Anti-MICA / B antibodies that block MICA / B shedding and methods of use

Abstract

To provide antibodies that specifically bind to MICA / B.SOLUTION: The present invention provides a monoclonal antibody or an antigen-binding fragment thereof, which specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. The MICA protein is membrane-bound MICA protein, soluble MICA protein, or both, or the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both. The monoclonal antibody or the antigen-binding fragment thereof comprises a heavy chain complementarity determining region and a light chain complementarity determining region each having a specific amino acid sequence.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 712,608, filed July 31, 2018, which is incorporated herein by reference in its entirety. Summary of the Invention

[0002] overview Disclosed herein are monoclonal antibodies that specifically bind to MICA / B, thereby modulating the immune response against diseased cells.

[0003] Disclosed herein in certain embodiments is a monoclonal antibody or antigen-binding fragment thereof comprising a light chain comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some embodiments, the monoclonal antibody or antigen-binding fragment thereof further comprises a heavy chain comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26.

[0004] In certain embodiments, disclosed herein is a monoclonal antibody or antigen-binding fragment thereof, comprising a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In certain embodiments, disclosed herein is a monoclonal antibody or antigen-binding fragment thereof, comprising a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In certain embodiments, disclosed herein is a monoclonal antibody or antigen-binding fragment thereof, comprising a light chain variable domain (VL) comprising an amino acid sequence at least 95% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In certain embodiments, disclosed herein is a monoclonal antibody or antigen-binding fragment thereof, comprising a light chain variable domain (VL) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In certain embodiments, disclosed herein is a monoclonal antibody or antigen-binding fragment thereof, comprising a light chain variable domain (VL) comprising an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. 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 as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20.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 95% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. 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 as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26.In some cases, the monoclonal antibody or antigen-binding fragment thereof specifically binds to the MICA protein, the MICB protein, or both the MICA and MICB proteins. In some cases, the monoclonal antibody or antigen-binding fragment thereof binds to the alpha-3 domain of the MICA protein, the MICB protein, or both the MICA 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 antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, an Fab, an F(ab')2, or a disulfide-linked Fv. In some cases, the monoclonal antibody or antigen-binding fragment thereof is an IgG or an IgM. In some cases, the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric.

[0005] In certain embodiments, disclosed herein is a monoclonal antibody or 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 as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In certain embodiments, disclosed herein is a monoclonal antibody or 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 as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In certain embodiments, disclosed herein is a monoclonal antibody or 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 as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In certain embodiments, disclosed herein is a monoclonal antibody or 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 as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In certain embodiments, disclosed herein is a monoclonal antibody or antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) comprising an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. 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 as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 95% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 99% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. 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 as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24.In some cases, the monoclonal antibody or antigen-binding fragment thereof specifically binds to the MICA protein, the MICB protein, or both the MICA and MICB proteins. In some cases, the monoclonal antibody or antigen-binding fragment thereof binds to the alpha-3 domain of the MICA protein, the MICB protein, or both the MICA 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 antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, an Fab, an F(ab')2, or a disulfide-linked Fv. In some cases, the monoclonal antibody or antigen-binding fragment thereof is an IgG or an IgM. In some cases, the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric.

[0006] In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody is Disclosed herein is a monoclonal antibody or antigen-binding fragment thereof, wherein the monoclonal antibody or antigen-binding fragment thereof does not have at least one CDR selected from the list comprising: TIFF0007734720000001.tif12128. In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementarity-determining region (CDR) having an amino acid sequence at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody is Disclosed herein is a monoclonal antibody or antigen-binding fragment thereof, wherein the monoclonal antibody or antigen-binding fragment thereof does not have at least one CDR selected from the list comprising: TIFF0007734720000002.tif10169. In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementarity determining region (CDR) having an amino acid sequence at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody is Disclosed herein is a monoclonal antibody or antigen-binding fragment thereof, wherein the monoclonal antibody or antigen-binding fragment thereof does not have at least one CDR selected from the list comprising: TIFF0007734720000003.tif11144. In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementarity determining region (CDR) having an amino acid sequence at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody is Disclosed herein is a monoclonal antibody or antigen-binding fragment thereof, which does not have at least one CDR selected from the list comprising: TIFF0007734720000004.tif11128. In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementarity determining region (CDR) having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody is Disclosed herein is a monoclonal antibody or antigen-binding fragment thereof that does not have at least one CDR selected from the list comprising: TIFF0007734720000005.tif11169. Optionally, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. Optionally, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. Optionally, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementarity 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 complementarity 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 complementarity 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 complementarity 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; and a heavy chain complementarity determining region 2 (CDR3) 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. (CDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 6 or SEQ ID NO: 14. Optionally, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 9, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 10, and a light chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 17, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 12, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 13, and a heavy chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 18, and a heavy chain complementarity 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 as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some cases, the monoclonal antibody or 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 as 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 as 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 as 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 as 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 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 as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some cases, the monoclonal antibody or antigen-binding fragment thereof specifically binds to the MICA protein, the MICB protein, or both the MICA and MICB proteins. In some cases, the monoclonal antibody or antigen-binding fragment thereof binds to the alpha-3 domain of the MICA protein, the MICB protein, or both the MICA and MICB proteins. In some cases, the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both. In some cases, the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both. In some cases, the monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, a Fab, a F(ab')2, or a disulfide-linked Fv. In some cases, the monoclonal antibody or antigen-binding fragment thereof is an IgG or an IgM. In some cases, the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric.

[0007] In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody is Disclosed herein is a monoclonal antibody or antigen-binding fragment thereof, wherein the monoclonal antibody or antigen-binding fragment thereof does not have at least one CDR selected from the list comprising: TIFF0007734720000006.tif11128. In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody is Disclosed herein is a monoclonal antibody or antigen-binding fragment thereof, wherein the monoclonal antibody or antigen-binding fragment thereof does not have at least one CDR selected from the list comprising: TIFF0007734720000007.tif11128. In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody is Disclosed herein is a monoclonal antibody or antigen-binding fragment thereof, wherein the monoclonal antibody or antigen-binding fragment thereof does not have at least one CDR selected from the list comprising: TIFF0007734720000008.tif11169. In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody is TIFF0007734720000009.tif11145. In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof is disclosed herein, wherein the monoclonal antibody or antigen-binding fragment thereof does not have at least one CDR selected from the list comprising: TIFF0007734720000009.tif11145. In certain embodiments, a monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody is Disclosed herein is a monoclonal antibody or antigen-binding fragment thereof that does not have at least one CDR selected from the list comprising: TIFF0007734720000010.tif12128. Optionally, the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17. Optionally, the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity determining region (CDR) having an amino acid sequence at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17. Optionally, the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity determining region (CDR) having an amino acid sequence at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17. In some cases, the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity determining region (CDR) having an amino acid sequence at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17. In some cases, the monoclonal antibody or antigen-binding fragment comprises a light chain complementarity determining region (CDR) having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity 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 complementarity 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 complementarity 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 complementarity 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 complementarity 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 complementarity determining region 3 (CDR3) 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. and a light chain complementarity 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. Optionally, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 12, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 13, and a heavy chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 18, and a heavy chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 9, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 10, and a light chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 17, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity 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 as SEQ ID NO:8, SEQ ID NO:16, or SEQ ID NO:20.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some cases, the monoclonal antibody or 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 as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20; and a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some cases, the monoclonal antibody or 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 as 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 as 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 as 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 as 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 as 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 as SEQ ID NO: 15. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as 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 as SEQ ID NO: 19.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some cases, the monoclonal antibody or antigen-binding fragment thereof specifically binds to the MICA protein, the MICB protein, or both the MICA and MICB proteins. In some cases, the monoclonal antibody or antigen-binding fragment thereof binds to the alpha-3 domain of the MICA protein, the MICB protein, or both the MICA and MICB proteins. In some cases, the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both. In some cases, the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both. In some cases, the monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, a Fab, a F(ab')2, or a disulfide-linked Fv. In some cases, the monoclonal antibody or antigen-binding fragment thereof is an IgG or an IgM. In some cases, the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric.

[0008] Disclosed herein, in certain embodiments, is a pharmaceutical composition comprising a monoclonal antibody or antigen-binding fragment thereof according to any one of the disclosures herein and a pharmaceutically acceptable carrier or excipient.

[0009] In certain embodiments, a method of treating cancer in an individual in need thereof comprises administering to the individual an effective amount of a monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody TIFF0007734720000011.tif11165. In certain embodiments, a method of treating cancer in an individual in need thereof, comprising administering to the individual an effective amount of a monoclonal antibody or antigen-binding fragment thereof, wherein the monoclonal antibody comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, TIFF0007734720000012.tif11144. 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 at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises: (a) a light chain complementarity determining region (CDR) having an amino acid sequence at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises: (a) a light chain complementarity determining region (CDR) having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementarity 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 complementarity 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 complementarity 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 complementarity 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; and a heavy chain complementarity determining region 2 (CDR3) 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. (CDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 6 or SEQ ID NO: 14. Optionally, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 9, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 10, and a light chain complementarity 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 complementarity determining region 17 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 12, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 13, and a heavy chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 18, and a heavy chain complementarity 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 as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some cases, the monoclonal antibody or 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 as SEQ ID NO:7, SEQ ID NO:15, or SEQ ID NO:19; and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO:8, SEQ ID NO:16, or SEQ ID NO:20. In some cases, the monoclonal antibody or 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 as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some cases, the monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins. In some cases, the monoclonal antibody or antigen-binding fragment thereof binds to the alpha-3 domain of the MICA protein, the MICB protein, or both the MICA and MICB proteins. In some cases, the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both. In some cases, the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both. In some cases, the monoclonal antibody or antigen-binding fragment thereof is selected from whole immunoglobulin, scFv, Fab, F(ab')2, or disulfide-linked Fv. In some cases, the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM. In some cases, the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric. In some cases, the monoclonal antibody or antigen-binding fragment thereof reduces the level of soluble MICA protein, soluble MICB protein, or both. In some cases, the monoclonal antibody or antigen-binding fragment thereof reduces shedding of soluble MICA protein, soluble MICB protein, or both.In some cases, the monoclonal antibody or antigen-binding fragment thereof inhibits shedding of soluble MICA protein, soluble MICB protein, or both. In some cases, the cancer is hepatocellular carcinoma.

