Anti-MICA / b antibodies blocking MICA / b deflection and methods

Abstract

Provided herein are antibodies that specifically bind to MICA / B having a heavy chain, a light chain, a variable heavy chain domain (VH), a variable light chain domain (VL), and a complementarity determining region (CDR) disclosed herein, as well as methods and uses thereof.

Description

[0001] This application is a divisional application of a Chinese invention patent application filed on July 30, 2019, with application number 201980062628.5 and invention name “Anti-MICA / B antibodies that block MICA / B shedding and methods of use thereof”.

[0002] Cross-references

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 712,608, filed on July 31, 2018, which is incorporated herein by reference in its entirety. SUMMARY OF THE INVENTION

[0005] Disclosed herein are monoclonal antibodies that specifically bind to MICA / B and thereby modulate the immune response against diseased cells.

[0006] In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain comprising an amino acid sequence 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. 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 set forth in SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26.

[0007] In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof, comprising 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 certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof, comprising a light chain variable domain (VL) comprising an amino acid sequence 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 certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof, comprising a light chain variable domain (VL) comprising an amino acid sequence 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 certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof, comprising a light chain variable domain (VL) comprising an amino acid sequence 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 certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising 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 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 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) 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 antigen-binding fragment thereof comprises a light chain comprising an amino acid sequence 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. In some cases, the monoclonal antibody or its antigen-binding fragment comprises a heavy chain containing 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. 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 MICB protein, or 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 complete 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.

[0008] In certain embodiments, disclosed herein is a monoclonal antibody or an antigen-binding fragment thereof, comprising 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 certain embodiments, disclosed herein is a monoclonal antibody or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) comprising an amino acid sequence 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 certain embodiments, disclosed herein is a monoclonal antibody or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) comprising an amino acid sequence 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 certain embodiments, disclosed herein is a monoclonal antibody or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth in SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising 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) 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 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. 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: 16 and a light chain variable domain (VL) comprising an amino acid sequence 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 MICB protein, or 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 complete 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.

[0009] In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof, comprising a light chain complementary determining region (CDR) having at least one amino acid sequence that is at least 80% identical to the amino acid sequence 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof, comprising a light chain complementary determining region (CDR) having at least one amino acid sequence that is at least 90% identical to the amino acid sequence 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof, comprising a light chain complementary determining region (CDR) having at least one amino acid sequence that is at least 95% identical to the amino acid sequence 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof, comprising a light chain complementary determining region (CDR) having at least one amino acid sequence that is at least 99% identical to the amino acid sequence 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a light chain complementary determining region (CDR) having at least one 100% identical amino acid sequence to 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY.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) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 10, a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18, and a heavy chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 1, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 9, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 10, and a light chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 13, and a heavy chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 18, and a heavy chain complementary determining region 3 (CDR3) having 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 or SEQ ID NO: 15, 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 or SEQ ID NO: 16. 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 or SEQ ID NO: 16, and 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 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) 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 set forth 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 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 specifically binds to a MICA protein, a MICB protein, or both a MICA and a MICB protein.In some cases, the monoclonal antibody or its antigen binding fragment binds to the α-3 domain of MICA protein, MICB protein, or both MICA and MICB protein. In some cases, the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both. In some cases, the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both. In some cases, the monoclonal antibody or its antigen binding fragment is selected from a complete immunoglobulin, scFv, Fab, F(ab')2 or a disulfide-connected 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.

[0010] In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof, comprising a heavy chain complementary determining region (CDR) having at least one amino acid sequence that is at least 80% identical to the amino acid sequence 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof, comprising a heavy chain complementary determining region (CDR) having at least one amino acid sequence that is at least 90% identical to the amino acid sequence 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain complementary determining region (CDR) having at least one amino acid sequence that is at least 95% identical to the amino acid sequence 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain complementary determining region (CDR) having at least one amino acid sequence that is at least 99% identical to the amino acid sequence 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof comprising a heavy chain complementarity determining region (CDR) having at least one 100% identical amino acid sequence to the amino acid sequence 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY.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) having an amino acid sequence at least 80% identical to one of SEQ ID NO:4 or SEQ ID NO:12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO:5, SEQ ID NO:13, or SEQ ID NO:18, a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to one of SEQ ID NO:6 or SEQ ID NO:14, a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO:1, SEQ ID NO:9, or SEQ ID NO:17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO:2 or SEQ ID NO:10, and a light chain complementary determining region 3 (CDR3) having an amino acid sequence 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) having an amino acid sequence at least 80% identical to SEQ ID NO:4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:5, and a heavy chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 13, and a heavy chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 18, and a heavy chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 1, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 9, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 10, and a light chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementary determining region 3 (CDR3) having 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) 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, and 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 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 or SEQ ID NO: 15, 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 or SEQ ID NO: 16. 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, and 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. 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: 16, and 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: 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 the amino acid sequence set forth in SEQ ID NO: 20, and 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: 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 antigen-binding fragment thereof comprises a light chain comprising an amino acid sequence 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. In some cases, the monoclonal antibody or its antigen-binding fragment specifically binds to a MICA protein, a 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 a MICA protein, a MICB protein, or 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 complete immunoglobulin, a scFv, a Fab, a F(ab')2, or a disulfide-linked Fv. In some cases, the monoclonal antibody or its antigen-binding fragment is an IgG or IgM. In some cases, the monoclonal antibody or its antigen-binding fragment is humanized or chimeric.

[0011] In certain embodiments, disclosed herein is a pharmaceutical composition comprising: a monoclonal antibody or antigen-binding fragment thereof according to any one of the embodiments herein; and a pharmaceutically acceptable carrier or excipient.

[0012] In certain embodiments, disclosed herein are methods 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY. In certain embodiments, disclosed herein are methods 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, the monoclonal antibody or antigen-binding fragment thereof comprising 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 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 the amino acid sequence 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 the amino acid sequence 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 the amino acid sequence 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 the amino acid sequence 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 complementary determining region (CDR) having an amino acid sequence that is at least 100% identical to 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 100% identical to 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) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 10, a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18, and a heavy chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO:1, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:2, and a light chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 9, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 10, and a light chain complementary determining region 3 (CDR3) having 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 17 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 1, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 13, and a heavy chain complementary determining region 3 (CDR3) having 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 the following: a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 18, and a heavy chain complementary determining region 3 (CDR3) having 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) 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 MICB protein, or 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 complete immunoglobulin, scFv, Fab, F(ab')2 or a disulfide-connected 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. In some cases, the cancer is hepatocellular carcinoma.

[0013] In certain embodiments, disclosed herein are methods of treating hepatocellular carcinoma 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY. In certain embodiments, disclosed herein are methods of treating hepatocellular carcinoma in an individual in need thereof, 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 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 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 the amino acid sequence 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 the amino acid sequence 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 the amino acid sequence 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 the amino acid sequence 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 complementary determining region (CDR) having an amino acid sequence that is at least 100% identical to 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 100% identical to 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) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 10, a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18, and a heavy chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO:1, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:2, and a light chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 9, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 10, and a light chain complementary determining region 3 (CDR3) having 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 17 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 1, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 13, and a heavy chain complementary determining region 3 (CDR3) having 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 the following: a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 18, and a heavy chain complementary determining region 3 (CDR3) having 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) 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 MICB protein, or 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 complete immunoglobulin, scFv, Fab, F(ab')2 or a disulfide-connected 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 antigen-binding fragment thereof reduces shedding of soluble MICA protein, soluble MICB protein, or both. In some cases, the monoclonal antibody or antigen-binding fragment thereof inhibits shedding of soluble MICA protein, soluble MICB protein, or both.

[0014] In certain embodiments, disclosed herein are methods of 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 antigen-binding fragment thereof, the monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementary determining region (CDR) having at least one amino acid sequence that is at least 80% identical to the amino acid sequence 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY. In certain embodiments, disclosed herein are methods of 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 antigen-binding fragment thereof, the monoclonal antibody or antigen-binding fragment thereof comprising a heavy chain complementarity determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth in SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody does not have at least one CDR selected from the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY. 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 the amino acid sequence 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 the amino acid sequence 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 the amino acid sequence 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 the amino acid sequence 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 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 complementarity determining region (CDR) having an amino acid sequence that is at least 95% identical to at least one of the amino acid sequences set forth 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 complementary determining region (CDR) having an amino acid sequence that is at least 100% identical to 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 100% identical to 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) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 10, a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18, and a heavy chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO:1, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:2, and a light chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 9, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 10, and a light chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementary determining region 3 (CDR3) having 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) having an amino acid sequence at least 80% identical to SEQ ID NO: 12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 13, and a heavy chain complementary determining region 3 (CDR3) having 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 the following: a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 18, and a heavy chain complementary determining region 3 (CDR3) having 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, 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) 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 MICB protein, or 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 complete 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 fragment is humanized or chimeric.In some cases, the monoclonal antibody or antigen-binding fragment thereof 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 in the individual. In some cases, the individual suffers from a cancer characterized by elevated levels of soluble MICA protein, soluble MICB protein, or both. In some cases, the cancer is hepatocellular carcinoma.

