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

Abstract

The present application provides antibodies specifically binding to MICA / B, or antigen-binding fragments thereof, having a heavy chain, a light chain, a heavy chain variable domain (VH), a light chain variable domain (VL), and a complementarity determining region (CDR), as well as methods and uses thereof. In certain aspects, the antibody or antigen-binding fragment thereof comprises one or more amino acid modifications that enhance effector function as compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or lacks fucosylation or comprises a reduced fucosylation.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This patent application claims priority to U.S. Provisional Patent Application Serial No. 63 / 393,188, filed on July 28, 2022, the entire contents of which are hereby incorporated by reference into the present invention.

[0003] References to Electronic Sequence Listings

[0004] The electronic sequence listing (67253WO01 Sequence Listing.xml; size: 42KB; creation date: 2023-07-27) is incorporated by reference into this application in its entirety. Summary of the invention

[0005] The present application discloses monoclonal antibodies that specifically bind to MICA / B and thereby modulate the immune response against diseased cells.

[0006] In certain embodiments, the monoclonal antibody or antigen-binding fragment thereof disclosed herein comprises a light chain comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in 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 at least 80% identical to the amino acid sequence shown in SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0007] In certain embodiments, the monoclonal antibody or antigen-binding fragment thereof disclosed in the present application comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In certain embodiments, the monoclonal antibody or antigen-binding fragment thereof disclosed in the present application comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In certain embodiments, the monoclonal antibody or antigen-binding fragment thereof disclosed in the present application comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In certain embodiments, the monoclonal antibody or antigen-binding fragment thereof disclosed in the present application comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO:7, SEQ ID NO:15 or SEQ ID NO:19; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucose typically detected in similar antibodies produced in mammalian expression systems.

[0008] In certain embodiments, the monoclonal antibody or antigen-binding fragment thereof disclosed herein comprises a light chain variable domain (VL) comprising an amino acid sequence that is 100% identical to the amino acid sequence set forth in 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 sequence set forth in 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 heavy chain variable domain (VH) comprising an amino acid sequence that is at least 90% identical to the amino acid sequence set forth in 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 heavy chain variable domain (VH) comprising an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in 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 heavy chain variable domain (VH) comprising an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:20; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucose typically detected in similar antibodies produced in mammalian expression systems.

[0009] 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 100% identical to the amino acid sequence set forth in 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) and a heavy chain variable domain (VH), wherein the light chain variable domain (VL) comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 7, and the heavy chain variable domain (VH) comprises 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) and a heavy chain variable domain (VH), wherein the light chain variable domain (VL) comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 15, and the heavy chain variable domain (VH) 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) and a heavy chain variable domain (VH), wherein the light chain variable domain (VL) comprises an amino acid sequence at least 80% identical to SEQ ID NO: 19, and the heavy chain variable domain (VH) comprises an amino acid sequence 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 at least 80% identical to the amino acid sequence shown in 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 at least 80% identical to the amino acid sequence shown in 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 and MICB proteins. In some cases, the monoclonal antibody or its antigen-binding fragment binds to the α-3 domain of the MICA protein, the α-3 domain of the MICB protein, or the α-3 domain of both the MICA and MICB proteins. 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 a whole immunoglobulin, scFv, Fab, F(ab')2, or a 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 antigen-binding fragment thereof is humanized or chimeric.

[0010] In certain embodiments, the monoclonal antibody or antigen-binding fragment thereof disclosed in the present application comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 8, SEQ ID NO: 16 or SEQ ID NO: 20; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0011] In certain embodiments, the monoclonal antibody or antigen-binding fragment thereof disclosed in the present application comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 90% identical to the amino acid sequence shown in SEQ ID NO: 8, SEQ ID NO: 16 or SEQ ID NO: 20; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0012] In certain embodiments, the monoclonal antibody or antigen-binding fragment thereof disclosed in the present application comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 8, SEQ ID NO: 16 or SEQ ID NO: 20; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0013] In certain embodiments, the monoclonal antibody or antigen-binding fragment thereof disclosed in the present application comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 99% identical to the amino acid sequence shown in SEQ ID NO: 8, SEQ ID NO: 16 or SEQ ID NO: 20; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0014] In certain embodiments, the monoclonal antibody or antigen-binding fragment thereof disclosed in the present application comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 8, SEQ ID NO: 16 or SEQ ID NO: 20; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0015] 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 sequence set forth in 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 light chain variable domain (VL) comprising an amino acid sequence that is at least 90% identical to the amino acid sequence set forth in 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 light chain variable domain (VL) comprising an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in 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 light chain variable domain (VL) comprising an amino acid sequence that is at least 99% identical to the amino acid sequence set forth in 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 light chain variable domain (VL) comprising an amino acid sequence that is 100% identical to the amino acid sequence set forth in 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 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 antigen-binding fragment thereof 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 antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 20 and a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 19. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26.In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain containing an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 21, SEQ ID NO: 23 or SEQ ID NO: 24. In some cases, the monoclonal antibody or its antigen-binding fragment specifically binds to the MICA protein, the MICB protein, or both the MICA and MICB proteins. In some cases, the monoclonal antibody or its antigen-binding fragment binds to the α-3 domain of the MICA protein, the α-3 domain of the MICB protein, or the α-3 domain of both the MICA and MICB proteins. 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 a whole immunoglobulin, scFv, Fab, F(ab')2 or a disulfide-linked Fv. In some cases, the monoclonal antibody or its antigen-binding fragment is IgG or IgM. In some cases, the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric.

[0016] In certain embodiments, the monoclonal antibodies or antigen-binding fragments thereof disclosed herein comprise a light chain complementary determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 1-3, 9-11 and 17, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0017] In certain embodiments, the monoclonal antibodies or antigen-binding fragments thereof disclosed herein comprise a light chain complementary determining region (CDR) having an amino acid sequence that is at least 90% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 1-3, 9-11 and 17, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0018] In certain embodiments, the monoclonal antibodies or antigen-binding fragments thereof disclosed herein comprise a light chain complementary determining region (CDR) having an amino acid sequence that is at least 95% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 1-3, 9-11 and 17, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0019] In certain embodiments, the monoclonal antibodies or antigen-binding fragments thereof disclosed herein comprise a light chain complementary determining region (CDR) having an amino acid sequence that is at least 99% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 1-3, 9-11 and 17, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0020] In certain embodiments, the monoclonal antibodies or antigen-binding fragments thereof disclosed in the present application comprise a light chain complementary determining region (CDR) having an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 1-3, 9-11 and 17, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to the unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucose typically detected in similar antibodies produced in mammalian expression systems.

[0021] In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementary 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 in SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementary 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 in SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementary 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 in SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementary 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 in SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence that is 100% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), a light chain complementary determining region 3 (CDR3), a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 13. NO:5, SEQ ID NO:13 or SEQ ID NO:18, and the heavy chain complementarity determining region 3 (CDR3) has an amino acid sequence at least 80% identical to one of SEQ ID NO:6 or SEQ ID NO:14.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:1, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:3. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:9, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:10, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:11. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO: 3. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:5, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:6.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 13, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO: 14. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 18, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence 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 at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to the amino acid sequence set forth in 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) and a heavy chain variable domain (VH), the light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 7 or SEQ ID NO: 15; the heavy chain variable domain (VH) comprises an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 8 or SEQ ID NO: 16. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) and a light chain variable domain (VL), the heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 8 or SEQ ID NO: 16, and the light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 7 or SEQ ID NO: 15.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 7, and a heavy chain variable domain (VH) comprising an amino acid sequence 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 at least 80% identical to SEQ ID NO: 15, and a heavy chain variable domain (VH) comprising an amino acid sequence 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) and a heavy chain variable domain (VH), wherein the light chain variable domain (VL) comprises an amino acid sequence at least 80% identical to SEQ ID NO: 19, and the heavy chain variable domain (VH) comprises an amino acid sequence 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 at least 80% identical to the amino acid sequence shown in 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 at least 80% identical to the amino acid sequence shown in 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 and MICB proteins. In some cases, the monoclonal antibody or its antigen-binding fragment binds to the α-3 domain of the MICA protein, the α-3 domain of the MICB protein, or the α-3 domain of both the MICA and MICB proteins. 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 a whole immunoglobulin, scFv, Fab, F(ab')2, or a 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.

[0022] In certain embodiments, the monoclonal antibodies or antigen-binding fragments thereof disclosed herein comprise a heavy chain complementary determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 4-6, 12-14 and 18, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0023] In certain embodiments, the monoclonal antibodies or antigen-binding fragments thereof disclosed herein comprise a heavy chain complementary determining region (CDR) having an amino acid sequence that is at least 90% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 4-6, 12-14 and 18, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0024] In certain embodiments, the monoclonal antibodies or antigen-binding fragments thereof disclosed herein comprise a heavy chain complementary determining region (CDR) having an amino acid sequence that is at least 95% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 4-6, 12-14 and 18, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0025] In certain embodiments, the monoclonal antibodies or antigen-binding fragments thereof disclosed in the present application comprise a heavy chain complementary determining region (CDR) having an amino acid sequence that is at least 99% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 4-6, 12-14 and 18, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to the unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0026] In certain embodiments, the monoclonal antibodies or antigen-binding fragments thereof disclosed in the present application comprise a heavy chain complementary determining region (CDR) having an amino acid sequence that is 100% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 4-6, 12-14 and 18, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to the unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0027] In some cases, the monoclonal antibody or antigen-binding fragment comprises a light chain complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17. In some cases, the monoclonal antibody or antigen-binding fragment comprises a light chain complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17. In some cases, the monoclonal antibody or antigen-binding fragment comprises a light chain complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17. In some cases, the monoclonal antibody or antigen-binding fragment comprises a light chain complementary 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 in 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 100% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 1-3, 9-11, and 17. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), a heavy chain complementary determining region 3 (CDR3), a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO:4 or SEQ ID NO:12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to one of SEQ ID NO:5, SEQ ID NO:13, or SEQ ID NO:18, the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to one of SEQ ID NO:6 or SEQ ID NO:14, the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO:1, SEQ ID NO:9, or SEQ ID NO:15. NO:17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to one of SEQ ID NO:2 or SEQ ID NO:10, and the light chain complementary determining region 3 (CDR3) has 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 antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:5, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:6. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 13, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO: 14. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:18, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:6. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:1, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:3.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:9, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:10, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:11. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO: 3. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to the amino acid sequence set forth in 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) and a light chain variable domain (VL), wherein the heavy chain variable domain (VH) comprises an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 8, SEQ ID NO: 16 or SEQ ID NO: 20; and the light chain variable domain (VL) comprises an amino acid sequence at least 80% identical to the amino acid sequence shown in 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 light chain variable domain (VL) and a heavy chain variable domain (VH), wherein the light chain variable domain (VL) comprises an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 7 or SEQ ID NO: 15; and the heavy chain variable domain (VH) comprises an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 8 or SEQ ID NO: 16.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the heavy chain variable domain (VH) comprises an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 8; and the light chain variable domain (VL) comprises an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 7. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the heavy chain variable domain (VH) comprises an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 16; and the light chain variable domain (VL) comprises an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 15. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the heavy chain variable domain (VH) comprises an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 20; and the light chain variable domain (VL) comprises an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 19. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a light chain comprising an amino acid sequence at least 80% identical to the amino acid sequence shown in SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some cases, the monoclonal antibody or its antigen-binding fragment specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins. In some cases, the monoclonal antibody or its antigen-binding fragment binds to the α-3 domain of the MICA protein, the α-3 domain of the MICB protein, or the α-3 domain of both the MICA and MICB proteins. 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 a whole immunoglobulin, scFv, Fab, F(ab')2, or a 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.

[0028] In certain embodiments, the present application discloses a pharmaceutical composition comprising: a monoclonal antibody or an antigen-binding fragment thereof according to any one of the contents of the present application; and a pharmaceutically acceptable carrier or excipient; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucose typically detected in similar antibodies produced in mammalian expression systems.

[0029] In certain embodiments, the present application discloses 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, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0030] In certain embodiments, the present application discloses 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, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementary 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 in SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0031] In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises: (a) a light chain complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementary 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 in 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 complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementary 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 in 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 complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementary 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 in 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 complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementary 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 in 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 100% identical to at least one of the amino acid sequences set forth in 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 100% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 4-6, 12-14, and 18.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), a light chain complementary determining region 3 (CDR3), a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 13. NO:5, SEQ ID NO:13 or SEQ ID NO:18, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to one of SEQ ID NO:6 or SEQ ID NO:14. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:1, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:3. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:9, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:10, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:11.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO: 3. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:5, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:6. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 13, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO: 14. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 18, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence 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 at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to SEQ ID NO: 7, and a heavy chain variable domain (VH) comprising an amino acid sequence 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 at least 80% identical to SEQ ID NO: 15, and a heavy chain variable domain (VH) comprising an amino acid sequence 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) and a heavy chain variable domain (VH), wherein the light chain variable domain (VL) comprises an amino acid sequence at least 80% identical to SEQ ID NO: 19, and the heavy chain variable domain (VH) comprises an amino acid sequence 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 at least 80% identical to the amino acid sequence shown in 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 at least 80% identical to the amino acid sequence shown in 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 and MICB proteins. In some cases, the monoclonal antibody or antigen-binding fragment thereof binds to the α-3 domain of a MICA protein, the α-3 domain of a MICB protein, or the α-3 domains of both MICA and MICB proteins.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 a whole immunoglobulin, scFv, Fab, F(ab')2, or a disulfide-linked 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. In some cases, the monoclonal antibody or its antigen-binding fragment reduces the level of soluble MICA protein, soluble MICB protein, or both. In some cases, the monoclonal antibody or its antigen-binding fragment reduces the shedding of soluble MICA protein, soluble MICB protein, or both. In some cases, the monoclonal antibody or its antigen-binding fragment inhibits the shedding of soluble MICA protein, soluble MICB protein, or both.

[0032] In certain embodiments, the present application discloses 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, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0033] In certain embodiments, the present application discloses 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, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementary 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 in SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0034] In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises: (a) a light chain complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementary 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 in 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 complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementary 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 in 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 complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementary 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 in 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 complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementary 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 in 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 100% identical to at least one of the amino acid sequences set forth in 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 100% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 4-6, 12-14, and 18.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), a light chain complementary determining region 3 (CDR3), a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 13. NO:5, SEQ ID NO:13 or SEQ ID NO:18, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to one of SEQ ID NO:6 or SEQ ID NO:14. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:1, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:3. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:9, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:10, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:11.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO: 3. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:5, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:6. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 13, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO: 14. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 18, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence 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 at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to SEQ ID NO: 7, and a heavy chain variable domain (VH) comprising an amino acid sequence 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 at least 80% identical to SEQ ID NO: 15, and a heavy chain variable domain (VH) comprising an amino acid sequence 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) and a heavy chain variable domain (VH), the light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 19, and the heavy chain variable domain (VH) comprising an amino acid sequence 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 at least 80% identical to the amino acid sequence shown in 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 at least 80% identical to the amino acid sequence shown in 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 and MICB proteins. In some cases, the monoclonal antibody or its antigen-binding fragment binds to the α3 domain of the MICB protein.In some cases, the monoclonal antibody or its antigen-binding fragment binds to the α-3 domain of the MICA protein, the α-3 domain of the MICB protein, or the α-3 domain of both the MICA and MICB proteins. 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 a whole immunoglobulin, scFv, Fab, F(ab')2, or a 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 fragment is humanized or chimeric. In some cases, the monoclonal antibody or its antigen-binding fragment reduces the level of soluble MICA protein, soluble MICB protein, or both. In some cases, the monoclonal antibody or its antigen-binding fragment reduces the 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.

[0035] In certain embodiments, the present application discloses a method for reducing the level of soluble MICA protein, soluble MICB protein, or both in an individual in need thereof, comprising administering to the individual an effective amount of a monoclonal antibody or an antigen-binding fragment thereof, wherein the monoclonal antibody or the antigen-binding fragment thereof comprises a light chain complementary determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY.