[0010] In certain embodiments, a method 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 comprising a light chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody is TIFF0007734720000013.tif11169. In certain embodiments, a method for 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 comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, Disclosed herein are methods in which the monoclonal antibody or antigen-binding fragment thereof does not have at least one CDR selected from the list comprising: TIFF0007734720000014.tif11169. 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 at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises: (a) a light chain complementarity determining region (CDR) having an amino acid sequence at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises: (a) a light chain complementarity determining region (CDR) having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementarity 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 complementarity 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 complementarity 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 complementarity 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; and a heavy chain complementarity determining region 2 (CDR3) 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. (CDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 6 or SEQ ID NO: 14. Optionally, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 9, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 10, and a light chain complementarity 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 complementarity determining region 17 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 12, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 13, and a heavy chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 18, and a heavy chain complementarity 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 as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some cases, the monoclonal antibody or 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 as SEQ ID NO:7, SEQ ID NO:15, or SEQ ID NO:19; and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO:8, SEQ ID NO:16, or SEQ ID NO:20. In some cases, the monoclonal antibody or 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 as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some cases, the monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins. In some cases, the monoclonal antibody or antigen-binding fragment thereof binds to the alpha-3 domain of the MICA protein, the MICB protein, or both the MICA and MICB proteins. In some cases, the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both. In some cases, the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both. In some cases, the monoclonal antibody or antigen-binding fragment thereof is selected from whole immunoglobulin, scFv, Fab, F(ab')2, or disulfide-linked Fv. In some cases, the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM. In some cases, the monoclonal antibody or fragment thereof is humanized or chimeric. In some cases, the monoclonal antibody or antigen-binding fragment thereof reduces 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.

[0011] In certain embodiments, a method for reducing levels of soluble MICA protein, soluble MICB protein, or both in an individual in need thereof comprises administering to the individual an effective amount of a monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody: TIFF0007734720000015.tif11128. In certain embodiments, a method for reducing levels 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 comprising a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody Disclosed herein are methods in which the monoclonal antibody or antigen-binding fragment thereof does not have at least one CDR selected from the list comprising: TIFF0007734720000016.tif11165. 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 at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 90% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises (a) a light chain complementarity determining region (CDR) having an amino acid sequence at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 95% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises: (a) a light chain complementarity determining region (CDR) having an amino acid sequence at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18.In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises: (a) a light chain complementarity determining region (CDR) having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17; and (b) a heavy chain complementarity determining region (CDR) having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementarity 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 complementarity 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 complementarity 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 complementarity 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; and a heavy chain complementarity determining region 2 (CDR3) 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. (CDR1) having an amino acid sequence at least 80% identical to one of SEQ ID NO: 6 or SEQ ID NO: 14. Optionally, the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 9, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 10, and a light chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 17, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 12, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 13, and a heavy chain complementarity 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 complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 18, and a heavy chain complementarity 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 as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some cases, the monoclonal antibody or 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 as SEQ ID NO:7, SEQ ID NO:15, or SEQ ID NO:19; and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO:8, SEQ ID NO:16, or SEQ ID NO:20. In some cases, the monoclonal antibody or 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 as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some cases, the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some cases, the monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins. In some cases, the monoclonal antibody or antigen-binding fragment thereof binds to the alpha-3 domain of the MICA protein, the MICB protein, or both the MICA and MICB proteins. In some cases, the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both. In some cases, the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both. In some cases, the monoclonal antibody or antigen-binding fragment thereof is selected from whole immunoglobulin, scFv, Fab, F(ab')2, or disulfide-linked Fv. In some cases, the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM. In some cases, the monoclonal antibody or fragment thereof is humanized or chimeric. In some cases, the monoclonal antibody or antigen-binding fragment thereof reduces or inhibits shedding of soluble MICA protein, soluble MICB protein, or both, thereby reducing the levels of soluble MICA protein, soluble MICB protein, or both in an individual.In some cases, the individual has a cancer characterized by elevated levels of soluble MICA protein, soluble MICB protein, or both. In some cases, the cancer is hepatocellular carcinoma.

[0012] In certain embodiments, the present application discloses any one monoclonal antibody or antigen-binding fragment thereof according to the disclosure herein for use in treating cancer in an individual in need thereof.In certain embodiments, the present application discloses any one monoclonal antibody or antigen-binding fragment thereof according to the disclosure herein for use in preparing a medicament for treating cancer in an individual in need thereof.In some cases, the cancer is hepatocellular carcinoma.

