an amino acid sequence that is at least 95% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 95% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity-determining region (CDR) having an amino acid sequence that is at least 99% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 99% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 4-6, 12-14, and 18.In some cases, the monoclonal antibody or its antigen-binding fragment comprises (a) a light-chain complementarity-determining region (CDR) having an amino acid sequence that is at least 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy-chain complementarity-determining region (CDR) having an amino acid sequence that is at least 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light-chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, a light-chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 2 or SEQ ID NO: 10, a light-chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 3 or SEQ ID NO: 11, a heavy-chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 4 or SEQ ID NO: 12, a heavy-chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18, and a heavy-chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 6 or SEQ ID NO: 14. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light-chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1, a light-chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and a light-chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 3. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light-chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 9, a light-chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 10, and a light-chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 11.In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 3. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 6. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 12, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 13, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 14. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 18, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 6. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown as SEQ ID NO: 7, SEQ ID NO: 15 or SEQ ID NO: 19. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown as SEQ ID NO: 8, SEQ ID NO: 16 or SEQ ID NO: 20..In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 7, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 8. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 15, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 16. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 19, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 20. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some cases, the monoclonal antibody or its antigen-binding fragment specifically binds to MICA protein, MICB protein, or both MICA protein and MICB protein. In some cases, the monoclonal antibody or its antigen-binding fragment specifically binds to the alpha-3 domain of MICB protein. In some cases, the monoclonal antibody or its antigen-binding fragment binds to the alpha-3 domain of MICA protein, MICB protein, or both MICA protein and MICB protein.In some cases, the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both. In some cases, the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both. In some cases, the monoclonal antibody or antigen-binding fragment thereof is selected from whole immunoglobulins, scFv, Fab, F(ab’)2, or disulfide-bonded Fv. In some cases, the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM. In some cases, the monoclonal antibody or fragment thereof is humanized or chimeric. In some cases, the monoclonal antibody or antigen-binding fragment thereof reduces the level of soluble MICA protein, soluble MICB protein, or both. In some cases, the monoclonal antibody or antigen-binding fragment thereof reduces shedding of soluble MICA protein, soluble MICB protein, or both. In some cases, the monoclonal antibody or antigen-binding fragment thereof inhibits shedding of soluble MICA protein, soluble MICB protein, or both.

[0033] In certain embodiments, a method of reducing the level of soluble MICA protein, soluble MICB protein, or both in an individual in need thereof, the method comprising administering to the individual an effective amount of a monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody does not have at least one CDR selected from the list consisting of SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY, is disclosed herein.

[0034] In certain embodiments, a method of reducing the level of soluble MICA protein, soluble MICB protein, or both in an individual in need thereof, the method comprising administering to the individual an effective amount of a monoclonal antibody or an antigen-binding fragment thereof comprising a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody does not have at least one CDR selected from the list consisting of SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY, is disclosed herein. In some cases, the monoclonal antibody or an antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or an antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or an antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18.In some cases, the monoclonal antibody or its antigen-binding fragment comprises: (a) a light chain complementarity-determining region (CDR) having an amino acid sequence that is at least 99% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 99% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or its antigen-binding fragment comprises: (a) a light chain complementarity-determining region (CDR) having an amino acid sequence that is at least 100% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 100% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 2 or SEQ ID NO: 10, a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 3 or SEQ ID NO: 11, a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 4 or SEQ ID NO: 12, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NO: 6 or SEQ ID NO: 14. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 3.In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 9, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 10, and a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 11. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 17, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 3. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 6. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 12, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 13, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 14. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 18, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 6.In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 15, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 16. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 19, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 20. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some cases, the monoclonal antibody or its antigen-binding fragment specifically binds to MICA protein, MICB protein, or both MICA protein and MICB protein.In some cases, the monoclonal antibody or antigen-binding fragment thereof binds to the alpha-3 domain of MICA protein, MICB protein, or both MICA protein and MICB protein. In some cases, the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both. In some cases, the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both. In some cases, the monoclonal antibody or antigen-binding fragment thereof is selected from whole immunoglobulins, scFv, Fab, F(ab’)2, or disulfide-linked Fv. In some cases, the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM. In some cases, the monoclonal antibody or fragment thereof is humanized or chimeric. In some cases, the monoclonal antibody or antigen-binding fragment thereof reduces or inhibits shedding of soluble MICA protein, soluble MICB protein, or both, thereby reducing the level of soluble MICA protein, soluble MICB protein, or both in an individual. In some cases, the individual has cancer characterized by elevated levels of soluble MICA protein, soluble MICB protein, or both.

[0035] In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof according to any one of the disclosures herein for use in the treatment of cancer in an individual in need thereof, wherein the antibody or antigen-binding fragment thereof comprises: a) one or more amino acid modifications for enhancing effector function as compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or has reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by mammalian expression systems, is disclosed herein.

[0036] In certain embodiments, a monoclonal antibody or an antigen-binding fragment thereof according to any one of the disclosures herein for use in the preparation of a medicament for treating cancer in an individual in need of treating cancer is disclosed herein. More specifically, the antibody or antigen-binding fragment thereof comprises: a) one or more amino acid modifications for enhancing effector function as compared to an unmodified monoclonal antibody or an antigen-binding fragment thereof; and / or b) lacks fucosylation or has reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by mammalian expression systems.

[0037] In certain embodiments, a monoclonal antibody or an antigen-binding fragment thereof that competitively binds to MICA / B with an antibody comprising a light chain variable domain (VL) having an amino acid sequence that is at least about 80% identical to the amino acid sequence shown as SEQ ID NO: 27 is disclosed herein. In certain embodiments, a monoclonal antibody or an antigen-binding fragment thereof that competitively binds to MICA / B with an antibody comprising a heavy chain variable domain (VH) having an amino acid sequence that is at least about 80% identical to the amino acid sequence shown as SEQ ID NO: 28, wherein the antibody or antigen-binding fragment thereof comprises: a) one or more amino acid modifications for enhancing effector function as compared to an unmodified monoclonal antibody or an antigen-binding fragment thereof; and / or b) lacks fucosylation or has reduced fucosylation as compared to the amount of fucose normally detected for similar antibodies produced by mammalian expression systems, is disclosed herein.

[0038] In certain embodiments, for the monoclonal antibodies or antigen-binding fragments thereof and methods described herein, the monoclonal antibodies or antigen-binding fragments thereof induce one or more of complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) by activating Fc receptor binding, and antibody-dependent cell phagocytosis (ADCP) in target cells. In certain embodiments, the monoclonal antibody or antigen-binding fragment thereof induces ADCC.

[0039] In certain embodiments of the monoclonal antibodies or antigen-binding fragments thereof described herein or of the methods described herein, the monoclonal antibody or antigen-binding fragment thereof comprises a mutation at amino acid 239 of the Fc region. In certain embodiments of the monoclonal antibodies or antigen-binding fragments thereof described herein or of the methods described herein, the monoclonal antibody or antigen-binding fragment thereof comprises a mutation at amino acid 332 of the Fc region. In certain embodiments of the monoclonal antibodies or antigen-binding fragments thereof described herein or of the methods described herein, the monoclonal antibody or antigen-binding fragment thereof comprises the mutation S239D in the Fc region. In certain embodiments of the monoclonal antibodies or antigen-binding fragments thereof described herein or of the methods described herein, the monoclonal antibody or antigen-binding fragment thereof comprises the mutation I332D in the Fc region. In certain embodiments of the monoclonal antibodies or antigen-binding fragments thereof described herein or of the methods described herein, the monoclonal antibody or antigen-binding fragment thereof comprises the mutations S239D and I332D in the Fc region. In certain embodiments of the monoclonal antibodies or antigen-binding fragments thereof described herein or of the methods described herein, the monoclonal antibody or antigen-binding fragment thereof contains less than 95%, less than 85%, less than 75%, less than 65%, less than 55%, less than 45%, less than 35%, less than 25%, less than 15%, or less than 5% of the amount of fucose normally detected for similar antibodies produced by mammalian expression systems.

[0040] In certain embodiments of the monoclonal antibodies or antigen-binding fragments thereof described herein or of the methods described herein, the monoclonal antibody or antigen-binding fragment thereof comprises one or more amino acid modifications of Table B and / or Table C.

[0041] In certain embodiments of the monoclonal antibodies or antigen-binding fragments thereof described herein or of the methods described herein, the monoclonal antibody or antigen-binding fragment thereof comprises one or more amino acid modifications of Table B and / or Table C.

[0042] In certain embodiments disclosed herein, the cancer is selected from the group consisting of carcinoma, lymphoma, blastoma, melanoma, and leukemia.

[0043] In certain embodiments disclosed herein, the cancer is selected from the group consisting of squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, Hodgkin and non-Hodgkin lymphoma, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer, such as hepatocellular carcinoma and hepatoma, bladder cancer, breast cancer, myeloma (e.g., multiple myeloma), salivary gland cancer, kidney cancer, such as renal cell carcinoma and Wilms tumor, basal cell carcinoma, melanoma, prostate cancer, vulvar cancer, thyroid cancer, testicular cancer, esophageal cancer, and various types of head and neck cancer.

[0044] In certain embodiments disclosed herein, the cancer is a primary cancer.

[0045] In certain embodiments disclosed herein, the cancer is a metastatic cancer.

[0046] In certain embodiments disclosed herein, the monoclonal antibody or antigen-binding fragment thereof increases the surface level of MICA protein, MICB protein, or both.

[0047] In certain embodiments disclosed herein, the monoclonal antibody or antigen-binding fragment thereof inhibits the shedding of MICA protein, MICB protein, or both.

[0048] In certain embodiments disclosed herein, a monoclonal antibody or antigen-binding fragment thereof increases the surface level of soluble MICA protein, soluble MICB protein, or both.

[0049] In certain embodiments disclosed herein, a monoclonal antibody or antigen-binding fragment thereof inhibits shedding of soluble MICA protein, soluble MICB protein, or both.

[0050] A method of increasing the surface level of soluble MICA protein, soluble MICB protein, or both in an individual in need thereof by inhibiting shedding, the method comprising administering to the individual an effective amount of a monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody does not have at least one CDR selected from the list consisting of SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY, is disclosed herein.

[0051] In certain embodiments, a method of increasing the surface level of soluble MICA protein, soluble MICB protein, or both in an individual in need thereof by inhibiting shedding, the method comprising administering to the individual an effective amount of a monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody does not have at least one CDR selected from the list consisting of SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY, is disclosed herein. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence that is at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18.In some cases, the monoclonal antibody or its antigen-binding fragment comprises (a) a light-chain complementarity-determining region (CDR) having an amino acid sequence that is at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy-chain complementarity-determining region (CDR) having an amino acid sequence that is at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or its antigen-binding fragment comprises (a) a light-chain complementarity-determining region (CDR) having an amino acid sequence that is at least 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and (b) a heavy-chain complementarity-determining region (CDR) having an amino acid sequence that is at least 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light-chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 1, 9, or 17, a light-chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 2 or 10, a light-chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 3 or 11, a heavy-chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 4 or 12, a heavy-chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 5, 13, or 18, and a heavy-chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to any one of SEQ ID NOs: 6 or 14. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light-chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 1, a light-chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and a light-chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 3.In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 9, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 10, and a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 11. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a light chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 17, a light chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and a light chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 3. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 6. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 12, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 13, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 14. In some cases, the monoclonal antibody or its antigen-binding fragment comprises at least one of a heavy chain complementarity-determining region 1 (CDR1) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity-determining region 2 (CDR2) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 18, and a heavy chain complementarity-determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to SEQ ID NO: 6.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequences shown as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequences shown as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequences shown as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequences shown as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 7, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 8. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 15, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 16. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 19, and a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 20. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequences shown as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequences shown as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some cases, the monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA protein and MICB protein.In some cases, the monoclonal antibody or antigen-binding fragment thereof binds to the alpha-3 domain of MICA protein, MICB protein, or both MICA protein and MICB protein. In some cases, the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both. In some cases, the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both. In some cases, the monoclonal antibody or antigen-binding fragment thereof is selected from whole immunoglobulin, scFv, Fab, F(ab’)2, or disulfide-bonded Fv. In some cases, the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM. In some cases, the monoclonal antibody or fragment thereof is humanized or chimeric. In some cases, the monoclonal antibody or antigen-binding fragment thereof inhibits shedding of soluble MICA protein, soluble MICB protein, or both, thereby increasing the surface level of soluble MICA protein, soluble MICB protein, or both in an individual. In some cases, the individual has cancer characterized by elevated levels of soluble MICA protein, soluble MICB protein, or both.