[0015] In certain embodiments, disclosed herein is a monoclonal antibody or an antigen-binding fragment thereof according to any one of the embodiments herein, which is used to treat cancer in an individual in need. In certain embodiments, disclosed herein is a monoclonal antibody or an antigen-binding fragment thereof according to any one of the embodiments herein, which is used to prepare a drug for treating cancer in an individual in need. In some cases, the cancer is hepatocellular carcinoma.

[0016] In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof that compete for binding 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. In certain embodiments, disclosed herein are monoclonal antibodies or antigen-binding fragments thereof that compete for binding to MICA / B with an antibody comprising: 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The features and advantages of the present invention will be understood by referring to the following detailed description and the following drawings which set forth illustrative embodiments utilizing the principles of the invention:

[0019] Figure 1 A- Figure 1 B in Figure 3 shows the antibody 3F9.E4 obtained by ELISA ( Figure 1 A) and 16F10.C12( Figure 1 B) Combination with MICA / B alleles.

[0020] Figure 2 Exemplified is the binding of antibody 3F9.E4 to cell surface MICA as assessed by staining of TRAMP C2 cells transfected with MICA*08 compared to parental TC2 cells.

[0021] Figure 3 Antibodies 3F9.E4 and 16F10.C12 were shown to inhibit MICA shedding from PLC / PRF / 5 cells.

[0022] Figure 4A-4BThe antibody 3F9.E4 ( Figure 4A ) and 16F10.C12( Figure 4B ) enhanced NK-92 cell-mediated cytotoxicity against PLC / PRF / 5 cells.

[0023] Figure 5 The anti-tumor activity of antibody 3F9 against B16 / MICA transfectants relative to isotype control (IC) is illustrated.

[0024] Figure 6A-6C exemplifies that a higher percentage of NKG2D-positive NK cells was observed in tumor infiltrating fluid (TIL) in 3F9 antibody-treated tumors compared to isotype controls ( Fig. 6A ), CD8+T cells ( Figure 6B ) and γδT cells ( Figure 6C ).

[0025] Figure 7A-7B The results show that treatment with 3F9 antibody reduced the level of soluble MICA in tumors in B16 / MICA transgenic animals ( Fig. 7A ) and surface MICA levels ( Figure 7B ).

[0026] Figure 8A-8C A competitive binding assay is exemplified to illustrate that all antibodies bind to a "structural" epitope and that antibody 3F9.E4 competes for binding to antibody PDI-1 ( Figure 8B ), antibody 16F10 binds to a slightly different but closely adjacent epitope to PDI-1 and 3F9 ( Figure 8C ). DETAILED DESCRIPTION OF THE INVENTION

[0028] In some embodiments, disclosed herein are monoclonal antibodies that specifically bind to MICA / B. In some embodiments, the MICA / B antibodies herein bind to a MICA / B protein or a fragment thereof and modulate an individual's immune response, thereby treating cancer (eg, hepatocellular carcinoma).

[0029] 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 can be used to regulate the immune response of individuals, such as individuals with cancer. Antibodies that bind to MICA / B and regulate its activity are needed to develop new therapies for treating cancer.

[0030] Certain terms

[0031] As used herein, "MICA / B" refers to MICA protein, MICB protein, or both MICA and MICB proteins, including their variants, isoforms, and species homologs to human MICA / B.

[0032] As used herein, "antibody" refers to a glycoprotein that exhibits binding specificity to a specific antigen. Antibodies typically contain variable domains and constant domains 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. There are three complementary determining regions (CDRs) in each variable domain, which form a loop in contact with the antigen surface in the heavy chain variable domain (VH) and the light chain variable domain (VL). Antibodies herein also include "antigen binding moiety" or antibody fragments that can bind to an antigen.

[0033] As used herein, a "chimeric" antibody is an antibody in which a portion of the heavy chain and / or light chain 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, and 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 having a human sequence substituted in the antibody sequence.

[0034] The terms "recipient", "individual", "subject", "host" and "patient" are used interchangeably herein and, in certain instances, 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, livestock and farm animals, as well as laboratory animals, zoo animals, sports animals or pets, such as dogs, horses, cats, cows, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys, etc. In some embodiments, the mammal is a human.

[0035] As used herein, the terms "treat", "treatment", and the like refer in certain cases to the administration of an agent or the performance of a procedure in order to obtain an effect. The effect may be preventive in terms of completely or partially preventing a disease or its symptoms, and / or the effect may be therapeutic in terms of achieving a partial or complete cure of a disease and / or symptoms of a disease. As used herein, "treatment" may include treating a disease or condition (e.g., cancer) in a mammal, particularly a human, and includes: (a) preventing a disease or symptom of a disease present 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., preventing its development; and (c) alleviating the disease, i.e., causing the disease to regress. Treatment may refer to any indicator of successful treatment or improvement or prevention of cancer, including any objective or subjective parameter, such as reduction; relief; alleviation of symptoms or making disease conditioning more tolerable to the patient; a slowing of the rate of deterioration or decline; or making the endpoint of deterioration less debilitating. Treatment or alleviation 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 a compound or agent of the invention to prevent or delay, alleviate or stop or inhibit the development of symptoms or conditions associated with a disease (e.g., cancer). The term "therapeutic effect" refers to the alleviation, elimination or prevention of a disease, disease symptom, or disease side effect in a subject.

[0036] In certain instances, 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.

[0037] As used herein, the singular forms "a", "an", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an antibody" includes a plurality of antibodies, and in some embodiments, reference to "an antibody" includes a plurality of antibodies, and so forth.

[0038] As used herein, all numerical values ​​or numerical ranges include all integers within or encompassing the range, as well as fractions of numerical values ​​or integers within or encompassing the range, unless the context clearly indicates otherwise. Thus, for example, a 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 1-5000 times includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times, etc., as well as 1.1, 1.2, 1.3, 1.4, 1.5 times, etc., 2.1, 2.2, 2.3, 2.4, 2.5 times, etc.

[0039] As used herein, "about" a number refers to a range that includes the number and ranges from 10% below the number to 10% above the number. An "about" range refers to 10% below the lower limit of the range to 10% above the upper limit of the range.

[0040] "Percent identity (%)" refers to the degree to which two sequences (nucleotides or amino acids) have identical residues at identical positions in an 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 specified as X% of the residues in the amino acid sequence are identical to the residues of the sequence disclosed in SEQ ID NO: Y. Typically, computer programs are used for such calculations. 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).

[0041] MICA / B

[0042] In some embodiments, disclosed herein are monoclonal antibodies that specifically bind to MICA / B. In some embodiments, disclosed herein are monoclonal antibodies that compete for binding to MICA / B.

[0043] 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, including 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 associate with 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 αβ and γδ CD8 + MICA / B is a ligand for the C-type lectin-like activating receptor NKG2D (Natural Killer Group 2D) on T cells. The interaction between MICA / B and NKG2D plays a role in tumor surveillance and immune response.

[0044] 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 between immune effector cells carrying NKG2D and stress or diseased cells expressing MICA / B ligands on the cell surface produces a cellular immune response against stress / disease cells, ultimately leading to the death of cells expressing MICA / B. In cancer cells, truncated MICA / B proteins (proteins lacking transmembrane domains and cytoplasmic tails, but retaining three extracellular domains containing α-1, α-2, and α-3 domains) often enter the blood through the action of proteases, and cause the downregulation (receptor internalization) of its expected receptor NKG2D on immune effector cells. In some cases, MICA / B glycoproteins are produced intracellularly, and they are not usually destined to be cell surface membrane-bound, but are incorporated into exosomes and released outside the cell, interacting with NKG2D receptors on immune cells outside the cell. These truncated or soluble MICA / B ligands shed from the cancer cell surface act like decoy molecules and lead to the activation of immune effector cells (such as 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.

[0045] Hepatocellular carcinoma (HCC)

[0046] 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 a subject, thereby treating cancer (eg, hepatocellular carcinoma).

[0047] 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 with 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 other causes that predispose individuals to the subsequent development of HCC.

[0048] Anti-MICA / B antibodies

[0049] Provided herein are 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 comprising a heavy chain variable domain (VH) and at least one light chain comprising a light chain variable domain (VL). Each VH and VL comprises three complementary determining regions (CDRs). The amino acid sequences of VH and VL and CDR determine the antigen binding specificity and antigen binding strength of the antibody. Table 1 summarizes the amino acid sequences of heavy and light chains, VH and VL and CDRs.