[0013] In certain embodiments, disclosed herein is a monoclonal antibody or antigen-binding fragment thereof that binds to MICA / B competitively 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 as SEQ ID NO: 27. In certain embodiments, disclosed herein is a monoclonal antibody or antigen-binding fragment thereof that binds to MICA / B competitively 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 as SEQ ID NO: 28. [The present invention 1001] A monoclonal antibody or antigen-binding fragment thereof, comprising a light chain comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. [The present invention 1002] The monoclonal antibody of the present invention 1001, further comprising a heavy chain comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. [The present invention 1003] A monoclonal antibody or antigen-binding fragment thereof, comprising a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. [The present invention 1004] 1003. A monoclonal antibody of the invention, wherein the light chain variable domain (VL) comprises an amino acid sequence at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. [The present invention 1005] The monoclonal antibody of the present invention 1003 further comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 80%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. [The present invention 1006] The monoclonal antibody of the present invention, 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. [The present invention 1007] The monoclonal antibody of the present invention, 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. [The present invention 1008] The monoclonal antibody of the present invention, 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. [The present invention 1009] The monoclonal antibody of the present invention, wherein 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 as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. [The present invention 1010] The monoclonal antibody of the present invention, wherein 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 as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. [The present invention 1011] The monoclonal antibody of the present invention 1003, wherein said monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins. [The present invention 1012] the monoclonal antibody or antigen-binding fragment thereof MICA protein, MICB protein, or both MICA and MICB proteins The monoclonal antibody of the present invention 1003, which binds to the alpha-3 domain of . [The present invention 1013] The monoclonal antibody of the present invention, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both. [The present invention 1014] The monoclonal antibody of the present invention, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both. [The present invention 1015] 1003. The monoclonal antibody of the present invention, wherein said monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, an Fab, an F(ab')2, or a disulfide-linked Fv. [The present invention 1016] The monoclonal antibody of the present invention, wherein said monoclonal antibody or antigen-binding fragment thereof is IgG or IgM. [The present invention 1017] The monoclonal antibody of the present invention, wherein said monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric. [The present invention 1018] A monoclonal antibody or 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 as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. [The present invention 1019] A monoclonal antibody of the invention 1018, wherein the heavy chain variable domain (VH) comprises an amino acid sequence at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. [The present invention 1020] The monoclonal antibody of the present invention further comprises a light chain variable domain (VL) comprising an amino acid sequence at least 80%, at least 90%, at least 95%, at least 99%, or 100% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. [The present invention 1021] The monoclonal antibody of the present invention, 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. [The present invention 1022] The monoclonal antibody of the present invention, 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. [The present invention 1023] The monoclonal antibody of the present invention, 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. [The present invention 1024] The monoclonal antibody of the present invention, wherein 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 as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. [The present invention 1025] The monoclonal antibody of the present invention, wherein 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 as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. [The present invention 1026] The monoclonal antibody of the present invention, wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins. [The present invention 1027] the monoclonal antibody or antigen-binding fragment thereof MICA protein, MICB protein, or both MICA and MICB proteins A monoclonal antibody of the present invention that binds to the alpha-3 domain of 1018. [The present invention 1028] The monoclonal antibody of the present invention 1026, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both. [The present invention 1029] The monoclonal antibody of the present invention 1026, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both. [The present invention 1030] The monoclonal antibody of the present invention, wherein said monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, an Fab, an F(ab')2, or a disulfide-linked Fv. [The present invention 1031] The monoclonal antibody of the present invention, wherein the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM. [The present invention 1032] The monoclonal antibody of the present invention, wherein said monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric. [The present invention 1033] A monoclonal antibody or antigen-binding fragment thereof, comprising a light chain complementarity-determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, wherein the monoclonal antibody is The monoclonal antibody or antigen-binding fragment thereof, which does not have at least one CDR selected from the list including TIFF0007734720000017.tif11169. [The present invention 1034] the light chain complementarity determining regions (CDRs) have an amino acid sequence at least 90%, at least 95%, at least 99%, or 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and the monoclonal antibody is A monoclonal antibody of the present invention 1033, which does not have at least one CDR selected from the list including TIFF0007734720000018.tif11128. [This invention 1035] The monoclonal antibody of the present invention 1033 further comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80%, at least 90%, at least 95%, at least 99%, or 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. [The present invention 1036] The monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementarity 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 complementarity 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 complementarity 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 complementarity 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; and a heavy chain complementarity determining region 2 (CDR3) 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. (CDR2), and a heavy chain complementarity 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. [This invention 1037] The monoclonal antibody of the present invention 1033, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 3. [The present invention 1038] The monoclonal antibody of the present invention 1033, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 9, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 10, and a light chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 11. [This invention 1039] The monoclonal antibody of the present invention 1033, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 17, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 3. [The present invention 1040] The monoclonal antibody of the present invention 1033, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 6. [The present invention 1041] A monoclonal antibody of the present invention 1033, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 12, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 13, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 14. [The present invention 1042] The monoclonal antibody of the present invention 1033, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 18, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 6. [This invention 1043] The monoclonal antibody of the present invention, 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 the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. [This invention 1044] The monoclonal antibody of the present invention, 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 set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. [This invention 1045] A monoclonal antibody of the present invention, 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 the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19; and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. [The present invention 1046] The monoclonal antibody of the present invention, 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. [This invention 1047] The monoclonal antibody of the present invention, 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. [This invention 1048] The monoclonal antibody of the present invention, 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. [This invention 1049] The monoclonal antibody of the present invention, wherein 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 as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. [The present invention 1050] The monoclonal antibody of the present invention, wherein 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 as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. [This invention 1051] The monoclonal antibody of the present invention, wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins. [This invention 1052] the monoclonal antibody or antigen-binding fragment thereof MICA protein, MICB protein, or both MICA and MICB proteins The monoclonal antibody of the present invention, 1033, which binds to the alpha-3 domain of . [This invention 1053] The monoclonal antibody of the present invention 1051, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both. [This invention 1054] The monoclonal antibody of the present invention 1051, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both. [This invention 1055] The monoclonal antibody of the present invention, wherein said monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, scFv, Fab, F(ab')2, or disulfide-linked Fv. [This invention 1056] The monoclonal antibody of the present invention, wherein the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM. [This invention 1057] The monoclonal antibody of the present invention, wherein said monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric. [This invention 1058] A monoclonal antibody or antigen-binding fragment thereof, comprising a heavy chain complementarity-determining region (CDR) having an amino acid sequence that is at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, wherein the monoclonal antibody is The monoclonal antibody or antigen-binding fragment thereof, which does not have at least one CDR selected from the list including TIFF0007734720000019.tif11169. [This invention 1059] the heavy chain complementarity determining regions (CDRs) have 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 set forth as SEQ ID NOs: 4-6, 12-14, and 18, and the monoclonal antibody is A monoclonal antibody of the present invention 1058, which does not have at least one CDR selected from the list including TIFF0007734720000020.tif11128. [The present invention 1060] The monoclonal antibody of the present invention 1058 further comprises a light chain complementarity determining region (CDR) having an amino acid sequence at least 80%, at least 90%, at least 95%, at least 99%, or 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17. [The present invention 1061] the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain complementarity 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 complementarity 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 complementarity 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 complementarity 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 complementarity 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; 1058. The monoclonal antibody of the present invention, comprising a light chain complementarity 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. [The present invention 1062] 1058. A monoclonal antibody of the present invention, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 6. [The present invention 1063] 1058. A monoclonal antibody of the present invention, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 12, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 13, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 14. [This invention 1064] 1058. A monoclonal antibody of the present invention, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 18, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 6. [This invention 1065] 1058. The monoclonal antibody of the present invention, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 3. [The present invention 1066] 1058. The monoclonal antibody of the present invention, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 9, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 10, and a light chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 11. [This invention 1067] 1058. The monoclonal antibody of the present invention, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 17, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 3. [The present invention 1068] 1058. The monoclonal antibody of the present invention, 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 the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. [The present invention 1069] The monoclonal antibody of the present invention, 1058, 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 the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. [The present invention 1070] The monoclonal antibody of the present invention, 1058, 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 the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20; and a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. [This invention 1071] The monoclonal antibody of the present invention, 1058, 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 set forth as SEQ ID NO: 8 and a light chain variable domain (VL) comprising an amino acid sequence that is at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 7. [This invention 1072] The monoclonal antibody of the present invention, 1058, 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 the amino acid sequence set forth as 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 as SEQ ID NO: 15. [This invention 1073] The monoclonal antibody of the present invention, 1058, 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 the amino acid sequence set forth as 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 as SEQ ID NO:19. [This invention 1074] The monoclonal antibody of the present invention, 1058, wherein 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 as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. [This invention 1075] 1058. The monoclonal antibody of the present invention, wherein 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 as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. [This invention 1076] The monoclonal antibody of the present invention, wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins. [This invention 1077] the monoclonal antibody or antigen-binding fragment thereof MICA protein, MICB protein, or both MICA and MICB proteins A monoclonal antibody of the present invention 1058, which binds to the alpha-3 domain of . [This invention 1078] The monoclonal antibody of the present invention 1076, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both. [This invention 1079] The monoclonal antibody of the present invention 1076, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both. [The present invention 1080] The monoclonal antibody of the present invention, wherein said monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, an Fab, an F(ab')2, or a disulfide-linked Fv. [This invention 1081] The monoclonal antibody of the present invention, wherein the monoclonal antibody or antigen-binding fragment thereof is IgG or IgM. [This invention 1082] The monoclonal antibody of the present invention, wherein said monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric. [This invention 1083] A pharmaceutical composition comprising any one of the monoclonal antibodies 1001 to 1082 of the present invention or an antigen-binding fragment thereof and a pharmaceutically acceptable carrier or excipient. [This invention 1084] 1. A method of treating cancer in an individual in need thereof, comprising administering to the individual an effective amount of a monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity-determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, The monoclonal antibody does not have at least one CDR selected from the list including TIFF0007734720000021.tif11128, The method. [This invention 1085] The monoclonal antibody or antigen-binding fragment thereof further comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, and the monoclonal antibody is The method of the present invention 1084, wherein the method does not have at least one CDR selected from the list including TIFF0007734720000022.tif11128. [This invention 1086] The monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementarity 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 complementarity 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 complementarity 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 complementarity 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; and a heavy chain complementarity determining region 2 (CDR3) 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. (CDR2), and a heavy chain complementarity 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. [This invention 1087] The method of claim 1084, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 3. [This invention 1088] The method of claim 1084, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 9, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 10, and a light chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 11. [This invention 1089] The method of claim 1084, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 17 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 3. [The present invention 1090] The method of claim 1084, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 6. [This invention 1091] The method of claim 1084, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 12, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 13, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 14. [This invention 1092] The method of claim 1084, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 18, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 6. [This invention 1093] The method of claim 1084, 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 the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. [This invention 1094] The method of claim 1084, 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 the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. [This invention 1095] The method of claim 1084, 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 the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19; and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. [This invention 1096] The method of claim 1084, 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. [This invention 1097] The method of claim 1084, 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. [This invention 1098] 1084. The method of claim 1084, 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. [This invention 1099] The method of claim 1084, wherein 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 as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. [The present invention 1100] The method of claim 1084, wherein 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 as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. [The present invention 1101] 1084. The method of claim 1084, wherein said monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins. [The present invention 1102] the monoclonal antibody or antigen-binding fragment thereof MICA protein, MICB protein, or both MICA and MICB proteins 1084. The method of claim 1084, wherein the antibody binds to the alpha-3 domain of the antibody. [The present invention 1103] 1102. The method of claim 1101, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both. [The present invention 1104] 1102. The method of claim 1101, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both. [This invention 1105] 1085. The method of claim 1084, wherein said monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, an Fab, an F(ab')2, or a disulfide-linked Fv. [The present invention 1106] 1085. The method of claim 1084, wherein said monoclonal antibody or antigen-binding fragment thereof is IgG or IgM. [This invention 1107] 1084. The method of claim 1084, wherein said monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric. [This invention 1108] the monoclonal antibody or antigen-binding fragment thereof Soluble MICA protein, soluble MICB protein, or both The method of the present invention 1084 reduces the level of [This invention 1109] the monoclonal antibody or antigen-binding fragment thereof Soluble MICA protein, soluble MICB protein, or both The method of the present invention 1084 reduces shedding. [The present invention 1110] the monoclonal antibody or antigen-binding fragment thereof Soluble MICA protein, soluble MICB protein, or both The method of the present invention 1084, which inhibits shedding of [The present invention 1111] The method of claim 1084, wherein the cancer is hepatocellular carcinoma. [The present invention 1112] 2. A method for treating a leukemia in an individual in need thereof, comprising administering to the individual an effective amount of a monoclonal antibody or antigen-binding fragment thereof comprising a light chain complementarity-determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17. Soluble MICA protein, soluble MICB protein, or both 1. A method for reducing the level of The monoclonal antibody does not have at least one CDR selected from the list including TIFF0007734720000023.tif11169, The method. [The present invention 1113] The monoclonal antibody or antigen-binding fragment thereof further comprises a heavy chain complementarity determining region (CDR) having an amino acid sequence at least 80% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18, and the monoclonal antibody is The method of the present invention 1112, wherein the method does not have at least one CDR selected from the list including TIFF0007734720000024.tif12128. [This invention 1114] The monoclonal antibody or antigen-binding fragment thereof comprises a light chain complementarity 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 complementarity 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 complementarity 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 complementarity 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; and a heavy chain complementarity determining region 2 (CDR3) 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. (CDR2), and a heavy chain complementarity 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. [This invention 1115] The method of claim 1112, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 3. [The present invention 1116] 1112. The method of claim 1112, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 9, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 10, and a light chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 11. [This invention 1117] The method of claim 1112, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 17, a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 3. [This invention 1118] The method of claim 1112, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 6. [This invention 1119] The method of claim 1112, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 12, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 13, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 14. [The present invention 1120] The method of claim 1112, wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least 80% identical to SEQ ID NO: 18, and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence at least 80% identical to SEQ ID NO: 6. [This invention 1121] The method of claim 1112, 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 the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. [This invention 1122] The method of claim 1112, 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 the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. [This invention 1123] The method of claim 1112, 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 the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19; and a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. [This invention 1124] The method of claim 1112, 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. [This invention 1125] 1112. The method of claim 1112, 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. [Invention 1126] 1112. The method of claim 1112, 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. [This invention 1127] 1112. The method of claim 1112, wherein 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 as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. [This invention 1128] 1112. The method of claim 1112, wherein 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 as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. [This invention 1129] 1112. The method of claim 1112, wherein said monoclonal antibody or antigen-binding fragment thereof specifically binds to MICA protein, MICB protein, or both MICA and MICB proteins. [The present invention 1130] the monoclonal antibody or antigen-binding fragment thereof MICA protein, MICB protein, or both MICA and MICB proteins The method of claim 1112, wherein the antibody binds to the alpha-3 domain of the antibody. [This invention 1131] 1129. The method of claim 1129, wherein the MICA protein is a membrane-bound MICA protein, a soluble MICA protein, or both. [This invention 1132] 1129. The method of claim 1129, wherein the MICB protein is a membrane-bound MICB protein, a soluble MICB protein, or both. [This invention 1133] 1113. The method of claim 1112, wherein said monoclonal antibody or antigen-binding fragment thereof is selected from a whole immunoglobulin, an scFv, an Fab, an F(ab')2, or a disulfide-linked Fv. [This invention 1134] 1112. The method of claim 1112, wherein said monoclonal antibody or antigen-binding fragment thereof is IgG or IgM. [This invention 1135] 1112. The method of claim 1112, wherein said monoclonal antibody or fragment thereof is humanized or chimeric. [This invention 1136] the monoclonal antibody or antigen-binding fragment thereof Soluble MICA protein, soluble MICB protein, or both thereby reducing or inhibiting shedding of the protein in said individual. Soluble MICA protein, soluble MICB protein, or both The method of the present invention 1112 reduces the level of [This invention 1137] The individual, Soluble MICA protein, soluble MICB protein, or both The method of claim 1112, wherein the patient has a cancer characterized by elevated levels of [This invention 1138] The method of claim 1137, wherein the cancer is hepatocellular carcinoma. [This invention 1139] A monoclonal antibody or antigen-binding fragment thereof that binds to MICA / B competitively 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 as SEQ ID NO: 27. [The present invention 1140] A monoclonal antibody or antigen-binding fragment thereof that binds to MICA / B competitively 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 as SEQ ID NO: 28. [Brief explanation of the drawings]

[0014] A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0015] [Figure 1] 1A-1B illustrate the binding of antibodies 3F9.E4 (FIG. 1A) and 16F10.C12 (FIG. 1B) to MICA / B alleles by ELISA. [Figure 2] 1 illustrates that antibody 3F9.E4 binds to cell surface MICA as assessed by staining of TRAMP C2 cells transfected with MICA*08 compared to parental TC2 cells. [Figure 3]1 illustrates that antibodies 3F9.E4 and 16F10.C12 inhibit MICA shedding from PLC / PRF / 5 cells. [Figure 4] Figures 4A-4B illustrate that antibodies 3F9.E4 (Figure 4A) and 16F10.C12 (Figure 4B) enhance NK-92 cell-mediated cytotoxicity of PLC / PRF / 5 cells. [Figure 5] 1 illustrates the antitumor activity of antibody 3F9 against B16 / MICA transfectants compared to an isotype control (IC). [Figure 6A] Figures 6A-6C illustrate that higher percentages of NKG2D-positive NK cells (Figure 6A), CD8+ T cells (Figure 6B), and γδ T cells (Figure 6C) were observed in tumor infiltrates (TILs) in 3F9 antibody-treated tumors compared to isotype controls. [Figure 6B] See legend to Figure 6A. [Figure 6C] See legend to Figure 6A. [Figure 7] Figures 7A-7B illustrate that treatment of MICA transgenic animals with 3F9 antibody in B16 / MICA reduces the levels of soluble MICA (Figure 7A) and surface MICA in the tumor (Figure 7B). [Figure 8A] Figures 8A-8C illustrate competitive binding assays showing that all antibodies bind to "structural" epitopes, with antibody 3F9.E4 competitively binding to antibody PDI-1 (Figure 8B), and antibody 16F10 binding to a slightly different but very similar epitope to PDI-1 and 3F9 (Figure 8C). [Figure 8B] See legend to Figure 8A. [Figure 8C] See legend to Figure 8A. DETAILED DESCRIPTION OF THE INVENTION

[0016] Detailed Description In some embodiments, disclosed herein are monoclonal antibodies that specifically bind to MICA / B. In some embodiments, the MICA / B antibodies herein bind to the MICA / B protein or a fragment thereof and modulate the immune response in an individual, thereby treating cancer (e.g., hepatocellular carcinoma).