[0052] A more complete understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description which illustrates embodiments exemplary of the principles of the invention and to the appended drawings below.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0070] Detailed Description Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which the methods described herein belong. Any reference to standard methods (e.g., ASTM, TAPPI, AATCC, etc.) refers to the latest version of the methods available at the time of filing of the present disclosure, unless otherwise indicated.

[0071] For any method disclosed herein that includes separate steps, the steps can be performed in any executable order. Also, if desired, any combination of two or more steps can be performed simultaneously.

[0072] All headings are for the convenience of the reader and, unless expressly so stated, are not to be used to limit the meaning of the text that follows the heading.

[0073] The terms “preferred” and “preferably” refer to embodiments of the invention that may provide a particular benefit under a particular set of circumstances. However, other embodiments may be preferred under the same or other circumstances. Further, the description of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.

[0074] The terms “comprising” and variations thereof do not have a limiting meaning when these terms appear in the specification and claims. Such terms are to be construed as implying the inclusion of the stated step or element or group of steps or elements, but not the exclusion of any other step or element or group of steps or elements.

[0075] “Consisting of” means including and limited to whatever follows the phrase “consisting of”. Thus, the phrase “consisting of” indicates that the recited elements are required or essential and that no other elements can be present. “Consisting essentially of” means including any elements limited to those recited after this phrase and other elements that do not interfere with or contribute to the activity or action specified in this disclosure for the recited elements. Thus, the phrase “consisting essentially of” indicates that the recited elements are required or essential, but that other elements may or may not be present, depending upon whether or not they materially affect the activity or action of the recited elements.

[0076] The singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. These articles refer to one or more than one (i.e., at least one). As used herein, the term "or" is generally used in its ordinary sense including "and / or" unless the context clearly dictates otherwise. The term "and / or" means any one or more of the items in a list joined by "and / or". By way of example, "x and / or y" means any element of the three-element set {(x), (y), (x, y)}. In other words, "x and / or y" means "one or both of x and y". As another example, "x, y, and / or z" means any element of the seven-element set {(x), (y), (z), (x, y), (x, z), (y, z), (x, y, z)}. In other words, "x, y and / or z" means "one or more of x, y and z".

[0077] When ranges are given, the endpoints include all numbers within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). Further, unless otherwise indicated or unless other interpretation is not apparent from the context and the understanding of one of ordinary skill in the art, values expressed as ranges can take on any specific value or subrange within the range, down to one tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. As used herein, a number "less than or equal to" (e.g., less than or equal to 50) includes that number (e.g., 50). The terms "in a range" or "within a range" (and similar descriptions) include the endpoints of the stated range.

[0078] Throughout this specification, references to "one aspect", "an aspect", "a particular aspect", or "some aspects" mean that the particular features, configurations, compositions, or characteristics described in connection with that aspect are included in at least one aspect of the present disclosure. Thus, the appearances of such phrases in various places throughout this specification are not necessarily referring to the same embodiment of the present disclosure. Furthermore, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more aspects.

[0079] Unless otherwise indicated, all numbers expressing components, molecular weights, etc. used in this specification and the claims are to be understood as being modified in all instances by the term "about". When used in connection with measured amounts herein, the term "about" refers to the variations in the measured amounts that would be expected by a person of ordinary skill in the art who takes the measurements and exercises a level of care commensurate with the purpose of the measurement and the precision of the measuring equipment used. The term "about" when used in connection with numerical values throughout this specification and the claims indicates the precision intervals well known and accepted by those of ordinary skill in the art. Generally, such precision intervals are + / - 10%. Accordingly, unless otherwise indicated to the contrary, the numerical parameters set forth in this specification and the claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the reported significant digits and by applying ordinary rounding techniques.

[0080] Although the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. However, all numerical values inherently contain a range necessarily resulting from the standard deviation found in their respective test measurements.

[0081] The term "exemplary" means serving as a non-limiting example, instance or illustration. As used herein, the terms "e.g.," and "for example" highlight a list of one or more non-limiting aspects, examples, instances or illustrations.

[0082] As used herein, the term "substantially" refers to a qualitative condition indicating all or almost all of the range or degree of the characteristic or property of interest. Biological and chemical phenomena rarely, if ever, go to completion and / or proceed to perfection, or achieve or avoid absolute results. Thus, the term "substantially" is used herein to capture the potential lack of perfection inherent in many biological and chemical phenomena. For example, "substantially" can refer to being within at least about 20%, or at least about 10%, or at least about 5% of the characteristic or property of interest.

[0083] The present invention is defined in the claims. However, the following is a non-exhaustive list of non-limiting exemplary aspects. Any one or more of the features of these aspects can be combined with any one or more of the features of another example, embodiment or aspect described herein.

[0084] In some embodiments, monoclonal antibodies that specifically bind to MICA / B are disclosed herein. In some embodiments, the MICA / B antibodies herein bind to MICA / B protein or a fragment thereof in an individual and modulate the immune response, thereby treating cancer.

[0085] Major histocompatibility complex class I-related chain A and B (MICA / B) are two stress-inducing ligands of the natural killer cell (NK) receptor NKG2D and play important roles in mediating cytotoxicity of NK and T cells. Soluble MICA / B secreted by diseased cells (e.g., cancer cells) desensitizes NK and T cells by binding to the NKG2D receptor, thereby suppressing the immune response. Therefore, modulation of MICA / B is useful for modulation of the immune response in an individual, for example, in an individual suffering from cancer. Antibodies that bind to MICA / B and modulate its activity are desirable for the development of novel therapeutic methods for the treatment of cancer. A particular terminology

[0086] As used herein, "MICA / B" refers to the MICA protein, the MICB protein, or both the MICA protein and the MICB protein, and includes their variants, isoforms, and species homologs of human MICA / B.

[0087] As used herein, "antibody" refers to a glycoprotein that exhibits binding specificity for a particular antigen. Antibodies often contain variable and constant domains in each of the heavy and light chains. Thus, most antibodies have a heavy chain variable domain (VH) and a light chain variable domain (VL) that together form the portion of the antibody that binds the antigen. Within each variable domain, there are three complementarity-determining regions (CDRs) that form loops in the heavy chain variable domain (VH) and the light chain variable domain (VL) that contact the surface of the antigen. Antibodies herein also include "antigen-binding portions" or fragments of the antibody that are capable of binding the antigen.

[0088] As used herein, a "chimeric" antibody has a portion of the heavy and / or light chain that is identical or homologous to the corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to the corresponding sequence in an antibody derived from a different species or belonging to a different antibody class or subclass, and is of course also a fragment of such an antibody, provided that such fragments exhibit the desired biological activity (see, e.g., Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851-6855 (1984)). "Humanized antibody" as used herein refers to a chimeric antibody having human sequences substituted in the antibody sequence.

[0089] As used herein, "effector function" refers to a biological activity mediated by the Fc region of an antibody, and this activity varies depending on the antibody isotype. Examples of antibody effector functions include receptor ligand blockade, agonism or antagonism, C1q binding that activates complement-dependent cytotoxicity (CDC), Fc receptor binding that activates antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cell phagocytosis (ADCP).

[0090] As used herein, "enhancement of effector function" refers to one or more modifications to the amino acid sequence of the Fc region of an antibody that increase the effector function of the Fc region, including but not limited to CDC, ADCC, and ADCP, compared to the same antibody without amino acid modifications (s).

[0091] The terms "recipient", "individual", "subject", "host", and "patient" are used interchangeably herein and, in some cases, refer to any mammalian subject for which a diagnosis, treatment or therapy is desired, particularly a human. "Mammal" for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, as well as laboratory animals, zoo animals, sport animals or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys, etc. In some embodiments, the mammal is a human.

[0092] As used herein, the terms "treatment", "treating", etc. in some cases refer to administering a drug or performing a procedure for the purpose of obtaining an effect. This effect may be preventive in the sense of completely or partially preventing a disease or its symptoms, and / or may be therapeutic in the sense of causing partial or complete cure of the disease and / or symptoms of the disease. "Treatment" as used herein can include the treatment of a disease or disorder (e.g., cancer) in a mammal, particularly a human, and (a) preventing the occurrence of a disease or symptoms of a disease in a subject who may have a predisposition to the disease (including diseases that may be associated with or caused by a primary disease) but has not yet been diagnosed as having it; (b) suppressing the disease, i.e., arresting its onset; and (c) alleviating the disease, i.e., causing regression of the disease. Treating can include any objective or subjective parameter, such as remission; alleviation; reduction of symptoms, or making the condition more tolerable to the patient; slowing the rate of degeneration or regression; or making the ultimate point of degeneration less debilitating, and can refer to any indication of success in the treatment, amelioration, or prevention of cancer. Treatment or amelioration of symptoms is based on one or more objective or subjective parameters, including the results of an examination by a physician. Thus, the term "treating" includes the administration of a compound or agent of the invention for preventing, delaying, alleviating, suppressing, or inhibiting the onset of symptoms or conditions associated with a disease (e.g., cancer). The term "therapeutic effect" refers to the reduction, disappearance, or prevention of a disease, symptoms of a disease, or side effects of a disease in a subject.

[0093] "Therapeutically effective amount" in some cases means an amount sufficient to effect the treatment of a disease when administered to a subject for treating the disease.

[0094] As used herein, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an antibody" includes a plurality of antibodies, and reference to "an antibody" may include multiple antibodies in some embodiments, and the like.

[0095] As used herein, all numerical values or numerical ranges include integers within such ranges or encompassing such ranges, and values or fractions of integers within or encompassing such ranges, unless the context clearly dictates otherwise. Thus, for example, reference to a range of 90 to 100% includes 91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so on. In another example, reference to a range of 1 to 5,000-fold includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20-fold, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5-fold, etc., 2.1, 2.2, 2.3, 2.4, 2.5-fold, etc., and so on.

[0096] "About" a number, as used herein, refers to a range that includes that number, extending from 10% below that number to 10% above that number. "About" a range refers to from 10% below the lower limit of that range to 10% above the upper limit of that range.

[0097] "Percent identity" refers to the degree to which two sequences (nucleotides or amino acids) have the same residues at the same positions in an alignment. For example, "an amino acid sequence is X% identical to SEQ ID NO: Y" refers to the percent identity of the amino acid sequence with respect to SEQ ID NO: Y, and is detailed as X% of the residues in the amino acid sequence being identical to the residues of the sequence disclosed in SEQ ID NO: Y. Generally, computer programs are utilized for such calculations. Exemplary programs for comparing and aligning pairs of sequences include ALIGN (Myers and Miller, 1988), FASTA (Pearson and Lipman, 1988; Pearson, 1990), and gapped BLAST (Altschul et al., 1997), BLASTP, BLASTN, or GCG (Devereux et al., 1984). MICA / B

[0098] In some embodiments, monoclonal antibodies that specifically bind to MICA / B are disclosed herein. In some embodiments, monoclonal antibodies that competitively bind to MICA / B are further disclosed herein.

[0099] Major histocompatibility complex (MHC) class I chain-related genes A and B proteins (MICA / B) are glycosylated polymorphic and membrane-anchored non-classical MHC class I proteins. MICA / B is related to MHC class I and has a similar domain structure including three extracellular Ig-like domains (alpha-1, alpha-2, and alpha-3), a transmembrane domain, and a C-terminal cytoplasmic tail. However, MICA / B does not associate with beta2-microglobulin, lacks a CD8 binding site, and does not present any antigens. MICA / B is a ligand for the C-type lectin-like activating receptor natural killer group 2D (NKG2D) on immune effector cells, including both NK cells, NKT cells, and alpha beta CD8 + T cells and gamma delta CD8 + T cells. The interaction between MICA / B and NKG2D contributes to tumor surveillance and the immune response.