[0036] In certain embodiments, the present application discloses a method for reducing the level of soluble MICA protein, soluble MICB protein, or both in an individual in need thereof, comprising administering to the individual an effective amount of a monoclonal antibody or an antigen-binding fragment thereof, wherein the monoclonal antibody or antigen-binding fragment thereof 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 shown in SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises: (a) a light chain complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementary 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 in 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 complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementary 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 in 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 complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementary 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 in 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 complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementary 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 in 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 100% identical to at least one of the amino acid sequences set forth in 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 100% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), a light chain complementary determining region 3 (CDR3), a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 13. NO:5, SEQ ID NO:13 or SEQ ID NO:18, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to one of SEQ ID NO:6 or SEQ ID NO:14. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:1, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:3.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:9, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:10, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:11. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO: 3. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:5, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:6. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 13, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO: 14.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 18, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence 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 at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to SEQ ID NO: 7, and a heavy chain variable domain (VH) comprising an amino acid sequence 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 at least 80% identical to SEQ ID NO: 15, and a heavy chain variable domain (VH) comprising an amino acid sequence 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 at least 80% identical to SEQ ID NO: 19, and a heavy chain variable domain (VH) comprising an amino acid sequence 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 at least 80% identical to the amino acid sequence shown in 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 at least 80% identical to the amino acid sequence shown in 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 the MICA protein, the MICB protein, or both the MICA and MICB proteins. In some cases, the monoclonal antibody or its antigen-binding fragment binds to the α-3 domain of the MICA protein, the α-3 domain of the MICB protein, or the α-3 domain of both the MICA and MICB proteins. 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 a whole immunoglobulin, scFv, Fab, F(ab')2 or a 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 fragment is humanized or chimeric. In some cases, the monoclonal antibody or its antigen binding fragment reduces or inhibits the shedding of soluble MICA protein, soluble MICB protein or both, thereby reducing the level of soluble MICA protein, soluble MICB protein or both of the individual. In some cases, the individual suffers from a cancer characterized by an increase in the level of soluble MICA protein, soluble MICB protein or both.

[0037] In certain embodiments, the present application discloses the use of a monoclonal antibody or an antigen-binding fragment thereof according to any one of the contents of the present application for treating cancer in an individual in need thereof; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucose typically detected in similar antibodies produced in mammalian expression systems.

[0038] In certain embodiments, the present application discloses the use of a monoclonal antibody or antigen-binding fragment thereof according to any one of the contents of the present application in the preparation of a medicament for treating cancer in an individual in need thereof. More specifically, the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucose typically detected in similar antibodies produced by mammalian expression systems.

[0039] In certain embodiments, the monoclonal antibodies or antigen-binding fragments thereof disclosed herein compete for binding to MICA / B with the following antibody: the antibody comprises a light chain variable domain (VL) having an amino acid sequence at least about 80% identical to the amino acid sequence set forth in SEQ ID NO: 27. In certain embodiments, the monoclonal antibodies or antigen-binding fragments thereof disclosed herein compete for binding to MICA / B with the following antibody: the antibody comprises a heavy chain variable domain (VH) having an amino acid sequence at least about 80% identical to the amino acid sequence set forth in SEQ ID NO: 28; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucosylation typically detected in similar antibodies produced in mammalian expression systems.

[0040] In certain embodiments, according to the monoclonal antibody or its antigen-binding fragment and method described in the present application, the monoclonal antibody or its antigen-binding fragment induces complement dependent cytotoxicity (CDC), Fc receptor binding to activate antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP) in target cells. In certain embodiments, the monoclonal antibody or its antigen-binding fragment induces ADCC.

[0041] In certain embodiments of the monoclonal antibody or antigen-binding fragment thereof described herein or 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 antibody or antigen-binding fragment thereof described herein or 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 antibody or antigen-binding fragment thereof described herein or the methods described herein, the monoclonal antibody or antigen-binding fragment thereof comprises a mutation at S239D of the Fc region. In certain embodiments of the monoclonal antibody or antigen-binding fragment thereof described herein or the methods described herein, the monoclonal antibody or antigen-binding fragment thereof comprises a mutation at I332D of the Fc region. In certain embodiments of the monoclonal antibody or antigen-binding fragment thereof described herein or the methods described herein, the monoclonal antibody or antigen-binding fragment thereof comprises a mutation at S239D and I332D of the Fc region. In certain embodiments of the monoclonal antibodies or antigen-binding fragments thereof described herein or the methods described herein, the monoclonal antibodies or antigen-binding fragments thereof contain 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 typically detected in similar antibodies produced by mammalian expression systems.

[0042] In certain embodiments of the monoclonal antibodies or antigen-binding fragments thereof described herein or the methods described herein, the monoclonal antibodies or antigen-binding fragments thereof comprise one or more amino acid modifications of Table B and / or Table C.

[0043] In certain embodiments of the monoclonal antibodies or antigen-binding fragments thereof described herein or the methods described herein, the monoclonal antibodies or antigen-binding fragments thereof comprise one or more amino acid modifications of Table B and / or Table C.

[0044] In certain embodiments, the cancer disclosed herein is selected from the group consisting of carcinoma, lymphoma, blastoma, melanoma and leukemia.

[0045] In certain embodiments, the cancer disclosed in the present application is selected from the group consisting of: squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, Hodgkin's lymphoma and non-Hodgkin's lymphoma, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer (such as liver cancer and hepatocellular carcinoma), bladder cancer, breast cancer, myeloma (such as 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.

[0046] In certain embodiments, the cancer disclosed herein is a primary cancer.

[0047] In certain embodiments, the cancer disclosed herein is a metastatic cancer.

[0048] In certain embodiments, the monoclonal antibodies or antigen-binding fragments thereof disclosed herein increase the surface level of MICA protein, MICB protein, or both.

[0049] In certain embodiments, the monoclonal antibodies or antigen-binding fragments thereof disclosed herein inhibit the shedding of MICA protein, MICB protein, or both.

[0050] In certain embodiments, the monoclonal antibodies or antigen-binding fragments thereof disclosed herein increase the surface level of soluble MICA protein, soluble MICB protein, or both.

[0051] In certain embodiments, the monoclonal antibodies or antigen-binding fragments thereof disclosed herein inhibit the shedding of soluble MICA protein, soluble MICB protein, or both.

[0052] In certain embodiments, the present application discloses a method for increasing the surface level of soluble MICA protein, soluble MICB protein, or both in an individual in need thereof by inhibition of shedding, comprising administering to the individual an effective amount of a monoclonal antibody or an antigen-binding fragment thereof, wherein the monoclonal antibody or the antigen-binding fragment thereof comprises a light chain complementary determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY.

[0053] In certain embodiments, the present application discloses a method for increasing the surface level of soluble MICA protein, soluble MICB protein, or both in an individual in need thereof by inhibition of shedding, comprising administering to the individual an effective amount of a monoclonal antibody or an antigen-binding fragment thereof, wherein the monoclonal antibody or the antigen-binding fragment thereof comprises a heavy chain complementary determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 4-6, 12-14 and 18, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises: (a) a light chain complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementary 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 in 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 complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementary 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 in 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 complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementary 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 in 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 complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementary 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 in 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 100% identical to at least one of the amino acid sequences set forth in 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 100% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), a light chain complementary determining region 3 (CDR3), a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 13. NO:5, SEQ ID NO:13 or SEQ ID NO:18, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to one of SEQ ID NO:6 or SEQ ID NO:14. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:1, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:3.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:9, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:10, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:11. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO: 3. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:5, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:6. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 13, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO: 14.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 18, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence 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 at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to the amino acid sequence set forth in 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 at least 80% identical to SEQ ID NO: 7, and a heavy chain variable domain (VH) comprising an amino acid sequence 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 at least 80% identical to SEQ ID NO: 15, and a heavy chain variable domain (VH) comprising an amino acid sequence 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 at least 80% identical to SEQ ID NO: 19, and a heavy chain variable domain (VH) comprising an amino acid sequence 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 at least 80% identical to the amino acid sequence shown in 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 at least 80% identical to the amino acid sequence shown in 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 the MICA protein, the MICB protein, or both the MICA and MICB proteins. In some cases, the monoclonal antibody or its antigen-binding fragment binds to the α-3 domain of the MICA protein, the α-3 domain of the MICB protein, or the α-3 domain of both the MICA and MICB proteins. 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 a whole immunoglobulin, scFv, Fab, F(ab')2 or a 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 fragment is humanized or chimeric. In some cases, the monoclonal antibody or its antigen binding fragment inhibits the shedding of soluble MICA protein, soluble MICB protein or both, thereby increasing the surface level of soluble MICA protein, soluble MICB protein or both of the individual. In some cases, the individual suffers from a cancer characterized by an increase in the level of soluble MICA protein, soluble MICB protein or both. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Features and advantages of the present invention may be obtained by referring to the following detailed description and accompanying drawings which set forth illustrative embodiments in which the principles of the invention are utilized:

[0055] Figure 1A-1B Example of antibody 3F9.E4 (tested by ELISA Figure 1A ) and 16F10.C12( Figure 1B ) in combination with the MICA / B allele.

[0056] Figure 2 Binding of the exemplary antibody 3F9.E4 to cell surface MICA was assessed by flow cytometric staining of TRAMP C2 cells transfected with MICA*08 compared to parental TC2 cells.

[0057] Figure 3 Exemplary antibodies 3F9.E4, 16F10.C12 and PDI-1 inhibited shedding of MICA from PLC / PRF / 5 cells.

[0058] Figure 4A-4B Example antibody 3F9.E4 ( Figure 4A ) and 16F10.C12( Figure 4B ) enhanced NK-92 cell-mediated cytotoxicity of PLC / PRF / 5 cells.

[0059] Figure 5 Antitumor activity against B16 / MICA transfectants relative to the isotype control (IC) antibody 3F9 is illustrated.

[0060] Figure 6A-6C Example A higher percentage of NKG2D-positive NK cells was observed in tumor infiltrates (TILs) of tumors treated with 3F9 antibody compared to isotype controls ( Fig. 6A ), CD8+T cells ( Figure 6B ) and γδT cells ( Figure 6C ).

[0061] Figure 7A-7B Example Treatment with 3F9 antibody reduced soluble MICA in tumors in B16 / MICA transgenic animals ( Fig. 7A ) and surface MICA( Figure 7B ) level.

[0062] Figure 8A-8C Example competition binding assay to illustrate that all antibodies bind to a "structural" epitope and that antibody 3F9.E4 competes for binding to antibody PDI-1 ( Figure 8B ), and antibody 16F10 binds to a slightly different but very close epitope to PDI-1 and 3F9 ( Figure 8C ).

[0063] Fig. 9 is used to determine the MICA / B antibodies and Fig.10 Table of Biacore binding assay parameters for the binding affinities of the indicated Fcγ receptors shown.

[0064] Fig.10 Table showing the results of Biacore binding assays of anti-MICA / B wild-type antibody ("CLN619-WT"), anti-MICA / B defucosylated antibody ("GLYMAXX"), anti-MICA / B antibody with two heavy chains S239D and I332E ("S239D and I332E"), or trastuzumab (positive control) to the indicated Fcγ receptors. Relative binding affinity is expressed according to the following scale: 10-8 Up to 10 -9 M(++++); 10 -7 (+++); 10 -6 (++); 10 -5 (+); detectable binding (+ / -); no detectable binding (-).

[0065] Fig.11 is a table showing the results of Biacore binding assays of 3F9H1L3L anti-MICA / B wild-type antibody ("3F9H1L3L"), 3F9H1L3L anti-MICA / B defucosylated antibody ("3F9H1L3L GLYMAXXX"), 3F9H1L3L anti-MICA / B antibody having two heavy chains S239D and I332E ("3F9H1L3LS239D and I332E"), or trastuzumab (positive control) to FcRn.

[0066] Fig.12 are graphs depicting the results of two replicate MICA / B cell surface stabilization experiments in PLC / PRF / 5 cancer cells after incubation with anti-MICA / B wild-type antibody ("CLN619 WT"), anti-MICA / B defucosylated antibody ("CLN-619GLYMAXX"), or anti-MICA / B antibody with heavy chain S239D / I332E mutations, stained with Alexafluor anti-MICA / B antibody (AF647MICA / MICB). The left graph shows the mean fluorescence intensity to determine the binding of MICA / B to PLC / PRF / 5 cells. The right graph shows controls depicting MICA / B binding to Hela cells that highly express MICA / B, which were incubated with an isotype control antibody (AF647 Mo IgG2a isotype control) or unstained Hela cells.

[0067] Fig.13Is a graph depicting luminescence, for ADCC activity, using a Promega ADCC bioassay, the bioassay includes Jurkat cells stably expressing FcγRIIIa and a luciferase gene regulated by an NFAT response element, co-cultured with HCT-116 cells or HCC1534 cells for 6 hours, the HCT-116 cells or HCC1534 cells having been incubated with anti-MICA / B wild-type antibody ("CLN619"), anti-MICA / B defucosylated antibody ("GLYMAXX"), or anti-MICA / B antibody (DM) with two heavy chain S239D and I332E mutations. Data are plotted as relative light units (RLU) versus Log10 [antibody], and EC50 is calculated by using a nonlinear fit log (agonist) versus response-variable slope (four parameters).

[0068] Fig.14 is a graph depicting the percentage of live HCT-116 target cells after 14 hours of incubation of anti-MICA / B wild-type antibody ("CLN619") or anti-MICA / B defucosylated antibody ("GLYMAXX") with donor PBMC effector cells at the indicated concentrations.

[0069] Fig.15A and Fig. 15B is a graph depicting the time to peri-morbidity endpoint (survival) in Balb / c SCID mice treated with MICA / B wild-type antibody ("CLN619") or anti-MICA / B defucosylated antibody ("GLYMAXX") and donor PBMC effector cells. Fig.15A Therapeutic dosing is described. Fig. 15B Prophylactic dosing is described.

[0070] Fig.16 is a graph depicting a comparison of in vivo efficacy studies conducted in a HCC1534 lung tumor xenograft model implanted in Balb / c SCID mice treated with either MICA / B wild-type antibody ("CLN619") or anti-MICA / B defucosylated antibody ("GLYMAXX") and donor PBMC effector cells.

[0071] Fig.17 Is to describe the use Figure 1. Representative batch of CLN-619 GlymaxX (defucosylated antibody) generated by the PCR technology. Production of non-fucosylated antibody by co-expression of heterologous GDP-6-deoxy-D-lyso-4-hexulose reductase. Defucosylation was measured using mass spectrometry. DETAILED DESCRIPTION

[0072] Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which the methods described in this application belong. Unless otherwise specified, any reference to standard methods (e.g., ASTM, TAPPI, AATCC, etc.) refers to the latest available version of the method at the time of filing this invention.

[0073] For any method disclosed in this application comprising discrete steps, the steps may be performed in any feasible order. Moreover, any combination of two or more steps may be performed simultaneously where appropriate.

[0074] Unless otherwise noted, all headings are for the convenience of the reader and should not be used to limit the meaning of the text that follows the heading.

[0075] The words "preferred" and "preferably" refer to embodiments of the present invention that may provide certain benefits under certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. In addition, the recitation of one or more preferred embodiments does not mean that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the present invention.

[0076] The terms "comprises / comprising / containing" and variations thereof do not have a limiting meaning when appearing in the specification and claims. Such terms will be understood to mean the inclusion of the stated steps or elements or groups of steps or elements but not the exclusion of any other steps or elements or groups of steps or elements.

[0077] "Consisting of" means including and limited to whatever is between the phrases "consisting of." Thus, the phrase "consisting of" indicates that the listed elements are required or mandatory, and no other elements may be present. "Consisting essentially of" means including any elements listed between the phrases, and limited to other elements that do not interfere with or contribute to the specified activity or action of the listed elements in the present invention. Thus, the phrase "consisting essentially of" indicates that the listed elements are required or mandatory, but other elements are optional and may or may not be present, depending on whether they have a substantial effect on the activity or action of the listed elements.

[0078] The singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. These articles refer to one or more than one (i.e., at least one). As used in this application, the term "or" is generally used in its ordinary sense, including "and / or", unless the content clearly dictates otherwise. The term "and / or" refers to any one or more items in a list connected by "and / or". For example, "x and / or y" represents any element in the three-element set {(x), (y), (x, y)}. In other words, "x and / or y" means "one or both of x and y". For another example, "x, y and / or z" refers to any element in 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".