[0017] Major histocompatibility complex class I-related chains A and B (MICA / B) are two stress-inducible ligands for the natural killer cell (NK) receptor NKG2D and play an important role in mediating NK and T cell cytotoxicity. Soluble MICA / B shed by diseased cells (e.g., cancer cells) reduces the sensitivity of NK and T cells through binding to the NKG2D receptor, thereby suppressing the immune response. Therefore, modulation of MICA / B is useful for modulating the immune response in individuals, e.g., individuals suffering from cancer. Antibodies that bind to and modulate MICA / B activity are desirable for the development of novel therapeutic agents for the treatment of cancer.

[0018] Certain technical terms As used herein, "MICA / B" refers to the MICA protein, the MICB protein, or both the MICA and MICB proteins, including their variants, isoforms, and species homologs of human MICA / B.

[0019] As used herein, "antibody" refers to a glycoprotein that exhibits binding specificity to a specific antigen. Antibodies often contain a variable domain and a constant domain in each of their heavy and light chains. Thus, 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. Within each variable domain are three complementarity-determining regions (CDRs) that form loops in the heavy chain variable domain (VH) and light chain variable domain (VL) that contact the surface of the antigen. As used herein, antibodies also include fragments of antibodies or "antigen-binding portions" that can bind to antigens.

[0020] As used herein, a "chimeric" antibody has a portion of its heavy and / or light chain that is identical or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, and to fragments of such antibodies, so long as the desired biological activity is exhibited (see, e.g., Morrison et al., Proc. Natl. Acad. Sci. USA 81:6851-6855 (1984)). As used herein, a "humanized antibody" refers to a chimeric antibody having human sequences substituted into the antibody sequence.

[0021] The terms "recipient," "individual," "subject," "host," and "patient" are used interchangeably herein and refer to any mammalian subject, particularly humans, for whom diagnosis, treatment, or therapy, as the case may be, is desired. "Mammal," for purposes of treatment, refers to any animal classified as a mammal, including humans, domestic and farm animals, as well as laboratory, zoo, sport, or pet animals, such as dogs, horses, cats, cows, sheep, goats, pigs, mice, rats, rabbits, guinea pigs, monkeys, etc. In some embodiments, the mammal is a human.

[0022] As used herein, the terms "treatment," "treating," and the like refer to administering an agent or performing a procedure, as the case may be, with the intent of achieving an effect. The effect may be prophylactic, in terms of completely or partially preventing a disease or its symptoms, and / or therapeutic, in terms of achieving a partial or complete cure of a disease and / or disease symptoms. As used herein, "treatment" may include the treatment of a disease or disorder (e.g., cancer) in a mammal, particularly a human, and includes: (a) preventing a disease or disease symptom (including, for example, a disease that may be associated with or caused by a primary disease) from occurring in a subject who may be predisposed to, but not yet diagnosed with, the disease; (b) arresting the disease, i.e., preventing its development; and (c) palliating the disease, i.e., causing regression of the disease. Treating can refer to any indication of the success of cancer treatment, improvement, or prevention, including any objective or subjective parameter, such as relief; remission; reduction of symptoms or making the disease state more tolerable to the patient; slowing the rate of degeneration or decline; or making the end point of degeneration less debilitating.Treatment or improvement of symptoms is based on one or more objective or subjective parameters, including the results of a physician's examination.Therefore, the term "treating" includes the administration of the compound or agent of the present invention to prevent or delay, alleviate, or inhibit or inhibit the onset of symptoms or conditions related to disease (e.g., cancer).The term "therapeutic effect" refers to the reduction, elimination, or prevention of disease, disease symptoms, or disease side effects in a subject.

[0023] A "therapeutically effective amount," as the case may be, means the amount that, when administered to a subject for treating a disease, is sufficient to effect treatment for that disease.

[0024] As used herein, the singular forms "a," "and," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "an antibody" includes a plurality of antibodies, reference to "an antibody" in some embodiments includes a multiplicity of antibodies, etc.

[0025] As used herein, all numerical values ​​or ranges include whole integers within or encompassing such ranges and fractional integers or values ​​within or encompassing such ranges, 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. In another example, reference to a range of 1 to 5,000 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.

[0026] As used herein, "about" a number refers to an inclusive range from 10% below that number to 10% above that number. "About" a range refers to a range from 10% below the lower limit of that range to 10% above the upper limit of that range.

[0027] "Percent (%) identity" refers to the degree to which two sequences (nucleotides or amino acids) have the same residues at the same positions in an alignment. For example, "an amino acid sequence is X% identical to SEQ ID NO: Y" refers to the % identity of an amino acid sequence to SEQ ID NO: Y, and describes that X% of the residues in the amino acid sequence are identical to the residues in the sequence disclosed in SEQ ID NO: Y. Generally, computer programs are used for such calculations. Exemplary programs for comparing and aligning pairs of sequences include ALIGN (Myers and Miller, 1988), FASTA (Pearson and Lipman, 1988; Pearson, 1990), and Gapped BLAST (Altschul et al., 1997), BLASTP, BLASTN, or GCG (Devereux et al., 1984).

[0028] MICA / B In some embodiments, disclosed herein are monoclonal antibodies that specifically bind to MICA / B. Further disclosed herein, in some embodiments, are monoclonal antibodies that competitively bind to MICA / B.

[0029] The major histocompatibility complex (MHC) class I chain-related gene A and gene B protein (MICA / B) is a glycosylated, polymorphic, membrane-anchored, non-classical MHC class I protein. MICA / B is related to MHC class I and has a similar domain structure, including three extracellular Ig-like domains (alpha-1, alpha-2, and alpha-3), a transmembrane domain, and a C-terminal cytoplasmic tail. However, MICA / B does not bind β2-microglobulin, lacks a CD8 binding site, and does not present any antigens. MICA / B is involved in the expression of NK, NKT, and αβ and γδ CD8 +MICA / B is a ligand for the C-type lectin-like activating receptor natural killer group 2D (NKG2D) on immune effector cells, including both T cells and IL-1. The interaction of MICA / B and NKG2D is involved in tumor surveillance and immune responses.

[0030] MICA / B proteins are normally expressed at low levels in normal cells but are induced to higher levels in stressed or transformed cells (e.g., cancer cells). Interaction between NKG2D-bearing immune effector cells and stressed or diseased cells expressing MICA / B ligands on their cell surface generates a cellular immune response against the stressed / pathological cells, leading to the death of the MICA / B-expressing cells. In cancer cells, truncated MICA / B proteins (proteins lacking the transmembrane domain and cytoplasmic tail but retaining three extracellular domains, including the alpha-1, alpha-2, and alpha-3 domains) are frequently shed into the blood by the action of proteases, resulting in downregulation of its intended receptor, NKG2D, on effector immune cells (receptor internalization). In some cases, MICA / B glycoproteins are produced intracellularly, but are not routinely bound to the cell surface membrane; instead, they are incorporated into exosomes and released extracellularly, where they interact with the NKG2D receptor on immune cells. These truncated or soluble MICA / B ligands shed from the surface of cancer cells act as decoy molecules, inhibiting NK, NKT, and various CD8 + This results in the downregulation of NKG2D receptors on immune effector cells such as T cells. In some cases, the formation of soluble MICA / B leads to an abnormal situation in which 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, thereby allowing cancer cells to hide from the immune system and grow unchecked.

[0031] Hepatocellular carcinoma (HCC) In some embodiments, the anti-MICA / B antibodies disclosed herein bind to the MICA / B protein or a fragment thereof and modulate the immune response in an individual, thereby treating cancer (e.g., hepatocellular carcinoma).

[0032] 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 C predispose individuals to the development of chronic liver disease and subsequent HCC. Obesity, diabetes, and alcohol abuse are some other factors that predispose individuals to subsequent HCC development.

[0033] Anti-MICA / B antibody Antibodies that specifically bind to MICA / B protein are provided herein. In some embodiments, the anti-MICA / B antibody comprises at least one heavy chain, and the anti-MICA / B antibody comprises at least one light chain. In some embodiments, the anti-MICA / B antibody comprises at least one heavy chain comprising a heavy chain variable domain (VH) and at least one light chain comprising a light chain variable domain (VL). Each VH and VL comprises three complementarity-determining regions (CDRs). The amino acid sequences of the VH and VL and CDRs determine the antigen-binding specificity and antigen-binding strength of the antibody. The amino acid sequences of the heavy and light chains, VH and VL, and CDRs are summarized in Table 1.

[0034] Table 1. Anti-MICA / B monoclonal antibody sequences TIFF0007734720000025.tif124170TIFF0007734720000026.tif234170TIFF0007734720000027.tif197170

[0035] In some embodiments, the antibody specifically binds to the MICA protein. In some embodiments, the antibody specifically binds to the MICB protein. In some embodiments, the antibody specifically binds to both the MICA and MICB proteins. In some embodiments, the antibody binds to the alpha-3 domain of the MICA protein. In some embodiments, the antibody binds to the alpha-3 domain of the MICB protein. In some embodiments, the antibody binds to the alpha-3 domain of both the MICA and MICB proteins. In some embodiments, the antibody binds to a MICA protein that is membrane-bound. In some embodiments, the antibody binds to a MICA protein that is soluble. In some embodiments, the antibody binds to a MICA protein that is both membrane-bound and soluble. In some embodiments, the antibody binds to a MICB protein that is membrane-bound. In some embodiments, the antibody binds to a MICB protein that is soluble. In some embodiments, the antibody binds to a MICB protein that is both membrane-bound and soluble.