[0050]

[0051]

[0052]

[0053]

[0054] 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 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 MICA protein and MICB protein. In some embodiments, the antibody binds to MICA protein, which is a membrane-bound MICA protein. In some embodiments, the antibody binds to MICA protein, which is a soluble MICA protein. In some embodiments, the antibody binds to MICA protein, which is both a membrane-bound MICA protein and a soluble MICA protein. In some embodiments, the antibody binds to MICB protein, which is a membrane-bound MICB protein. In some embodiments, the antibody binds to MICB protein, which is a soluble MICA protein. In some embodiments, the antibody binds to MICB protein, which is both a membrane-bound MICB protein and a soluble MICB protein.

[0055] 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 complete immunoglobulin, scFv, Fab, F(ab')2, or a disulfide-linked 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.

[0056] MICA / B antibody heavy and light chains

[0057] Disclosed herein are antibodies that specifically bind to MICA / B with a light chain. In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth 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.

[0058] Also disclosed herein are antibodies that specifically bind to MICA / B with heavy chains. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth 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.

[0059] Also disclosed herein are antibodies that bind to MICA / B comprising a light chain and a heavy chain. In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth 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 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 at least about 75%, 80%, 81%, 82%, 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.

[0060] In some embodiments, the antibody that binds 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 set forth in SEQ ID NO:21, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:22.

[0061] In some embodiments, the antibody that binds 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 set forth in SEQ ID NO:23, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:25.

[0062] In some embodiments, the antibody that binds 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 set forth in SEQ ID NO:23, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:26.

[0063] In some embodiments, the antibody that binds 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 set forth in SEQ ID NO:24, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:25.

[0064] In some embodiments, the antibody that binds 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 set forth in SEQ ID NO:24, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:26.

[0065] MICA / B antibody variable domain

[0066] Disclosed herein are antibodies that specifically bind to MICA / B, which have 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 set forth in SEQ ID NO:7, SEQ ID NO:15, or SEQ ID NO:19. In some embodiments, 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, 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.

[0067] Also disclosed herein are antibodies that specifically bind to MICA / B, which have 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 set forth in SEQ ID NO:8, SEQ ID NO:16, or SEQ ID NO:20. In some embodiments, 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, 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.

[0068] Also disclosed herein are antibodies that bind to MICA / B comprising a light chain variable domain (VL) and a heavy chain variable domain (VH). In some embodiments, the antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth 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 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, 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 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.

[0069] In some embodiments, the antibody that binds 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, 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 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, VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:7, and VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:8.

[0070] In some embodiments, the antibody that binds 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, 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 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, VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:15, and VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:16.

[0071] In some embodiments, the antibody that binds 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, 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 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, VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:19, and VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:20.

[0072] MICA / B antibody complementarity determining region

[0073] Disclosed herein are antibodies that specifically bind to MICA / B, having a light chain comprising a light 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 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 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.

[0074] Also disclosed herein are antibodies that specifically bind to MICA / B, which have 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 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 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.

[0075] Also disclosed herein are antibodies that bind to MICA / B 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 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 MICA / B comprises a light chain CDR sequence having at least one amino acid sequence that is at least about 75%, 80%, 81%, 82%, 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 NOs: 1-3, 9-11, and 17, and a light chain CDR sequence having at least one amino acid sequence that is at least about 75%, 80%, 81%, 82%, 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 NOs: 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.

[0076] In some embodiments, an antibody that binds MICA / B comprises a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least about 70% identical to one of SEQ ID NO:1, SEQ ID NO:9, or SEQ ID NO:17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least about 70% identical to one of SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:10, a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least about 70% identical to one of SEQ ID NO:3 or SEQ ID NO:11, a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least about 70% identical to one of SEQ ID NO:4 or SEQ ID NO:12, a heavy chain complementary determining region 2 (CDR2) having 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 a heavy chain complementary determining region 3 (CDR3) having 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 MICA / B comprises a light chain complementary determining region 1 (CDR1) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, having a light chain complementary determining region 1 (CDR1) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17. NO:10, a light 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:10, a light 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:3 or SEQ ID NO:11, a light 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:4 or SEQ ID NO:12, a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one of SEQ ID NO:5, SEQ ID NO:13 or SEQ ID NO:18, a 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:6 or SEQ ID NO:7. NO:14 has a heavy chain complementary determining region 3 (CDR3) that is at least about 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 the amino acids in NO:14.In some embodiments, an antibody that binds MICA / B comprises a light chain complementary determining region 1 (CDR1) having an amino acid sequence that is 100% identical to one of SEQ ID NO:1, SEQ ID NO:9, or SEQ ID NO:17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence that is 100% identical to one of SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:10, a light chain complementary determining region 3 (CDR3) having an amino acid sequence that is 100% identical to one of SEQ ID NO:3 or SEQ ID NO:11, a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence that is 100% identical to one of SEQ ID NO:4 or SEQ ID NO:12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence that is 100% identical to one of SEQ ID NO:5, SEQ ID NO:13, or SEQ ID NO:18, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence that is 100% identical to one of SEQ ID NO:6 or SEQ ID NO:14.

[0077] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:1, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:2, and a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:3. In some embodiments, the antibody that binds MICA / B comprises at least one of: a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:1, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:2, and a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: NO:3. In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:1, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:2, and a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:3.

[0078] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:9, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:10, and a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:11. In some embodiments, the antibody that binds MICA / B comprises at least one of: a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:9, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:10, and a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:11. NO: 11. In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 10, and a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 11.

[0079] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:17, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:2, and a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:3. In some embodiments, the antibody that binds MICA / B comprises at least one of: a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:17, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:2, and a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: NO:3. In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 3.

[0080] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:6. In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:5, a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: The heavy chain CDR3 of the amino acid sequence of SEQ ID 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 of SEQ ID NO: 6. In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 6.

[0081] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence shown in SEQ ID NO:12, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence shown in SEQ ID NO:13, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence shown in SEQ ID NO:14. In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:12, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:13, a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:14. NO: 14. In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 14.

[0082] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence shown in SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence shown in SEQ ID NO:18, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence shown in SEQ ID NO:6. In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:18, a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:19, The heavy chain CDR3 of the amino acid sequence of SEQ ID 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 of SEQ ID NO: 6. In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 6.

[0083] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:1, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:2, a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:3, a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:6.In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:1, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:2, a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: NO:3, a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:4, a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:4, NO:5, and a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth in SEQ ID NO:6, and a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth in SEQ ID NO:6.In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:1, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:2, a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:3, a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:6.

[0084] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:9, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:10, a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:11, a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:12, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:13, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:14.In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:9, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:10, a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:11, NO:11 has a light chain CDR3 that is at least about 75%, 80%, 81%, 82%, 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, a heavy chain CDR1 that is at least about 75%, 80%, 81%, 82%, 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, NO:13 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:13, and a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth in SEQ ID NO:14.In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:9, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:10, a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:11, a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:12, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:13, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:14.

[0085] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:17, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:2, a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:3, a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:18, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:6.In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:17, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:2, a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: NO:3, a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:4, a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:4, NO:18 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:18, and a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth in SEQ ID NO:6.In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:17, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:2, a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:3, a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:18, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:6.

[0086] In some embodiments, the antibody that binds MICA / B does not have at least one CDR selected from the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY.

[0087] Competitive Binding

[0088] In some embodiments, disclosed herein are antibodies that compete for binding to MICA / B with an antibody comprising: 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: 27. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth 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.

[0089] In some embodiments, disclosed herein are antibodies that compete for binding to MICA / B with an antibody comprising: 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: 28. In some embodiments, the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth 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.

[0090] In some embodiments, disclosed herein are antibodies that compete for binding to MICA / B with an antibody comprising: 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:27 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: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, VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:27, and VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:28.

[0091] Treatments and uses

[0092] Provided herein are methods of treating cancer (eg, hepatocellular carcinoma) in an individual in need thereof comprising administering an anti-MICA / B antibody disclosed herein.

[0093] Also provided herein are methods of reducing the level of soluble MICA / B protein in an individual in need thereof comprising administering an anti-MICA / B antibody disclosed herein.

[0094] Also provided herein are methods of alleviating or suppressing an immunosuppressive environment by preventing or blocking the interaction between soluble MICA / B and NKG2D receptor in an individual in need thereof, comprising administering an anti-MICA / B antibody disclosed herein.

[0095] 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.

[0096] In some embodiments, the antibody that binds 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 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 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.

[0097] In some embodiments, an antibody that binds 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 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.