[0079] In the case of a given range, the endpoints include all numbers in the range (e.g., 1 to 5 include 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). In addition, unless otherwise specified or otherwise apparent from the context and understanding of those of ordinary skill in the art, the values ​​expressed as ranges can adopt any specific value or subrange within the range described in different embodiments of the present invention, up to one-tenth of the unit of the lower limit of the range, unless the context clearly specifies otherwise. Here, "up to" a number (e.g., up to 50) includes the number (e.g., 50). The term "in a range" or "within a range" (and similar expressions) includes the endpoints of the range.

[0080] References to "one aspect", "aspect", "certain aspects" or "some aspects" in this specification refer to specific features, configurations, compositions or characteristics described in connection with the aspect being included in at least one aspect of the present disclosure. Therefore, the appearance of such phrases in different locations throughout this specification does not necessarily refer to the same embodiment of the present invention. In addition, specific features, configurations, compositions or characteristics may be combined in any appropriate manner in one or more aspects.

[0081] Unless otherwise stated, all numerals used in this specification and claims to represent the number of components, molecular weight, etc. should be understood to be modified by the term "approximately" in all cases. As related to the measured amount in this application, the term "approximately" refers to the variation of the measured amount expected by the skilled person in the art to measure and take a cautious level that matches the precision of the measurement target and the measurement equipment used. The term "approximately" is used together with the numerical values ​​in this specification and claims to represent the accuracy interval familiar to and accepted by the skilled person in the art. Usually, such an accuracy interval is + / -10%. Therefore, unless otherwise stated to the contrary, the numerical parameters specified in this specification and claims are approximate values ​​that can vary according to the desired properties to be obtained by the present invention. At least, rather than attempting to limit the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be interpreted according to the number of reported significant figures and applying ordinary rounding techniques.

[0082] Notwithstanding that 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. All numerical values, however, inherently include ranges necessarily resulting from the standard deviation found in their respective testing measurements.

[0083] The term "exemplary" refers to serving as a non-limiting example, scenario or illustration. As used in this application, the terms "such as", "such as" and "for example" list one or more non-limiting aspects, examples, scenarios or illustrations.

[0084] As used in the present application, the term "substantially" refers to the qualitative conditions that show all or nearly all ranges or degrees of a characteristic or property of interest. Biological and chemical phenomena rarely, if ever, complete and / or proceed to complete or achieve or avoid absolute results. Therefore, the present application uses the term "substantially" to capture the inherent potential lack of completeness in many biological and chemical phenomena. For example, "substantially" can refer to at least about 20%, or at least about 10%, or at least about 5% of a characteristic or property of interest.

[0085] The invention is defined in the claims. However, the following is a non-exhaustive list of non-limiting exemplary aspects. Any one or more features of these aspects can be combined with any one or more features of another example, embodiment or aspect described in this application.

[0086] In some embodiments, disclosed herein are monoclonal antibodies that specifically bind to MICA / B. In some embodiments, the MICA / B antibodies in the present application bind to MICA / B proteins or fragments thereof and modulate immune responses in individuals, thereby treating cancer.

[0087] Major histocompatibility complex class I-related chains A and B (MICA / B) are two stress-induced ligands of the natural killer cell (NK) receptor NKG2D, and play an important role in mediating the cytotoxicity of NK and T cells. Soluble MICA / B shed by diseased cells (e.g., cancer cells) desensitizes NK and T cells by binding to the NKG2D receptor, thereby inhibiting the immune response. Therefore, regulation of MICA / B helps regulate the immune response of an individual (e.g., an individual with cancer). Antibodies that bind to MICA / B and regulate its activity are ideal for developing novel therapeutic agents for treating cancer.

[0088] Certain terms

[0089] As used herein, "MICA / B" refers to MICA protein, MICB protein, or both MICA and MICB proteins, including their variants, isoforms, and species homologs of human MICA / B.

[0090] As used in this application, "antibody" refers to a glycoprotein that exhibits binding specificity to a specific antigen. Antibodies generally contain a variable domain and a constant domain in each of the heavy and light chains. Therefore, most antibodies have a heavy chain variable domain (VH) and a light chain variable domain (VL), which together form the portion of the antibody that binds to the antigen. Each variable domain has three complementary determining regions (CDRs), which form loops that contact the surface of the antigen in the heavy chain variable domain (VH) and the light chain variable domain (VL). The antibodies of the present application also include "antigen binding moiety" or antibody fragments that can bind to an antigen.

[0091] As used herein, a "chimeric" antibody is an antibody having a portion of a heavy chain and / or light chain that is identical or homologous to a 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 a corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, as long as they exhibit the desired biological activity (see, e.g., Morrison et al., Proc. Natl. Acad. Sci. USA 81: 6851-6855 (1984)). A "humanized antibody" herein refers to a chimeric antibody in which a human sequence is substituted in the antibody sequence.

[0092] As used herein, "effector function" refers to those biological activities mediated by the Fc region of an antibody, which activity may vary depending on the antibody isotype. Examples of antibody effector functions include receptor ligand blocking, agonism, or antagonism, C1q binding to activate complement dependent cytotoxicity (CDC), Fc receptor binding to activate antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP).

[0093] As used herein, "enhanced effector function" refers to one or more modifications to the amino acid sequence of the Fc region of an antibody, thereby increasing the effector function of the Fc region, including but not limited to CDC, ADCC and ADCP, compared to the same antibody without the amino acid modification.

[0094] The terms "recipient", "individual", "subject", "host" and "patient" are used interchangeably in this application and, in some cases, refer to any mammalian subject, particularly a human, for whom diagnosis, treatment or therapy is desired. "Mammal" for therapeutic purposes refers to any animal classified as a mammal, including humans, domestic and farm animals, as well as laboratory, zoo, sport 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.

[0095] As used in this application, the terms "treat", "treatment", and the like, in certain cases refer to the administration of an agent or the performance of a procedure for the purpose of obtaining an effect. The effect may be preventive, i.e., preventing a disease or its symptoms in whole or in part, and / or may be therapeutic, i.e., curing a disease and / or its symptoms in part or in whole. "Treatment" as used in this application may include treatment of a disease or condition (e.g., cancer) in a mammal, particularly a human, and includes: (a) preventing the occurrence of a disease or a symptom of a disease in a subject who may be susceptible to the disease but has not yet been diagnosed with the disease (e.g., including a disease that may be associated with or caused by a primary disease); (b) inhibiting the disease, i.e., arresting its development; (c) alleviating the disease, i.e., causing regression of the disease. Treatment may refer to any sign of success in the treatment or improvement or prevention of cancer, including any objective or subjective parameter, such as ablation; alleviation; symptom relief or making the patient more tolerable to the disease condition; slowing the rate of degeneration or decline; or making the final point of degeneration less debilitating. Treatment or amelioration of symptoms is based on one or more objective or subjective parameters; including the results of a physician's examination. Therefore, the term "treatment" includes the administration of compounds or agents of the present invention to prevent or delay, alleviate or stagnate or inhibit the development of symptoms or conditions associated with a disease (e.g., cancer). The term "therapeutic effect" refers to reducing, eliminating or preventing a subject's disease, symptoms of a disease, or side effects of a disease.

[0096] In some cases, a "therapeutically effective amount" refers to an amount that, when administered to a subject for treating a disease, is sufficient to effect treatment for the disease.

[0097] As used herein, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an antibody" includes a plurality of antibodies, and in some embodiments reference to "an antibody" includes a plurality of antibodies, and so on.

[0098] As used herein, all numerical values ​​or numerical ranges include all integers in or covering such ranges and fractions of values ​​or integers in or covering such ranges, unless the context clearly indicates otherwise. Thus, for example, reference to a range of 90-100% 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 1-5,000 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 forth.

[0099] The term "about" a number as used herein means a range including the number, ranging from 10% below the number to 10% above the number. The term "about" range means from 10% below the lower limit of the range to 10% above the upper limit of the range.

[0100] "Percent (%) identity" refers to the extent to which two sequences (nucleotides or amino acids) have identical residues at identical positions in the alignment. For example, "an amino acid sequence is X% identical to SEQ ID NO:Y" refers to the percent identity of an amino acid sequence to SEQ ID NO:Y, and is elaborated as X% of the residues in the amino acid sequence are identical to the residues in the sequence disclosed in SEQ ID NO:Y. Typically, such calculations are performed using computer programs. Exemplary programs for comparing and aligning sequence pairs 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).

[0101] MICA / B

[0102] In some embodiments, the present application discloses monoclonal antibodies that specifically bind to MICA / B. In some embodiments, the present application further discloses monoclonal antibodies that competitively bind to MICA / B.

[0103] Major histocompatibility complex (MHC) class I chain-related gene A and gene B proteins (MICA / B) are glycosylated, polymorphic, and membrane-anchored nonclassical MHC class I proteins. MICA / B are related to MHC class I and have a similar domain structure, which includes three extracellular Ig-like domains (α-1, α-2, and α-3), a transmembrane domain, and a C-terminal cytoplasmic tail. However, MICA / B does not bind to β2-microglobulin, lacks a CD8 binding site, and does not present any antigen. MICA / B is a key target of immune effector cells (including NK, NKT, and αβCD8 + T cells and γδCD8 + MICA / B is a ligand for the C-type lectin-like activating receptor natural killer group 2D (NKG2D) on T cells. The interaction between MICA / B and NKG2D plays a role in tumor surveillance and immune response.

[0104] MICA / B proteins are usually expressed at low levels in normal cells, but are induced to higher levels in stressed or transformed cells (e.g., cancer cells). The interaction of immune effector cells carrying NKG2D with stressed or diseased cells expressing MICA / B ligands on their cell surfaces generates a cellular immune response against stressed / diseased cells, ultimately leading to cell death expressing MICA / B. In cancer cells, truncated MICA / B proteins (proteins that lack the transmembrane domain and cytoplasmic tail but retain three extracellular domains including the α-1, α-2, and α-3 domains) are often shed into the blood by the action of proteases and lead to downregulation of their intended receptor NKG2D on effector immune cells (receptor internalization). In some cases, MICA / B glycoproteins are produced intracellularly and are usually not bound to the cell surface membrane, but are instead incorporated into exosomes and released outside the cell, where they interact with NKG2D receptors on immune cells. These truncated or soluble MICA / B ligands shed from the cancer cell surface function like decoy molecules and lead to the activation of immune effector cells (e.g., NK, NKT, and various CD8 + In some cases, the formation of soluble MICA / B leads to an unusual situation where the effectors of the innate defense system (whose natural role is to seek out and destroy transformed cells) are shut down by the immunosuppressive effects of these decoy ligand molecules, allowing cancer cells to evade the immune system and grow unchecked.

[0105] Treating cancer

[0106] In some embodiments, the anti-MICA / B antibodies disclosed herein bind to a MICA / B protein or a fragment thereof and modulate an immune response in an individual, thereby treating cancer.

[0107] The term "treatment" or "treatment" as used herein refers to a clinical intervention that alters the natural progression of a disease in a treated subject. The expected therapeutic effect includes, but is not limited to, preventing the occurrence of a disease, alleviating symptoms, reducing any direct or indirect pathological consequences of a disease, preventing metastasis, delaying disease progression, improving or alleviating the condition, and / or improving prognosis.

[0108] As used herein, the terms "cancer", "tumor", "cancerous" and malignant refer to or describe a physiological disease in mammals that is generally 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, carcinomas (e.g., adenocarcinomas), lymphomas, blastomas, melanomas and leukemias. More specific examples of such cancers include, for example, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, Hodgkin's lymphoma and non-Hodgkin's lymphoma, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer (e.g., liver cancer 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.

[0109] As cancer cells grow and multiply, they form cancerous masses, which are tumors that invade and damage nearby tissues and organs. Malignant tumors are cancers, and while they are usually resectable, they may, and often do, regrow. The cells of a malignant tumor can and do invade and damage nearby tissues and organs. In addition, cancer cells may leave the site of the malignancy and migrate through the blood or lymphatic system to form new lesions in distant organs. This migration of cancer to distant sites is called metastasis.

[0110] Hepatocellular carcinoma (HCC) is a primary malignant tumor of the liver that occurs primarily in individuals with underlying chronic liver disease and cirrhosis. The tumor progresses through local expansion, intrahepatic spread, and distant metastasis. Hepatitis B and hepatitis C predispose individuals to the development of chronic liver disease and, subsequently, HCC. Obesity, diabetes, and alcohol abuse are some other causes that predispose individuals to the subsequent development of HCC.

[0111] Anti-MICA / B antibodies

[0112] The application provides antibodies that specifically bind to MICA / B proteins. 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 containing a heavy chain variable domain (VH) and at least one light chain containing a light chain variable domain (VL). Each of VH and VL comprises three complementary determining regions (CDRs). The amino acid sequences of VH, VL and CDR determine the antigen binding specificity and antigen binding strength of the antibody. The amino acid sequences of heavy and light chains, VH and VL and CDR are summarized in Table 1.

[0113]

[0114]

[0115]

[0116]

[0117] In some embodiments, the antibody specifically binds to MICA protein. In some embodiments, the antibody specifically binds to MICB protein. In some embodiments, the antibody specifically binds to both MICA protein and MICB protein. In some embodiments, the antibody binds to the α-3 domain of MICA protein. In some embodiments, the antibody binds to the α-3 domain of MICB protein. In some embodiments, the antibody binds to the α-3 domain of both MICA protein and MICB protein. In some embodiments, the MICA protein bound by the antibody is a membrane-bound MICA protein. In some embodiments, the MICA protein bound by the antibody is a soluble MICA protein. In some embodiments, the MICA protein bound by the antibody is both a membrane-bound MICA protein and a soluble MICA protein. In some embodiments, the MICB protein bound by the antibody is a membrane-bound MICB protein. In some embodiments, the MICB protein bound by the antibody is a soluble MICB protein. In some embodiments, the MICB protein bound by the antibody is a membrane-bound MICB protein. In some embodiments, the MICB protein bound by the antibody is a soluble MICB protein. In some embodiments, the MICB protein bound by the antibody is a membrane-bound MICB protein and a soluble MICB protein.

[0118] In some embodiments, the antibody that specifically binds to MICA / B is a monoclonal antibody. In some embodiments, the antibody is an antigen binding fragment. In some embodiments, the antibody is selected from a whole immunoglobulin, scFv, Fab, F(ab')2, or a disulfide bonded Fv. In some embodiments, the antibody is an IgG or IgM. In some embodiments, the antibody is humanized. In some embodiments, the antibody is chimeric.

[0119] MICA / B antibody heavy and light chains

[0120] The present application discloses antibodies with light chains that specifically bind to MICA / B. 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 shown in 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 shown in 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 shown in SEQ ID NO:21, SEQ ID NO:23, or SEQ ID NO:24.

[0121] The present application further discloses an antibody having a heavy chain that specifically binds to MICA / B. 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 shown in 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 shown in 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 shown in SEQ ID NO:22, SEQ ID NO:25, or SEQ ID NO:26.

[0122] The present application also discloses an antibody comprising a light chain and a heavy chain that binds to MICA / B. 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 shown in 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 in 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 in 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 in 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 in 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 in SEQ ID NO:22, SEQ ID NO:25, or SEQ ID NO:26.

[0123] In some embodiments, the 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 in 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 in 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 in 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 in SEQ ID NO:22. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:21, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:22.

[0124] In some embodiments, the 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 in 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 in 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 in 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 in SEQ ID NO:25. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:23, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:25.

[0125] In some embodiments, the 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 in 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 in 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 in 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 in 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 in SEQ ID NO:23, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:26.

[0126] In some embodiments, the 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 in SEQ ID NO:24, and a heavy chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in 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 in 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 in SEQ ID NO:25. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:24, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:25.

[0127] In some embodiments, the 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 in SEQ ID NO:24, and a heavy chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in 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 in 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 in 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 in SEQ ID NO:24, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:26.

[0128] MICA / B antibody Fc region

[0129] 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 herein by reference in its entirety. The Fc region may be a naturally occurring Fc region, or a modified Fc region as described in the art or elsewhere in the present invention.