[0036] In some embodiments, the antibody that specifically binds to MICA / B is a monoclonal antibody. In some embodiments, the antibody is an antigen-binding fragment. In some embodiments, the antibody is selected from a whole immunoglobulin, an scFv, an Fab, an F(ab')2, or a disulfide-linked Fv. In some embodiments, the antibody is an IgG or an IgM. In some embodiments, the antibody is humanized. In some embodiments, the antibody is chimeric.

[0037] MICA / B antibody heavy and light chains Disclosed herein are antibodies that specifically bind to MICA / B and have a light chain. In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some embodiments, the light chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:21, SEQ ID NO:23, or SEQ ID NO:24.

[0038] Further disclosed herein are antibodies that specifically bind to MICA / B, having a heavy chain. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some embodiments, the heavy chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some embodiments, the heavy chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:22, SEQ ID NO:25, or SEQ ID NO:26.

[0039] 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 at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24, and a heavy chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24, and the heavy chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24, and the heavy chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26.

[0040] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 21 and a heavy chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 22. In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 21, and the heavy chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 22. In some embodiments, the light chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 21, and the heavy chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 22.

[0041] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 23 and a heavy chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 25. In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 23, and the heavy chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 25. In some embodiments, the light chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 23, and the heavy chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 25.

[0042] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 23 and a heavy chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 23, and the heavy chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 23, and the heavy chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 26.

[0043] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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 as SEQ ID NO: 25. In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 24, and the heavy chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 25. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 24, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 25.

[0044] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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 as SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 24, and the heavy chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 24, and the heavy chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 26.

[0045] MICA / B antibody variable domains Disclosed herein are antibodies that specifically bind to MICA / B, having a light chain comprising a light chain variable domain (VL). In some embodiments, the antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some embodiments, the VL has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:7, SEQ ID NO:15, or SEQ ID NO:19.

[0046] Further disclosed herein are antibodies that specifically bind to MICA / B, having a heavy chain comprising a heavy chain variable domain (VH). In some embodiments, the antibody that binds to MICA / B comprises a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some embodiments, the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some embodiments, the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO:8, SEQ ID NO:16, or SEQ ID NO:20.

[0047] 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 at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19, and a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19, and the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19, and the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20.

[0048] In some embodiments, the antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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 as SEQ ID NO: 8. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 7, and the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the VL has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 7, and the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 8.

[0049] In some embodiments, the antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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 as SEQ ID NO: 16. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 15, and the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 16. In some embodiments, the VL has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 15, and the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0050] In some embodiments, the antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 19 and a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 20. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 19, and the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 20. In some embodiments, the VL has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 19, and the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 20.

[0051] MICA / B antibody complementarity determining regions Disclosed herein are antibodies that specifically bind to MICA / B, having a light chain comprising a light chain complementarity determining region (CDR). In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR sequence having an amino acid sequence at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17. In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR sequence having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17. In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR sequence having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17.

[0052] Further disclosed herein are antibodies that specifically bind to MICA / B, having a heavy chain comprising a heavy chain complementarity determining region (CDR). In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR sequence having an amino acid sequence at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR sequence having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR sequence having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18.

[0053] Also disclosed herein are antibodies that bind to MICA / B, comprising light chain complementarity determining regions (CDRs) and heavy chain complementarity determining regions (CDRs). In some embodiments, the antibodies that bind to MICA / B comprise a light chain CDR sequence having an amino acid sequence at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and a heavy chain CDR sequence having an amino acid sequence at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some embodiments, an antibody that binds to MICA / B has a light chain CDR sequence having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and a light chain CDR sequence having a sequence identical to at least one of the amino acid sequences set forth as SEQ ID NOs: In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR sequence having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and a heavy chain CDR sequence having an amino acid sequence at least about 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18.

[0054] In some embodiments, an antibody that binds to MICA / B has a light chain complementarity 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 complementarity determining region 2 (CDR2) having an amino acid sequence at least about 70% identical to one of SEQ ID NO: SEQ ID NO: 2, or SEQ ID NO: 10; a light chain complementarity 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 complementarity 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; and a heavy chain complementarity determining region 2 (CDR3) 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. (CDR2), and a heavy chain complementarity 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 to MICA / B has a light chain complementarity determining region 1 (CDR1) that 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 one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, SEQ ID NO: 2, or SEQ ID NO: a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11; and a light chain complementarity determining region 3 (CDR3) having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 4 or SEQ ID NO: a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18; and a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18. and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 6 or SEQ ID NO: 14.In some embodiments, an antibody that binds to MICA / B has a light chain complementarity determining region 1 (CDR1) having an amino acid sequence 100% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17; a light chain complementarity determining region 2 (CDR2) having an amino acid sequence 100% identical to one of SEQ ID NO: SEQ ID NO: 2, or SEQ ID NO: 10; a light chain complementarity determining region 3 (CDR3) having an amino acid sequence 100% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11; a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence 100% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12; and a heavy chain complementarity determining region 2 (CDR3) having an amino acid sequence 100% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18. (CDR2), and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence 100% identical to one of SEQ ID NO: 6 or SEQ ID NO: 14.

[0055] In some embodiments, an antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 3. In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: In some embodiments, the antibody that binds to MICA / B comprises at least one light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 2, and at least one light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 3.

[0056] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 10, and a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 11. In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 10, and a light chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: In some embodiments, the antibody that binds to MICA / B comprises at least one light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 11. In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 10, and at least one light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 11.

[0057] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 3. In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: In some embodiments, the antibody that binds to MICA / B comprises at least one light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 2, and at least one light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 3.

[0058] In some embodiments, an antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 6. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4; a heavy chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 5; In some embodiments, the antibody that binds to MICA / B comprises at least one heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 5, and at least one heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 6.

[0059] In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 14. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 12; a heavy chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 13; In some embodiments, the antibody that binds to MICA / B comprises at least one heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 14. In some embodiments, the antibody that binds to MICA / B comprises at least one heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 14.

[0060] In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 6. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4; a heavy chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 18; In some embodiments, the antibody that binds to MICA / B comprises at least one heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 18, and at least one heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 6.

[0061] In some embodiments, an antibody that binds to MICA / B comprises at least one of: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 1; a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 2; a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 3; a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 4; a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 5; and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 6.In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 1; a light chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 2; a light chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 3; a heavy chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4; and at least one heavy chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 6.In some embodiments, an antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 6.

[0062] In some embodiments, an antibody that binds to MICA / B comprises at least one of: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 9; a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 10; a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 11; a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 12; a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 13; and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 14.In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 9; a light chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 10; a light chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 11; a heavy chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 12; 13, and at least one heavy chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 14.In some embodiments, an antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 10, a light chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 11, a heavy chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 14.

[0063] In some embodiments, an antibody that binds to MICA / B comprises at least one of: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 17; a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 2; a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 3; a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 4; a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 18; and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 6.In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 17; a light chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 2; a light chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 3; a heavy chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4; 18, and at least one heavy chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 6.In some embodiments, an antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 6.

[0064] In some embodiments, the antibody that binds to MICA / B does not have at least one CDR selected from the list including: TIFF0007734720000028.tif11128.

[0065] competitive join Disclosed herein are antibodies that bind to MICA / B competitively 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 as 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 as SEQ ID NO: 27. In some embodiments, the VL has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 27.

[0066] Disclosed herein are antibodies that bind to MICA / B competitively 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 as 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 as SEQ ID NO: 28. In some embodiments, the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 28.

[0067] In some embodiments, disclosed herein are antibodies that bind to MICA / B competitively 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 as 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 as SEQ ID NO: 28. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 27, and the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 28. In some embodiments, the VL has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 27, and the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 28.

[0068] Methods of Treatment and Use 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.

[0069] Further provided herein is a method of reducing the level of soluble MICA / B protein in an individual in need thereof, comprising administration of the anti-MICA / B antibodies disclosed herein.

[0070] Also provided herein are methods for alleviating or inhibiting an immunosuppressive environment by preventing or blocking the interaction between soluble MICA / B and the NKG2D receptor in an individual in need thereof, comprising administering the anti-MICA / B antibodies disclosed herein.

[0071] In some embodiments, antibodies that bind to MICA / B comprise a light chain CDR sequence having an amino acid sequence at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17. In some embodiments, antibodies that bind to MICA / B comprise a light chain CDR sequence having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17. In some embodiments, antibodies that bind to MICA / B comprise a light chain CDR sequence having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17.

[0072] In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR sequence having an amino acid sequence at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR sequence having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR sequence having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18.

[0073] In some embodiments, an antibody that binds to MICA / B comprises a light chain CDR sequence having an amino acid sequence at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and a heavy chain CDR sequence having an amino acid sequence at least about 70% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18. In some embodiments, an antibody that binds to MICA / B comprises a light chain CDR sequence having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and a heavy chain CDR sequence having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR sequence having an amino acid sequence 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 1-3, 9-11, and 17, and a heavy chain CDR sequence having an amino acid sequence at least about 100% identical to at least one of the amino acid sequences set forth as SEQ ID NOs: 4-6, 12-14, and 18.

[0074] In some embodiments, an antibody that binds to MICA / B has a light chain complementarity 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 complementarity determining region 2 (CDR2) having an amino acid sequence at least about 70% identical to one of SEQ ID NO: SEQ ID NO: 2, or SEQ ID NO: 10; a light chain complementarity 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 complementarity 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; and a heavy chain complementarity determining region 2 (CDR3) 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. (CDR2), and a heavy chain complementarity 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 to MICA / B has a light chain complementarity determining region 1 (CDR1) that 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 one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17, SEQ ID NO: 2, or SEQ ID NO: a light chain complementarity determining region 2 (CDR2) having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11; and a light chain complementarity determining region 3 (CDR3) having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 4 or SEQ ID NO: a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18; and a heavy chain complementarity determining region 2 (CDR2) having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18. and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to one of SEQ ID NO: 6 or SEQ ID NO: 14.In some embodiments, an antibody that binds to MICA / B has a light chain complementarity determining region 1 (CDR1) having an amino acid sequence 100% identical to one of SEQ ID NO: 1, SEQ ID NO: 9, or SEQ ID NO: 17; a light chain complementarity determining region 2 (CDR2) having an amino acid sequence 100% identical to one of SEQ ID NO: SEQ ID NO: 2, or SEQ ID NO: 10; a light chain complementarity determining region 3 (CDR3) having an amino acid sequence 100% identical to one of SEQ ID NO: 3 or SEQ ID NO: 11; a heavy chain complementarity determining region 1 (CDR1) having an amino acid sequence 100% identical to one of SEQ ID NO: 4 or SEQ ID NO: 12; and a heavy chain complementarity determining region 2 (CDR3) having an amino acid sequence 100% identical to one of SEQ ID NO: 5, SEQ ID NO: 13, or SEQ ID NO: 18. (CDR2), and a heavy chain complementarity determining region 3 (CDR3) having an amino acid sequence 100% identical to one of SEQ ID NO: 6 or SEQ ID NO: 14.