[0100] MICA / B protein is usually expressed at low levels in normal cells, but is induced to higher levels in stressed or transformed cells (e.g., cancer cells). The interaction between immune effector cells bearing NKG2D and stressed or diseased cells expressing MICA / B ligand on their cell surface gives rise to a cellular immune response against the stressed / diseased cells, and ultimately, the MICA / B-expressing cells will die. In cancer cells, truncated MICA / B protein (a protein that lacks the transmembrane domain and cytoplasmic tail but retains three extracellular domains including alpha-1, -2, and -3 domains) is often released into the blood by the action of proteases, resulting in downmodulation (receptor internalization) of its intended receptor NKG2D on immune effector cells. In some cases, MICA / B glycoprotein is produced intracellularly, and the glycoprotein is not uniformly destined to become cell surface membrane-bound. Instead, it is incorporated into exosomes and released outside the cell where it interacts with the NKG2D receptor on immune cells. These truncated or soluble MICA / B ligands released from the surface of cancer cells function like decoy molecules and cause downmodulation of the NKG2D receptor on immune effector cells such as NK, NKT, and various CD8 + T cells. In some cases, the formation of soluble MICA / B results in an anomalous situation where effectors of the innate defense mechanism, whose natural role is to search for and destroy transformed cells, are halted by the immunosuppressive action of these decoy ligand molecules, thereby enabling cancer cells to hide from the immune system and grow without being suppressed. Targeting of cancer

[0101] In some embodiments, the anti-MICA / B antibodies disclosed herein bind to MICA / B protein or fragments thereof in an individual and modulate the immune response, thereby treating cancer.

[0102] As used herein, the term "treatment" or "treating" refers to a clinical intervention that modifies the natural course of a disease in a subject being treated. Desirable therapeutic effects include, but are not limited to, preventing the occurrence of a disease, alleviating symptoms, reducing any direct or indirect pathological consequence of the disease, preventing metastasis, delaying disease progression, improving or alleviating a condition, and / or improving prognosis.

[0103] As used herein, the terms "cancer", "tumor", "cancerous", and malignant refer to or describe a physiological disease in a mammal that is typically characterized by unregulated cell growth. Examples of cancers that can be treated by the compositions of the present invention include, but are not limited to, carcinoma (e.g., adenocarcinoma), lymphoma, blastoma, melanoma, and leukemia. More specific examples of such cancers include, for example, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, Hodgkin and non-Hodgkin lymphoma, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer, e.g., hepatocarcinoma and hepatocellular carcinoma, bladder cancer, breast cancer, myeloma (e.g., multiple myeloma), salivary gland cancer, kidney cancer, e.g., renal cell carcinoma and Wilms tumor, basal cell carcinoma, melanoma, prostate cancer, vulvar cancer, thyroid cancer, testicular cancer, esophageal cancer, and various types of head and neck cancer.

[0104] As a result of the growth and proliferation of cancerous cells, a cancerous tumor is formed, which is a tumor that invades and destroys adjacent tissues and organs. Malignant tumors are cancers, and they are often, but not always, resectable and often, but not always, recur. The cells of a malignant tumor can invade and destroy nearby tissues and organs. In addition, cancer cells can leave the site of the malignant lesion and move through the blood or the lymphatic system to form new lesions in distant organs. This movement of cancer to a distant site is called metastasis.

[0105] Hepatocellular carcinoma (HCC) is a primary liver malignancy that mainly occurs in individuals with chronic underlying liver diseases and cirrhosis. The tumor progresses with local increase, intrahepatic spread, and distant metastasis. Hepatitis B and C are predisposing factors for the development of chronic liver diseases in individuals and the subsequent occurrence of HCC. Obesity, diabetes, and alcohol abuse are some other causes that are predisposing factors for the subsequent occurrence of HCC in individuals. Anti-MICA / B antibody

[0106] Antibodies that specifically bind to MICA / B protein are provided herein. In some embodiments, the anti-MICA / B antibody comprises at least one heavy chain, and the anti-MICA / B antibody comprises at least one light chain. In some embodiments, the anti-MICA / B antibody comprises at least one heavy chain comprising a heavy chain variable domain (VH) and at least one light chain comprising a light chain variable domain (VL). Each of VH and VL comprises three complementarity determining regions (CDRs). The amino acid sequences of VH, VL, and CDRs determine the antigen-binding specificity and antigen-binding strength of the antibody. The amino acid sequences of the heavy and light chains, VH, VL, and CDRs are summarized in Table 1.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

[0107] In some embodiments, the antibody specifically binds to the MICA protein. In some embodiments, the antibody specifically binds to the MICB protein. In some embodiments, the antibody specifically binds to both the MICA protein and the MICB protein. In some embodiments, the antibody binds to the alpha-3 domain of the MICA protein. In some embodiments, the antibody binds to the alpha-3 domain of the MICB protein. In some embodiments, the antibody binds to the alpha-3 domains of both the MICA protein and the MICB protein. In some embodiments, the antibody binds to the MICA protein that is the membrane-bound MICA protein. In some embodiments, the antibody binds to the MICA protein that is the soluble MICA protein. In some embodiments, the antibody binds to the MICA protein that is both the membrane-bound MICA protein and the soluble MICA protein. In some embodiments, the antibody binds to the MICB protein that is the membrane-bound MICB protein. In some embodiments, the antibody binds to the MICB protein that is the soluble MICB protein. In some embodiments, the antibody binds to the MICB protein that is both the membrane-bound MICB protein and the soluble MICB protein.

[0108] In some embodiments, the antibody that specifically binds to MICA / B is a monoclonal antibody. In some embodiments, the antibody is an antibody-binding fragment. In some cases, the antibody is selected from whole immunoglobulins, scFv, Fab, F(ab’)2, or disulfide-bonded Fv. In some embodiments, the antibody is IgG or IgM. In some embodiments, the antibody is humanized. In some embodiments, the antibody is chimeric. MICA / B antibody heavy and light chains

[0109] Antibodies that specifically bind to MICA / B having a light chain are disclosed herein. In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some embodiments, the light chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24.

[0110] Antibodies that specifically bind to MICA / B having a heavy chain are further disclosed herein. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some embodiments, the heavy chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some embodiments, the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26.

[0111] Also disclosed herein are antibodies that specifically bind to MICA / B having a light chain and a heavy chain. In some embodiments, the antibody that binds to MICA / B has a light chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence shown as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24, and a heavy chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence shown as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence shown as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24, and the heavy chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence shown as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26.

[0112] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 21, and a heavy chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 22. In some embodiments, the light chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 21, and the heavy chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 22. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 21, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 22.

[0113] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 23, and a heavy chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 25. In some embodiments, the light chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 23, and the heavy chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 25. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 23, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 25.

[0114] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 23, and a heavy chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 23, and the heavy chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 23, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 26.

[0115] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 24, and a heavy chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 25. In some embodiments, the light chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 24, and the heavy chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 25. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 24, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 25.

[0116] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 24, and a heavy chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 24, and the heavy chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 24, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 26. Fc region of the MICA / B antibody

[0117] The structures of the Fc regions of various immunoglobulins and the glycosylation sites contained therein are known in the art. See Schroeder and Cavacini, J. Allergy Clin. Immunol., 2010, 125:S41-52, which is incorporated by reference in its entirety. The Fc region can be a naturally occurring Fc region or a modified Fc region as described in the art or elsewhere in this disclosure.

[0118] Unless otherwise specified, the numbering of amino acid residues in the Fc region or constant region conforms to the EU numbering system, also called the EU index, as described in Kabat et al, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. The "Fc polypeptide" of the dimeric Fc, as used herein, refers to one of the two polypeptides that form the dimeric Fc domain capable of stable self-association, i.e., the polypeptide containing the C-terminal constant region of the immunoglobulin heavy chain. For example, the Fc polypeptide of dimeric IgG Fc contains the IgG CH2 and IgG CH3 constant domain sequences. Fc can be of classes IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0119] The terms "Fc receptor" and "FcR" are used to describe receptors that bind to the Fc region of an antibody. For example, an FcR can be a native sequence human FcR. In general, FcRs are those that bind to IgG antibodies (gamma receptors), including the receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. The FcγRII receptor includes FcγRIIA ("activating receptor") and FcγRIIB ("inhibitory receptor"), which have similar amino acid sequences that mainly differ in their cytoplasmic domains. Other isotypes of immunoglobulins can also be bound by certain FcRs (see, for example, Janeway et al., Immuno Biology: the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999)). The activating receptor FcγRIIA contains an immunoreceptor activation tyrosine motif (ITAM) in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an immunoreceptor inhibitory tyrosine motif (ITIM) in its cytoplasmic domain (reviewed in Daeoron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those that will be identified in the future, are encompassed by the term "FcR" herein. This term also includes the neonatal receptor, FcRn, which is involved in the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976); and Kim et al., J. Immunol. 24:249 (1994)).

[0120] Modification of the CH2 domain can affect the binding of FcR to Fc. Some amino acid modifications of the Fc region are known in the art for selectively altering the affinity of Fc for different Fc gamma receptors. In some embodiments, the Fc comprises one or more modifications to facilitate selective binding of Fc-gamma receptors. Exemplary mutations that alter the binding of FcRs to Fc are listed below: S298A / E333A / K334A, S298A / E333A / K334A / K326A (Lu Y, Vernes JM, Chiang N, et al. J Immunol Methods. 2011 Feb 28;365(1-2):132-41); F243L / R292P / Y300L / V305I / P396L, F243L / R292P / Y300L / L235V / P396L (Stavenhagen JB, Gorlatov S, Tuaillon N, et al. Cancer Res. 2007 Sep 15;67(18):8882-90; Nordstrom JL, Gorlatov S, Zhang W, et al. Breast Cancer Res. 2011 Nov 30;13(6):R123); F243L (Stewart R, Thom G, Levens M, et al. Protein Eng Des Sel. 2011 Sep;24(9):671-8.), S298A / E333A / K334A (Shields RL, Namenuk AK, Hong K, et al. J Biol Chem. 2001 Mar 2;276(9):6591-604); S239D / I332E / A330L, S239D / I332E (Lazar GA, Dang W, Karki S, et al. Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4005-10); S239D / S267E, S267E / L328F (Chu SY, Vostiar I, Karki S, et al. Mol Immunol.(in 2008 Sep;45(15):3926-33), Ser298Ala / Glu333Ala / Lys334Ala, Ser239Asp / Ala330Leu / Ile332Glu, Ser239Asp / Ile332Glu, Gly236Ala / Ser239Asp / Ala330Leu / Ile332Glu, Gly236Ala, Leu234Tyr / Gly236Trp / Ser298Ala, Phe243Leu / Arg292Pro / Tyr300Leu / Val305Ile / Pro396Leu, Lys326Trp / Glu333Ser, Lys326Ala / Glu333Ala, Lys326Met / Glu333Ser, Cys221Asp / Asp222Cys, Ser267Glu / His268Phe / Ser324Thr, His268Phe / Ser324Thr, Glu345Arg, and other mutations listed in (Saunders KO. Front Immunol. 2019 Jun 7;10:1296); S239D / D265S / S298A / I332E, S239E / S298A / K326A / A327H, G237F / S298A / A330L / I332E, S239D / I332E / S298A, S239D / K326E / A330L / I332E / S298A, G236A / S239D / D270L / I332E, S239E / S267E / H268D, L234F / S267E / N325L, G237F / V266L / S267D and other mutations listed in WO2011 / 120134 and WO2011 / 120135 incorporated herein by reference. Mutations are listed on page 283 in Therapeutic Antibody Engineering (by William R. Strohl and Lila M. Strohl, Woodhead Publishing series in Biomedicine No 11, ISBN 1 907568 37 9, Oct 2012).