[0098] In some embodiments, an antibody that binds MICA / B comprises a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least about 70% identical to one of SEQ ID NO:1, SEQ ID NO:9, or SEQ ID NO:17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least about 70% identical to one of SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:10, a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least about 70% identical to one of SEQ ID NO:3 or SEQ ID NO:11, a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least about 70% identical to one of SEQ ID NO:4 or SEQ ID NO:12, a heavy chain complementary determining region 2 (CDR2) having 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 a heavy chain complementary determining region 3 (CDR3) having 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 MICA / B comprises a light chain complementary determining region 1 (CDR1) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, having a light chain complementary determining region 1 (CDR1) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17. NO:10, a light 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:10, a light 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:3 or SEQ ID NO:11, a light 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:4 or SEQ ID NO:12, a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to one of SEQ ID NO:5, SEQ ID NO:13 or SEQ ID NO:18, a 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:6 or SEQ ID NO:7. NO:14 has a heavy chain complementary determining region 3 (CDR3) that is at least about 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 the amino acids in NO:14.In some embodiments, an antibody that binds MICA / B comprises a light chain complementary determining region 1 (CDR1) having an amino acid sequence that is 100% identical to one of SEQ ID NO:1, SEQ ID NO:9, or SEQ ID NO:17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence that is 100% identical to one of SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:10, a light chain complementary determining region 3 (CDR3) having an amino acid sequence that is 100% identical to one of SEQ ID NO:3 or SEQ ID NO:11, a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence that is 100% identical to one of SEQ ID NO:4 or SEQ ID NO:12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence that is 100% identical to one of SEQ ID NO:5, SEQ ID NO:13, or SEQ ID NO:18, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence that is 100% identical to one of SEQ ID NO:6 or SEQ ID NO:14.

[0099] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:1, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:2, and a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:3. In some embodiments, the antibody that binds MICA / B comprises at least one of: a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:1, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:2, and a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: NO:3. In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:1, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:2, and a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:3.

[0100] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:9, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:10, and a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:11. In some embodiments, the antibody that binds MICA / B comprises at least one of: a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:9, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:10, and a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:11. NO: 11. In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 10, and a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 11.

[0101] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:17, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:2, and a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:3. In some embodiments, the antibody that binds MICA / B comprises at least one of: a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:17, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:2, and a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: NO:3. In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 3.

[0102] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:6. In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:5, a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: The heavy chain CDR3 of the amino acid sequence of SEQ ID 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 of SEQ ID NO: 6. In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 6.

[0103] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence shown in SEQ ID NO:12, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence shown in SEQ ID NO:13, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence shown in SEQ ID NO:14. In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:12, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:13, a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:14. NO: 14. In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO: 14.

[0104] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence shown in SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence shown in SEQ ID NO:18, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence shown in SEQ ID NO:6. In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:18, a heavy chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:19, The heavy chain CDR3 of the amino acid sequence of SEQ ID 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 of SEQ ID NO: 6. In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence of SEQ ID NO: 6.

[0105] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:1, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:2, a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:3, a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:6.In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:1, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:2, a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: NO:3, a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:4, a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:4, NO:5 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:5, and a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence shown in SEQ ID NO:6.In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:1, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:2, a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:3, a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:5, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:6.

[0106] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:9, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:10, a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:11, a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:12, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:13, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:14.In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:9, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:10, a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:11, NO:11 has a light chain CDR3 that is at least about 75%, 80%, 81%, 82%, 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, a heavy chain CDR1 that is at least about 75%, 80%, 81%, 82%, 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, NO:13 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:13, and a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth in SEQ ID NO:14.In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:9, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:10, a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:11, a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:12, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:13, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:14.

[0107] In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:17, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:2, a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:3, a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:18, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth in SEQ ID NO:6.In some embodiments, the antibody that binds MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:17, a light chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:2, a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: NO:3, a light chain CDR3 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:4, a heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:4, NO:18 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:18, and a heavy chain CDR2 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth in SEQ ID NO:6.In some embodiments, the antibody that binds to MICA / B comprises at least one of the following: a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:17, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:2, a light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:3, a heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:18, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:6.

[0108] In some embodiments, the antibody that binds MICA / B does not have at least one CDR selected from the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY.

[0109] In some embodiments, the antibody that binds 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.

[0110] In some embodiments, the antibody that binds 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.

[0111] In some embodiments, the antibody that binds 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 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, 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 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.

[0112] In some embodiments, the antibody that binds 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, 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 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, VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:7, and VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:8.

[0113] In some embodiments, the antibody that binds 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, 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 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, VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:15, and VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:16.

[0114] In some embodiments, the antibody that binds 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, 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 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, VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:19, and VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:20.

[0115] In some embodiments, the antibody that binds 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.

[0116] In some embodiments, the antibody that binds 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.

[0117] Also disclosed herein are antibodies that bind to MICA / B comprising a light chain and a heavy chain. In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence that is at least about 70% identical to the amino acid sequence set forth 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 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 at least about 75%, 80%, 81%, 82%, 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.

[0118] In some embodiments, the antibody that binds 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 set forth in SEQ ID NO:21, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:22.

[0119] In some embodiments, the antibody that binds 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 set forth in SEQ ID NO:23, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:25.

[0120] In some embodiments, the antibody that binds 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 set forth in SEQ ID NO:23, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:26.

[0121] In some embodiments, the antibody that binds 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 set forth in SEQ ID NO:24, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:25.

[0122] In some embodiments, the antibody that binds 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 set forth in SEQ ID NO:24, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:26.

[0123] In some embodiments, the antibody competes for binding to MICA / B with an antibody comprising 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: 27. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth 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.

[0124] In some embodiments, the antibody competes for binding to MICA / B with an antibody comprising 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: 28. In some embodiments, the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth 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.

[0125] In some embodiments, the antibody competes for MICA / B binding with an antibody comprising: 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:27, 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: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, VL has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:27, and VH has an amino acid sequence that is 100% identical to the amino acid sequence set forth in SEQ ID NO:28.

[0126] 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 and MICB proteins. 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 the MICA protein and the MICB protein. In some embodiments, the antibody binds to the MICA protein, which is a membrane-bound MICA protein. In some embodiments, the antibody binds to the MICA protein, which is a soluble MICA protein. In some embodiments, the antibody binds to the MICA protein, which is both a membrane-bound MICA protein and a soluble MICA protein. In some embodiments, the antibody binds to the MICB protein, which is a membrane-bound MICB protein. In some embodiments, the antibody binds to the MICB protein, which is a soluble MICA protein. In some embodiments, the antibody binds to the MICB protein, which is a membrane-bound MICB protein. In some embodiments, the antibody binds to the MICB protein, which is a soluble MICA protein. In some embodiments, the antibody binds to the MICB protein, which is both a membrane-bound MICB protein and a soluble MICB protein.

[0127] 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 complete immunoglobulin, scFv, Fab, F(ab')2, or a disulfide-linked 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.

[0128] 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.

[0129] It is contemplated that any suitable route of administration is used with the methods disclosed herein. In some embodiments, the antibody is administered by intravenous administration. In some embodiments, the antibody is administered by subcutaneous administration. In some embodiments, the antibody is administered 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 into an ointment, lotion, or emulsion. In some embodiments, the antibody is formulated into a solution. In some embodiments, the antibody is formulated for topical, oral, buccal, or nasal administration.

[0130] In some embodiments, the individual is monitored prior to administration of the antibody. Symptoms are determined and their severity is assessed. As described herein or known to those skilled in the art, the antibodies as described herein are administered alone or multiple times over time or in combination with other treatments. In some embodiments, the individual is monitored to determine the efficacy of the treatment regimen. In some embodiments, the treatment regimen is modified in response to preliminary treatment results, so that the treatment dose or frequency or dose and frequency are changed to achieve the desired subject response level in terms of symptom relief, side effect reduction, or a combination of symptom relief and side effect reduction.