[0075] In some embodiments, an antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 3. In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: In some embodiments, the antibody that binds to MICA / B comprises at least one light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 2, and at least one light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 3.

[0076] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 10, and a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 11. In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 10, and a light chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: In some embodiments, the antibody that binds to MICA / B comprises at least one light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 11. In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 10, and at least one light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 11.

[0077] In some embodiments, the antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 3. In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 2, and a light chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: In some embodiments, the antibody that binds to MICA / B comprises at least one light chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 2, and at least one light chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 3.

[0078] In some embodiments, an antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 6. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4; a heavy chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 5; In some embodiments, the antibody that binds to MICA / B comprises at least one heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 5, and at least one heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 6.

[0079] In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 14. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 12; a heavy chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 13; In some embodiments, the antibody that binds to MICA / B comprises at least one heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 14. In some embodiments, the antibody that binds to MICA / B comprises at least one heavy chain CDR1 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 14.

[0080] In some embodiments, the antibody that binds to MICA / B comprises at least one of a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 6. In some embodiments, the antibody that binds to MICA / B comprises a heavy chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4; a heavy chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 18; In some embodiments, the antibody that binds to MICA / B comprises at least one heavy chain CDR1 having an amino acid sequence that is at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 18, and at least one heavy chain CDR3 having an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 6.

[0081] In some embodiments, an antibody that binds to MICA / B comprises at least one of: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 1; a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 2; a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 3; a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 4; a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 5; and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 6.In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 1; a light chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 2; a light chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 3; a heavy chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4; and at least one heavy chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 6.In some embodiments, an antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 1, a light chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 5, and a heavy chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 6.

[0082] In some embodiments, an antibody that binds to MICA / B comprises at least one of: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 9; a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 10; a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 11; a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 12; a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 13; and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 14.In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 9; a light chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 10; a light chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 11; a heavy chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 12; 13, and at least one heavy chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 14.In some embodiments, an antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 9, a light chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 10, a light chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 11, a heavy chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 12, a heavy chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 13, and a heavy chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 14.

[0083] In some embodiments, an antibody that binds to MICA / B comprises at least one of: a light chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 17; a light chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 2; a light chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 3; a heavy chain CDR1 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 4; a heavy chain CDR2 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 18; and a heavy chain CDR3 having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 6.In some embodiments, the antibody that binds to MICA / B comprises a light chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 17; a light chain CDR2 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 2; a light chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 3; a heavy chain CDR1 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 4; 18, and at least one heavy chain CDR3 having an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 6.In some embodiments, an antibody that binds to MICA / B comprises at least one of a light chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 17, a light chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 2, a light chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 3, a heavy chain CDR1 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 4, a heavy chain CDR2 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 18, and a heavy chain CDR3 having an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 6.

[0084] In some embodiments, the antibody that binds to MICA / B does not have at least one CDR selected from the list including: TIFF0007734720000029.tif11128.

[0085] In some embodiments, an antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19. In some embodiments, the VL has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19.

[0086] In some embodiments, an antibody that binds to MICA / B comprises a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some embodiments, the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some embodiments, the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20.

[0087] In some embodiments, the antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19, and a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19, and the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 7, SEQ ID NO: 15, or SEQ ID NO: 19, and the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 8, SEQ ID NO: 16, or SEQ ID NO: 20.

[0088] In some embodiments, the antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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 as SEQ ID NO: 8. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 7, and the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 8. In some embodiments, the VL has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 7, and the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 8.

[0089] In some embodiments, the antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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 as SEQ ID NO: 16. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 15, and the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 16. In some embodiments, the VL has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 15, and the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 16.

[0090] In some embodiments, the antibody that binds to MICA / B comprises a light chain variable domain (VL) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 19 and a heavy chain variable domain (VH) having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 20. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 19, and the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 20. In some embodiments, the VL has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 19, and the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 20.

[0091] In some embodiments, an antibody that binds to MICA / B comprises a light chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24. In some embodiments, the light chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24.

[0092] In some embodiments, an antibody that binds to MICA / B comprises a heavy chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some embodiments, the heavy chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some embodiments, the heavy chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26.

[0093] 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 at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24, and a heavy chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24, and the heavy chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24, and the heavy chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO: 26.

[0094] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 21 and a heavy chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 22. In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 21, and the heavy chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 22. In some embodiments, the light chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 21, and the heavy chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 22.

[0095] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 23 and a heavy chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 25. In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 23, and the heavy chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 25. In some embodiments, the light chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 23, and the heavy chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 25.

[0096] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 23 and a heavy chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 23, and the heavy chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 23, and the heavy chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 26.

[0097] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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 as SEQ ID NO: 25. In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 24, and the heavy chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 25. In some embodiments, the light chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 24, and the heavy chain has an amino acid sequence that is 100% identical to the amino acid sequence set forth as SEQ ID NO: 25.

[0098] In some embodiments, the antibody that binds to MICA / B comprises a light chain having an amino acid sequence at least about 70% identical to the amino acid sequence set forth as 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 as SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 24, and the heavy chain has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth as SEQ ID NO: 26. In some embodiments, the light chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 24, and the heavy chain has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 26.

[0099] In some embodiments, the antibody binds to MICA / B competitively 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 as 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 as SEQ ID NO: 27. In some embodiments, the VL has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 27.

[0100] In some embodiments, the antibody binds to MICA / B competitively 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 as 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 as SEQ ID NO: 28. In some embodiments, the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 28.

[0101] In some embodiments, the antibody binds to MICA / B competitively 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 as 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 as SEQ ID NO: 28. In some embodiments, the VL has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 27, and the VH has an amino acid sequence at least about 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth as SEQ ID NO: 28. In some embodiments, the VL has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 27, and the VH has an amino acid sequence 100% identical to the amino acid sequence set forth as SEQ ID NO: 28.

[0102] In some embodiments, the antibody specifically binds to the MICA protein. In some embodiments, the antibody specifically binds to the MICB protein. In some embodiments, the antibody specifically binds to both the MICA and MICB proteins. In some embodiments, the antibody binds to the alpha-3 domain of the MICA protein. In some embodiments, the antibody binds to the alpha-3 domain of the MICB protein. In some embodiments, the antibody binds to the alpha-3 domain of both the MICA and MICB proteins. In some embodiments, the antibody binds to a MICA protein that is membrane-bound. In some embodiments, the antibody binds to a MICA protein that is soluble. In some embodiments, the antibody binds to a MICA protein that is both membrane-bound and soluble. In some embodiments, the antibody binds to a MICB protein that is membrane-bound. In some embodiments, the antibody binds to a MICB protein that is soluble. In some embodiments, the antibody binds to a MICB protein that is both membrane-bound and soluble.

[0103] In some embodiments, the antibody that specifically binds to MICA / B is a monoclonal antibody. In some embodiments, the antibody is an antigen-binding fragment. In some embodiments, the antibody is selected from a whole immunoglobulin, an scFv, an Fab, an F(ab')2, or a disulfide-linked Fv. In some embodiments, the antibody is an IgG or an IgM. In some embodiments, the antibody is humanized. In some embodiments, the antibody is chimeric.

[0104] In some embodiments, the antibodies disclosed herein reduce the level of soluble MICA protein. In some embodiments, the antibodies disclosed herein reduce the level of soluble MICB protein. In some embodiments, the antibodies disclosed herein reduce the level of both soluble MICA protein and soluble MICB protein. In some embodiments, the antibodies disclosed herein reduce the shedding of soluble MICA protein. In some embodiments, the antibodies disclosed herein reduce the shedding of soluble MICB protein. In some embodiments, the antibodies disclosed herein reduce the shedding of both soluble MICA protein and soluble MICB protein. In some embodiments, the antibodies disclosed herein inhibit the shedding of soluble MICA protein. In some embodiments, the antibodies disclosed herein inhibit the shedding of soluble MICB protein. In some embodiments, the antibodies disclosed herein inhibit the shedding of both soluble MICA protein and soluble MICB protein.

[0105] Any suitable route of administration is contemplated for use in the methods disclosed herein. In some embodiments, the antibody is administered intravenously. In some embodiments, the antibody is administered subcutaneously. In some embodiments, the antibody is administered locally. In some embodiments, the antibody is administered systemically (e.g., intravenously, intramuscularly, subcutaneously, intradermally, orally, intranasally, sublingually). In some embodiments, the antibody is formulated as a salve, lotion, or emulsion. In some embodiments, the antibody is formulated as a solution. In some embodiments, the antibody is formulated for topical, oral, buccal, or nasal administration.

[0106] In some embodiments, the individual is monitored before administering the antibody. Symptoms are identified and their severity is assessed. The antibodies described herein are administered over time, either singly or in combination, alone or in combination with additional treatments, as discussed herein or known to those skilled in the art. In some embodiments, the individual is monitored to determine the effectiveness of the treatment regimen. In some embodiments, the treatment regimen is modified according to preliminary treatment results, such that the treatment dose or frequency or dose and frequency are modified to achieve the desired level of subject response in terms of symptom alleviation, reduction of side effects, or a combination of symptom alleviation and reduction of side effects.