[0121] In certain embodiments, the MICA / B antibodies disclosed herein include one or more mutations at amino acid positions in the Fc region, including mutations at amino acids 239 and / or 332 of the heavy chain. In certain embodiments, the MICA / B antibody includes the S239D and / or I332E mutations. In some embodiments, the antibodies described herein include one or more modifications to enhance its ability to mediate effector functions. Such modifications are known in the art and include glycosylation or manipulation of the affinity of Fc for activating receptors, primarily FCGR3a for ADCC, and C1q for CDC. Table B below summarizes various designs reported in the literature for effector function manipulation. Thus, in certain embodiments, the antibodies described herein may include a dimeric Fc comprising one or more amino acid modifications as set forth in Table B that result in enhanced effector function.

[0122] Table B: CH2 Domain and Effector Function Manipulation

Table B-1

Table B-2

[0123] Fc modifications that reduce FcγR and / or complement binding and / or decrease effector function are known in the art. Recent publications have described strategies used in the manipulation of antibodies with reduced effector activity or silencing (see Strohl, WR (2009), Curr Opin Biotech 20:685-691, and Strohl, WR and Strohl LM, "Antibody Fc engineering for optimal antibody performance" In Therapeutic Antibody Engineering, Cambridge: Woodhead Publishing (2012), pp 225-249). These strategies include reducing effector function by modification of glycosylation, use of IgG2 / IgG4 scaffolds, or introduction of mutations in the hinge or CH2 region of Fc. For example, US Patent Application Publication No. 2011 / 0212087 (Strohl), International Patent Publication No. WO2006 / 105338 (Xencor), US Patent Application Publication No. 2012 / 0225058 (Xencor), US Patent Application Publication No. 2012 / 0251531 (Genentech), and Strop et al ((2012) J. Mol. Biol. 420: 204-219) describe specific modifications for reducing FcγR or complement binding to Fc.

[0124] Specific, non-limiting examples of known amino acid modifications for reducing FcγR or complement binding to Fc are identified in Table C below: Table C: Modifications for Reducing FcγR or Complement Binding to Fc

Table C-1

Table C-2

[0125] Antibodies with reduced fucose content have been reported to have increased affinity for Fc receptors, such as FcγRIIIa. Thus, in certain embodiments, the anti-MICA / B antibodies or antigen-binding fragments thereof described herein have reduced or no fucose content. Such antibodies can be produced using a variety of techniques known to those of skill in the art. For example, the antibody can be expressed in cells that are deficient or lacking in the ability to fucosylate. In certain embodiments, a cell line in which both alleles of α1,6-fucosyltransferase are knocked out can be used to produce antibodies with reduced fucose content. The POTELLIGENT® system (Lonza) is an example of such a system that can be used to produce antibodies with reduced fucose content. In certain embodiments, antibodies or antigen-binding fragments thereof with reduced or no fucose content can be produced, for example, by (i) culturing the cells under conditions that prevent or reduce fucosylation; (ii) post-translational removal of fucose (e.g., by fucosidase enzyme); (iii) post-translational addition of the desired carbohydrate, e.g., after recombinant expression of a non-glycosylated glycoprotein; or (iv) purification of the glycoprotein to select for non-fucosylated antibodies or antigen-binding fragments thereof. See, for example, Longmore G D & Schachter H (1982) Carbohydr Res 100: 365-92 and Imai-Nishiya H et al., (2007) BMC Biotechnol. 7: 84 for methods for producing antibodies or antigen-binding fragments thereof with no or reduced fucose content.

[0126] Methods for producing antibodies that have little or no fucose at the Fc glycosylation site (Asn 297 EU numbering) without changing the amino acid sequence are well known in the art. The Glymaxx® technology (ProBioGen AG) is based on the introduction of genes for enzymes that redirect the cellular pathway of fucose biosynthesis to the cells used for antibody production. This prevents the addition of the sugar "fucose" to the N-linked antibody carbohydrate moiety by the antibody-producing cells. (von Horsten et al. (2010) Glycobiology. 2010 Dec; 20 (12):1607-18). Another approach for obtaining antibodies with reduced fucosylation levels can be found in U.S. Patent No. 8,409,572, which teaches that the cell line for antibody production can be selected based on their ability to yield lower levels of fucosylation, based on the fact that the antibody can be fully afucosylated (which means that the antibody contains no detectable fucose), or that the antibody can be partially afucosylated (which means that the isolated antibody contains less than 95%, less than 85%, less than 75%, less than 65%, less than 55%, less than 45%, less than 35%, less than 25%, less than 15% or less than 5% of the amount of fucose normally detected for similar antibodies produced by mammalian expression systems). In certain embodiments, the antibody can be afucosylated to improve effector function.

[0127] Methods for producing antibodies that have little or no fucose at the Fc glycosylation site (Asn 297 EU numbering) without changing the amino acid sequence are well known in the art. The GlymaxX® technology (ProBioGen AG) is based on the introduction of genes for enzymes that redirect the cellular pathway of fucose biosynthesis to the cells used for antibody production. This prevents the addition of the sugar "fucose" to the N-linked antibody carbohydrate moiety by the antibody-producing cells. (von Horsten et al. (2010) Glycobiology. 2010 Dec; 20 (12):1607-18). Examples of cell lines capable of producing defucosylated antibodies include CHO-DG44 that stably overexpresses the bacterial oxidoreductase GDP-6-deoxy-D-lyxo-4-hexulose reductase (RMD) (see Henning von Horsten et al., Glycobiol 2010, 20:1607-1618) or Lec13 CHO cells that are deficient in protein fucosylation (Ripka et al., Arch. Biochem. Biophys., 1986, 249:533-545; see US Patent Publication No. 2003 / 0157108, WO2004 / 056312, each of which is incorporated herein by reference in its entirety), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene or FUT8 knockout CHO cells (Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87: 614-622; Kanda et al., Biotechnol. Bioeng., 2006, 94:680-688; and WO2003 / 085107, each of which is incorporated herein by reference in its entirety). Another approach for obtaining antibodies with reduced fucosylation levels can be found in US Patent No. 8,409,572, which teaches selecting cell lines for antibody production for their ability to produce lower levels of fucosylation in the antibody.

[0128] Examples of cell lines capable of producing defucosylated antibodies include CHO-DG44 that stably overexpresses the bacterial oxidoreductase GDP-6-deoxy-D-lyxo-4-hexulose reductase (RMD) (see Henning von Horsten et al., Glycobiol 2010, 20:1607-1618) or Lec13 CHO cells lacking protein fucosylation (Ripka et al., Arch. Biochem. Biophys., 1986, 249:533-545; see US Patent Publication No. 2003 / 0157108, WO2004 / 056312, each of these references is incorporated herein by reference in its entirety), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene or FUT8 knockout CHO cells (e.g., Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87: 614-622; Kanda et al., Biotechnol. Bioeng., 2006, 94:680-688; and WO2003 / 085107, each of these references is incorporated herein by reference in its entirety).

[0129] Antibodies can be fully defucosylated (meaning they do not contain detectable fucose) or they can be partially defucosylated, which means that the isolated antibody contains less than 95%, less than 85%, less than 75%, less than 65%, less than 55%, less than 45%, less than 35%, less than 25%, less than 15% or less than 5% of the amount of fucose normally detected for similar antibodies produced by mammalian expression systems.

[0130] In some embodiments, the antibodies provided herein include an IgG1 domain with reduced fucose content at position Asn 297 compared to a naturally occurring IgG1 domain. Such Fc domains are known to have enhanced ADCC. See Shields et al., J. Biol. Chem., 2002, 277:26733-26740, which is incorporated herein by reference in its entirety. In some embodiments, such antibodies contain no fucose at position Asn 297. The amount of fucose can be determined using any suitable method, such as those described in WO2008 / 077546, which is incorporated herein by reference in its entirety. MICA / B antibody variable domain

[0131] Antibodies that specifically bind to MICA / B and have a light chain that includes a variable light chain domain (VL) are disclosed herein. In some embodiments, the antibody that binds to MICA / B includes a variable light chain domain (VL) having an amino acid sequence that is at least about 70% identical to the amino acid sequence shown as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some embodiments, the VL has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence shown as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19.

[0132] Antibodies that specifically bind to MICA / B and have a heavy chain comprising a heavy chain variable domain (VH) are disclosed herein. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain variable domain (VH) having an amino acid sequence that is at least about 70% identical to the amino acid sequence shown as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some embodiments, the VH has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence shown as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some embodiments, the VH has an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20.

[0133] Antibodies that bind to MICA / B and comprise a light chain variable domain (VL) and a heavy chain variable domain (VH) are also disclosed herein. In some embodiments, the antibody that binds to MICA / B has a light chain variable domain (VL) having an amino acid sequence that is at least about 70% identical to the amino acid sequence shown as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19, and a heavy chain variable domain (VH) having an amino acid sequence that is at least about 70% identical to the amino acid sequence shown as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some embodiments, the VL has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence shown as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19, and the VH has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence shown as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20.

[0134] In some embodiments, the antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence that is at least about 70% identical to the amino acid sequence shown as SEQ ID NO: 7, and a heavy chain variable domain (VH) having an amino acid sequence that is at least about 70% identical to the amino acid sequence shown as SEQ ID NO: 8. In some embodiments, the VL has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown as SEQ ID NO: 7, and the VH has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown as SEQ ID NO: 8. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 7, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 8.

[0135] In some embodiments, the antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 15, and a heavy chain variable domain (VH) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 16. In some embodiments, the VL has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 15, and the VH has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 16. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 15, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0136] In some embodiments, the antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 19, and a heavy chain variable domain (VH) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 20. In some embodiments, the VL has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 19, and the VH has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 20. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 19, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 20. MICA / B antibody complementarity determining region

[0137] Antibodies that specifically bind to MICA / B and have a light chain comprising a light chain complementarity determining region (CDR) are disclosed herein. In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR sequence having an amino acid sequence that is at least about 70% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 1-3, 9-11, and 17. In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR sequence having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 1-3, 9-11, and 17. In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR sequence having an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 1-3, 9-11, and 17.

[0138] Antibodies that specifically bind to MICA / B and have a heavy chain comprising a heavy chain complementarity determining region (CDR) are further disclosed herein. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR sequence having an amino acid sequence that is at least about 70% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 4-6, 12-14, and 18. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR sequence having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 4-6, 12-14, and 18. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR sequence having an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown as SEQ ID NOs: 4-6, 12-14, and 18.

[0139] Antibodies that bind to MICA / B and contain light chain complementarity determining regions (CDRs) and heavy chain complementarity determining regions (CDRs) are also disclosed herein. In some embodiments, an antibody that binds to MICA / B has a light chain CDR sequence having an amino acid sequence that is at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and a heavy chain CDR sequence having an amino acid sequence that is at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some embodiments, an antibody that binds to MICA / B has a light chain CDR sequence having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and a heavy chain CDR sequence having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some embodiments, an antibody that binds to MICA / B has a light chain CDR sequence having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and a heavy chain CDR sequence having an amino acid sequence that is at least about 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18.

[0140] In some embodiments, the antibody that binds to MICA / B has a light chain complementarity determining region 1 (CDR1) having an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, a light chain complementarity determining region 3 (CDR3) having an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 6 or SEQ ID NO: 14.In some embodiments, the antibody that binds to MICA / B has a light chain complementarity determining region 1 (CDR1) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 1, SEQ ID NO: 9 or SEQ ID NO: 17, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, a light chain complementarity determining region 3 (CDR3) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 3 or SEQ ID NO: 11, a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 5, SEQ ID NO: 13 or SEQ ID NO: 18, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 6 or SEQ ID NO: 14.In some embodiments, the antibody that binds to MICA / B has a light chain complementarity determining region 1 (CDR1) having an amino acid sequence that is 100% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence that is 100% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, a light chain complementarity determining region 3 (CDR3) having an amino acid sequence that is 100% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence that is 100% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence that is 100% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence that is 100% identical to one of SEQ ID NO: 6 or SEQ ID NO: 14.

[0141] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 3. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 3. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 3.

[0142] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 10, and a light chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 11. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 10, and a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 11. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 10, and a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 11.