[0130] Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD, 1991. The "Fc polypeptide" of the dimeric Fc used herein refers to one of the two polypeptides that form the dimeric Fc domain, i.e., a polypeptide comprising the C-terminal constant region of the immunoglobulin heavy chain, capable of stable self-association. For example, the Fc polypeptide of the dimeric IgG Fc comprises an IgG CH2 constant domain sequence and an IgG CH3 constant domain sequence. Fc can be IgA, IgD, IgE, IgG, and IgM classes, some of which can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0131] The terms "Fc receptor" and "FcR" are used to describe receptors that bind to the Fc region of an antibody. For example, FcR can be a human FcR of a native sequence. Typically, FcR is a receptor (a gamma receptor) that binds to IgG antibodies and includes FcγRI, FcγRII and FcγRIII subclass receptors, including allelic variants and alternative splicing forms of these receptors. FcγRII receptors include FcγRIIA (a "activating receptor") and FcγRIIB (a "inhibiting receptor"), which have similar amino acid sequences, mainly different in their cytoplasmic domains. Other isotypes of immunoglobulins can also bind to certain FcRs (see, e.g., Janeway et al., Immuno Biology: the immune system in health and disease, (ElsevierScience Ltd., NY) (4th edition, 1999)). The activating receptor FcγRIIA contains an immunoreceptor tyrosine activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain ( 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 Haas et al., J. Lab. Clin. Med. 126: 330-41 (1995). Other FcRs, including those identified as FcRs in the future, are encompassed by the term "FcR" in this application. The term also includes the neonatal receptor FcRn, which is responsible for 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)).

[0132] Modifications in the CH2 domain can affect the binding of FcR to Fc. Many amino acid modifications in the Fc region known in the art are used to selectively change the affinity of Fc for different Fcγ receptors. In some aspects, Fc comprises one or more modifications to promote selective binding of Fc-γ receptors. Listed below are exemplary mutations that alter FcR binding to Fc: 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 USA., 2006 Mar 14; 103(11): 4005-10); S239D / S267E, S267E / L328F (Chu SY, Vostiar et al., Proc Natl Acad Sci USA., 2006 Mar 14; 103(11): 4005-10); I, Karki S et al., Mol Immunol.2008Sep;45(15):3926-33),Ser298Ala / Glu333Ala / Lys334Ala,Ser239Asp / Ala330Leu / Ile332Glu,Ser239Asp / Il e332Glu、Gly236Ala / Ser239Asp / Ala330Leu / Ile332Glu、Gly236Ala、Leu234Tyr / Gly236Trp / Ser298Ala、Phe243Le u / Arg292Pro / Tyr300Leu / Val305Ile / Pro396Leu、Lys326Trp / Glu333Ser、Lys326Ala / Glu333Ala、Lys326Met / Glu3 33Ser, Cys221Asp / Asp222Cys, Ser267Glu / His268Phe / Ser324Thr, His268Phe / Ser324Thr, Glu345Arg and in (Saunders KO.Front Immunol.2019Jun 7; 10:1296); S239D / D265S / S298A / I332E, S239E / S298A / K326A / A327H, G237F / S298A / A330L / I332E, S239D / I332E / S298A, S239D / K326E / A330L / I332E / S29 8A, G236A / S239D / D270L / I332E, S239E / S267E / H268D, L234F / S267E / N325L, G237F / V266L / S267D and other mutations listed in WO2011 / 120134 and WO2011 / 120135, which patent applications are incorporated herein by reference. Therapeutic Antibody Engineering (William R. Strohl and Lila M. Strohl, Woodhead Publishing series in Biomedicine No 11, ISBN 1 907568 37 9, Oct 2012) lists mutations on page 283. .

[0133] In certain embodiments, the MICA / B antibodies disclosed herein comprise one or more mutations at amino acid positions in the Fc region, including mutations at amino acid positions 239 and / or 332 of the heavy chain. In certain embodiments, the MICA / B antibodies comprise S239D and / or I332E mutations. In some embodiments, the antibodies described herein comprise one or more modifications to improve their ability to mediate effector functions. Such modifications are known in the art and include defucosylation, or modification of the affinity of Fc for activating receptors (mainly FCGR3a, for ADCC) and for C1q (for CDC). Table B below summarizes various designs for effector function modification reported in the literature. Therefore, in an embodiment, the antibodies described herein may include a dimeric Fc comprising one or more amino acid modifications that confer improved effector functions as indicated in Table B.

[0134] Table B: CH2 domain and effector function modification

[0135]

[0136]

[0137] Fc modifications that reduce FcgR and / or complement binding and / or effector function are known in the art. Recent publications describe strategies for modifying antibodies to reduce or silence their effector activity (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 glycosylation modification, using IgG2 / IgG4 scaffolds, or introducing mutations in the hinge or CH2 region of Fc. For example, U.S. Patent Publication No. 2011 / 0212087 (Strohl), International Patent Publication No. WO 2006 / 105338 (Xencor), U.S. Patent Publication No. 2012 / 0225058 (Xencor), U.S. Patent Publication No. 2012 / 0251531 (Genentech), and Strop et al. ((2012) J. Mol. Biol. 420:204-219) describe specific modifications that reduce binding of FcgR or complement to Fc.

[0138] Specific, non-limiting examples of amino acid modifications known to reduce FcgR or complement binding to Fc include those identified below in Table C:

[0139] Table C: Modifications that reduce FcgR or complement binding to Fc

[0140]

[0141]

[0142] Defucosylated MICA / B antibodies and MICA / B antibodies with reduced fucose content

[0143] It is reported that antibodies with reduced fucose content have increased affinity for Fc receptors (e.g., FcγRIIIa). Therefore, in certain embodiments, the anti-MICA / B antibodies or antigen-binding fragments thereof described herein have reduced fucose content or no fucose content. Such antibodies can be produced using techniques known to those skilled in the art. For example, the antibodies can be expressed in cells that are defective in fucosylation ability or lack fucosylation ability. In a specific example, a cell line in which both alleles of α1,6-fucosyltransferase are knocked out can be used to produce antibodies with reduced fucose content. POTELLIGENTR TM The Lonza system 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 with reduced or no fucose content can be produced by, for example: (i) culturing cells under conditions that prevent or reduce fucosylation; (ii) removing fucose after translation (e.g., using fucosidase); (iii) adding the desired carbohydrate after translation, for example, after recombinant expression of non-glycosylated glycoproteins; or (iv) purifying glycoproteins to select antibodies or antigen-binding fragments thereof that are not fucosylated. Methods for producing antibodies or antigen-binding fragments thereof with no or reduced fucose content are described, for example, Longmore G D & Schachter H (1982) Carbohydr Res 100: 365-92 and Imai-Nishiya H et al., (2007) BMC Biotechnol. 7: 84.

[0144] Methods for generating antibodies with 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 technology (ProBioGen AG) is based on introducing an enzyme gene into cells used to produce antibodies that deflects the cellular pathway for fucose biosynthesis. This prevents the antibody-producing cells from adding the sugar "fucose" to N-linked antibody sugar moieties (von Horsten et al. (2010) Glycobiology. 2010 Dec; 20(12): 1607-18). Another method of obtaining antibodies with lower levels of fucosylation is described in U.S. Pat. No. 8,409,572, which teaches selecting cell lines for antibody production for the ability of the cells to produce antibodies with lower levels of fucosylation, which antibodies may be completely defucosylated (meaning they contain no detectable fucose) or they may be partially defucosylated, meaning that the isolated antibodies contain 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 typically detected in similar antibodies produced by mammalian expression systems. In embodiments, the antibodies may be defucosylated to improve effector function.

[0145] Methods for generating antibodies with 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 technology (ProBioGen AG) is based on introducing an enzyme gene into cells used to produce antibodies that deflects the cellular pathway for fucose biosynthesis. This prevents the antibody-producing cells from adding the sugar "fucose" to N-linked antibody sugar moieties (von Horsten et al. (2010) Glycobiology. 2010 Dec; 20(12): 1607-18). Examples of cell lines capable of producing defucosylated antibodies include: CHO-DG44, which stably overexpresses the bacterial oxidoreductase GDP-6-deoxy-D-lyso-4-hexulose reductase (RMD) (see Henning von Horsten et al., Glycobiol 2010, 20: 1607-1618); or Lec13 CHO cells, which lack protein fucosylation (see Ripka et al., Arch. Biochem. Biophys., 1986, 249: 533-545; U.S. Patent Publication No. 2003 / 0157108; WO 2003 / 0157109). 2004 / 056312; each of which is incorporated by reference in its entirety); and knockout cell lines, such as CHO cells knocked out for the α-1,6-fucosyltransferase gene or FUT8 (see Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87:614-622; Kanda et al., Biotechnol. Bioeng., 2006, 94:680-688; and WO 2003 / 085107; each of which is incorporated by reference in its entirety). Another method for obtaining antibodies with lower levels of fucosylation can be found in U.S. Pat. No. 8,409,572, which teaches selecting cell lines for antibody production based on the ability of the cells to produce antibodies with lower levels of fucosylation.

[0146] Examples of cell lines capable of producing defucosylated antibodies include: CHO-DG44, which stably overexpresses the bacterial oxidoreductase GDP-6-deoxy-D-lyso-4-hexulose reductase (RMD) (see Henning von Horsten et al., Glycobiol 2010, 20: 1607-1618); or Lec13 CHO cells, which lack protein fucosylation (see Ripka et al., Arch. Biochem. Biophys., 1986, 249: 533-545; U.S. Patent Publication No. 2003 / 0157108; WO 2003 / 0157109). 2004 / 056312; each of which is incorporated by reference in its entirety); and knockout cell lines, such as CHO cells in which the α-1,6-fucosyltransferase gene or FUT8 is knocked out (see Yamane-Ohnuki et al., Biotech. Bioeng., 2004, 87:614-622; Kanda et al., Biotechnol. Bioeng., 2006, 94:680-688; and WO 2003 / 085107; each of which is incorporated by reference in its entirety).

[0147] The antibodies may be completely defucosylated (meaning that they contain no detectable fucose) or they may be partially defucosylated, meaning 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 in similar antibodies produced in mammalian expression systems.

[0148] In some aspects, the antibodies provided herein comprise an IgG1 domain having reduced fucose content at position Asn 297 compared to a naturally occurring IgG1 domain. Such Fc domains are known to have improved ADCC. See Shields et al., J. Biol. Chem., 2002, 277: 26733-26740, which is incorporated by reference in its entirety. In some aspects, such antibodies do not comprise any fucose at position Asn 297. The amount of fucose can be determined using any suitable method, such as the method described in WO 2008 / 077546, which is incorporated by reference in its entirety.

[0149] MICA / B antibody variable domain

[0150] The present application discloses an antibody that specifically binds to MICA / B, the antibody having a light chain comprising a light chain variable domain (VL). 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 in 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 in 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 in SEQ ID NO:7, SEQ ID NO:15, or SEQ ID NO:19.

[0151] The present application further discloses an antibody that specifically binds to MICA / B, the antibody having a heavy chain comprising a heavy chain variable domain (VH). 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 in 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 in 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 in SEQ ID NO:8, SEQ ID NO:16, or SEQ ID NO:20.

[0152] The present application also discloses an antibody comprising a light chain variable domain (VL) and a heavy chain variable domain (VH) that binds to MICA / B. 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 in 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 in 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 set forth in 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 set forth in 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 in 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 in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:20.

[0153] In some embodiments, the 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 in SEQ ID NO:7, and a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in 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 in 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 in SEQ ID NO:8. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:7, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:8.

[0154] In some embodiments, the 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 in SEQ ID NO:15, and a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in 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 in 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 in SEQ ID NO:16. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:15, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:16.

[0155] In some embodiments, the 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 in 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 in 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 in 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 in SEQ ID NO:20. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:19, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:20.

[0156] MICA / B antibody complementarity determining region

[0157] The present application discloses antibodies that specifically bind to MICA / B, the antibodies having a light chain comprising a light chain complementary determining region (CDR). In some embodiments, the antibodies that bind to MICA / B comprise 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 in SEQ ID NOs: 1-3, 9-11, and 17. In some embodiments, the antibodies that bind to MICA / B comprise 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 in 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 in SEQ ID NOs: 1-3, 9-11, and 17.

[0158] The present application further discloses an antibody that specifically binds to MICA / B, the antibody having a heavy chain comprising a heavy chain complementary determining region (CDR). 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 in 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 in 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 in SEQ ID NOs:4-6, 12-14, and 18.

[0159] The present application also discloses an antibody that specifically binds to MICA / B, the antibody comprising a light chain complementary determining region (CDR) and a heavy chain complementary determining region (CDR). 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 in 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 shown in 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 in SEQ ID NOs: 1-3, 9-11, and 17, and 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 in 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 in SEQ ID NOs: 1-3, 9-11, and 17, and 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 in SEQ ID NOs: 4-6, 12-14, and 18.

[0160] In some embodiments, an antibody that binds to MICA / B comprises a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), a light chain complementary determining region 3 (CDR3), a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has 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, the light chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, the light chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 13. The heavy chain complementarity determining region 3 (CDR3) has an amino acid sequence at least about 70% identical to one of SEQ ID NO:5, SEQ ID NO:13 or SEQ ID NO:18, and the heavy chain complementarity determining region 3 (CDR3) has an amino acid sequence at least about 70% identical to one of SEQ ID NO:6 or SEQ ID NO:14.In some embodiments, an antibody that binds to MICA / B comprises a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), a light chain complementary determining region 3 (CDR3), a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) 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 one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, and the light chain complementary determining region 2 (CDR2) 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 one of SEQ ID NO: 2, SEQ ID NO: 9, or SEQ ID NO: 17. %, 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:10, the light chain complementary determining region 3 (CDR3) having 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 one of SEQ ID NO:3 or SEQ ID NO:11, the heavy chain complementary determining region 1 (CDR1) having 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 one of SEQ ID NO:4 or SEQ ID NO:5 NO:12, the heavy chain complementary 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, the heavy chain complementary 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:7. : The amino acid sequence of one of NO:14 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.In some embodiments, an antibody that binds to MICA / B comprises a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), a light chain complementary determining region 3 (CDR3), a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence that is 100% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence that is 100% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, the light chain complementary determining region 3 (CDR3) has an amino acid sequence that is 100% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence that is 100% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence that is 100% identical to one of SEQ ID NO: 13. NO:5, SEQ ID NO:13 or SEQ ID NO:18, and the heavy chain complementarity determining region 3 (CDR3) has 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, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:1, the light chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:2, and the light chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:3. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 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 of SEQ ID NO:1, and the light chain CDR2 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 of SEQ ID NO:1. NO:2 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 in SEQ ID NO:2, and the light chain CDR3 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 in SEQ ID NO:3. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:1, the light chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:2, and the light chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:3.

[0162] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:9, the light chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:10, and the light chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:11. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 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 of SEQ ID NO:9, and the light chain CDR2 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 of SEQ ID NO:9. NO:10 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 of SEQ ID NO:10, and the light chain CDR3 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 of SEQ ID NO:11. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:9, the light chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:10, and the light chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:11.

[0163] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:17, the light chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:2, and the light chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:3. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 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 of SEQ ID NO:17, and the light chain CDR2 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 of SEQ ID NO:17. NO:2 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 in SEQ ID NO:2, and the light chain CDR3 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 in SEQ ID NO:3. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:17, the light chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:2, and the light chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:3.

[0164] In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:4, the heavy chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:5, and the heavy chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:6. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 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 of SEQ ID NO:4, and the heavy chain CDR2 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 of SEQ ID NO:4. NO:5 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 of SEQ ID NO:5, and the heavy chain CDR3 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 of SEQ ID NO:6. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:4, the heavy chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:5, and the heavy chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:6.

[0165] In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:12, the heavy chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:13, and the heavy chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:14. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 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 of SEQ ID NO: 12, and the heavy chain CDR2 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 of SEQ ID NO: 12. NO:13 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 of SEQ ID NO:13, and the heavy chain CDR3 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 of SEQ ID NO:14. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:12, the heavy chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:13, and the heavy chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:14.