[0107] The therapeutically effective amount or dosage is from about 0.01 mg / kg to about 20 mg / kg, for example, about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 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, about 2.9 mg / kg, about 2.9 mg / kg, about 2.9 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 2.9 mg / kg, about 2.9 mg / kg, about 2. mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, approximately 3.3 mg / kg, approximately 3.4 mg / kg, approximately 3.5 mg / kg, approximately 3.6 mg / kg, approximately 3.7 mg / kg, approximately 3.8 mg / kg, approximately 3.9 mg / kg, approximately 4 mg / kg, approximately 4.1 mg / kg, approximately 4.2 mg / kg, approximately 4.3 mg / kg, approximately 4.4 mg / kg, approximately 4.5 mg / kg, approximately 4.6 mg / kg, approximately 4.7 mg / kg, approximately 4.8 mg / kg, approximately 4.9 mg / kg, approximately 5 mg / kg, approximately 5.1 mg / kg, approximately 5.2 mg / kg, approximately 5.3 mg / kg, approximately 5.4 mg / kg, approximately 5.5 mg / kg, approximately 5.6 mg / kg, approximately 5.7 mg / kg, approximately 5.8 mg / kg, approximately 5.9 mg / kg, approximately 6 mg / kg, approximately 6.1 mg / kg, approximately 6.2 mg / kg, approximately 6.3 mg / kg, about 6.4 mg / kg, about 6.5 mg / kg, about 6.6 mg / kg, about 6.7 mg / kg, about 6.8 mg / kg, about 6.9 mg / kg, about 7 mg / kg, about 7.1 mg / kg, about 7.2 mg / kg, about 7.3 mg / kg, about 7.4 mg / kg, about 7.5 mg / kg, about 7.6 mg / kg, about 7.7 mg / kg, about 7.8 mg / kg, about 7.9 mg / kg, about 8 mg / kg, about 8.1 mg / kg, about 8.2 mg / kg, about 8.3 mg / kg, about 8.4 mg / kg, about 8.5 mg / kg, about 8.6 mg / kg, about 8.7 mg / kg, about 8.8 mg / kg, about 8.9 mg / kg, about 9 mg / kg, about 9.1 mg / kg, about 9.2 mg / kg, about 9.3 mg / kg, about 9.4 mg / kg, about 9.5 mg / kg, about 9.6 mg / kg, about 9.7 mg / kg, about 9.8 mg / kg, about 9.9 mg / kg, about 10 mg / kg, about 10.1 mg / kg, about 10.2 mg / kg, about 10.3 mg / kg, about 10.4 mg / kg, about 10.5 mg / kg, about 10.6 mg / kg, about 10.7 mg / kg, about 10.8 mg / kg, about 10.9 mg / kg, about 11 mg / kg, about 11.1 mg / 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 13.5 mg / kg, about 13.6 mg / kg, about 13.7 mg / kg, about 13.8 mg / kg, about 13.9 mg / kg, about 14 mg / kg, about 14.1 mg / kg, about 14.2 mg / kg, about 14.3 mg / kg, about 14.4 mg / kg, about 14.5 mg / kg, about 14.6 mg / kg, about 14.7 mg / kg, about 14.8 mg / kg, about 14.9 mg / kg, about 15 mg / kg, about 15.1 mg / kg, about 15.2 mg / kg, about 15.3 mg / kg, about 15.4 mg / kg, about 15.5 mg / kg, about 15.6 mg / kg, about 15.7 mg / kg, about 15.8 mg / kg, about 15.9 mg / kg, about 16 mg / kg, about 16.1 mg / kg, about 16.2 mg / kg, about 16.3 mg / kg, about 16.4 mg / kg, about 16.5 mg / kg5 mg / kg, about 16.6 mg / kg, about 16.7 mg / kg, about 16.8 mg / kg, about 16.9 mg / kg, about 17 mg / kg, about 17.1 mg / kg, about 17.2 mg / kg, about 17.3 mg / kg, about 17.4 mg / kg, about 17.5 mg / kg, about 17.6 mg / kg, about 17.7 mg / kg, about 17.8 mg / kg, about 17.9 mg / kg, about 18 mg / kg, about 18.1 mg / kg, about 18.2 mg / kg, about 18.3 mg / kg, about 18.4 mg / kg, about 18.5 mg / kg, about 18.6 mg / kg, about 18.7 mg / kg, about 18.8 mg / kg, about 18.9 mg / kg, about 19 mg / kg, about 19.1 mg / kg, approximately 19.2 Therapeutically effective amounts or dosages are contemplated to include doses of 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. Therapeutically effective amounts or dosages are contemplated to include doses of about 0.1 mg / kg to about 2.0 mg / kg in some cases.

[0108] The methods of treatment herein include one or more administrations of anti-MICA / B antibodies at the doses disclosed herein. In some embodiments, the methods include one administration of anti-MICA / B antibodies. In some embodiments, the methods include two administrations of anti-MICA / B antibodies. In some embodiments, the methods include three administrations of anti-MICA / B antibodies. In some embodiments, the methods include four administrations of anti-MICA / B antibodies. In some embodiments, the methods include five administrations of anti-MICA / B antibodies. In some embodiments, the methods include six administrations of anti-MICA / B antibodies. In some embodiments, one or more administrations of anti-MICA / B antibodies are administered daily. In some embodiments, one or more administrations of anti-MICA / B antibodies are administered weekly. In some embodiments, one or more administrations of anti-MICA / B antibodies are administered every two weeks. In some embodiments, one or more administrations of anti-MICA / B antibodies are administered monthly. In some embodiments, one or more administrations of anti-MICA / B antibodies are administered every three months. In some embodiments, one or more doses of anti-MICA / B antibodies are administered every six months. In some embodiments, one or more doses of anti-MICA / B antibodies are administered annually.

[0109] In some embodiments, the methods of treatment disclosed herein are monotherapy. In some embodiments, the methods of treatment disclosed herein are combination therapy. In some embodiments, the combination therapy involves administration of an anti-MICA / B antibody in combination with another therapeutic agent. In some embodiments, the therapeutic agent comprises a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent includes, but is not limited to, cytotoxic agents, antimetabolites (e.g., antifolates, 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., cephalotaxines, camptothecin derivatives, quinoline alkaloids), alkylating agents (e.g., alkyl sulfonates, ethyleneimines, nitrogen mustards, nitrosoureas, platinum derivatives, triazenes, etc.), alkaloids, terpenoids, kinase inhibitors, and immune checkpoint inhibitors. In some embodiments, the anti-MICA / B antibodies disclosed herein are administered in combination with a therapeutic agent that induces an immune response. In some embodiments, the anti-MICA / B antibodies disclosed herein are administered in combination with a therapeutic agent that inhibits downregulation of an immune response. In some embodiments, inducing an immune response comprises upregulating NK cell activation or activity. In some embodiments, inducing an immune response comprises upregulating T cell activation or activity. In some embodiments, the immune checkpoint inhibitor target comprises PD-1. In some embodiments, the immune checkpoint inhibitor target comprises PD-L1. In some embodiments, the immune checkpoint inhibitor comprises pembrolizumab, nivolumab, cemiplimab, AMP-224, AMP-514, PDR001, atezolizumab, avelumab, durvalumab, BMS-936559, and CK-301.

[0110] Pharmaceutical Compositions Also disclosed herein are pharmaceutical compositions comprising the anti-MICA / B antibodies disclosed herein and a pharmaceutically acceptable carrier or excipient.

[0111] In some embodiments, excipients for use in 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.

[0112] In some embodiments, the composition further comprises an additional therapeutic agent. In some embodiments, the therapeutic agent is a chemotherapeutic agent. Chemotherapeutic agents can include, among others, cytotoxic agents, antimetabolites (e.g., antifolates, 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., cephalotaxines, camptothecin derivatives, quinoline alkaloids), alkylating agents (e.g., alkyl sulfonates, ethyleneimines, nitrogen mustards, nitrosoureas, platinum derivatives, triazenes, etc.), alkaloids, terpenoids, and kinase inhibitors.

[0113] In some embodiments, the antibody and the therapeutic agent are in the same formulation. In some embodiments, the antibody and the therapeutic agent are in different formulations. In some embodiments, the antibodies described herein are used prior to administration of other therapeutic agents. In some embodiments, the antibodies described herein are used simultaneously with administration of other therapeutic agents. In some embodiments, the antibodies described herein are used after administration of other therapeutic agents.

[0114] In some embodiments, pharmaceutical preparations are made to be compatible with specific local, regional or systemic administration or delivery route.Therefore, pharmaceutical preparations comprise carriers, diluents or excipients that are suitable for administration by specific route.Specific non-limiting examples of the administration route of compositions herein are parenteral, for example, intravenous, intraarterial, intradermal, intramuscular, subcutaneous, intrapleural, transdermal (topical), transmucosal, intracranial, intraspinal, intraocular, rectal, oral (nutrient), mucosal administration and any other formulation that is suitable for treatment method or administration protocol.

[0115] In some embodiments, solutions or suspensions used for parenteral administration include: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; 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 isotonicity such as sodium chloride or dextrose. In some embodiments, the pH is adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

[0116] Pharmaceutical preparations for injection include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate buffered saline (PBS). In some embodiments, the carrier is a solvent or dispersion medium containing, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), or suitable mixtures thereof. Fluidity is maintained in some embodiments by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Antibacterial and antifungal agents include, for example, parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. Isotonic agents, for example, sugars; polyalcohols such as mannitol or sorbitol; or sodium chloride are included in some embodiments of the composition. In some cases, an agent which delays absorption is also included; in some embodiments, for example, aluminum monostearate or gelatin prolongs absorption of the injectable compositions.

[0117] In some embodiments, sterile injectable preparations are prepared by incorporating the active composition in the required amount in suitable solvent with one or combination of above-mentioned components.Generally, dispersion is prepared by incorporating the active composition into a sterile vehicle that contains basic dispersion medium and any other components.For the preparation of sterile injectable solution, the method of preparation includes, for example, vacuum drying and freeze-drying, which produces powder of active ingredient and any additional desired components from its previously prepared solution.

[0118] For transmucosal or transdermal administration, penetrants suitable for the barrier to be permeated are used in the formulation.Such penetrants are known in the art, and for example, for transmucosal administration, include surfactants, bile salts, and fusidic acid derivatives.In some embodiments, transmucosal administration is achieved through the use of nasal sprays, inhalation devices (e.g., aspirators) or suppositories.For transdermal administration, active compounds are formulated into ointments, salves, gels, creams, or patches.

[0119] In some embodiments, pharmaceutical formulations are prepared with carriers that will protect them from rapid elimination from the body, such as time-release formulations or time-delay materials, such as glyceryl monostearate or glyceryl stearate. In some embodiments, the formulations are also delivered using articles of manufacture such as implants and microencapsulated delivery systems to achieve local, regional, or systemic delivery or controlled- or sustained-release. [Example]

[0120] The following examples are given for the purpose of illustrating various aspects of the present invention and are not meant to limit the invention in any way. The examples, along with the methods described herein, represent presently preferred embodiments and are exemplary and are not intended as limitations on the scope of the invention. Modifications therein and other uses encompassed within the spirit of the invention as defined by the claims will occur to those skilled in the art.

[0121] Example 1. Antibody binding kinetics measurement Affinity kinetics were determined using a ForteBio Octet Red 96 analyzer. Briefly, anti-MICA / B mAb (30 μg / ml) was captured on Dip and Read™ anti-mouse IgG Fc Capture (AMC) Biosensors (ForteBio) in an assay buffer of PBS + 0.1% BSA + 0.02% Tween-20 (pH 7.2) at room temperature. After washing the sensors in assay buffer, purified 6×His-MICA in a 2-fold dilution series was incubated for 5 minutes in assay buffer.* 08 or 6×His-MICA * The binding kinetics of the antibody to the protein antigen was determined by incubation with 04 protein (100 nM). The sensor was then incubated in assay buffer for 10 minutes to determine the dissociation kinetics. The resulting kinetic parameters were calculated using the ForteBio Analysis Suite 8.0 using a 1:1 model. The results of these assays are shown in Table 2.