[0143] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 3. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 3. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 3.

[0144] In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 6. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 6. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 6.

[0145] In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 14. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 14. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 14.

[0146] In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 6. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 6. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 6.

[0147] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 6.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 6.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 6.

[0148] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 10, a light chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 11, a heavy chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 14.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 10, a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 11, a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 14.In some embodiments, an antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:9, a light chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:10, a light chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:11, a heavy chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:12, a heavy chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:13, and a heavy chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:14.

[0149] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 6.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 6.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 6.

[0150] In some embodiments, the antibody that binds to MICA / B does not have at least one CDR selected from the list comprising SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY. Competitive binding

[0151] In some embodiments, antibodies are disclosed herein that competitively bind to MICA / B with an antibody comprising a light chain variable domain (VL) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 27. In some embodiments, the VL has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 27. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 27.

[0152] In some embodiments, antibodies are disclosed herein that competitively bind to MICA / B with an antibody comprising a heavy chain variable domain (VH) having an amino acid sequence that is at least about 70% identical to the amino acid sequence shown as SEQ ID NO: 28. In some embodiments, the VH has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence shown as SEQ ID NO: 28. In some embodiments, the VH has an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 28.

[0153] In some embodiments, antibodies are disclosed herein that competitively bind to MICA / B with an antibody comprising a light chain variable domain (VL) having an amino acid sequence that is at least about 70% identical to the amino acid sequence shown as SEQ ID NO: 27 and a heavy chain variable domain (VH) having an amino acid sequence that is at least about 70% identical to the amino acid sequence shown as SEQ ID NO: 28. In some embodiments, the VL has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown as SEQ ID NO: 27, and the VH has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown as SEQ ID NO: 28. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 27, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 28. Methods of treatment and methods of use

[0154] Methods are provided herein for treating cancer in an individual in need of treating cancer, the methods comprising administering an anti-MICA / B antibody disclosed herein.

[0155] A method for decreasing or increasing the level of soluble MICA / B protein in an individual in need of decreasing or increasing the level of soluble MICA / B protein, the method comprising administering an anti-MICA / B antibody disclosed herein, is further provided herein.

[0156] A method for alleviating or inhibiting an immunosuppressive environment by preventing, blocking or enhancing the interaction between soluble MICA / B and the NKG2D receptor in an individual in need of alleviating or inhibiting the immunosuppressive environment by preventing, blocking or enhancing the interaction between soluble MICA / B and the NKG2D receptor, the method comprising administering an anti-MICA / B antibody disclosed herein, is also provided herein.

[0157] In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR sequence having an amino acid sequence that is at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17. In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR sequence having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17. In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR sequence having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17.

[0158] In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR sequence having an amino acid sequence that is at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR sequence having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR sequence having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18.

[0159] In some embodiments, an antibody that binds to MICA / B comprises a light chain CDR sequence having an amino acid sequence that is at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and a heavy chain CDR sequence having an amino acid sequence that is at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some embodiments, an antibody that binds to MICA / B comprises a light chain CDR sequence having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and a heavy chain CDR sequence having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some embodiments, an antibody that binds to MICA / B comprises a light chain CDR sequence having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and a heavy chain CDR sequence having an amino acid sequence that is at least about 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18.

[0160] In some embodiments, the antibody that binds to MICA / B has a light chain complementarity determining region 1 (CDR1) having an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, a light chain complementarity determining region 3 (CDR3) having an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 6 or SEQ ID NO: 14.In some embodiments, the antibody that binds to MICA / B has a light chain complementarity determining region 1 (CDR1) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 1, SEQ ID NO: 9 or SEQ ID NO: 17, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, a light chain complementarity determining region 3 (CDR3) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 3 or SEQ ID NO: 11, a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 5, SEQ ID NO: 13 or SEQ ID NO: 18, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 6 or SEQ ID NO: 14.In some embodiments, the antibody that binds to MICA / B comprises a light chain complementarity determining region 1 (CDR1) having an amino acid sequence that is 100% identical to one of SEQ ID NO:1, SEQ ID NO:9 or SEQ ID NO:17, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence that is 100% identical to one of SEQ ID NO:2 or SEQ ID NO:10, a light chain complementarity determining region 3 (CDR3) having an amino acid sequence that is 100% identical to one of SEQ ID NO:3 or SEQ ID NO:11, a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence that is 100% identical to one of SEQ ID NO:4 or SEQ ID NO:12, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence that is 100% identical to one of SEQ ID NO:5, SEQ ID NO:13 or SEQ ID NO:18, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence that is 100% identical to one of SEQ ID NO:6 or SEQ ID NO:14.

[0161] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 3. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 3. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 3.

[0162] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:9, a light chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:10, and a light chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:11. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:9, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:10, and a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:11. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:9, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:10, and a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:11.

[0163] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 3. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 3. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 3.

[0164] In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 6. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 6. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 6.

[0165] In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 14. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 14. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 14.

[0166] In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 6. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 6. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 6.

[0167] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 6.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 6.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 6.

[0168] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 10, a light chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 11, a heavy chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 14.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 10, a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 11, a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 14.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 10, a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 11, a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 14.

[0169] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 6.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 6.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 6.

[0170] In some embodiments, the antibody that binds to MICA / B does not have at least one CDR selected from the list comprising SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY.

[0171] In some embodiments, the antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence that is at least about 70% identical to the amino acid sequence shown as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some embodiments, the VL has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence shown as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence shown as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19.

[0172] In some embodiments, an antibody that binds MICA / B comprises a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:8, SEQ ID NO:16, or SEQ ID NO:20. In some embodiments, the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO:8, SEQ ID NO:16, or SEQ ID NO:20. In some embodiments, the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:8, SEQ ID NO:16, or SEQ ID NO:20.

[0173] In some embodiments, an antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:7, SEQ ID NO:15, or SEQ ID NO:19, and a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:8, SEQ ID NO:16, or SEQ ID NO:20. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:7, SEQ ID NO:15 or SEQ ID NO:19, and the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:20. In some embodiments, the VL has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:7, SEQ ID NO:15 or SEQ ID NO:19, and the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:20.

[0174] In some embodiments, the antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 7, and a heavy chain variable domain (VH) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the VL has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 7, and the VH has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 7, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 8.

[0175] In some embodiments, the antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 15, and a heavy chain variable domain (VH) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 16. In some embodiments, the VL has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 15, and the VH has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 16. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 15, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0176] In some embodiments, the antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 19, and a heavy chain variable domain (VH) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 20. In some embodiments, the VL has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 19, and the VH has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 20. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 19, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 20.

[0177] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23 or SEQ ID NO: 24. In some embodiments, the light chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23 or SEQ ID NO: 24. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23 or SEQ ID NO: 24.

[0178] In some embodiments, an antibody that binds to MICA / B comprises a heavy chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some embodiments, the heavy chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some embodiments, the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26.

[0179] Also disclosed herein are antibodies that bind to MICA / B and comprise a light chain and a heavy chain. In some embodiments, an antibody that binds to MICA / B comprises a light chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24, and a heavy chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24, and the heavy chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26.

[0180] In some embodiments, an antibody that binds to MICA / B comprises a light chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:21, and a heavy chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:22. In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:21, and the heavy chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:22. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:21, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:22.

[0181] In some embodiments, an antibody that binds to MICA / B comprises a light chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:23, and a heavy chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO:25. In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:23, and the heavy chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO:25. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:23, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO:25.

[0182] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 23, and a heavy chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 23, and the heavy chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 23, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 26.

[0183] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 24, and a heavy chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 25. In some embodiments, the light chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 24, and the heavy chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 25. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 24, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 25.

[0184] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 24, and a heavy chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 24, and the heavy chain has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 24, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 26.

[0185] In some embodiments, the antibody competitively binds to MICA / B with an antibody comprising a light chain variable domain (VL) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 27. In some embodiments, the VL has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 27. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 27.

[0186] In some embodiments, the antibody competitively binds to MICA / B with an antibody comprising a heavy chain variable domain (VH) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 28. In some embodiments, the VH has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 28. In some embodiments, the VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 28.

[0187] In some embodiments, the antibody competitively binds to MICA / B with an antibody comprising a light chain variable domain (VL) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 27, and a heavy chain variable domain (VH) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 28. In some embodiments, the VL has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 27, and the VH has an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 28. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 27, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 28.

[0188] In some embodiments, the antibody specifically binds to the MICA protein. In some embodiments, the antibody specifically binds to the MICB protein. In some embodiments, the antibody specifically binds to both the MICA protein and the MICB protein. In some embodiments, the antibody binds to the alpha-3 domain of the MICA protein. In some embodiments, the antibody binds to the alpha-3 domain of the MICB protein. In some embodiments, the antibody binds to the alpha-3 domains of both the MICA protein and the MICB protein. In some embodiments, the antibody binds to the MICA protein that is a membrane-bound MICA protein. In some embodiments, the antibody binds to the MICA protein that is a soluble MICA protein. In some embodiments, the antibody binds to the MICA protein that is both a membrane-bound MICA protein and a soluble MICA protein. In some embodiments, the antibody binds to the MICB protein that is a membrane-bound MICB protein. In some embodiments, the antibody binds to the MICB protein that is a soluble MICB protein. In some embodiments, the antibody binds to the MICB protein that is both a membrane-bound MICB protein and a soluble MICB protein.

[0189] In some embodiments, the antibody that specifically binds to MICA / B is a monoclonal antibody. In some embodiments, the antibody is an antibody-binding fragment. In some cases, the antibody is selected from whole immunoglobulins, scFv, Fab, F(ab’)2, or disulfide-bonded Fv. In some embodiments, the antibody is IgG or IgM. In some embodiments, the antibody is humanized. In some embodiments, the antibody is chimeric.

[0190] In some embodiments, the antibodies disclosed herein reduce the level of soluble MICA protein. In some embodiments, the antibodies disclosed herein reduce the level of soluble MICB protein. In some embodiments, the antibodies disclosed herein reduce the levels of both soluble MICA protein and soluble MICB protein. In some embodiments, the antibodies disclosed herein reduce shedding of soluble MICA protein. In some embodiments, the antibodies disclosed herein reduce shedding of soluble MICB protein. In some embodiments, the antibodies disclosed herein reduce shedding of both soluble MICA protein and soluble MICB protein. In some embodiments, the antibodies disclosed herein inhibit shedding of soluble MICA protein. In some embodiments, the antibodies disclosed herein inhibit shedding of soluble MICB protein. In some embodiments, the antibodies disclosed herein inhibit shedding of both soluble MICA protein and soluble MICB protein.

[0191] In some embodiments, the antibodies disclosed herein increase the surface level of MICA protein. In some embodiments, the antibodies disclosed herein increase the surface level of MICB protein. In some embodiments, the antibodies disclosed herein increase the levels of both MICA protein and MICB protein. In some embodiments, the antibodies disclosed herein reduce shedding of MICA protein. In some embodiments, the antibodies disclosed herein reduce shedding of MICB protein. In some embodiments, the antibodies disclosed herein reduce shedding of both MICA protein and MICB protein. In some embodiments, the antibodies disclosed herein inhibit shedding of soluble MICA protein. In some embodiments, the antibodies disclosed herein inhibit shedding of soluble MICB protein. In some embodiments, the antibodies disclosed herein inhibit shedding of both soluble MICA protein and soluble MICB protein.

[0192] Any suitable route of administration is contemplated for use in the methods disclosed herein. In some embodiments, the antibody is administered by intravenous administration. In some embodiments, the antibody is administered by subcutaneous administration. In some embodiments, the antibody is administered locally. In some embodiments, the antibody is administered systemically (e.g., intravenously, intramuscularly, subcutaneously, intradermally, orally, intranasally, sublingually). In some embodiments, the antibody is formulated as a patch, lotion, or emulsion. In some embodiments, the antibody is formulated as a solution. In some embodiments, the antibody is formulated for topical, oral, buccal, or nasal administration.