[0166] In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:4, the heavy chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:18, and the heavy chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:6. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 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 of SEQ ID NO:4, and the heavy chain CDR2 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 of SEQ ID NO:4. NO:18 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 of SEQ ID NO:18, and the heavy chain CDR3 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 of SEQ ID NO:6. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:4, the heavy chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:18, and the heavy chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:6.

[0167] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:1, the light chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:2, the light chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:3, the heavy chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:4, the heavy chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:5, and the heavy chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:6.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 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 of SEQ ID NO:1, and the light chain CDR2 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 of SEQ ID NO:1. NO:2 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 of SEQ ID NO:2, the light chain CDR3 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 of SEQ ID NO:3, and the heavy chain CDR1 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 of SEQ ID NO: NO:4 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 of SEQ ID NO:4, the heavy chain CDR2 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 of SEQ ID NO:5, the heavy chain CDR3 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 of SEQ ID NO:5 The amino acid sequence shown in NO:6 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.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:1, the light chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:2, the light chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:3, the heavy chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:4, the heavy chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:5, and the heavy chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:6.

[0168] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:9, the light chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:10, the light chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:11, the heavy chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:12, the heavy chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:13, and the heavy chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:14.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 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 of SEQ ID NO:9, and the light chain CDR2 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 of SEQ ID NO:9. NO:10 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 of SEQ ID NO:11, the light chain CDR3 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 of SEQ ID NO:11, and the heavy chain CDR1 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 of SEQ ID NO:11 NO:12 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 of SEQ ID NO:13, the heavy chain CDR2 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 of SEQ ID NO:14, the heavy chain CDR3 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 of SEQ ID NO:15, The amino acid sequence shown in NO:14 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.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:9, the light chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:10, the light chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:11, the heavy chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:12, the heavy chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:13, and the heavy chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:14.

[0169] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:17, the light chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:2, the light chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:3, the heavy chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:4, the heavy chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:18, and the heavy chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:6.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 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 of SEQ ID NO:17, and the light chain CDR2 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 of SEQ ID NO:17. NO:2 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 of SEQ ID NO:2, the light chain CDR3 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 of SEQ ID NO:3, and the heavy chain CDR1 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 of SEQ ID NO: NO:4 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 of SEQ ID NO:4, the heavy chain CDR2 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 of SEQ ID NO:18, the heavy chain CDR3 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 of SEQ ID NO:19, The amino acid sequence shown in NO:6 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.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:17, the light chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:2, the light chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:3, the heavy chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:4, the heavy chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:18, and the heavy chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in 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 following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY.

[0171] Competitive Binding

[0172] In some embodiments, the present application discloses an antibody that competitively binds to MICA / B with the following antibody: the antibody 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 in 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 in 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 in SEQ ID NO: 27.

[0173] In some embodiments, the present application discloses an antibody that competitively binds to MICA / B with the following antibody: the antibody comprises 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 in 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 in 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 in SEQ ID NO: 28.

[0174] In some embodiments, the present application discloses an antibody that competitively binds to MICA / B with the following antibody: the antibody comprises a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to the amino acid sequence shown in SEQ ID NO:27, and a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence shown in 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 in 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 in SEQ ID NO:28. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:27, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:28.

[0175] Treatment and use

[0176] The present application provides a method of treating cancer in an individual in need thereof, the method comprising administering an anti-MICA / B antibody disclosed herein.

[0177] The present application further provides a method of reducing or increasing the level of soluble MICA / B protein in an individual in need thereof, the method comprising administering an anti-MICA / B antibody disclosed herein.

[0178] The present application also provides a method for alleviating or inhibiting an immunosuppressive environment in an individual in need thereof by preventing, blocking or enhancing the interaction between soluble MICA / B and NKG2D receptor, the method comprising administering the anti-MICA / B antibody disclosed in the present application.

[0179] 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 in 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 in 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 in SEQ ID NOs: 1-3, 9-11, and 17.

[0180] 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 in 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 in 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 in SEQ ID NOs: 4-6, 12-14, and 18.

[0181] 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 in 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 in 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 in 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 in SEQ ID NOs: 4-6, 12-14, and 18. 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 in SEQ ID NOs: 1-3, 9-11, and 17, and 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 in SEQ ID NOs: 4-6, 12-14, and 18.

[0182] In some embodiments, an antibody that binds to MICA / B comprises a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), a light chain complementary determining region 3 (CDR3), a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has 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, the light chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, the light chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least about 70% identical to one of SEQ ID NO: 13. The heavy chain complementarity determining region 3 (CDR3) has an amino acid sequence at least about 70% identical to one of SEQ ID NO:5, SEQ ID NO:13 or SEQ ID NO:18, and the heavy chain complementarity determining region 3 (CDR3) has an amino acid sequence at least about 70% identical to one of SEQ ID NO:6 or SEQ ID NO:14.In some embodiments, an antibody that binds to MICA / B comprises a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), a light chain complementary determining region 3 (CDR3), a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) 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 one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, and the light chain complementary determining region 2 (CDR2) 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 one of SEQ ID NO: 2, SEQ ID NO: 9, or SEQ ID NO: 17. %, 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:10, the light chain complementary determining region 3 (CDR3) having 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 one of SEQ ID NO:3 or SEQ ID NO:11, the heavy chain complementary determining region 1 (CDR1) having 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 one of SEQ ID NO:4 or SEQ ID NO:5 NO:12, the heavy chain complementary 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, the heavy chain complementary 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:13, : The amino acid sequence of one of NO:14 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.In some embodiments, an antibody that binds to MICA / B comprises a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), a light chain complementary determining region 3 (CDR3), a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence that is 100% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence that is 100% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, the light chain complementary determining region 3 (CDR3) has an amino acid sequence that is 100% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence that is 100% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence that is 100% identical to one of SEQ ID NO: 13. NO:5, SEQ ID NO:13 or SEQ ID NO:18, and the heavy chain complementarity determining region 3 (CDR3) has an amino acid sequence that is 100% identical to one of SEQ ID NO:6 or SEQ ID NO:14.

[0183] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:1, the light chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:2, and the light chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:3. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 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 of SEQ ID NO:1, and the light chain CDR2 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 of SEQ ID NO:1. NO:2 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 in SEQ ID NO:2, and the light chain CDR3 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 in SEQ ID NO:3. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:1, the light chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:2, and the light chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:3.

[0184] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:9, the light chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:10, and the light chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:11. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 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 of SEQ ID NO:9, and the light chain CDR2 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 of SEQ ID NO:9. NO:10 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 of SEQ ID NO:10, and the light chain CDR3 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 of SEQ ID NO:11. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:9, the light chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:10, and the light chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:11.

[0185] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:17, the light chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:2, and the light chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:3. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 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 of SEQ ID NO:17, and the light chain CDR2 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 of SEQ ID NO:17. NO:2 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 in SEQ ID NO:2, and the light chain CDR3 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 in SEQ ID NO:3. In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, and a light chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:17, the light chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:2, and the light chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:3.

[0186] In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:4, the heavy chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:5, and the heavy chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:6. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 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 of SEQ ID NO:4, and the heavy chain CDR2 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 of SEQ ID NO:4. NO:5 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 of SEQ ID NO:5, and the heavy chain CDR3 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 of SEQ ID NO:6. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:4, the heavy chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:5, and the heavy chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:6.

[0187] In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:12, the heavy chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:13, and the heavy chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:14. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 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 of SEQ ID NO: 12, and the heavy chain CDR2 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 of SEQ ID NO: 12. NO:13 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 of SEQ ID NO:13, and the heavy chain CDR3 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 of SEQ ID NO:14. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:12, the heavy chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:13, and the heavy chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:14.

[0188] In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:4, the heavy chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:18, and the heavy chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:6. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 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 of SEQ ID NO:4, and the heavy chain CDR2 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 of SEQ ID NO:4. NO:18 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 of SEQ ID NO:18, and the heavy chain CDR3 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 of SEQ ID NO:6. In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the heavy chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:4, the heavy chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:18, and the heavy chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:6.

[0189] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:1, the light chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:2, the light chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:3, the heavy chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:4, the heavy chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:5, and the heavy chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:6.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 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 of SEQ ID NO:1, and the light chain CDR2 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 of SEQ ID NO:1. NO:2 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 of SEQ ID NO:2, the light chain CDR3 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 of SEQ ID NO:3, and the heavy chain CDR1 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 of SEQ ID NO: NO:4 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 of SEQ ID NO:4, the heavy chain CDR2 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 of SEQ ID NO:5, the heavy chain CDR3 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 of SEQ ID NO:5 The amino acid sequence shown in NO:6 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.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:1, the light chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:2, the light chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:3, the heavy chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:4, the heavy chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:5, and the heavy chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:6.

[0190] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:9, the light chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:10, the light chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:11, the heavy chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:12, the heavy chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:13, and the heavy chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:14.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 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 of SEQ ID NO:9, and the light chain CDR2 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 of SEQ ID NO:9. NO:10 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 of SEQ ID NO:11, the light chain CDR3 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 of SEQ ID NO:11, and the heavy chain CDR1 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 of SEQ ID NO:11 NO:12 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 of SEQ ID NO:13, the heavy chain CDR2 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 of SEQ ID NO:14, the heavy chain CDR3 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 of SEQ ID NO:15, The amino acid sequence shown in NO:14 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.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:9, the light chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:10, the light chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:11, the heavy chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:12, the heavy chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:13, and the heavy chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:14.

[0191] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:17, the light chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:2, the light chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:3, the heavy chain CDR1 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:4, the heavy chain CDR2 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:18, and the heavy chain CDR3 has an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:6.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 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 of SEQ ID NO:17, and the light chain CDR2 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 of SEQ ID NO:17. NO:2 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 of SEQ ID NO:2, the light chain CDR3 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 of SEQ ID NO:3, and the heavy chain CDR1 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 of SEQ ID NO: NO:4 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 of SEQ ID NO:4, the heavy chain CDR2 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 of SEQ ID NO:18, the heavy chain CDR3 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 of SEQ ID NO:19, The amino acid sequence shown in NO:6 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.In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1, a light chain CDR2, a light chain CDR3, a heavy chain CDR1, a heavy chain CDR2, and a heavy chain CDR3, wherein the light chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:17, the light chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:2, the light chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:3, the heavy chain CDR1 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:4, the heavy chain CDR2 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:18, and the heavy chain CDR3 has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:6.

[0192] In some embodiments, the antibody that binds to MICA / B does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY.

[0193] In some embodiments, an 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 in 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 set forth in 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 set forth in SEQ ID NO:7, SEQ ID NO:15, or SEQ ID NO:19.

[0194] In some embodiments, an 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 set forth in 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 set forth in 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 set forth in SEQ ID NO:8, SEQ ID NO:16, or SEQ ID NO:20.

[0195] In some embodiments, the 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 in SEQ ID NO:7, SEQ ID NO:15, or SEQ ID NO:19, and the antibody that binds to 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 in 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 set forth in 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 set forth in 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 in 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 in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:20.

[0196] In some embodiments, the 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 in SEQ ID NO:7, and a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in 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 in 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 in SEQ ID NO:8. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:7, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:8.

[0197] In some embodiments, the 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 in SEQ ID NO:15, and a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in 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 in 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 in SEQ ID NO:16. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:15, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:16.

[0198] In some embodiments, the 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 in 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 in 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 in 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 in SEQ ID NO:20. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:19, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:20.

[0199] 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 in 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 in 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 in SEQ ID NO:21, SEQ ID NO:23, or SEQ ID NO:24.

[0200] 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 in 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 in 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 in SEQ ID NO:22, SEQ ID NO:25, or SEQ ID NO:26.

[0201] The present application also discloses an antibody comprising a light chain and a heavy chain that specifically binds to MICA / B. 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 shown in 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 in 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 in 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 in 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 in 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 in SEQ ID NO:22, SEQ ID NO:25, or SEQ ID NO:26.

[0202] In some embodiments, the 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 in 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 in 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 in 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 in SEQ ID NO:22. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:21, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:22.

[0203] In some embodiments, the 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 in 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 in 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 in 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 in SEQ ID NO:25. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:23, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:25.

[0204] In some embodiments, the 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 in 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 in 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 in 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 in 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 in SEQ ID NO:23, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:26.

[0205] In some embodiments, the 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 in SEQ ID NO:24, and a heavy chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in 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 in 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 in SEQ ID NO:25. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:24, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:25.

[0206] In some embodiments, the 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 in SEQ ID NO:24, and a heavy chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in 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 in 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 in 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 in SEQ ID NO:24, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:26.

[0207] In some embodiments, the antibody that competes for binding to MICA / B with the following antibody: the antibody 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 in 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 in 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 in SEQ ID NO: 27.

[0208] In some embodiments, the antibody that competes for binding to MICA / B with the following antibody: the antibody comprises 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 in 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 in 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 in SEQ ID NO: 28.

[0209] In some embodiments, the antibody competes for binding to MICA / B with the following antibody: the antibody comprises a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to the amino acid sequence shown in SEQ ID NO:27, and a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence shown in 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 in 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 in SEQ ID NO:28. In some embodiments, the VL has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:27, and the VH has an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:28.

[0210] 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 α-3 domain of the MICA protein. In some embodiments, the antibody binds to the α-3 domain of the MICB protein. In some embodiments, the antibody binds to the α-3 domain of both the MICA protein and the MICB protein. In some embodiments, the MICA protein bound by the antibody is a membrane-bound MICA protein. In some embodiments, the MICA protein bound by the antibody is a soluble MICA protein. In some embodiments, the MICA protein bound by the antibody is both a membrane-bound MICA protein and a soluble MICA protein. In some embodiments, the MICB protein bound by the antibody is a membrane-bound MICB protein. In some embodiments, the MICB protein bound by the antibody is a soluble MICB protein. In some embodiments, the MICB protein bound by the antibody is both a membrane-bound MICB protein and a soluble MICB protein.

[0211] In some embodiments, the antibody that specifically binds to MICA / B is a monoclonal antibody. In some embodiments, the antibody is an antigen binding fragment. In some embodiments, the antibody is selected from a whole immunoglobulin, scFv, Fab, F(ab')2, or a disulfide bonded Fv. In some embodiments, the antibody is an IgG or IgM. In some embodiments, the antibody is humanized. In some embodiments, the antibody is chimeric.

[0212] In some embodiments, the antibodies disclosed herein reduce the level of soluble MICA proteins. In some embodiments, the antibodies disclosed herein reduce the level of soluble MICB proteins. In some embodiments, the antibodies disclosed herein reduce the levels of soluble MICA proteins and soluble MICB proteins. In some embodiments, the antibodies disclosed herein reduce the shedding of soluble MICA proteins. In some embodiments, the antibodies disclosed herein reduce the shedding of soluble MICB proteins. In some embodiments, the antibodies disclosed herein reduce the shedding of soluble MICA proteins and soluble MICB proteins. In some embodiments, the antibodies disclosed herein inhibit the shedding of soluble MICA proteins. In some embodiments, the antibodies disclosed herein inhibit the shedding of soluble MICB proteins. In some embodiments, the antibodies disclosed herein inhibit the shedding of soluble MICA proteins and soluble MICB proteins.

[0213] 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 MICA protein and MICB protein. In some embodiments, the antibodies disclosed herein reduce the shedding of MICA protein. In some embodiments, the antibodies disclosed herein reduce the shedding of MICB protein. In some embodiments, the antibodies disclosed herein reduce the shedding of MICA protein and MICB protein. In some embodiments, the antibodies disclosed herein inhibit the shedding of soluble MICA protein. In some embodiments, the antibodies disclosed herein inhibit the shedding of soluble MICB protein. In some embodiments, the antibodies disclosed herein inhibit the shedding of soluble MICA protein and soluble MICB protein.

[0214] Any suitable route of administration for the methods disclosed herein is contemplated. In some embodiments, the antibody is administered intravenously. In some embodiments, the antibody is administered subcutaneously. In some embodiments, the antibody is administered topically. 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 an ointment, lotion, or emulsion. In some embodiments, the antibody is formulated as a solution. In some embodiments, the antibody is formulated for topical, oral, oral, or nasal administration.