[0131] It is contemplated that a therapeutically effective amount or dose includes 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 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 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 .2mg / kg, about 1.3mg / kg, about 1.4mg / kg, about 1.5mg / kg, about 1.6mg / kg, about 1.7mg / kg, about 1.8mg / kg, about 1.9mg / kg, about 2mg / kg, about 2.1mg / kg, about 2.2mg / kg, about 2.3mg / kg, about 2.4mg / kg, about 2.5mg / kg, about 2.6mg / kg, about 2.7mg / kg, about 2.8mg / kg, about 2.9mg / kg, about 3mg / kg, about 3.1mg / kg, about 3.2mg / kg, about 3.3mg / kg, about 3.4mg / kg, about 3.5mg / kg, about 3.6mg / kg, about 3.7mg / kg g / 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 10.2mg / kg, about 10.3mg / kg, about 10.4mg / kg, about 10.5mg / kg, about 10.6mg / kg, about 10.7mg / kg, about 10.8mg / kg, about 10.9mg / kg, about 11mg / kg, about 11.1mg / kg, about 11.2 mg / kg, about 11.3 mg / kg, about 11.4 mg / kg, about 11.5 mg / kg, about 11.6 mg / kg, about 11.7 mg / kg, about 11.8 mg / kg, about 11.9 mg / kg, about 12 mg / kg, about 12.1 mg / kg, about 12.2 mg / kg, about 12.3 mg / kg, about 12.4 mg / kg, about 12.5 mg / kg, about 12.6 mg / kg, about 12.7 mg / kg, about 12.8 mg / kg, about 12.9 mg / kg, about 13 mg / kg, about 13.1 mg / kg, about 13.2 mg / kg, about 13.3 mg / kg, about 13.4 mg / kg, about 13. 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 18.1 mg / kg, about 18.2 mg / kg, about 18.3 mg / kg, about 18.4 mg / kg, about 18.5 mg / kg, about 18.6 mg / kg, about 18.7 mg / kg, about 18.8 mg / kg, about 18.9 mg / kg, about 19 mg / kg, about 19.1 mg / kg, about 19.2 mg / kg, about 19.3 mg / kg, about 19.4 mg / kg, about 19.5 mg / kg, about 19.6 mg / kg, about 19.7 mg / kg, about 19.8 mg / kg, about 19.9 mg / kg, or about 20 mg / kg. In some cases, it is contemplated that the therapeutically effective amount or dose includes a dose of about 0.1 mg / kg to about 2.0 mg / kg. .

[0132] The treatment methods herein include administering anti-MICA / B antibodies once or more at a dose disclosed herein. In some embodiments, the method includes administering anti-MICA / B antibodies once. In some embodiments, the method includes administering anti-MICA / B antibodies twice. In some embodiments, the method includes administering anti-MICA / B antibodies three times. In some embodiments, the method includes administering anti-MICA / B antibodies four times. In some embodiments, the method includes administering anti-MICA / B antibodies five times. In some embodiments, the method includes administering anti-MICA / B antibodies six times. In some embodiments, anti-MICA / B antibodies are administered once or more every day. In some embodiments, anti-MICA / B antibodies are administered once or more every week. In some embodiments, anti-MICA / B antibodies are administered once or more every two weeks. In some embodiments, anti-MICA / B antibodies are administered once or more every month. In some embodiments, anti-MICA / B antibodies are administered once or more every three months. In some embodiments, anti-MICA / B antibodies are administered once or more every six months. In some embodiments, anti-MICA / B antibodies are administered once or more every year.

[0133] In some embodiments, the treatment methods disclosed herein are monotherapy. In some embodiments, the treatment methods disclosed herein are combination therapy. In some embodiments, combination therapy includes co-administration of anti-MICA / B antibodies with another therapeutic agent. In some embodiments, therapeutic agents include chemotherapeutic agents. In some embodiments, chemotherapeutic agents include but are not limited to cytotoxic agents, antimetabolites (e.g., folic acid antagonists, purine analogs, pyrimidine analogs, etc.), topoisomerase inhibitors (e.g., camptothecin derivatives, anthracenediones, anthracyclines, epipodophyllotoxins, quinoline alkaloids, etc.), anti-microtubule agents (e.g., taxanes, vinca alkaloids), protein synthesis inhibitors (e.g., cephalotaxine, camptothecin derivatives, quinoline alkaloids), alkylating agents (e.g., alkyl sulfonates, ethyleneimines, nitrogen mustards, nitrosoureas, platinum derivatives, triazenes, etc.), alkaloids, terpenes, kinase inhibitors, and immune checkpoint inhibitors. In some embodiments, anti-MICA / B antibodies disclosed herein are co-administered with therapeutic agents that induce immune responses. In some embodiments, the anti-MICA / B antibodies disclosed herein are co-administered with therapeutic agents that inhibit the downregulation of immune responses. In some embodiments, inducing an immune response includes activating or upregulating the activity of NK cells. In some embodiments, inducing an immune response includes activating or upregulating the activity of T cells. In some embodiments, immune checkpoint inhibitor targets include PD-1. In some embodiments, immune checkpoint inhibitor targets include PD-L1. In some embodiments, immune checkpoint inhibitors include Pembrolizumab, Nivolumab, Cemiplimab, AMP-224, AMP-514, PDR001, Atezolizumab, Avelumab, Durvalumab, BMS-936559, and CK-301.

[0134] Pharmaceutical composition

[0135] Also disclosed herein are pharmaceutical compositions comprising an anti-MICA / B antibody disclosed herein and a pharmaceutically acceptable carrier or excipient.

[0136] In some embodiments, excipients used 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.

[0137] In some embodiments, the composition further comprises other therapeutic agents. In some embodiments, the therapeutic agent is a chemotherapeutic agent. Chemotherapeutic agents can include, in particular, cytotoxic agents, antimetabolites (e.g., folic acid antagonists, purine analogs, pyrimidine analogs, etc.), topoisomerase inhibitors (e.g., camptothecin derivatives, anthracenediones, anthracyclines, epipodophyllotoxins, quinoline alkaloids, etc.), antimicrotubule agents (e.g., taxanes, vinca alkaloids), protein synthesis inhibitors (e.g., cephalotaxine, camptothecin derivatives, quinoline alkaloids), alkylating agents (e.g., alkyl sulfonates, ethyleneimines, nitrogen mustards, nitrosoureas, platinum derivatives, triazenes, etc.), alkaloids, terpenes, and kinase inhibitors.

[0138] In some embodiments, the antibody and therapeutic agent are in the same formulation. In some embodiments, the antibody and therapeutic agent are in different formulations. In some embodiments, the antibodies described herein are used before administering other therapeutic agents. In some embodiments, the antibodies described herein are used simultaneously with administering other therapeutic agents. In some embodiments, the antibodies described herein are used after administering other therapeutic agents.

[0139] In some embodiments, the pharmaceutical preparation is compatible with a specific local, regional or systemic administration or delivery route. Therefore, the pharmaceutical preparation includes a carrier, diluent or excipient suitable for administration by a specific route. Specific non-limiting examples of the administration route of the composition herein are parenteral, such as intravenous, intraarterial, intradermal, intramuscular, subcutaneous, intrapleural, transdermal (topical), transmucosal, intracranial, intraspinal, intraocular, rectal, oral (digestive tract), mucosal administration, and any other dosage form suitable for a therapeutic method or an administration regimen.

[0140] In some embodiments, solutions or suspensions for parenteral administration include: a sterile diluent, such as water for injection, saline solution, fixed oil, 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, pH is adjusted with an acid or base, such as hydrochloric acid or sodium hydroxide.

[0141] Pharmaceutical preparations for injection include sterile aqueous solutions (when soluble in water) 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 for injection, Cremophor EL TM(BASF, Parsippany, NJ) or phosphate buffered saline (PBS). In some embodiments, the carrier is a solvent or dispersion medium, which includes, 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 dispersion, 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, such as a 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.

[0142] In some embodiments, sterile injectable preparations are prepared by incorporating the desired amount of the active composition into an appropriate solvent with one or a combination of the above ingredients. Typically, dispersions are prepared by incorporating the active composition into a sterile vehicle containing a basic dispersion medium and any other ingredients. In the case of sterile powders for preparing sterile injectable solutions, preparation methods include, for example, vacuum drying and freeze drying, which produce a powder of the active ingredient and any other desired ingredients from a previously prepared solution.

[0143] For transmucosal or transdermal administration, a penetrant suitable for the barrier to be penetrated is used in the formulation. Such penetrants are known in the art and include, for example, detergents, bile salts, and fusidic acid derivatives for transmucosal administration. 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.

[0144] In some embodiments, the pharmaceutical preparations are prepared with carriers that prevent rapid elimination from the body (e.g., controlled release formulations or time-delay materials, such as glyceryl monostearate or glyceryl stearate). In some embodiments, the preparations are also delivered using articles such as implants and microencapsulated delivery systems to achieve local, regional or systemic delivery or controlled or sustained release. Example

[0145] The following examples are given for the purpose of illustrating various embodiments of the present invention and are not meant to limit the present invention in any way. The examples and methods described herein are currently representative of preferred embodiments, are exemplary, and are not intended to limit the scope of the present invention. Those skilled in the art will recognize changes therein and other uses that are included in the spirit of the present invention as defined by the scope of the claims.

[0146] Example 1. Antibody Binding Kinetics Measurement

[0147] Affinity kinetics were determined on a ForteBio Octet Red96 analyzer. Briefly, the affinity kinetics were measured 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 binding 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 by ForteBio Analysis Suite 8.0 using a 1:1 model. The results of these assays are shown in Table 2.