[0193] In some embodiments, the individual is monitored prior to administration of the antibody. Symptoms are identified and their severity is evaluated. The antibodies described herein are administered once or multiple times over time, either alone or in combination with additional treatments, as discussed herein or as known to those of skill in the art. In some embodiments, the individual is monitored such that the effectiveness of the treatment regimen is determined. In some embodiments, the treatment regimen is modified according to the pretreatment performance, and thus the treatment dose or frequency or dose and frequency are changed to reach the desired level of response of the subject, taking into account symptom relief, side effect reduction, or a combination of symptom relief and side effect reduction.

[0194] The therapeutically effective amount or dosage is, in some cases, a dosage of about 0.01 mg / kg to about 20 mg / kg, for example, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4 mg / kg, about 4.1 mg / kg, about 4.2 mg / kg, about 4.3 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, about 4.6 mg / kg, about 4.7 mg / kg, about 4.8 mg / kg, about 4.9 mg / kg, about 5 mg / kg, about 5.1 mg / kg, about 5.2 mg / kg, about 5.3 mg / kg, about 5.4 mg / kg, about 5.5 mg / kg, about 5.6 mg / kg, about 5.7 mg / kg, about 5.8 mg / kg, about 5.9 mg / kg, about 6 mg / kg, about 6.1 mg / kg, about 6.2 mg / kg, about 6.3 mg / kg, about 6.4 mg / kg, about 6.5 mg / kg, about 6.6 mg / kg, about 6.7 mg / kg, about 6.8 mg / kg, about 6.9 mg / kg, about 7 mg / kg, about 7.1 mg / kg, about 7.2 mg / kg, about 7.3 mg / kg, about 7.4 mg / kg, about 7.5 mg / kg, about 7.6 mg / kg, about 7.7 mg / kg, about 7.8 mg / kg, about 7.9 mg / kg, about 8 mg / kg, about 8.1 mg / kg, about 8.2 mg / kg, about 8.3 mg / kg, about 8.4 mg / kg, about 8.5 mg / kg, about 8.6 mg / kg, about 8.7mg / kg, about 8.8mg / kg, about 8.9mg / kg, about 9mg / kg, about 9.1mg / kg, about 9.2mg / kg, about 9.3mg / kg, about 9.4mg / kg, about 9.5mg / kg, about 9.6mg / kg, about 9.7mg / kg, about 9.8mg / kg, about 9.9mg / kg, about 10mg / kg, about 10.1mg / kg, about 10.2mg / kg, about 10.3mg / kg, about 10.4mg / kg, about 10.5mg / kg, about 10.6mg / kg, about 10.7mg / kg, about 10.8mg / kg, about 10.9mg / kg, about 11mg / kg, about 11 .1mg / kg, about 11.2mg / kg, about 11.3mg / kg, about 11.4mg / kg, about 11.5mg / kg, about 11.6mg / kg, about 11.7mg / kg, about 11.8mg / kg, about 11.9mg / kg, about 12mg / kg, about 12.1mg / kg, about 12.2mg / kg, about 12.3mg / kg, about 12.4mg / kg, about 12.5mg / kg, about 12.6mg / kg, about 12.7mg / kg, about 12.8mg / kg, about 12.9mg / kg, about 13mg / kg, about 13.1mg / kg, about 13.2mg / kg, about 13.3mg / kg, about 13.4 mg / kg, about 13.5 mg / kg, about 13.6 mg / kg, about 13.7 mg / kg, about 13.8 mg / kg, about 13.9 mg / kg, about 14 mg / kg, about 14.1 mg / kg, about 14.2 mg / kg, about 14.3 mg / kg, about 14.4 mg / kg, about 14.5 mg / kg, about 14.6 mg / kg, about 14.7 mg / kg, about 14.8 mg / kg, about 14.9 mg / kg, about 15 mg / kg, about 15.1 mg / kg, about 15.2 mg / kg, about 15.3 mg / kg, about 15.4 mg / kg, about 15.5 mg / kg, about 15.6 mg / kg, about 15.7 mg / kg, about 15.8 mg / kg, about 15.9 mg / kg, about 16 mg / kg, about 16.1 mg / kg, about 16.2 mg / kg, about 16.3 mg / kg, about 16.4 mg / kg, about 16.5 mg / kg, about 16.6 mg / kg, about 16.7 mg / kg, about 16.8 mg / kg, about 16.9 mg / kg, about 17 mg / kg, about 17.1 mg / kg, about 17.2 mg / kg, about 17.3 mg / kg, about 17.4 mg / kg, about 17.5 mg / kg, about 17.6 mg / kg, about 17.7 mg / kg, about 17.8 mg / kg, about 17.Dosages of 9 mg / kg, about 18 mg / kg, about 18.1 mg / kg, about 18.2 mg / kg, about 18.3 mg / kg, about 18.4 mg / kg, about 18.5 mg / kg, about 18.6 mg / kg, about 18.7 mg / kg, about 18.8 mg / kg, about 18.9 mg / kg, about 19 mg / kg, about 19.1 mg / kg, about 19.2 mg / kg, about 19.3 mg / kg, about 19.4 mg / kg, about 19.5 mg / kg, about 19.6 mg / kg, about 19.7 mg / kg, about 19.8 mg / kg, about 19.9 mg / kg, or about 20 mg / kg are contemplated. In some cases, a therapeutically effective amount or dosage is contemplated to include dosages of about 0.1 mg / kg to about 2.0 mg / kg.

[0195] The treatment methods herein include one or more administrations of an anti-MICA / B antibody at the dosages disclosed herein. In some embodiments, the method includes one administration of the anti-MICA / B antibody. In some embodiments, the method includes two administrations of the anti-MICA / B antibody. In some embodiments, the method includes three administrations of the anti-MICA / B antibody. In some embodiments, the method includes four administrations of the anti-MICA / B antibody. In some embodiments, the method includes five administrations of the anti-MICA / B antibody. In some embodiments, the method includes six administrations of the anti-MICA / B antibody. In some embodiments, one or more administrations of the anti-MICA / B antibody are administered daily. In some embodiments, one or more administrations of the anti-MICA / B antibody are administered weekly. In some embodiments, one or more administrations of the anti-MICA / B antibody are administered every other week. In some embodiments, one or more administrations of the anti-MICA / B antibody are administered every three weeks. In some embodiments, one or more administrations of the anti-MICA / B antibody are administered monthly. In some embodiments, one or more administrations of the anti-MICA / B antibody are administered every three months. In some embodiments, one or more administrations of the anti-MICA / B antibody are administered every six months. In some embodiments, one or more administrations of the anti-MICA / B antibody are administered annually.

[0196] In some embodiments, the treatment methods disclosed herein are monotherapies. In some embodiments, the treatment methods disclosed herein are combination therapies. In some embodiments, the combination therapy includes administration of an anti-MICA / B antibody in combination with another therapeutic agent. In some embodiments, the therapeutic agent includes a chemotherapeutic agent. In some embodiments, chemotherapeutic agents include cytotoxic agents, antimetabolites (e.g., folic acid antagonists, purine analogs, pyrimidine analogs, etc.), topoisomerase inhibitors (e.g., camptothecin derivatives, anthracenediones, anthracyclines, epipodophyllotoxins, quinoline alkaloids, etc.), microtubule inhibitors (e.g., taxanes, vinca alkaloids), protein synthesis inhibitors (e.g., cephalotaxine, camptothecin derivatives, quinoline alkaloids), alkylating agents (e.g., alkyl sulfonates, ethyleneimines, nitrogen mustards, nitrosoureas, platinum derivatives, triazenes, etc.), alkaloids, terpenoids, kinase inhibitors, and immune checkpoint inhibitors, but are not limited thereto. In some embodiments, the anti-MICA / B antibodies disclosed herein are administered in combination with a therapeutic agent that induces an immune response. In some embodiments, the anti-MICA / B antibodies disclosed herein are administered in combination with a therapeutic agent that inhibits the downregulation of an immune response. In some embodiments, inducing an immune response includes activating or upregulating the activity of NK cells. In some embodiments, inducing an immune response includes activating or upregulating the activity of T cells. In some embodiments, immune checkpoint inhibitor targets include PD-1. In some embodiments, immune checkpoint inhibitor targets include PD-L1. In some embodiments, immune checkpoint inhibitors include pembrolizumab, nivolumab, cemiplimab, AMP-224, AMP-514, PDR001, atezolizumab, avelumab, durvalumab, BMS-936559, and CK-301. In certain embodiments, the anti-MICA / B antibodies described herein are administered in combination with radiation therapy. In certain embodiments, the anti-MICA / B antibodies described herein are administered in combination with one or more cell therapies. Pharmaceutical composition

[0197] Also disclosed herein are pharmaceutical compositions comprising the anti-MICA / B antibodies disclosed herein and a pharmaceutically acceptable carrier or additive.

[0198] In some embodiments, additives for use with the compositions disclosed herein include maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, histidine, glycine, sodium chloride, potassium chloride, calcium chloride, zinc chloride, water, dextrose, N-methylpyrrolidone, dimethyl sulfoxide, N,N-dimethylacetamide, ethanol, propylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, and the surfactant polyoxyethylene-sorbitan monooleate.

[0199] In some embodiments, the composition further comprises an additional therapeutic agent. In some embodiments, the therapeutic agent is a chemotherapeutic agent. Chemotherapeutic agents include, among others, cytotoxic agents, antimetabolites (e.g., folic acid antagonists, purine analogs, pyrimidine analogs, etc.), topoisomerase inhibitors (e.g., camptothecin derivatives, anthracenedione, anthracyclines, epipodophyllotoxins, quinoline alkaloids, etc.), microtubule inhibitors (e.g., taxanes, vinca alkaloids), protein synthesis inhibitors (e.g., cephalotaxine, camptothecin derivatives, quinoline alkaloids), alkylating agents (e.g., alkyl sulfonates, ethyleneimines, nitrogen mustards, nitrosoureas, platinum derivatives, triazenes, etc.), alkaloids, terpenoids, and kinase inhibitors.

[0200] In some embodiments, the antibody and the therapeutic agent are in the same formulation. In some embodiments, the antibody and the therapeutic agent are in different formulations. In some embodiments, the antibodies described herein are used prior to the administration of other therapeutic agents. In some embodiments, the antibodies described herein are used in combination with the administration of other therapeutic agents. In some embodiments, the antibodies described herein are used after the administration of other therapeutic agents.

[0201] In some embodiments, the pharmaceutical formulation is made to be compatible with a particular topical, local or systemic administration or delivery route. Thus, the pharmaceutical formulation includes carriers, diluents or additives suitable for administration by a particular route. Specific, non-limiting examples of the administration routes of the compositions herein are parenteral, for example, intravenous, intraarterial, intradermal, intramuscular, subcutaneous, intrapleural, transdermal (topical), transmucosal, intracranial, intraspinal, intraocular, rectal, oral (dietary), mucosal administration, and any other formulation suitable for a treatment method or administration protocol.

[0202] In some embodiments, the solutions or suspensions used for parenteral application contain a sterile diluent, for example, water for injection, saline solution, fixed oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; antibacterial agents, for example, benzyl alcohol or methylparaben; antioxidants, for example, ascorbic acid or sodium bisulfate; chelating agents, for example, ethylenediaminetetraacetic acid; buffers, for example, acetate, citrate or phosphate; and agents for adjusting isotonicity, for example, sodium chloride or dextrose. In some embodiments, the pH is adjusted with an acid or a base, for example, hydrochloric acid or sodium hydroxide.

[0203] Injectable pharmaceutical preparations include sterile aqueous solutions (if water-soluble) or dispersion solutions, and sterile powders for the immediate preparation of sterile injectable solutions or dispersion solutions. Suitable carriers for intravenous administration include physiological saline, bacteriostatic water, Cremophor EL (trademark) (BASF, Parsippany, N.J.), or phosphate buffered saline (PBS). In some embodiments, the carrier is, for example, a solvent or dispersion medium containing water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol, etc.), or a suitable mixture thereof. Fluidity is maintained in some embodiments, for example, by the use of coating agents such as lecithin, in the case of dispersion solutions by maintaining the required particle size, and by the use of surfactants. Antibacterial and antifungal agents include, for example, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. Isotonic agents, such as sugars; polyhydric alcohols, such as mannitol or sorbitol; or sodium chloride are included in the composition in some embodiments. In some cases, agents that delay absorption are also included, and in some embodiments, for example, aluminum monostearate, or gelatin prolongs the absorption of the injectable composition.