[0215] In some embodiments, the individual is monitored before the antibody is administered. Symptoms are identified and their severity is assessed. Antibodies as described herein are administered alone or in combination with other treatments, as discussed herein or known to those skilled in the art, in single or multiple administrations over time. In some embodiments, the individual is monitored to determine the effectiveness of the treatment regimen. In some embodiments, the treatment regimen is modified based on preliminary treatment results so that the dosage or frequency or dosage and frequency of the treatment are changed to achieve the desired subject response level based on symptom relief, side effect relief, or a combination of symptom relief and side effect relief.

[0216] A therapeutically effective amount or dose is contemplated to include a dose 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 3.4 mg / kg about 3.3mg / kg, about 3.4mg / kg, about 3.5mg / kg, about 3.6mg / kg, about 3.7mg / kg, about 3.8mg / kg, about 3.9mg / kg, about 4mg / kg, about 4.1mg / kg, about 4.2mg / kg, about 4.3mg / kg, about 4.4mg / kg, about 4.5mg / kg, about 4.6mg / kg, about 4.7mg / kg, about 4.8mg / kg, about 4.9mg / kg, about 5mg / kg, about 5.1mg / kg, about 5.2mg / kg, about 5.3mg / kg, about 5.4mg / kg, about 5.5mg / kg, about 5.6mg / kg, about 5.7mg / kg, about 5.8mg / kg, about 5.9mg / kg, about 6mg / kg, about 6.1mg / kg, about 6.2mg / kg, about 6.3mg / kg, about 6.4mg / kg, about 6.5mg / kg, about 6.6mg / kg, about 6.7mg / kg, about 6.8mg / kg, about 6.9mg / kg, about 7mg / kg, about 7.1mg / kg, about 7.2mg / kg, about 7.3mg / kg, about 7.4mg / kg, about 7.5mg / kg, about 7.6mg / kg, about 7.7mg / kg, about 7.8mg / kg, about 7.9mg / kg, about 8mg / kg, about 8.1mg / kg, about 8.2mg / kg, about 8.3mg / kg, about 8.4mg / kg, about 8.5mg / kg, about 8.6mg / 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 11. 0.2mg / 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 13.4mg / kg, about 13.5mg / kg, about 13.6mg / kg, about 13.7mg / kg, about 13.8mg / kg, about 13.9mg / kg, about 14mg / kg, about 14.1mg / kg, about 14.2mg / kg, about 14.3mg / kg, about 14 .4mg / kg, about 14.5mg / kg, about 14.6mg / kg, about 14.7mg / kg, about 14.8mg / kg, about 14.9mg / kg, about 15mg / kg, about 15.1mg / kg, about 15.2mg / kg, about 15.3mg / kg, about 15.4mg / kg, about 15.5mg / kg, about 15.6mg / kg, about 15.7mg / kg, about 15.8mg / kg, about 15.9mg / kg, about 16mg / kg, about 16.1mg / kg, about 16.2mg / kg, about 16.3mg / kg, about 16.4mg / kg, about 16.5mg / kg, about 16.6mg / kg, about 16.7mg / kg, about 16.8mg / kg, about 16.9mg / kg, about 17mg / kg, about 17.1mg / kg, about 17.2mg / kg, about 17.3mg / kg, about 17.4mg / kg, about 17.5mg / kg, about 17.6mg / kg, about 17.7mg / kg, about 17.8mg / kg, about 17.9mg / kg, about 18mg / kg, about 18.1mg / kg, about 18.2mg / kg, about In some cases, a therapeutically effective amount or dose is contemplated to include a dose of about 0.1 mg / kg to about 2.0 mg / kg. .

[0217] The treatment methods of the present application include one or more administrations of anti-MICA / B antibodies at a dosage disclosed herein. In some embodiments, the method includes one administration of anti-MICA / B antibodies. In some embodiments, the method includes two administrations of anti-MICA / B antibodies. In some embodiments, the method includes three administrations of anti-MICA / B antibodies. In some embodiments, the method includes four administrations of anti-MICA / B antibodies. In some embodiments, the method includes five administrations of anti-MICA / B antibodies. In some embodiments, the method includes six administrations of anti-MICA / B antibodies. In some embodiments, one or more administrations of anti-MICA / B antibodies are implemented every day. In some embodiments, one or more administrations of anti-MICA / B antibodies are implemented weekly. In some embodiments, one or more administrations of anti-MICA / B antibodies are implemented every two weeks. In some embodiments, one or more administrations of anti-MICA / B antibodies are implemented every three weeks. In some embodiments, one or more administrations of anti-MICA / B antibodies are implemented monthly. In some embodiments, one or more administrations of anti-MICA / B antibodies are implemented 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.

[0218] In some embodiments, the treatment method disclosed in the present application is monotherapy. In some embodiments, the treatment method disclosed in the present application is combination therapy. In some embodiments, combination therapy includes anti-MICA / B antibodies and other therapeutic agents. In some embodiments, the therapeutic agent includes a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent includes but is not limited to: cytotoxic agents, antimetabolites (e.g., folic acid antagonists, purine analogs, pyrimidine analogs, etc.), topoisomerase inhibitors (e.g., camptothecin derivatives, anthracene dione, anthracycline antibiotics, epipodophyllotoxins, quinoline alkaloids, etc.), anti-microtubule agents (e.g., taxanes, vinca alkaloids), protein synthesis inhibitors (e.g., cephalotaxine, camptothecin derivatives, quinoline alkaloids), alkylating agents (e.g., alkyl sulfonates, ethyleneimine, nitrogen mustard, nitrosoureas, platinum derivatives, triazenes, etc.), alkaloids, terpenes, kinase inhibitors and immune checkpoint inhibitors. In some embodiments, the anti-MICA / B antibodies disclosed in the present application are administered in combination with therapeutic agents that induce immune responses. In some embodiments, the anti-MICA / B antibodies disclosed herein are administered in combination with therapeutic agents that inhibit immune response downregulation. 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, the immune checkpoint inhibitor target includes PD-1. In some embodiments, the immune checkpoint inhibitor target includes PD-L1. In some embodiments, the immune checkpoint inhibitor includes pembrolizumab, nivolumab, cemiplizumab, AMP-224, AMP-514, PDR001, atezolizumab, avelumab, durvalumab (Durvalumab), BMS-936559 and CK-301. In certain embodiments, the anti-MICA / B antibodies described in the present application are administered in combination with radiotherapy. In certain embodiments, the anti-MICA / B antibodies described in the present application are administered in combination with one or more cell therapies.

[0219] Pharmaceutical composition

[0220] The present application also discloses a pharmaceutical composition comprising the anti-MICA / B antibody disclosed in the present application and a pharmaceutically acceptable carrier or excipient.

[0221] In some embodiments, excipients 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.

[0222] In some embodiments, the composition further comprises another therapeutic agent. In some embodiments, the therapeutic agent is a chemotherapeutic agent. The chemotherapeutic agent may include a cytotoxic agent, an antimetabolite (e.g., a folic acid antagonist, a purine analog, a pyrimidine analog, etc.), a topoisomerase inhibitor (e.g., a camptothecin derivative, anthracenedione, anthracycline antibiotics, epipodophyllotoxins, quinoline alkaloids, etc.), an antimicrotubule agent (e.g., a taxane, a vinca alkaloid), a protein synthesis inhibitor (e.g., a cephalotaxine, a camptothecin derivative, a quinoline alkaloid), an alkylating agent (e.g., an alkyl sulfonate, ethyleneimine, a nitrogen mustard, a nitrosourea, a platinum derivative, a triazene, etc.), an alkaloid, a terpenoid, a kinase inhibitor, etc.

[0223] 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 before the administration of other therapeutic agents. In some embodiments, the antibodies described herein are used simultaneously with the administration of other therapeutic agents. In some embodiments, the antibodies described herein are used after the administration of other therapeutic agents.

[0224] In some embodiments, pharmaceutical preparation is made to be compatible with specific local, regional or systemic administration or delivery route.Therefore, pharmaceutical preparation comprises carrier, diluent or excipient suitable for being used by specific approach.The specific non-limiting example for the route of administration of the composition of the application is parenteral, such as intravenous, intraarterial, intradermal, intramuscular, subcutaneous, intrapleural, percutaneous (topical), through mucosa, intracranial, intraspinal, intraocular, rectal, oral (digestion), mucosal administration, and any other preparation applicable to the method for treating or applying experimental scheme.

[0225] In some embodiments, solutions or suspensions for parenteral administration include: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerol, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfate; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and agents for adjusting tonicity such as sodium chloride or dextrose. In some embodiments, the pH is adjusted with an acid or base (e.g., hydrochloric acid or sodium hydroxide).

[0226] Pharmaceutical preparations for injection include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL TM(BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In some embodiments, the carrier is a solvent or dispersion medium containing, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), or a suitable mixture thereof. In some embodiments, fluidity is maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the case of a dispersant, and by using a surfactant. Antibacterial and antifungal agents include, for example, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In some embodiments, an isotonic agent (e.g., sugar; a polyol such as mannitol or sorbitol; or sodium chloride) is included in the composition. In some cases, an agent that delays absorption is also included, in some embodiments, for example, aluminum monostearate or gelatin prolongs the absorption of the injectable composition.

[0227] In some embodiments, the sterile injection formulation is prepared by mixing the required amount of the active composition in an appropriate solvent with one or a combination of the above ingredients. Typically, the dispersion is prepared by incorporating the active composition into a sterile vehicle containing an alkaline dispersion medium and any other ingredients. For sterile powders for preparing sterile injection solutions, preparation methods include, for example, vacuum drying and freeze drying, which produce a powder of the active ingredient and any additional desired ingredients from a previously prepared solution.

[0228] For transmucosal or transdermal administration, penetrants suitable for the barrier to be penetrated are used in the formulation. Such penetrants are known in the art and include, for example, for transmucosal administration, detergents, bile salts and fusidic acid derivatives. In some embodiments, transmucosal administration is accomplished by using nasal sprays, inhalation devices (e.g., aspirators) or suppositories. For transdermal administration, the active compound is formulated into an ointment, salves, gels, creams or patches.

[0229] In some embodiments, the pharmaceutical preparations are prepared with carriers that prevent rapid elimination from the body, such as controlled release formulations or time-delay materials, such as glyceryl monostearate or glyceryl stearate. In some embodiments, the preparations are also delivered using preparations such as implants and microencapsulated delivery systems to achieve local, regional or systemic delivery or controlled or sustained release.

[0230] Example

[0231] The following examples are for the purpose of illustrating various embodiments of the present invention and are not intended to limit the present invention in any way. These examples and the methods described in this application currently represent preferred embodiments, are exemplary, and are not intended to be limiting of the scope of the present invention. Other uses encompassed by the spirit of the present invention as defined by the variations and claims will occur to those skilled in the art.

[0232] Example 1. Antibody Binding Kinetics Measurement

[0233] Affinity kinetics were determined on a ForteBio Octet Red96 analyzer. Briefly, the affinity kinetics were determined at room temperature in an assay buffer of PBS + 0.1% BSA + 0.02% Tween-20 (pH 7.2) at Dip and Read TM Anti-MICA / B mAb (30 μg / ml) was captured on an anti-mouse IgG Fc capture (AMC) biosensor (ForteBio). The sensor was washed in assay buffer and then incubated with purified 6xHis-MICA*08 or 6xHis-MICA*04 protein (100 nM) in a 2-fold dilution series in assay buffer for 5 minutes to determine the association kinetics of the antibody to the protein antigen. The sensor was then incubated in assay buffer for 10 minutes to determine the dissociation kinetics. The resulting kinetic parameters were calculated using the 1:1 model using ForteBio Analysis Suite 8.0. The results of these assays are shown in Table 2.

[0234] Table 2. Kinetic measurements of anti-MICA / B antibodies and MICA antigen by biofilm interferometry.

[0235] Antibody KD(M) kon(1 / Ms) kdis(1 / s) 3F9.E4 1.18E-09 3.83E+05 4.21E-04 16F10.C12 6.45E-09 9.33E+04 5.48E-04

[0236] Example 2. Binding of Antibodies to MICA / B Alleles

[0237] 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 on high-binding 96-well microplates (Corning #9018) at 100 ng per well in 100 μl. The next morning, the coated ELISA plates were washed three times with TBS-Tween-20 (pH 7.4) and then blocked in SuperBlock T20 blocking buffer (Pierce #37536). After blocking, the ELISA plates were washed once with TBS-T and incubated with serially diluted anti-MICA antibodies (0-1 μg / ml) at room temperature for approximately two hours. After incubation, the ELISA plate was washed three times with TBS-T and then incubated with goat anti-mouse IgG (H+L)-HRP conjugate (ThermoFisher Scientific #626520) at room temperature with shaking (~400 rpm) for 45 minutes. After incubation, the ELISA plate was washed three times with TBS-T and incubated with ultrasensitive liquid substrate TMB (Sigma #T4444) with 100 μL per well until sufficient color development. The reaction was terminated with 1N sulfuric acid with 100 μL per well. The optical density (OD) value was measured at 450 nm using a microplate reader. The results of this assay are shown in Figure 1A-1B shown.

[0238] Example 3. Antibody Binding to Cell Surface MICA

[0239] Mouse prostate cancer TRAMP-C2 cells (TC2) (ATCC, Manassas, VA) were used to generate a stable cell line expressing the MICA*08 allele (TC2-MICA-08). The binding of anti-MICA antibodies to TC2-MICA-08 was analyzed by flow cytometry. Briefly, the cells were first stained with LIVE / DEAD near-infrared stain (Thermo) at 4°C for 30 minutes and then washed once by centrifugation with FACS buffer (1 mM EDTA, 25 mM HEPES, 2% FBS in 1X PBS solution). Approximately 2-3 × 10 5TC2-MICA-08 cells were incubated with 100 μl of FACS buffer containing 500 ng of anti-MICA antibody at 4°C for 30 min, followed by incubation with 100 μl of 2 μg / ml PE-conjugated goat anti-mouse IgG (Biolegend, San Diego, CA) secondary antibody at 4°C for 30 min. The cells were then washed once and the cell pellet was resuspended in FACS buffer for FACS analysis gated on live cells. A significantly higher PE fluorescence signal was observed for TC2-MICA-08 cells compared to parental TC2 cells, indicating that the anti-MICA mAb bound to surface-expressed MICA. The results of this assay are shown in Figure 2. Figure 2 shown.

[0240] Example 4. Antibodies inhibit MICA shedding in PLC / PRF / 5 cells

[0241] 4×10 4 PLC / PRF / 5 cells (hepatocellular carcinoma) (ATCC, Manassas, VA) were plated in 96-well plates and incubated overnight at 37°C. The cells were then treated with 100 μl of complete medium (MEM+10% FBS, Thermo, Grand Island, NY) containing anti-MICA antibodies that bind to the MICAα3 domain and negative control antibodies, respectively, and incubated for another day at 37°C. Cell supernatants containing shed MICA were used to determine soluble MICA levels by ELISA. Briefly, 96-well plates were coated with 100 μl of 2 μg / ml anti-human MICA / B (clone BAMO1, MBL, Japan) at 4°C overnight. The plates were blocked and then incubated with cell supernatants and MICA standards for 2 hours. After incubation, the plates were washed and then incubated with 1 μg / ml of proprietary biotin-conjugated anti-human MICA / MICB mAb clone 10E9 for 1 hour. Next, 100 μl of HRP-conjugated streptavidin (HRP-SA) (R&D Systems, Minneapolis, MN) was added to the wells and incubated for 30 minutes. Samples were developed with TMB for 4 minutes, terminated with 1N sulfuric acid, and detected by absorbance at 450 nm. Soluble MICA levels were interpolated from the standard curve. The results of this assay are shown in Figure 3 shown.

[0242] Example 5. Antibodies enhance NK-92 cell-mediated cytotoxicity against PLC / PRF / 5 cells

[0243] PLC / PRF / 5 cells (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 with anti-MICA antibodies (10 μg / ml) that bind to the MICA α3 domain for 24 hours and then labeled with Calcein AM (1 μM) for 3 hours at 37°C, 5% CO2. The wells were washed and NK-92 cells (effectors) suspended in RPMI-1640 containing 10% FBS were added to the wells at various effector: target (E:T) ratios as shown 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 multi-label microplate reader (Perkin Elmer). An isotype-matched non-reactive immunoglobulin (R&D) antibody was used as a control. The results of this assay are shown in Figure 2. Figure 4A-4B shown.