[0148] Table 2. Kinetic measurements of anti-MICA / B antibodies against MICA antigen by BioLayer interferometry.

[0149] 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

[0150] Example 2. Binding of Antibodies to MICA / B Alleles

[0151] Recombinant MICA*01, CA*02, MICA*04, MICA*08, MICA*09 and MICB proteins were diluted to 1 μg / ml in 50 mM sodium carbonate buffer at pH 9.6 and coated on high binding 96-well microplates (Corning #9018) at 100 ng per well in 100 ul. The next morning, the coated ELISA plates were washed three times with TBS-Tween-20 at 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 3 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 3 times with TBS-T and incubated with ultrasensitive liquid substrate TMB (Sigma #T4444) (100ul per well) until sufficient for color development. The reaction was terminated with 1N sulfuric acid (100ul per well). The optical density (OD) value was measured at 450nm using a microplate reader. The results of this assay are shown in Figure 1 A to Figure 1 B in.

[0152] Example 3. Binding of Antibodies to Cell Surface MICA

[0153] Mouse prostate adenocarcinoma 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, cells were first stained with LIVE / DEAD Near IR Stain (Thermo) for 30 minutes at 4°C and then washed once by centrifugation with FACS buffer (1X PBS with 1 mM EDTA, 25 mM HEPES, 2% FBS). Approximately 2-3 x 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 minutes, 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 minutes. The cells were then washed once and the cell pellet was resuspended in FACS buffer for FACS analysis gated on live cells. Significantly higher PE fluorescence signals were observed for TC2-MICA-08 cells compared to parental TC2 cells, indicating that the anti-MICA mAb binds to surface expressed MICA. The results of this assay are shown in Figure 2 .

[0154] Example 4. Antibodies inhibit MICA shedding from PLC / PRF / 5 cells

[0155] 4x10 4 PLC / PRF / 5 cells (hepatocellular carcinoma) (ATCC, Manassas, VA) were distributed 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 and negative control antibodies that bind to the MICA α3 domain, respectively, and incubated for another day at 37°C. Cell supernatants containing shed MICA were used to determine the level of soluble MICA by ELISA. In brief, 96-well plates were coated overnight at 4°C with 100 μl of 2 μg / ml anti-human MICA / B (clone BAMO1, MBL, Japan). The plates were blocked and then incubated with cell supernatants and MICA standards for 2 hours. After incubation, the plates were washed and then incubated with 1 μg / ml proprietary anti-human MICA / MICB mAb (clone 10E9 conjugated to biotin) 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, stopped with 1N sulfuric acid, and absorbance was measured at 450 nm. Soluble MICA levels were interpolated from the standard curve. The results of this assay are shown in Figure 3 .

[0156] Example 5. Antibodies enhance NK-92 cell-mediated cytotoxicity against PLC / PRF / 5 cells

[0157] PLC / PRF / 5 (target) cells were suspended in RPMI-1640 containing 10% FBS and plated in 96-well flat-bottom plates (Costar) at 6000 cells / well. 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 then NK-92 cells (effectors) suspended in RPMI-1640 containing 10% FBS were added to the wells at various effector: target (E:T) ratios specified and co-cultured with the target cells for 4 hours. At the end of the culture, the supernatant was removed, replaced with PBS, and the calcein AM signal was measured using a VICTOR Multilabel plate reader (Perkin Elmer). An isotype-matched non-reactive immunoglobulin (R&D) antibody was used as a control. The results of this assay are shown in FIG. 4A to FIG. 4B .

[0158] Example 6. Efficacy of 3F9.E4 in in vivo tumor therapy (survival) and tumor-infiltrating lymphocytes in tumor-bearing mice NKG2S expression in cells

[0159] MICA transgenic mice (MICAgen) were inoculated with 4 B16F10-MICA*01 cells (B16 transfectants) were injected into the mice and, on day 11, when tumors reached the desired threshold size, mice were treated with 3F9.E4 or isotype control (arrows indicate injection days) (log-rank test). Results are shown in Figure 5 .

[0160] When high tumor burden was reached, mice were sacrificed and tumor-infiltrating lymphocytes were analyzed for NKG2D expression (SFI) on NK cells, CD8αβT cells, and γδT cells. The NKG2D expression intensity (SFI) of NKG2D-expressing cells is shown in FIG. 6A to FIG. 6C Each symbol represents the analysis of a single mouse. (One-way ANOVA + Tukey's multiple comparison test).

[0161] Example 7. In vitro MICA expression in B16-transfected tumors and detection of soluble MICA in the serum of tumor-bearing mice

[0162] MICA transgenic mice (MICAgen) were inoculated with 4 B16F10-MICA*01 cells (B16 transfectants) were added and mice were treated with 3F9.E4 or BAMO3 or isotype control on day 11 when tumors reached the desired threshold size. 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 α2 domain of MICA (≠BAMO3 and 3F9). Each symbol represents the analysis of a single mouse. The results are shown in Figure 7B sMICA in serum was also analyzed using AMO1 / BAMO1 sandwich ELISA. Each symbol represents a single mouse (unpaired t-test). The results are shown in Fig. 7A .

[0163] Example 8. Epitope binning

[0164] MICA * 04-His protein (30 μg / ml) was immobilized on a Ni-NTA (FortrBio, # 18-5101) biosensor tip for a biolayer interference measurement instrument (Octet Red, ForteBio) for 300 s. The baseline signal was measured again for 60 s, and then the biosensor tip was immersed in a well containing 1 mM or 0.5 mM primary antibody for 300 s. After this process, the biosensor was immersed in a well containing 100 nM or 50 nM second mAb for 300 s. 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 the addition of 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 intermediate competition, while levels of ≤ 33% are considered competitive. The results of this assay are shown in FIG. 8A to FIG. 8C .

[0165] The present disclosure also relates to the following embodiments:

[0166] 1. A monoclonal antibody or an antigen-binding fragment thereof, comprising at least one of a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 1, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 3, and at least one of a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 6.

[0167] 2. The monoclonal antibody of embodiment 1, 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.

[0168] 3. The monoclonal antibody of embodiment 1 or embodiment 2, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 90% or 100% identical to SEQ ID NO: 1, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 90% or 100% identical to SEQ ID NO: 2, and a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 90% or 100% identical to SEQ ID NO: 3.

[0169] 4. The monoclonal antibody of embodiment 1 or embodiment 2, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 90% or 100% identical to SEQ ID NO:4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 90% or 100% identical to SEQ ID NO:5, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 90% or 100% identical to SEQ ID NO:6.

[0170] 5. A monoclonal antibody or an antigen-binding fragment thereof, comprising 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.

[0171] 6. The monoclonal antibody of embodiment 5, further comprising 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.

[0172] 7. A monoclonal antibody or an antigen-binding fragment thereof, comprising 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.

[0173] 8. The monoclonal antibody of embodiment 7, 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.

[0174] 9. The monoclonal antibody of embodiment 7, further comprising a heavy chain variable domain (VH) comprising 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.

[0175] 10. The monoclonal antibody of embodiment 7, 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.

[0176] 11. The monoclonal antibody of embodiment 7, 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.

[0177] 12. The monoclonal antibody of embodiment 7, 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.

[0178] 13. The monoclonal antibody of embodiment 7, 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.

[0179] 14. The monoclonal antibody of embodiment 7, 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.

[0180] 15. The monoclonal antibody of embodiment 7, wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins.

[0181] 16. The monoclonal antibody of embodiment 7, wherein the monoclonal antibody or antigen-binding fragment thereof binds to the α-3 domain of the MICA protein, the MICB protein, or both the MICA and MICB proteins.

[0182] 17. The monoclonal antibody of embodiment 15, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both.

[0183] 18. The monoclonal antibody of embodiment 15, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both.

[0184] 19. The monoclonal antibody of embodiment 7, wherein the monoclonal antibody or antigen-binding fragment thereof is selected from a complete immunoglobulin, scFv, Fab, F(ab')2, or disulfide-linked Fv.

[0185] 20. The monoclonal antibody of embodiment 7, wherein the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM.

[0186] 21. The monoclonal antibody of embodiment 7, wherein the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric.

[0187] 22. A monoclonal antibody or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:20.

[0188] 23. The monoclonal antibody of embodiment 22, 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.

[0189] 24. The monoclonal antibody of embodiment 22 further comprises a light chain variable domain (VL) comprising 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.

[0190] 25. The monoclonal antibody of embodiment 22, 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.

[0191] 26. The monoclonal antibody of embodiment 22, 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.

[0192] 27. The monoclonal antibody of embodiment 22, 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.

[0193] 28. The monoclonal antibody of embodiment 22, 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.

[0194] 29. The monoclonal antibody of embodiment 22, 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.