[0204] In some embodiments, the sterile injectable preparation is prepared by incorporating the required amount of the active compound in a suitable solvent together with one or a combination of the above components. Generally, dispersion solutions are prepared by incorporating the active compound into a sterile vehicle containing a base dispersion medium and any other components. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation methods include, for example, vacuum drying and lyophilization that yield the powder of the active ingredient with any additional desired components added from its pre-prepared solution.

[0205] For transmucosal or transdermal administration, penetration enhancers suitable for the barrier to be penetrated are used in the formulation. Such penetration enhancers are known in the art and include, for example, surfactants, bile salts, and fusidic acid derivatives for transmucosal administration. In some embodiments, transmucosal administration is accomplished by use of a nasal spray, an inhalation device (e.g., an aspirator), or a suppository. For transdermal administration, the active compound is formulated in an ointment, a plaster, a gel, a cream, or a patch.

[0206] In some embodiments, the pharmaceutical formulation is prepared using a carrier that protects against rapid elimination from the body, such as a controlled release formulation or a time delay material, such as glyceryl monostearate or glyceryl stearate. The formulation may also, in some embodiments, be delivered using manufactured articles such as implants and microencapsulation delivery systems to achieve local, topical, or systemic delivery or controlled or sustained release.

Examples

[0207] The following examples are given for the purpose of illustrating various embodiments of the invention and are not intended to limit the invention in any way. Together with the methods described herein, these examples currently represent the preferred embodiments and are exemplary and not intended to limit the scope of the invention. Those modifications and other uses that are encompassed by the spirit of the invention as defined by the claims will be apparent to those skilled in the art. (Example 1) Measurement of Antibody Binding Kinetics

[0208] The affinity kinetics were determined using a ForteBio Octet Red96 analyzer. Briefly, anti-MICA / B mAb (30 μg / ml) was captured using a Dip and Read™ anti-mouse IgG Fc capture (AMC) biosensor (ForteBio) at room temperature in an assay buffer of PBS + 0.1% BSA + 0.02% Tween®-20 (pH 7.2). The sensor was washed in the assay buffer and then incubated in the assay buffer for 5 minutes with a two-fold dilution series of purified 6×His-MICA*08 or 6×His-MICA*04 protein (100 nM) to determine the association kinetics of the antibody and protein antigen. The sensor was then incubated in the assay buffer for 10 minutes to determine the dissociation kinetics. The resulting kinetic parameters were calculated using the 1:1 model in the ForteBio analysis suite 8.0. The results of these assays are shown in Table 2. Table 2. Kinetic measurements of anti-MICA / B antibodies against MICA antigens by biolayer interferometry

Table 2

[0209] Recombinant MICA*01, MICA*02, MICA*04, MICA*08, MICA*09, and MICB proteins were diluted to 1 μg / ml in 50 mM sodium carbonate buffer, pH 9.6, and coated at 100 ng in 100 μl per well on a high-binding 96-well microplate (Corning #9018). The next morning, the coated ELISA plates were washed three times with TBS-Tween®-20, pH 7.4, and then blocked with SuperBlock T20 blocking buffer (Pierce #37536). After blocking, the ELISA plates were washed once with TBS-T and incubated for approximately 2 hours at room temperature with serially diluted anti-MICA antibodies (0 - 1 μg / ml). After incubation, the ELISA plates were washed three times with TBS-T, and then incubated for 45 minutes at room temperature with shaking (approximately 400 rpm) with goat anti-mouse IgG (H+L)-HRP conjugate (ThermoFisher Scientific #626520). After incubation, the ELISA plates were washed three times with TBS-T and incubated with 100 μl per well of Super Sensitive Liquid Substrate TMB (Sigma #T4444) until sufficient color development occurred. The reaction was stopped with 100 μl per well of 1 N sulfuric acid. Optical density (OD) values were measured at 450 nm using a microplate reader. The results of this assay are shown in FIGS. 1A - 1B. (Example 3) Antibody Binding to Cell Surface MICA

[0210] Using mouse prostate adenocarcinoma TRAMP-C2 cells (TC2) (ATCC, Manassas, VA), a stable cell line expressing the MICA*08 allele (TC2-MICA-08) was generated. Binding of anti-MICA antibody to TC2-MICA-08 was analyzed by flow cytometry. Briefly, cells were first stained with a LIVE / DEAD Near IR Stain (Thermo) for 30 minutes at 4°C and then washed once by centrifugation using FACS buffer (1X PBS, 1 mM EDTA, 25 mM HEPES, 2% FBS). Approximately 2 - 3×10 5 TC2-MICA-08 cells were incubated with 100 μl of FACS buffer containing 500 ng of anti-MICA antibody for 30 minutes at 4°C, followed by incubation with 100 μl of 2 μg / ml PE-conjugated goat anti-mouse IgG (Biolegend, San Diego, CA) secondary Ab for 30 minutes at 4°C. Cells were then washed once and the cell pellet was resuspended in FACS buffer for FACS analysis with gating on live cells. A significantly higher PE fluorescence signal was observed in TC2-MICA-08 cells compared to parental TC2 cells showing binding of anti-MICA mAb to MICA expressed on the surface. Results for this assay are shown in Figure 2. (Example 4) Antibodies inhibit shedding of MICA from PLC / PRF / 5 cells

[0211] 4×10 4Individual PLC / PRF / 5 cells (hepatocellular carcinoma) (ATCC, Manassas, VA) were plated in 96-well plates and incubated overnight at 37°C. Subsequently, the cells were treated with 100 μl of complete medium (MEM + 10% FBS, Thermo, Grand Island, NY) containing anti-MICA antibody that binds to the MICA α3 domain and a negative control antibody, respectively, and incubated for an additional day at 37°C. The cell supernatant containing the secreted MICA was used to determine the level of soluble MICA by ELISA. Briefly, 96-well plates were coated overnight at 4°C with 100 μl of 2 μg / ml anti-human MICA / B (clone BAMO1, MBL, Japan). The plates were blocked and then incubated for 2 hours with the cell supernatant and MICA standards. After incubation, the plates were washed and then incubated for 1 hour with 1 μg / ml proprietary anti-human MICA / MICB mAb, clone 10E9 conjugated to biotin. Next, 100 μl of HRP-conjugated streptavidin (HRP-SA) (R&D Systems, Minneapolis, MN) was added to the wells and incubated for 30 minutes. The samples were developed with TMB for 4 minutes, stopped with 1N sulfuric acid, and detected by absorbance at 450 nm. The soluble MICA levels were interpolated from the standard curve. The results for this assay are shown in Figure 3. (Example 5) Antibodies enhance NK-92 cell-mediated cytotoxicity against PLC / PRF / 5 cells

[0212] PLC / PRF / 5 (target) cells were suspended in RPMI-1640 containing 10% FBS and plated at 6000 cells / well in 96-well flat-bottom plates (Costar). The cells were then incubated for 24 hours with an anti-MICA antibody (10 μg / ml) that binds to the MICA α3 domain, and then labeled with calcein AM (1 μM) for 3 hours at 37 °C and 5% CO2. The wells were washed and then NK-92 cells (effectors) suspended in RPMI-1640 containing 10% FBS were added to the wells at various effector-to-target (E:T) ratios as indicated and co-cultured with the target cells for 4 hours. At the end of the culture, the supernatant was removed, replaced with PBS, and the calcein AM signal was measured using a VICTOR Multilabel plate reader (Perkin Elmer). An isotype-matched non-reactive immunoglobulin (R&D) antibody was used as a control. The results for this assay are shown in FIGS. 4A-4B. (Example 6) Efficacy (survival time) of 3F9.E4 and NKG2D expression by tumor-infiltrating lymphocytes in in vivo tumor treatment in tumor-bearing mice

[0213] MICA transgenic mice (MICAgen) were inoculated with 10 4 individual B16F10-MICA*01 cells (B16 transfectant), and on day 11 when the tumor reached the desired threshold size, the mice were treated with 3F9.E4 or an isotype control (arrows indicate the injection days) (log-rank test). The results are shown in FIG. 5.

[0214] Mice with a high tumor load were sacrificed, and tumor-infiltrating lymphocytes were analyzed for NKG2D expression (SFI) by NK cells, CD8 αβ T cells, and γδ T cells. The NKG2D expression intensity (SFI) of NKG2D-expressing cells is shown in FIGS. 6A-6C. Each symbol represents the analysis of an individual mouse. (One-way ANOVA + Tukey's multiple comparison test). (Example 7) Detection of MICA expression by B16 transfectant tumors ex vivo and soluble MICA in sera of tumor-bearing mice

[0215] MICA transgenic mice (MICAgen) were inoculated with 10 4 individual B16F10-MICA*01 cells (B16 transfectants), and on day 11 when the tumors reached the desired threshold size, the mice were treated with 3F9.E4 or BAMO3 or isotype control. Mice were sacrificed when they reached a high tumor burden, single tumor cells were isolated, and analyzed for MICA expression by mAb AMO1 staining (one-way ANOVA + Tukey's multiple comparison test). AMO1 binds to the a1a2-domain of MICA (≠BAMO3 and 3F9). Each symbol represents the analysis of an individual mouse. The results are shown in Fig. 7B. Serum was also analyzed for sMICA using an AMO1 / BAMO1 sandwich ELISA. Each symbol represents an individual mouse (unpaired t-test). The results are shown in Fig. 7A. (Example 8) Epitope binning

[0216] The MICA*04-His protein (30 μg / ml) was immobilized for 300 s on a Ni-NTA (ForteBio, #18-5101) biosensor chip for use with an instrument for biolayer interferometry (Octet Red, ForteBio). After measuring the baseline signal again for 60 s, the biosensor chip was immersed for 300 s in wells containing 1 mM or 0.5 mM primary antibody. After this process, the biosensor was immersed for 300 s in wells containing 100 nM or 50 nM secondary mAb. The percent binding of the secondary mAb in the presence of the primary mAb was determined by comparing the maximum signal of the secondary mAb after addition of the primary mAb with the maximum signal of the secondary mAb alone. An mAb was considered non-competitive if the maximum binding of the secondary mAb was ≧66% of its non-competitive binding. Levels between 33% and 66% of its non-competitive binding were considered moderate competition, and ≦33% was considered competitive. The results for this assay are shown in Figs. 8A-8C. (Example 9) Parameters defining the binding of the Fc-enhanced antibody to the human Fcγ receptor

[0217] The binding of the anti-MICA / B 3F9H1L3L antibody to the human Fcγ receptor was measured by Biacore. The parameters of each Fcγ receptor tested for Biacore analysis are shown in Figure 9. Trastuzumab was used as an IgG1 control. (Example 10) Human Fcγ receptor binding

[0218] Figure 10 shows the results of the Biacore analysis. The binding to FcγR1 is similar for the wild-type 3F9H1L3L antibody, afucosylated 3F9H1L3L (3F9H1L3L "GLYMAXX"), and 3F9H1L3L with the two heavy-chain S239D and I332E mutations. Both afucosylated 3F9H1L3L and 3F9H1L3L with the two heavy-chain S239D and I332E mutations have a higher affinity for FcγRII and FcγRIII compared to the wild-type antibody 3F9H1L3L. (Example 11) Binding of the Fc-enhanced anti-MICA / B antibody to FcRn

[0219] The binding of the anti-MICA / B 3F9H1L3L antibody to human FcRn was measured by Biacore. Figure 11 shows the results of the Biacore analysis. The binding to FcRn is similar for the wild-type 3F9H1L3L antibody, afucosylated 3F9H1L3L (3F9H1L3L "GLYMAXX"), and 3F9H1L3L with the two heavy-chain S239D and I332E mutations at pH 6.0. The binding was pH-dependent. (Example 12) The Fc-enhanced anti-MICA / B antibody binds to and stabilizes MICA / B on the cancer cell surface, similar to the WT anti-MICA / B antibody