[0244] Example 6. Efficacy of 3F9.E4 on in vivo tumor therapy (survival rate) and NKG2D expression of tumor-infiltrating lymphocytes in tumor-bearing mice

[0245] Use 10 4 MICA transgenic mice (MICAgen) were inoculated with B16F10-MICA*01 cells (B16 transfectants), and on day 11, when tumors reached the desired threshold size, mice were treated with 3F9.E4 or isotype control (arrows indicate injection day) (log-rank test). Figure 5 shown.

[0246] When mice reached high tumor burden, they were sacrificed and tumor-infiltrating lymphocytes NK cells, CD8αβT cells, and γδT cells were analyzed for NKG2D expression (SFI). FIG. 6A to FIG. 6C Each symbol represents the analysis of a single mouse. (One-way ANOVA + Tukey's multiple comparison test).

[0247] Example 7. In vitro MICA expression in B16-transfected tumors and detection of soluble MICA in the serum of tumor-bearing mice

[0248] Use 10 4MICA transgenic mice (MICAgen) were inoculated with 10 B16F10-MICA*01 cells (B16 transfectants) and on day 11, when tumors reached the desired threshold size, mice were treated with 3F9.E4 or BAMO3 or isotype control. Mice were sacrificed when high tumor burden was reached and isolated single tumor cells were analyzed for MICA expression by staining with mAb AMO1 (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 a single mouse. The results are shown in Figure 7B As shown. The serum was also analyzed for sMICA using an AMO1 / BAMO1 sandwich ELISA. Each symbol represents the analysis of a single mouse (unpaired t-test). The results are shown in Fig. 7A shown.

[0249] Example 8. Epitope binning

[0250] MICA*04-His protein (30 μg / ml) was immobilized on the Ni-NTA (FortrBio, #18-5101) biosensor tip of the biofilm interferometry instrument (Octet Red, ForteBio) for 300 seconds. The baseline signal was measured again for 60 seconds, and then the biosensor tip was immersed in a well containing 1 mM or 0.5 mM primary antibody for 300 seconds. After this process, the biosensor was immersed in a well containing 100 nM or 50 nM second mAb for 300 seconds. The binding percentage of the second mAb in the presence of the first mAb was determined by comparing the maximum signal of the second mAb after adding the first mAb with the maximum signal of the second mAb alone. If the maximum binding of the second mAb is ≥66% of its uncompeted binding, the mAb is considered non-competitive. Levels of 33% to 66% of its uncompeted binding are considered moderately competitive, and ≤33% are considered competitive. The results of this assay are shown in FIG. 8A to FIG. 8C shown.

[0251] Example 9. Defining parameters for Fc-enhanced antibody binding to human Fcγ receptors

[0252] Binding of anti-MICA / B 3F9H1L3L antibodies to human Fcγ receptors was measured by Biacore, where the parameters for each Fcγ receptor tested in the Biacore analysis were as follows: Fig. 9 Trastuzumab was used as IgG1 control.

[0253] Example 10. Human Fcγ Receptor Binding

[0254] Fig.10The results of Biacore analysis are shown. For wild-type 3F9H1L3L antibody, defucosylated 3F9H1L3L (3F9H1L3L "GLYMAXX") and 3F9H1L3L with two heavy chain S239D and I332E mutations, their binding to FcγR1 is similar. Compared with wild-type antibody 3F9H1L3L, defucosylated 3F9H1L3L and 3F9H1L3L with two heavy chain S239D and I332E mutations have higher affinity for FcγRII and FcγRIII.

[0255] Example 11. Fc-enhanced binding of anti-MICA / B antibodies to FcRn

[0256] Binding of anti-MICA / B 3F9H1L3L antibody to human FcRn was measured by Biacore. Fig.11 Results of Biacore analysis are shown. Binding to FcRn at pH 6.0 was similar for wild-type 3F9H1L3L antibody, defucosylated 3F9H1L3L (3F9H1L3L "GLYMAXX"), and 3F9H1L3L with two heavy chain mutations S239D and I332E, and was pH-dependent.

[0257] Example 12. Fc-enhanced anti-MICA / B antibodies bind and stabilize MICA / B on the surface of cancer cells, similar to wild-type (WT) anti-MICA / B antibodies

[0258] 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 performed on day 1, and 20,000 cells were seeded in each well of a 96-well assay plate. The cells were incubated overnight at 37°C / 5% CO2. On day 2, cells were treated with a starting concentration of 10ug / mL and a 7-point 3-fold serial dilution of the test anti-MICA / B antibody. The cells were incubated for another 24 hours at 37°C / 5% CO2. On day 3, cells were collected in 96-well plates. Cells were washed and incubated with AlexaFluor 647 MICA / B diluted 1 / 50 in FACS buffer (PBS, 1% BSA, 0.1% NaN3) on ice for 30 minutes. Human IgG1 and Alexafluor 547 mouse IgG2aK isotype controls were included to confirm binding specificity. After 30 min, the cells were washed and fixed. Fluorescence was then measured using an Attune NxT Focus Cytometer (ThermoFisher). Fig.12These results demonstrate that Fc-enhanced anti-MICA / B antibodies bind and stabilize MICA / B on the surface of cancer cells, similar to wild-type (WT) anti-MICA / B antibodies.

[0259] Example 13. Fc-enhanced anti-MICA / B antibodies induce ADCC to a greater extent than wild-type anti-MICA / B antibodies

[0260] To confirm that Fc-enhanced anti-MICA / B antibodies can induce increased ADCC compared to wild-type or fucosylated MICA / B antibodies, the Promega ADCC Bioassay Complete Kit was used to measure ADCC of anti-MICA / B 3F9H1L3L antibody (CLN-619) using two target cell lines (HCC1534 cells expressing high levels of MICA and HCT-116 cells expressing low levels of MICA). Jurkat cells expressing the high affinity variant (V) or low affinity variant (F) of FcγRIIIa were added to target cells with anti-MICA / B 3F9H1L3L wild-type antibody (CLN-619), anti-MICA / B 3F9H1L3L defucosylated antibody ("GLYMAXX"), and anti-MICA / B 3F9H1L3L antibody with two heavy chain S239D and I332E mutations ("CLN-619DM") and incubated for 6 hours. After 6 hours, luminescence ( Fig.13 Under all conditions tested, anti-MICA / B antibodies with enhanced effector function resulted in significantly more ADCC in both cell lines compared to wild-type anti-MICA / B antibodies when cells were co-incubated with Jurkat cells expressing either the high-affinity variant or the low-affinity variant of FcγRIIIa.

[0261] The ability of Fc-enhanced anti-MICA / B antibodies to induce cell killing was also determined. Fast red dye was used to label HCT-116 target cells. Cells were seeded at 5000 cells / well in black clear bottom 96-well plates. Target cells were incubated at 37°C / 5% CO2 for 24 hours. On day 3, NKG2D expressing effector cells were seeded onto target cells at a 40:1 effector:target ratio. Co-cultures were incubated in medium containing Cytotox green dye at a final assay concentration of 0.25 μM to monitor cell killing. The live cell imaging system measured fluorescence every 30 min for 24 h to monitor cell killing. Fig.14It is shown that incubation of HCT-116 cells with a defucosylated anti-MICA / B 3F9H1L3L antibody (CLN-619GLYMAXX) resulted in a dose-dependent decrease in the percentage of cells with or without the addition of NKG2D effector cells. Wild-type anti-MICA / B 3F9H1L3L antibody (CLN-619WT) also resulted in a decrease in the percentage of HCT-116 cells incubated with NKG2D effector cells; however, the decrease in cells was not as pronounced as with the defucosylated anti-MICA / B 3F9H1L3L antibody.

[0262] These results suggest that anti-MICA / B antibodies with enhanced Fc function increase the ability of anti-MICA / B antibodies to induce ADCC and cancer cell death.

[0263] Example 14. Efficacy measured by survival analysis

[0264] In the HCT-116-Luc human colon tumor xenograft model, the efficacy of CLN-619WT was compared head-to-head with CLN-619Glymaxx (defucosylated) as a single agent, administered as a preventive treatment starting on day 1 or as a therapeutic treatment starting on day 4. Female Balb / c SCID mice were inoculated intraperitoneally (IP) to simulate disseminated disease. Treatment was given IP twice a week. Bioluminescence imaging (BLI) was performed to monitor the progression of disseminated disease. Important endpoints were assessment of the treatment effect on tumor growth inhibition measured by BLI (not shown), time to peri-morbidity endpoint (survival) as Fig.15A The study ended on day 61, when the last mouse reached a peri-moribund state. Survival analysis was performed using the log-rank test using Graphpad software. Fig. 15B As shown, all CLN-619WT-treated and CLN-619Glymaxx-treated groups (including preventive and therapeutic) resulted in a significant increase in survival compared to their respective higG1 control groups. In the preventive setting, CLN-619WT and CLN-619Glymaxx were not significantly different from each other. In the therapeutic setting, CLN-619Glymaxx at a dose of 10 mg / kg was statistically superior to CLN-619 at a dose of 10 mg / kg (P=0.003).

[0265] In vivo efficacy studies were performed in a HCC1534 lung tumor xenograft model implanted in Balb / c SCID mice, comparing CLN-619WT and CLN-619Glymaxx head-to-head. Fig.16As shown, treatment with CLN-619WT, CLN-619Glymaxx or hIgG1 control started on day 1, the day the tumor cells were implanted. Treatment was implemented by IP injection twice a week for 4 weeks. The dose range was 0.01 to 1 mg / kg of CLN-619 test article and 1 mg / kg of hIgG1 control antibody. The study was terminated on day 40, and statistical analysis was calculated based on day 40. Statistical analysis took into account multiple comparisons, using one-way ANOVA and Tukey multiple comparisons, and analyzed in graphpad. In the HCC1534 cell line, no efficacy differences were observed between WT and Fc-enhanced antibodies at any dose.

[0266] The technology works on the principle that in the absence of fucose, cells are unable to synthesize GDP-fucose via the salvage pathway. The de novo pathway (the main source of activated GDP-L-fucose) is effectively blocked by enzymatic conversion of the intermediate GDP-4-keto-6-deoxymannose to GDP-D-rhamnose (an end product that does not normally appear in vertebrate cells). Non-fucosylated antibodies are produced by co-expressing heterologous GDP-6-deoxy-D-lyso-4-hexulose reductase. Briefly, antibodies are digested with proteases to produce three subunits ((scFc, light chain, and Fd'), and the subunits are analyzed by reverse phase LC-MS. Defucosylation is measured using mass spectrometry. Using A representative batch of CLN-619Glymaxx (defucosylated antibody) produced by the technology is shown in Fig.17 shown.

[0267] Although the application has shown and described the preferred embodiments of the present invention, it is obvious to those skilled in the art that such embodiments are provided only by way of example. Without departing from the present invention, those skilled in the art will now expect many changes, variations and substitutions. It should be understood that various alternatives of the embodiments described in the application may be adopted. The accompanying claims are intended to define the scope of the present invention, and encompass methods and structures within the scope of these claims and their equivalents.

Claims

1. A monoclonal antibody or an antigen-binding fragment thereof, comprising a light chain, wherein the light chain comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 21, SEQ ID NO: 23 or SEQ ID NO: 24; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucose typically detected in similar antibodies produced in mammalian expression systems.

2. The monoclonal antibody according to claim 1, further comprising a heavy chain, wherein the heavy chain comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 22, SEQ ID NO: 25 or SEQ ID NO: 26; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucose typically detected in similar antibodies produced in mammalian expression systems.

3. A monoclonal antibody or an antigen-binding fragment thereof, comprising a light chain variable domain (VL), wherein the light chain variable domain (VL) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 7, SEQ ID NO: 15 or SEQ ID NO: 19; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucose typically detected in similar antibodies produced in mammalian expression systems.

4. The monoclonal antibody of claim 3, wherein the light chain variable domain (VL) comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:7, SEQ ID NO:15 or SEQ ID NO:

19.

5. The monoclonal antibody according to claim 3, further comprising a heavy chain variable domain (VH), wherein the heavy chain variable domain (VH) comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence shown in SEQ ID NO: 8, SEQ ID NO: 16 or SEQ ID NO:

20.

6. The monoclonal antibody of claim 3, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 7 and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO:

8.

7. The monoclonal antibody of claim 3, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 15 and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO:

16.

8. The monoclonal antibody of claim 3, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 19 and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO:

20.

9. The monoclonal antibody of claim 3, wherein 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 in SEQ ID NO:21, SEQ ID NO:23 or SEQ ID NO:

24.

10. The monoclonal antibody of claim 3, wherein 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 in SEQ ID NO:22, SEQ ID NO:25 or SEQ ID NO:

26.

11. The monoclonal antibody according to claim 3, wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins.

12. The monoclonal antibody of claim 3, wherein the monoclonal antibody or antigen-binding fragment thereof binds to the α-3 domain of the MICA protein, the α-3 domain of the MICB protein, or the α-3 domains of both the MICA and MICB proteins.

13. The monoclonal antibody according to claim 11, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both.

14. The monoclonal antibody of claim 11, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both.

15. The monoclonal antibody of claim 3, wherein the monoclonal antibody or antigen-binding fragment thereof is selected from whole immunoglobulin, scFv, Fab, F(ab')2 or disulfide-linked Fv.

16. The monoclonal antibody of claim 3, wherein the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM.

17. The monoclonal antibody of claim 3, wherein the monoclonal antibody or antigen-binding fragment thereof is humanized or chimerized.

18. A monoclonal antibody or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH), wherein the heavy chain variable domain (VH) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 8, SEQ ID NO: 16 or SEQ ID NO: 20; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucose typically detected in similar antibodies produced in mammalian expression systems.

19. The monoclonal antibody of claim 18, wherein the heavy chain variable domain (VH) comprises an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:

20.

20. The monoclonal antibody of claim 18, further comprising a light chain variable domain (VL), wherein the light chain variable domain (VL) comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence shown in SEQ ID NO:7, SEQ ID NO:15 or SEQ ID NO:

19.

21. The monoclonal antibody of claim 18, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 8 and a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO:

7.

22. The monoclonal antibody of claim 18, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 16 and a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO:

15.

23. The monoclonal antibody of claim 18, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 20 and a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO:

19.

24. The monoclonal antibody of claim 18, wherein 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 in SEQ ID NO:22, SEQ ID NO:25 or SEQ ID NO:

26.

25. The monoclonal antibody of claim 18, wherein 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 in SEQ ID NO:21, SEQ ID NO:23 or SEQ ID NO:

24.

26. The monoclonal antibody of claim 18, wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins.

27. The monoclonal antibody of claim 18, wherein the monoclonal antibody or antigen-binding fragment thereof binds to the α-3 domain of the MICA protein, the α-3 domain of the MICB protein, or the α-3 domains of both the MICA and MICB proteins.

28. The monoclonal antibody of claim 26, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both.

29. The monoclonal antibody of claim 26, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both.

30. The monoclonal antibody of claim 18, wherein the monoclonal antibody or antigen-binding fragment thereof is selected from whole immunoglobulin, scFv, Fab, F(ab')2, or disulfide-linked Fv.

31. The monoclonal antibody of claim 18, wherein the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM.

32. The monoclonal antibody of claim 18, wherein the monoclonal antibody or antigen-binding fragment thereof is humanized or chimerized.

33. A monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementary determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 1-3, 9-11 and 17, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucose typically detected in similar antibodies produced in mammalian expression systems.

34. The monoclonal antibody of claim 33, wherein the light chain complementary determining region (CDR) has an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 1-3, 9-11 and 17, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY.

35. The monoclonal antibody of claim 33, further comprising a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 99% or 100% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 4-6, 12-14 and 18.

36. The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), a light chain complementary determining region 3 (CDR3), a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 4 or SEQ ID NO:

5. The heavy chain complementary determining region 2 (CDR2) has 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 the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to one of SEQ ID NO:6 or SEQ ID NO:

14.

37. The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 1, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:

3.

38. The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 9, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 10, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:

11.

39. The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:

3.

40. The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:5, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:

6.