[0195] 30. The monoclonal antibody of embodiment 22, wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins.

[0196] 31. The monoclonal antibody of embodiment 22, wherein the monoclonal antibody or antigen-binding fragment thereof binds to the α-3 domain of the MICA protein, the MICB protein, or both the MICA and MICB proteins.

[0197] 32. The monoclonal antibody of embodiment 30, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both.

[0198] 33. The monoclonal antibody of embodiment 30, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both.

[0199] 34. The monoclonal antibody of embodiment 22, wherein the monoclonal antibody or antigen-binding fragment thereof is selected from a complete immunoglobulin, scFv, Fab, F(ab')2, or disulfide-linked Fv.

[0200] 35. The monoclonal antibody of embodiment 22, wherein the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM.

[0201] 36. The monoclonal antibody of embodiment 22, wherein the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric.

[0202] 37. A monoclonal antibody or antigen-binding fragment thereof, comprising a light chain complementary determining region (CDR) having at least one amino acid sequence that is at least 80% identical to the amino acid sequence 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY.

[0203] 38. The monoclonal antibody of embodiment 37, wherein the light 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: 1-3, 9-11 and 17, wherein the monoclonal antibody does not have at least one CDR selected from the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY.

[0204] 39. The monoclonal antibody of embodiment 37, further comprising a heavy chain complementarity determining region (CDR) having at least one 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:4-6, 12-14 and 18.

[0205] 40. The monoclonal antibody of embodiment 37, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 10, a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 6 or SEQ ID NO: 7. A heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to that of NO:14.

[0206] 41. The monoclonal antibody of embodiment 37, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of: a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:1, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:2, and a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:3.

[0207] 42. The monoclonal antibody of embodiment 37, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of: a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:9, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:10, and a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:11.

[0208] 43. The monoclonal antibody of embodiment 37, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of: a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 3.

[0209] 44. The monoclonal antibody of embodiment 37, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of: a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:5, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:6.

[0210] 45. The monoclonal antibody of embodiment 37, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of: a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 13, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 14.

[0211] 46. ​​The monoclonal antibody of embodiment 37, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of: a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:18, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:6.

[0212] 47. The monoclonal antibody of embodiment 37, wherein 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 shown in SEQ ID NO:7, SEQ ID NO:15 or SEQ ID NO:19.

[0213] 48. The monoclonal antibody of embodiment 37, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:20.

[0214] 49. The monoclonal antibody of embodiment 37, wherein 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 shown 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 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.

[0215] 50. The monoclonal antibody of embodiment 37, 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.

[0216] 51. The monoclonal antibody of embodiment 37, 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.

[0217] 52. The monoclonal antibody of embodiment 37, 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.

[0218] 53. The monoclonal antibody of embodiment 37, 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.

[0219] 54. The monoclonal antibody of embodiment 37, 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.

[0220] 55. The monoclonal antibody of embodiment 37, wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins.

[0221] 56. The monoclonal antibody of embodiment 37, wherein the monoclonal antibody or antigen-binding fragment thereof binds to the α-3 domain of the MICA protein, the MICB protein, or both the MICA and MICB proteins.

[0222] 57. The monoclonal antibody of embodiment 55, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both.

[0223] 58. The monoclonal antibody of embodiment 55, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both.

[0224] 59. The monoclonal antibody of embodiment 37, wherein the monoclonal antibody or antigen-binding fragment thereof is selected from a complete immunoglobulin, scFv, Fab, F(ab')2, or disulfide-linked Fv.

[0225] 60. The monoclonal antibody of embodiment 37, wherein the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM.

[0226] 61. The monoclonal antibody of embodiment 37, wherein the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric.

[0227] 62. A monoclonal antibody or antigen-binding fragment thereof, comprising a heavy chain complementary determining region (CDR) having at least one amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:4-6, 12-14 and 18, wherein the monoclonal antibody does not have at least one CDR selected from the list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY.

[0228] 63. The monoclonal antibody of embodiment 62, 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY.

[0229] 64. The monoclonal antibody of embodiment 62 further comprises a light chain complementary determining region (CDR) having at least one 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.

[0230] 65. The monoclonal antibody of embodiment 62, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO:4 or SEQ ID NO:12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO:5, SEQ ID NO:13, or SEQ ID NO:18, a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to one of SEQ ID NO:6 or SEQ ID NO:14, a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO:1, SEQ ID NO:9, or SEQ ID NO:17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO:2 or SEQ ID NO:10, and a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to one of SEQ ID NO:3 or SEQ ID NO:11.

[0231] 66. The monoclonal antibody of embodiment 62, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of: a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:5, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:6.

[0232] 67. The monoclonal antibody of embodiment 62, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of: a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 13, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 14.

[0233] 68. The monoclonal antibody of embodiment 62, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of: a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:18, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:6.

[0234] 69. The monoclonal antibody of embodiment 62, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of: a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:1, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:2, and a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:3.

[0235] 70. The monoclonal antibody of embodiment 62, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of: a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:9, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:10, and a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:11.

[0236] 71. The monoclonal antibody of embodiment 62, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of: a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 3.

[0237] 72. The monoclonal antibody of embodiment 62, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:20.

[0238] 73. The monoclonal antibody of embodiment 62, wherein 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 shown in SEQ ID NO:7, SEQ ID NO:15 or SEQ ID NO:19.

[0239] 74. The monoclonal antibody of embodiment 62, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:20, and a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, SEQ ID NO:15 or SEQ ID NO:19.

[0240] 75. The monoclonal antibody of embodiment 62, wherein the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8, and a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7.

[0241] 76. The monoclonal antibody of embodiment 62, wherein the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:16, and a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:15.

[0242] 77. The monoclonal antibody of embodiment 62, wherein the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:20, and a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:19.

[0243] 78. The monoclonal antibody of embodiment 62, 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.

[0244] 79. The monoclonal antibody of embodiment 62, 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.

[0245] 80. The monoclonal antibody of embodiment 62, 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.

[0246] 81. The monoclonal antibody of embodiment 62, wherein the monoclonal antibody or antigen-binding fragment thereof binds to the α-3 domain of the MICA protein, the MICB protein, or both the MICA and MICB proteins.

[0247] 82. The monoclonal antibody of embodiment 80, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both.

[0248] 83. The monoclonal antibody of embodiment 80, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both.

[0249] 84. The monoclonal antibody of embodiment 62, wherein the monoclonal antibody or antigen-binding fragment thereof is selected from a complete immunoglobulin, a scFv, a Fab, a F(ab')2, or a disulfide-linked Fv.

[0250] 85. The monoclonal antibody of embodiment 62, wherein the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM.

[0251] 86. The monoclonal antibody of embodiment 62, wherein the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric.

[0252] 87. A pharmaceutical composition comprising: the monoclonal antibody or antigen-binding fragment thereof according to any one of embodiments 1 to 86; and a pharmaceutically acceptable carrier or excipient.

[0253] 88. A method for treating cancer in an individual in need thereof, comprising administering to the individual an effective amount of a monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementary determining region (CDR) having at least one amino acid sequence that is at least 80% identical to the amino acid sequence 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY.

[0254] 89. The method of embodiment 88, wherein the monoclonal antibody or antigen-binding fragment thereof further comprises a heavy chain complementarity determining region (CDR) having at least one amino acid sequence that is at least 80% identical to the amino acid sequence 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY.

[0255] 90. The method of embodiment 88, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO:1, SEQ ID NO:9, or SEQ ID NO:17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO:, SEQ ID NO:2, or SEQ ID NO:10, a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to one of SEQ ID NO:3 or SEQ ID NO:11, a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO:4 or SEQ ID NO:12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO:5, SEQ ID NO:13, or SEQ ID NO:18, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to one of SEQ ID NO:6 or SEQ ID NO:14.

[0256] 91. The method of embodiment 88, wherein the monoclonal antibody or its antigen-binding fragment comprises at least one of the following: a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:1, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:2, and a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:3.

[0257] 92. The method of embodiment 88, wherein the monoclonal antibody or its antigen-binding fragment comprises at least one of the following: a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:9, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:10, and a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:11.

[0258] 93. The method of embodiment 88, wherein the monoclonal antibody or its antigen-binding fragment comprises at least one of the following: a light chain complementary determining region 17 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:1, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:2, and a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:3.

[0259] 94. The method of embodiment 88, wherein the monoclonal antibody or its antigen-binding fragment comprises at least one of the following: a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:5, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:6.

[0260] 95. The method of embodiment 88, wherein the monoclonal antibody or its antigen-binding fragment comprises at least one of the following: a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:13, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:14.

[0261] 96. The method of embodiment 88, wherein the monoclonal antibody or its antigen-binding fragment comprises at least one of the following: a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:18, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:6.