[0220] To confirm that anti-MICA / B antibodies and Fc-enhanced anti-MICA / B antibodies stabilize MICA / B on the surface of cancer cells, MICA / B cell surface stabilization experiments were performed in Hela cells and PLC / PRF / 5 cells. The experiment was conducted on the first day by seeding 20,000 cells per well of a 96-well assay plate. The cells were incubated overnight at 37°C / 5% CO2. On the second day, the cells were treated with test anti-MICA / B antibodies at a starting concentration of 10 ug / mL and 7-point 3-fold serial dilutions. The cells were further incubated at 37°C / 5% CO2 for 24 hours. On the third day, the cells were harvested into 96-well plates. The cells were washed and incubated on ice for 30 minutes with 1 / 50 diluted AlexaFluor 647 MICA / B in FACS buffer (PBS, 1% BSA, 0.1% NaN3). Human IgG1 and Alexafluor 547 mouse IgG2aK isotype controls were included to confirm binding specificity. After 30 minutes, the cells were washed and fixed. Fluorescence was then measured using an Attune NxT focusing cytometer (ThermoFisher). The results are shown in Figure 12. These results confirm that the Fc-enhanced anti-MICA / B antibody binds to and stabilizes MICA / B on the cancer cell surface, similar to the WT anti-MICA / B antibody. (Example 13) Fc-enhanced anti-MICA / B antibodies induce ADCC to a higher extent than wild-type anti-MICA / B antibodies

[0221] To confirm that the Fc-enhanced anti-MICA / B antibody can induce improved ADCC compared to wild-type or fucosylated MICA / B antibodies, the ADCC of the anti-MICA / B 3F9H1L3L antibody (CLN-619) was measured using the Promega ADCC Bioassay Complete Kit with two target cell lines: HCC1534 cells that express high levels of MICA and HCT-116 cells that express low levels of MICA. Jurkat cells expressing the high-affinity variant (V) or low-affinity variant (F) of FcγRIIIa were added to the target cells together with the anti-MICA / B 3F9H1L3L wild-type antibody (CLN-619), the anti-MICA / B 3F9H1L3L afucosylated antibody (“GLYMAXX”), and the anti-MICA / B 3F9H1L3L antibody with two heavy-chain S239D and I332E mutations (“CLN-619 DM”) and incubated for 6 hours. After 6 hours, the luminescence that was measured was measured luminescence (Figure 13). Anti-MICA / B antibodies with enhanced effector function result in significantly greater ADCC in both cell lines under all conditions tested compared to the wild-type anti-MICA / B antibody when the cells are co-cultured with Jurkat cells expressing either the high-affinity or low-affinity variant of FcγRIIIa.

[0222] The ability of the Fc-enhanced anti-MICA / B antibody to induce cell killing was also determined. On day 1, HCT-116 target cells were labeled with Cytolight® rapid red dye. The cells were seeded at 5000 cells / well in black clear-bottom 96-well plates. The target cells were incubated at 37 °C / 5% CO2 for 24 hours. On day 3, NKG2D-expressing effector cells were seeded onto the target cells at an effector-to-target cell ratio of 40:1. The co-cultures were incubated in medium containing Cytotox green dye at a final assay concentration of 0.25 μM to monitor cell killing. Fluorescence was measured every 30 minutes for 24 hours using an Incucyte® live cell imaging system to monitor cell killing. Figure 14 shows that HCT-116 cells incubated with either afucosylated anti-MICA / B 3F9H1L3L antibody (CLN-619 GLYMAXX) with or without the addition of NKG2D effector cells caused a dose-dependent decrease in the percentage of cells. The wild-type anti-MICA / B 3F9H1L3L antibody (CLN-619WT) also caused a decrease in the percentage of HCT-116 cells upon incubation with NKG2D effector cells, but the reduction in cells was not as pronounced as that with the afucosylated anti-MICA / B 3F9H1L3L antibody.

[0223] These results indicate that the anti-MICA / B antibody with enhanced Fc function increases the ability of the anti-MICA / B antibody to induce ADCC and cancer cell death. (Example 14) Efficacy measured by survival time analysis

[0224] The efficacy of CLN-619 WT was directly compared to CLN-619 Glymaxx (afucosylated) as a single agent administered as a prophylactic treatment starting on day 1 or as a therapeutic treatment starting on day 4 in an HCT-116-Luc human colon tumor xenograft model. Female Balb / c SCID mice were inoculated intraperitoneally (IP) to model disseminated disease. Treatments were administered IP twice weekly. Bioluminescence imaging (BLI) was performed to monitor the progression of disseminated disease. The significance endpoint was the evaluation of the treatment effect on tumor growth inhibition measured by BLI (not shown). The time to an endpoint near the diseased state (survival time) is shown in Figure 15A. The study was terminated on day 61 when the last mouse reached a moribund state. Survival time analysis was performed by log-rank test using Graphpad software. All of the prophylactic and therapeutic CLN-619 WT and CLN-619 Glymaxx treatment groups resulted in a significant extension of survival time compared to their respective higG1 control groups as shown in Figure 15B. In the prophylactic setting, there was no significant difference between CLN-619 WT and CLN-619 Glymaxx. In the therapeutic setting, CLN-619 Glymaxx administered at 10 mg / kg was statistically superior to CLN-619 administered at 10 mg / kg (P = 0.003).

[0225] The in vivo efficacy study of CLN-619 WT and CLN-619 Glymaxx was directly compared in a HCC1534 lung tumor xenograft model transplanted into Balb / c SCID mice. As shown in Figure 16, treatment with CLN-619 WT, CLN-619 Glymaxx or hIgG1 control started on day 1, the day of tumor cell transplantation. The treatment was administered twice a week for 4 weeks by IP injection. The doses ranged from 0.01 to 1 mg / kg of the CLN-619 test substance and 1 mg / kg of the hIgG1 control antibody. The study was terminated on day 40 and statistical analysis was calculated based on day 40. The statistical analysis consisted of multiple comparisons using one-way ANOVA and Tukey multiple comparisons, and the analysis was performed with GraphPad. No efficacy differences were observed between WT and Fc-enhanced at any dose in the HCC1534 cell line.

[0226] The operating principle of GlymaxX® Technology is in the absence of fucose, and cells cannot synthesize GDP-fucose by the salvage pathway. The de novo pathway, the major source of activated GDP-L-fucose, is efficiently blocked by the enzymatic conversion of the intermediate GDP-4-keto-6-deoxy-mannose to GDP-D-rhamnose, a dead end product that generally does not exist in vertebrate cells. Production of afucosylated antibodies by co-expression of heterologous GDP-6-deoxy-D-lyxo-4-hexulose reductase. Briefly, the antibody was digested with protease to yield three subunits (scFc, light chain, and Fd'), and the subunits were analyzed by reverse-phase LC-MS. Afucosylation was measured using mass spectrometry-based analysis. A representative lot of CLN-619 Glymaxx (afucosylated antibody) generated using GlymaxX® Technology is shown in Figure 17.

[0227] Preferred embodiments of the present invention are shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided by way of example only. A very large number of variations, changes and substitutions that do not depart from the present invention will now occur to those skilled in the art. It should be understood that various alternative means of the embodiments described herein can be used. It is intended that the scope of the present invention be defined by the following claims and thereby cover methods and structures within the scope of these claims and their equivalents.

Claims

1. (i) a light chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24, and a heavy chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26; or (ii) A light chain variable domain (VL) containing an amino acid sequence that is at least 80% identical to the amino acid sequence shown as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19, and a heavy chain variable domain (VH) containing an amino acid sequence that is at least 80% identical to the amino acid sequence shown as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO:

20. A monoclonal antibody or its antigen-binding fragment, comprising: a) comprising one or more amino acid modifications to enhance effector function compared to an unmodified monoclonal antibody or its antigen-binding fragment; and / or b) Deficiting fucosylation or containing reduced fucosylation compared to the amount of fucose typically detected for similar antibodies produced by mammalian expression systems, A monoclonal antibody or its antigen-binding fragment.

2. The monoclonal antibody according to claim 1, wherein the monoclonal antibody or its antigen-binding fragment specifically binds to MICA protein, MICB protein, or both MICA protein and MICB protein.

3. The monoclonal antibody according to claim 1 or claim 2, wherein the monoclonal antibody or its antigen-binding fragment is selected from whole immunoglobulin, scFv, Fab, F(ab')2, or disulfide-bonded Fv.

4. The monoclonal antibody according to claim 1 or claim 2, wherein the monoclonal antibody or its antigen-binding fragment is IgG or IgM.

5. The monoclonal antibody according to claim 1 or claim 2, wherein the monoclonal antibody or its antigen-binding fragment is humanized or a chimeric antibody.

6. The monoclonal antibody or its antigen-binding fragment (i) Mutation at amino acid 239 in the Fc region; (ii) Mutation at amino acid 332 in the Fc region; (iii) Mutation S239D in the Fc region; (iv) Mutation I332D in the Fc region; and / or (v) One or more amino acid modifications from Table B and / or Table C A monoclonal antibody or its antigen-binding fragment according to claim 1 or claim 2, comprising:

7. The monoclonal antibody or its antigen-binding fragment according to claim 1 or 2, wherein the monoclonal antibody or its antigen-binding fragment contains less than 95% of the amount of fucose normally detected for a similar antibody produced by a mammalian expression system.

8. A monoclonal antibody or an antigen-binding fragment thereof, wherein the monoclonal antibody or its antigen-binding fragment comprises: a light chain complementarity determination region 1 (LCDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17; a light chain complementarity determination region 2 (LCDR2) having an amino acid sequence at least 80% identical to either SEQ ID NO: 2, or SEQ ID NO: 10; a light chain complementarity determination region 3 (LCDR3) having an amino acid sequence at least 80% identical to either SEQ ID NO: 3, or SEQ ID NO: 11; a heavy chain complementarity determination region 1 (HCDR1) having an amino acid sequence at least 80% identical to either SEQ ID NO: 4, or SEQ ID NO: 12; a heavy chain complementarity determination region 2 (HCDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18; and a heavy chain complementarity determination region 3 (HCDR3) having an amino acid sequence at least 80% identical to either SEQ ID NO: 6, or SEQ ID NO:

14.

9. The monoclonal antibody or its antigen-binding fragment according to claim 8, wherein the monoclonal antibody or its antigen-binding fragment specifically binds to MICA protein, MICB protein, or both MICA protein and MICB protein.

10. The monoclonal antibody or its antigen-binding fragment according to claim 8 or 9, wherein the monoclonal antibody or its antigen-binding fragment is selected from whole immunoglobulin, scFv, Fab, F(ab')2, or disulfide-bonded Fv.

11. The monoclonal antibody or its antigen-binding fragment according to claim 8 or 9, wherein the monoclonal antibody or its antigen-binding fragment is IgG or IgM.

12. The monoclonal antibody or its antigen-binding fragment according to claim 8 or 9, wherein the monoclonal antibody or its antigen-binding fragment is humanized or a chimeric.

13. The antibody or its antigen-binding fragment a) comprising one or more amino acid modifications to enhance effector function compared to an unmodified monoclonal antibody or its antigen-binding fragment; and / or b) Deficiting fucosylation or containing reduced fucosylation compared to the amount of fucose typically detected for similar antibodies produced by mammalian expression systems, A monoclonal antibody or its antigen-binding fragment according to claim 8 or claim 9.

14. The monoclonal antibody or its antigen-binding fragment (i) Mutation at amino acid 239 in the Fc region; (ii) Mutation at amino acid 332 in the Fc region; (iii) Mutation S239D in the Fc region; (iv) Mutation I332D in the Fc region; and / or (v) One or more amino acid modifications from Table B and / or Table C A monoclonal antibody or its antigen-binding fragment according to claim 8 or 9, comprising:

15. The monoclonal antibody or its antigen-binding fragment according to claim 8 or 9, wherein the monoclonal antibody or its antigen-binding fragment contains less than 95% of the amount of fucose typically detected for a similar antibody produced by a mammalian expression system.

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