41. The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 13, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

14.

42. The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:18, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:

6.

43. The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL), wherein the light chain variable domain (VL) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, SEQ ID NO:15 or SEQ ID NO:

19.

44. The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH), wherein the heavy chain variable domain (VH) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:

20.

45. The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) and a heavy chain variable domain (VH), wherein the light chain variable domain (VL) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, SEQ ID NO:15 or SEQ ID NO:19; and the heavy chain variable domain (VH) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:

20.

46. ​​The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO:7 and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO:

8.

47. The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 15 and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO:

16.

48. The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 19 and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO:

20.

49. The monoclonal antibody of claim 33, wherein 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 in SEQ ID NO:21, SEQ ID NO:23 or SEQ ID NO:

24.

50. The monoclonal antibody of claim 33, wherein 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 in SEQ ID NO:22, SEQ ID NO:25 or SEQ ID NO:

26.

51. The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both a MICA and a MICB protein.

52. The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof binds to the α-3 domain of the MICA protein, the α-3 domain of the MICB protein, or the α-3 domains of both the MICA and MICB proteins.

53. The monoclonal antibody of claim 51, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both.

54. The monoclonal antibody of claim 51, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both.

55. The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof is selected from whole immunoglobulin, scFv, Fab, F(ab')2, or disulfide-linked Fv.

56. The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM.

57. The monoclonal antibody of claim 33, wherein the monoclonal antibody or antigen-binding fragment thereof is humanized or chimerized.

58. 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 shown in SEQ ID NOs: 4-6, 12-14 and 18, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucose typically detected in similar antibodies produced in mammalian expression systems.

59. The monoclonal antibody of claim 58, wherein the heavy chain complementarity determining region (CDR) has an amino acid sequence that is at least 90%, at least 95%, at least 99% or 100% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 4-6, 12-14 and 18, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY.

60. The monoclonal antibody of claim 58, further comprising a light chain complementary determining region (CDR) having an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 99% or 100% identical to the amino acid sequence shown in SEQ ID NOs: 1-3, 9-11 and 17.

61. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), a heavy chain complementary determining region 3 (CDR3), a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO:4 or SEQ ID NO:12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to one of SEQ ID NO:5, SEQ ID NO:13, or SEQ ID NO:18, the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to one of SEQ ID NO:6 or SEQ ID NO:14, the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO:1, SEQ ID NO:9, or SEQ ID NO:

15. NO:17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to one of SEQ ID NO:2 or SEQ ID NO:10, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to one of SEQ ID NO:3 or SEQ ID NO:

11.

62. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:5, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:

6.

63. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 13, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:

14.

64. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:18, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:

6.

65. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 1, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:

3.

66. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 9, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 10, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:

11.

67. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO: 2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:

3.

68. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH), wherein the heavy chain variable domain (VH) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:

20.

69. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL), wherein the light chain variable domain (VL) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, SEQ ID NO:15 or SEQ ID NO:

19.

70. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the heavy chain variable domain (VH) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:20; and the light chain variable domain (VL) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, SEQ ID NO:15 or SEQ ID NO:

19.

71. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the heavy chain variable domain (VH) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 8; and the light chain variable domain (VL) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:

7.

72. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the heavy chain variable domain (VH) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 16; and the light chain variable domain (VL) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:

15.

73. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the heavy chain variable domain (VH) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 20; and the light chain variable domain (VL) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:

19.

74. The monoclonal antibody of claim 58, wherein 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 in SEQ ID NO:22, SEQ ID NO:25, or SEQ ID NO:

26.

75. The monoclonal antibody of claim 58, wherein 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 in SEQ ID NO:21, SEQ ID NO:23, or SEQ ID NO:

24.

76. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both a MICA and a MICB protein.

77. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof binds to the α-3 domain of the MICA protein, the α-3 domain of the MICB protein, or the α-3 domains of both the MICA and MICB proteins.

78. The monoclonal antibody of claim 76, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both.

79. The monoclonal antibody of claim 76, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both.

80. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, scFv, Fab, F(ab')2, or a disulfide-linked Fv.

81. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM.

82. The monoclonal antibody of claim 58, wherein the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric.

83. A pharmaceutical composition comprising: The monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1 to 82; and pharmaceutically acceptable carriers or excipients.

84. 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, the monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucose typically detected in similar antibodies produced in mammalian expression systems.

85. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof further 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 shown in SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY.

86. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), a light chain complementary determining region 3 (CDR3), a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, and the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 4 or SEQ ID NO:

5. The heavy chain complementary determining region 2 (CDR2) has 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 the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to one of SEQ ID NO:6 or SEQ ID NO:

14.

87. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 1, the light chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

3.

88. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to SEQ ID NO:9, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to SEQ ID NO:10, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to SEQ ID NO:

11.

89. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 17 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 1, the light chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

3.

90. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO:4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO:5, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

6.

91. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 13, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

14.

92. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO:4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO:18, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

6.

93. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL), wherein the light chain variable domain (VL) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, SEQ ID NO:15 or SEQ ID NO:

19.

94. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH), wherein the heavy chain variable domain (VH) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:

20.

95. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) and a heavy chain variable domain (VH), wherein the light chain variable domain (VL) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, SEQ ID NO:15 or SEQ ID NO:19; and the heavy chain variable domain (VH) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:

20.

96. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO:7 and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO:

8.

97. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 15 and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO:

16.

98. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 19 and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO:

20.

99. The method of claim 84, wherein 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 in SEQ ID NO:21, SEQ ID NO:23, or SEQ ID NO:

24.

100. The method of claim 84, wherein 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 in SEQ ID NO:22, SEQ ID NO:25, or SEQ ID NO:

26.

101. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both a MICA and a MICB protein.

102. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof binds to the α-3 domain of the MICA protein, the α-3 domain of the MICB protein, or the α-3 domains of both the MICA and MICB proteins.

103. The method of claim 101, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both.

104. The method of claim 101, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both.

105. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, scFv, Fab, F(ab')2, or a disulfide-linked Fv.

106. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM.

107. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric.

108. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof reduces the level of soluble MICA protein, soluble MICB protein, or both.

109. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof reduces shedding of soluble MICA protein, soluble MICB protein, or both.

110. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof inhibits shedding of soluble MICA protein, soluble MICB protein, or both.

111. The method of claim 84, wherein the cancer is selected from the group consisting of carcinoma, lymphoma, blastoma, melanoma, and leukemia.

112. The method of claim 84, wherein the cancer is selected from the group consisting of: squamous cell carcinoma; small cell lung cancer; non-small cell lung cancer; gastrointestinal cancer; Hodgkin's lymphoma and non-Hodgkin's lymphoma; pancreatic cancer; glioblastoma; glioma; cervical cancer; ovarian cancer; liver cancer, such as hepatocellular carcinoma and bladder cancer; breast cancer; myeloma, such as 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.

113. The method of claim 84, wherein the cancer is a primary cancer.

114. The method of claim 84, wherein the cancer is a metastatic cancer.

115. 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, the monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementary 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 in SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucose typically detected in similar antibodies produced in mammalian expression systems.

116. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof further 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 shown in SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY.

117. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), a light chain complementary determining region 3 (CDR3), a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, and the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 4 or SEQ ID NO:

5. The heavy chain complementary determining region 2 (CDR2) has 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 the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to one of SEQ ID NO:6 or SEQ ID NO:

14.

118. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 1, the light chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

3.

119. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO:9, the light chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO:10, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

11.

120. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

3.

121. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO:4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO:5, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

6.

122. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 13, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

14.

123. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO:4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO:18, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

6.

124. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL), and the light chain variable domain (VL) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, SEQ ID NO:15, or SEQ ID NO:

19.

125. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH), wherein the heavy chain variable domain (VH) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:

20.

126. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) and a heavy chain variable domain (VH), wherein the light chain variable domain (VL) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, SEQ ID NO:15 or SEQ ID NO:19; and the heavy chain variable domain (VH) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:

20.

127. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO:7 and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO:

8.

128. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 15 and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO:

16.

129. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to SEQ ID NO: 19 and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to SEQ ID NO:

20.

130. The method of claim 115, wherein 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 in SEQ ID NO:21, SEQ ID NO:23, or SEQ ID NO:

24.

131. The method of claim 115, wherein 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 in SEQ ID NO:22, SEQ ID NO:25, or SEQ ID NO:

26.

132. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both a MICA and a MICB protein.

133. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof binds to the α-3 domain of the MICA protein, the α-3 domain of the MICB protein, or the α-3 domains of both the MICA and MICB proteins.

134. The method of claim 132, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both.

135. The method of claim 132, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both.

136. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, scFv, Fab, F(ab')2, or a disulfide-linked Fv.

137. The method of claim 115, wherein the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM.

138. The method of claim 115, wherein the monoclonal antibody or fragment thereof is humanized or chimeric.

139. The method of claim 115, wherein 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 the individual.

140. The method of claim 115, wherein the individual has a cancer characterized by elevated levels of soluble MICA protein, soluble MICB protein, or both.

141. The method of claim 140, wherein the cancer is selected from the group consisting of carcinoma, lymphoma, blastoma, melanoma, and leukemia.

142. The method of claim 140, wherein the cancer is selected from the group consisting of: squamous cell carcinoma; small cell lung cancer; non-small cell lung cancer; gastrointestinal cancer; Hodgkin's lymphoma and non-Hodgkin's lymphoma; pancreatic cancer; glioblastoma; glioma; cervical cancer; ovarian cancer; liver cancer, such as hepatocellular carcinoma and bladder cancer; breast cancer; myeloma, such as 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.

143. The method of claim 140, wherein the cancer is a primary cancer.

144. The method of claim 140, wherein the cancer is a metastatic cancer.

145. A monoclonal antibody or 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 at least about 80% identical to the amino acid sequence set forth in SEQ ID NO:

27.

146. A monoclonal antibody or antigen-binding fragment thereof that competitively binds to MICA / B with the following antibody: the antibody comprises a heavy chain variable domain (VH) having an amino acid sequence that is at least about 80% identical to the amino acid sequence set forth in SEQ ID NO:28; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucose typically detected in similar antibodies produced in mammalian expression systems.

147. The monoclonal antibody or antigen binding fragment thereof according to any one of claims 1-82, 145 or 146, or the method according to any one of claims 83-144, wherein the monoclonal antibody or antigen binding fragment thereof induces one or more of complement dependent cytotoxicity (CDC), Fc receptor binding to activate antibody dependent cellular cytotoxicity (ADCC), and antibody dependent cellular phagocytosis (ADCP) in target cells.

148. The monoclonal antibody or antigen binding fragment thereof or method of claim 147, wherein the monoclonal antibody or antigen binding fragment thereof induces ADCC.

149. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 1-82, 145 or 146, or the method of any one of claims 83-144, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a mutation at amino acid 239 of the Fc region.

150. The monoclonal antibody or antigen-binding fragment thereof of any one of claims 1-82, 145 or 146, or the method of any one of claims 83-144, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a mutation at amino acid 332 of the Fc region.

151. The monoclonal antibody or antigen-binding fragment thereof or method of claim 149, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a mutation of S239D in the Fc region.

152. The monoclonal antibody or antigen-binding fragment thereof or method according to claim 150, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a mutation of I332D in the Fc region.

153. The monoclonal antibody or antigen-binding fragment thereof or method according to claim 149 or 150, wherein the monoclonal antibody or antigen-binding fragment thereof comprises mutations S239D and I332D in the Fc region.

154. The monoclonal antibody or antigen-binding fragment thereof or method of any of the above claims, wherein the monoclonal antibody or antigen-binding fragment thereof comprises 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 typically detected in similar antibodies produced in mammalian expression systems.

155. The monoclonal antibody or antigen-binding fragment thereof or method according to any of the above claims, wherein the monoclonal antibody or antigen-binding fragment thereof comprises one or more amino acid modifications of Table B and / or Table C.

156. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof increases the surface level of MICA protein, MICB protein, or both.

157. The method of claim 159, wherein the monoclonal antibody or antigen-binding fragment thereof inhibits shedding of MICA protein, MICB protein, or both.

158. The method of claim 84, wherein the monoclonal antibody or antigen-binding fragment thereof increases the surface level of soluble MICA protein, soluble MICB protein, or both.

159. The method of claim 161, wherein the monoclonal antibody or antigen-binding fragment thereof inhibits shedding of soluble MICA protein, soluble MICB protein, or both.

160. A method of increasing the surface 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, the monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementary determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences shown in SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY; wherein the antibody or antigen-binding fragment thereof: a) comprises one or more amino acid modifications that enhance effector function compared to an unmodified monoclonal antibody or antigen-binding fragment thereof; and / or b) lacks fucosylation or comprises reduced fucosylation compared to the amount of fucose typically detected in similar antibodies produced in mammalian expression systems.

161. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof further 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 shown in SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody does not have at least one CDR selected from the following list, the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY.

162. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), a light chain complementary determining region 3 (CDR3), a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 2 or SEQ ID NO: 10, the light chain complementary determining region 3 (CDR3) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, and the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence at least 80% identical to one of SEQ ID NO: 4 or SEQ ID NO:

5. The heavy chain complementary determining region 2 (CDR2) has 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 the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to one of SEQ ID NO:6 or SEQ ID NO:

14.

163. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO:1, the light chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO:2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

3.

164. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO:9, the light chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO:10, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

11.

165. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1), a light chain complementary determining region 2 (CDR2), and a light chain complementary determining region 3 (CDR3), wherein the light chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 17, the light chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 2, and the light chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

3.

166. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO:4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO:5, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

6.

167. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 12, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO: 13, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

14.

168. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1), a heavy chain complementary determining region 2 (CDR2), and a heavy chain complementary determining region 3 (CDR3), wherein the heavy chain complementary determining region 1 (CDR1) has an amino acid sequence that is at least 80% identical to SEQ ID NO:4, the heavy chain complementary determining region 2 (CDR2) has an amino acid sequence that is at least 80% identical to SEQ ID NO:18, and the heavy chain complementary determining region 3 (CDR3) has an amino acid sequence that is at least 80% identical to SEQ ID NO:

6.

169. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL), and the light chain variable domain (VL) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, SEQ ID NO:15, or SEQ ID NO:

19.

170. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH), wherein the heavy chain variable domain (VH) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:

20.

171. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) and a heavy chain variable domain (VH), wherein the light chain variable domain (VL) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, SEQ ID NO:15 or SEQ ID NO:19; and the heavy chain variable domain (VH) comprises an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:

20.

172. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) and a heavy chain variable domain (VH), wherein the light chain variable domain (VL) comprises an amino acid sequence at least 80% identical to SEQ ID NO:7, and the heavy chain variable domain (VH) comprises an amino acid sequence at least 80% identical to SEQ ID NO:

8.

173. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) and a heavy chain variable domain (VH), wherein the light chain variable domain (VL) comprises an amino acid sequence at least 80% identical to SEQ ID NO: 15, and the heavy chain variable domain (VH) comprises an amino acid sequence at least 80% identical to SEQ ID NO:

16.

174. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) and a heavy chain variable domain (VH), wherein the light chain variable domain (VL) comprises an amino acid sequence at least 80% identical to SEQ ID NO: 19, and the heavy chain variable domain (VH) comprises an amino acid sequence at least 80% identical to SEQ ID NO:

20.

175. The method of claim 163, wherein 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 in SEQ ID NO:21, SEQ ID NO:23, or SEQ ID NO:

24.

176. The method of claim 163, wherein 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 in SEQ ID NO:22, SEQ ID NO:25, or SEQ ID NO:

26.

177. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both a MICA and a MICB protein.

178. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof binds to the α-3 domain of the MICA protein, the α-3 domain of the MICB protein, or the α-3 domains of both the MICA and MICB proteins.

179. The method of claim 179, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both.

180. The method of claim 179, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both.

181. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, scFv, Fab, F(ab')2, or a disulfide-linked Fv.

182. The method of claim 163, wherein the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM.

183. The method of claim 163, wherein the monoclonal antibody or fragment thereof is humanized or chimeric.

184. The method of claim 163, wherein 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 the individual.

185. The method of claim 163, wherein the individual has a cancer characterized by elevated levels of soluble MICA protein, soluble MICB protein, or both.

Images