[0262] 97. The method described in embodiment 88, wherein the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, SEQ ID NO:15 or SEQ ID NO:19.

[0263] 98. The method of embodiment 88, wherein the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:20.

[0264] 99. The method of embodiment 88, wherein the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown 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 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.

[0265] 100. The method of embodiment 88, wherein the monoclonal antibody or its antigen-binding fragment 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.

[0266] 101. The method of embodiment 88, wherein the monoclonal antibody or its antigen-binding fragment 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.

[0267] 102. The method of embodiment 88, wherein the monoclonal antibody or its antigen-binding fragment 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.

[0268] 103. The method of embodiment 88, wherein the monoclonal antibody or its antigen-binding fragment comprises a light chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:21, SEQ ID NO:23 or SEQ ID NO:24.

[0269] 104. The method of embodiment 88, 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.

[0270] 105. The method of embodiment 88, wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins.

[0271] 106. The method of embodiment 88, wherein the monoclonal antibody or antigen-binding fragment thereof binds to the α-3 domain of the MICA protein, the MICB protein, or both the MICA and MICB proteins.

[0272] 107. The method of embodiment 105, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both.

[0273] 108. The method of embodiment 105, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both.

[0274] 109. The method described in embodiment 88, wherein the monoclonal antibody or antigen-binding fragment thereof is selected from a complete immunoglobulin, scFv, Fab, F(ab')2 or a disulfide-linked Fv.

[0275] 110. The method of embodiment 88, wherein the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM.

[0276] 111. The method of embodiment 88, wherein the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric.

[0277] 112. The method of embodiment 88, wherein the monoclonal antibody or antigen-binding fragment thereof reduces the level of soluble MICA protein, soluble MICB protein, or both.

[0278] 113. The method of embodiment 88, wherein the monoclonal antibody or antigen-binding fragment thereof reduces the shedding of soluble MICA protein, soluble MICB protein, or both.

[0279] 114. The method of embodiment 88, wherein the monoclonal antibody or antigen-binding fragment thereof inhibits the shedding of soluble MICA protein, soluble MICB protein, or both.

[0280] 115. The method of embodiment 88, wherein the cancer is hepatocellular carcinoma.

[0281] 116. 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 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG, and NYGNYLFDY.

[0282] 117. The method of embodiment 116, wherein the monoclonal antibody or antigen-binding fragment thereof further comprises a heavy chain complementary determining region (CDR) having at least one amino acid sequence that is at least 80% identical to the amino acid sequence 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 list comprising: SASQGISNYLN, TSLLHSG, QQYSKFPRT, GYTFTNYGMN, INTYTGEPTYADDFKG and NYGNYLFDY.

[0283] 118. The method of embodiment 116, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 10, a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11, a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 6 or SEQ ID NO: 7. A heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence that is at least 80% identical to that of NO:14.

[0284] 119. The method of embodiment 116, wherein the monoclonal antibody or its antigen-binding fragment comprises at least one of the following: a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:1, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:2, and a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:3.

[0285] 120. The method of embodiment 116, wherein the monoclonal antibody or its antigen-binding fragment comprises at least one of the following: a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:9, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:10, and a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:11.

[0286] 121. The method of embodiment 116, wherein the monoclonal antibody or its antigen-binding fragment comprises at least one of the following: a light chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:17, a light chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:2, and a light chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:3.

[0287] 122. The method of embodiment 116, wherein the monoclonal antibody or its antigen-binding fragment comprises at least one of the following: a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:5, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:6.

[0288] 123. The method of embodiment 116, wherein the monoclonal antibody or its antigen-binding fragment comprises at least one of the following: a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:12, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:13, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:14.

[0289] 124. The method of embodiment 116, wherein the monoclonal antibody or its antigen-binding fragment comprises at least one of the following: a heavy chain complementary determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO:4, a heavy chain complementary determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO:18, and a heavy chain complementary determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO:6.

[0290] 125. The method described in embodiment 116, wherein the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:7, SEQ ID NO:15, or SEQ ID NO:19.

[0291] 126. The method described in embodiment 116, wherein the monoclonal antibody or its antigen-binding fragment comprises a heavy chain variable domain (VH) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:8, SEQ ID NO:16 or SEQ ID NO:20.

[0292] 127. The method described in embodiment 116, wherein the monoclonal antibody or its antigen-binding fragment comprises a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown 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 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.

[0293] 128. The method described in embodiment 116, wherein the monoclonal antibody or its antigen-binding fragment 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.

[0294] 129. The method described in embodiment 116, wherein the monoclonal antibody or its antigen-binding fragment 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.

[0295] 130. The method of embodiment 116, wherein the monoclonal antibody or its antigen-binding fragment 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.

[0296] 131. The method of embodiment 116, wherein the monoclonal antibody or its antigen-binding fragment comprises a light chain comprising an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:21, SEQ ID NO:23 or SEQ ID NO:24.

[0297] 132. The method of embodiment 116, 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.

[0298] 133. The method of embodiment 116, wherein the monoclonal antibody or its antigen-binding fragment specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins.

[0299] 134. The method of embodiment 116, wherein the monoclonal antibody or antigen-binding fragment thereof binds to the α-3 domain of the MICA protein, the MICB protein, or both the MICA and MICB proteins.

[0300] 135. The method of embodiment 116, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both.

[0301] 136. The method of embodiment 116, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both.

[0302] 137. The method described in embodiment 116, wherein the monoclonal antibody or antigen-binding fragment thereof is selected from a complete immunoglobulin, scFv, Fab, F(ab')2 or a disulfide-linked Fv.

[0303] 138. The method of embodiment 116, wherein the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM.

[0304] 139. The method of embodiment 116, wherein the monoclonal antibody or fragment thereof is humanized or chimeric.

[0305] 140. The method of embodiment 116, wherein the monoclonal antibody or antigen-binding fragment thereof 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 in the individual.

[0306] 141. The method of embodiment 116, wherein the individual has a cancer characterized by elevated levels of soluble MICA protein, soluble MICB protein, or both.

[0307] 142. The method of embodiment 141, wherein the cancer is hepatocellular carcinoma.

[0308] 143. A monoclonal antibody or antigen-binding fragment thereof that competes for MICA / B binding with an antibody comprising: a light chain variable domain (VL) having an amino acid sequence that is at least about 80% identical to the amino acid sequence set forth in SEQ ID NO:27.

[0309] 144. A monoclonal antibody or antigen-binding fragment thereof that competes for MICA / B binding with an antibody comprising: a heavy chain variable domain (VH) having an amino acid sequence that is at least about 80% identical to the amino acid sequence set forth in SEQ ID NO:28.

[0310] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Without departing from the present invention, those skilled in the art will now appreciate that many variations, changes and substitutions may be employed. It should be understood that various alternatives to the embodiments described herein may be employed. It is intended that the scope of the present invention be limited by the following claims, and that methods and structures and their equivalents within the scope of these claims are thus encompassed.

Claims

1. A monoclonal antibody or an antigen-binding fragment thereof, comprising Light chain complementarity determining regions (LCDR) 1-3 and heavy chain complementarity determining regions (HCDR) 1-3 are shown below: LCDR1 is SEQ ID NO:17, LCDR2 is SEQ ID NO:2, LCDR3 is SEQ ID NO:3, HCDR1 is SEQ ID NO:4, HCDR2 is SEQ ID NO:18 and HCDR3 is SEQ ID NO:

6.

2. A monoclonal antibody or an antigen-binding fragment thereof, comprising a light chain variable domain (VL) consisting of an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO: 19 and a heavy chain variable domain (VH) consisting of an amino acid sequence that is 100% identical to the amino acid sequence shown in SEQ ID NO:

20.

3. The monoclonal antibody or antigen-binding fragment of claim 1 or 2, wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins.

4. The monoclonal antibody or antigen-binding fragment of claim 3, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both.

5. The monoclonal antibody or antigen-binding fragment of claim 3, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both.

6. The monoclonal antibody or antigen-binding fragment of claim 1 or 2, wherein the monoclonal antibody or antigen-binding fragment thereof is selected from intact immunoglobulin, scFv, Fab, F(ab')2 or disulfide-linked Fv.

7. The monoclonal antibody or antigen-binding fragment of claim 1 or 2, wherein the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM.

8. The monoclonal antibody or antigen-binding fragment of claim 1 or 2, wherein the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric.

9. A pharmaceutical composition comprising: the monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1 to 8; and a pharmaceutically acceptable carrier or excipient.

10. Use of the monoclonal antibody or antigen-binding fragment thereof as claimed in any one of claims 1 to 8 or the pharmaceutical composition as claimed in claim 9 in the preparation of a medicament for treating hepatocellular carcinoma.

Images