[0122] Table 2. Kinetics of anti-MICA / B antibodies against MICA antigen measured by BioLayer interferometry. TIFF0007734720000030.tif25128

[0123] Example 2. Antibody binding to the MICA / B allele Recombinant MICA * 01. MICA * 02. MICA * 04. MICA * 08. MICA *09 and MICB proteins were diluted to 1 μg / ml in 50 mM sodium carbonate buffer, pH 9.6, and coated onto a high-binding 96-well microplate (Corning #9018) at 100 ng per well in 100 μl. The following morning, the coated ELISA plate was washed three times with TBS-Tween-20, pH 7.4, and then blocked in SuperBlock T20 Blocking Buffer (Pierce #37536). After blocking, the ELISA plate was washed once with TBS-T and incubated with serially diluted anti-MICA antibodies (0–1 μg / ml) at room temperature for approximately 2 hours. After incubation, the ELISA plate was washed three times with TBS-T and then incubated with goat anti-mouse IgG (H+L)-HRP conjugate (ThermoFisher Scientific #626520) for 45 minutes at room temperature with shaking (approximately 400 rpm). After incubation, the ELISA plate was washed three times with TBS-T and incubated with 100 μl of Super Sensitive Liquid Substrate TMB (Sigma #T4444) per well until sufficient color development was achieved. The reaction was stopped with 100 μl of 1 N sulfuric acid per well. Optical density (OD) values ​​were measured at 450 nm using a microplate reader. The results of this assay are shown in Figure 1A-B.

[0124] Example 3. Antibody binding to cell surface MICA Mouse prostate adenocarcinoma TRAMP-C2 cells (TC2) (ATCC, Manassas, VA) were used to express MICA. * A stable cell line (TC2-MICA-08) expressing the 08 allele was generated. Anti-MICA antibody binding 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, then washed once by centrifugation in FACS buffer (1 mM EDTA, 25 mM HEPES, 2% FBS in 1x PBS). Approximately 2–3 × 10 cells were collected. 5TC2-MICA-08 cells were incubated with 100 μl of FACS buffer containing 500 ng of anti-MICA antibody for 30 minutes at 4°C, followed by 100 μl of 2 μg / ml PE-conjugated goat anti-mouse IgG (Biolegend, San Diego, CA) secondary Ab for 30 minutes at 4°C. Cells were then washed once, and the cell pellet was resuspended in FACS buffer for live cell-gated FACS analysis. A significantly higher PE fluorescence signal was observed in TC2-MICA-08 cells compared to parental TC2 cells, indicating binding of the anti-MICA mAb to surface-expressed MICA. The results of this assay are shown in Figure 2.

[0125] Example 4. Antibodies inhibit MICA shedding from PLC / PRF / 5 cells 4×10 4PLC / PRF / 5 cells (hepatocellular carcinoma) (ATCC, Manassas, VA) were plated in a 96-well plate and incubated overnight at 37°C. The cells were then treated with 100 μl of Complete Media (MEM + 10% FBS, Thermo Scientific, Grand Island, NY) containing an anti-MICA antibody that binds to the MICA α3 domain and a negative control antibody, respectively, and incubated for an additional day at 37°C. The cell supernatant containing shed MICA was used to determine the level of soluble MICA by ELISA. Briefly, a 96-well plate was coated with 100 μl of 2 μg / ml anti-human MICA / B (clone BAMO1, MBL, Japan) overnight at 4°C. The plate was blocked and then incubated with the cell supernatant and MICA standard for 2 hours. After incubation, the plates were washed and then incubated with 1 μg / ml of a proprietary biotin-conjugated anti-human MICA / MICB mAb, clone 10E9, for 1 hour. Next, 100 μl of HRP-conjugated streptavidin (HRP-SA) (R&D Systems, Minneapolis, MN) was added to the wells and incubated for 30 minutes. Samples were developed with TMB for 4 minutes, stopped with 1 N sulfuric acid, and detected by absorbance at 450 nm. Soluble MICA levels were interpolated from the standard curve. The results of this assay are shown in Figure 3.

[0126] Example 5. Antibodies enhance NK-92 cell-mediated cytotoxicity against PLC / PRF / 5 cells PLC / PRF / 5 (target) cells were suspended in RPMI-1640 with 10% FBS and plated at 6,000 cells / well in 96-well flat-bottom plates (Costar). The cells were then incubated with an anti-MICA antibody (10 μg / ml) that binds to the MICA α3 domain for 24 hours, followed by labeling with calcein AM (1 μM) for 3 hours at 37°C, 5% CO2. Wells were washed, and NK-92 cells (effector) suspended in RPMI-1640 with 10% FBS were then added to the wells at various effector-to-target (E:T) ratios as indicated and co-cultured with the target cells for 4 hours. At the end of the incubation period, the supernatant was removed and 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 Figure 4A-B.

[0127] Example 6. Efficacy of 3F9.E4 in tumor treatment in vivo (survival) and NKG2S expression by tumor-infiltrating lymphocytes in tumor-bearing mice 10 in MICA transgenic mice (MICAgen) 4 B16F10-MICA * Mice were inoculated with 3F9.01 cells (B16 transfectants) and treated with 3F9.E4 or isotype control on day 11, when tumors reached the desired threshold size (arrows indicate days of injection) (log-rank test). The results are shown in Figure 5.

[0128] Mice were sacrificed when they reached a high tumor burden, and tumor-infiltrating lymphocytes were analyzed for NKG2D expression (SFI) by NK cells, CD8 αβ T cells, and γδ T cells. The NKG2D expression intensity (SFI) of NKG2D-expressing cells is shown in Figures 6A-6C. Each symbol represents the analysis of an individual mouse. (One-way ANOVA + Tukey's multiple comparison test).

[0129] Example 7. MICA expression by B16 transfectant tumors ex vivo and detection of soluble MICA in the serum of tumor-bearing mice 10 in MICA transgenic mice (MICAgen) 4 B16F10-MICA *Mice were inoculated with 01 cells (B16 transfectants) and treated with 3F9.E4 or BAMO3 or isotype control on day 11, when tumors reached a desired threshold size. Mice were sacrificed when high tumor burden was reached, and isolated single tumor cells were analyzed for MICA expression by mAb AMO1 staining (one-way ANOVA + Tukey's multiple comparison test). AMO1 binds to the a1a2-domain of MICA (≠ BAMO3 and 3F9). Each symbol represents the analysis of an individual mouse. Results are shown in Figure 7B. Serum was also analyzed for sMICA using an AMO1 / BAMO1 sandwich ELISA. Each symbol represents the analysis of an individual mouse (unpaired t-test). Results are shown in Figure 7A.

[0130] Example 8. Epitope binning MICA * O4-His protein (30 μg / ml) was immobilized on a Ni-NTA (FortrBio, #18-5101) biosensor chip in a Biolayer Interferometry System (Octet Red, ForteBio) for 300 seconds. The baseline signal was measured again for 60 seconds before the biosensor chip was immersed in a well containing 1 mM or 0.5 mM primary antibody for 300 seconds. Following this process, the biosensor was immersed in a well containing 100 nM or 50 nM of a second mAb for 300 seconds. The percent binding of the second mAb in the presence of the first mAb was determined by comparing the maximum signal of the second mAb after the first mAb was added to the maximum signal of the second mAb alone. A mAb was considered non-competitive if its maximum binding was 66% or greater than its non-competitive binding. Levels between 33% and 66% of non-competitive binding were considered intermediate, and binding below 33% was considered competitive. The results of this assay are shown in Figures 8A-8C.

[0131] While 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. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments described herein may be employed. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0132] Sequence information SEQUENCE LISTING <110> CULLINAN MICA CORP. <120> ANTI-MICA / B ANTIBODIES THAT BLOCK MICA / B SHEDDING AND METHODS OF USE <150> US 62 / 712,608 <151> 2018-07-31 <160> 34 <170> PatentIn version 3.5 <210> 1 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 1 Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Asn Thr Tyr Leu Tyr 1 5 10 15 <210> 2 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 2 Arg Met Ser Asn Leu Ala Ser 1 5 <210> 3 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 3 Met Gln His Leu Glu Tyr Pro Phe Thr 1 5 <210> 4 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 4 Gly Phe Thr Phe Ser Asn Tyr Ala Met Ser 1 5 10 <210> 5 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 5 Tyr Ile Ser Pro Gly Gly Asp Tyr Ile Tyr Tyr Ala Asp Thr Val Lys 1 5 10 15 Gly <210> 6 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 6 Asp Arg Arg His Tyr Gly Ser Tyr Ala Met Asp Tyr 1 5 10 <210> 7 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 7 Asp Ile Val Met Thr Gln Ala Ala Pro Ser Val Pro Val Thr Pro Gly 1 5 10 15 Glu Ser Val Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Arg Pro Gly Gln Ser 35 40 45 Pro Gln Leu Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Arg Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 110 <210> 8 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 8 Glu Val Gln Leu Gln Glu Ser Gly Glu Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Trp Val 35 40 45 Ala Tyr Ile Ser Pro Gly Gly Asp Tyr Ile Tyr Tyr Ala Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Arg Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Thr Thr Asp Arg Arg His Tyr Gly Ser Tyr Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Ile Ser Val Thr Val Ser Ser 115 120 <210> 9 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 9 Thr Ala Ser Ser Ser Val Ser Ser Asn Tyr Leu His 1 5 10 <210> 10 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 10 Thr Thr Ser Asn Leu Ala Ser 1 5 <210> 11 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 11 His Gln Phe His Arg Ser Pro Phe Thr 1 5 <210> 12 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 12 Gly Phe Ser Leu Thr Ala Phe Gly Val Asn 1 5 10 <210> 13 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 13 Met Ile Trp Gly Asp Gly Asn Thr Asp Tyr Asn Ser Thr Leu Arg Ser 1 5 10 15 <210> 14 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 14 Glu Thr Tyr Tyr Gly Asn Tyr Ala Gly Leu Gly Tyr 1 5 10 <210> 15 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 15 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Ile Gly 1 5 10 15 Glu Arg Val Thr Met Thr Cys Thr Ala Ser Ser Ser Val Ser Ser Asn 20 25 30 Tyr Leu His Trp Tyr Gln Gln Lys Pro Arg Ser Ser Pro Lys Leu Trp 35 40 45 Ile Tyr Thr Thr Ser Asn Leu Ala Ser Gly Val Pro Thr Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu 65 70 75 80 Ala Glu Asp Ala Ala Thr Tyr Tyr Cys His Gln Phe His Arg Ser Pro 85 90 95 Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 16 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 16 Glu Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln 1 5 10 15 Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ala Phe 20 25 30 Gly Val Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Gly Met Ile Trp Gly Asp Gly Asn Thr Asp Tyr Asn Ser Thr Leu Arg 50 55 60 Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu 65 70 75 80 Lys Leu Asn Ser Leu Gln Thr Asp Asp Thr Ala Arg Tyr Phe Cys Ala 85 90 95 Arg Glu Thr Tyr Tyr Gly Asn Tyr Ala Gly Leu Gly Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ala 115 120 <210> 17 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 17 Arg Ser Ser Lys Ser Leu Leu His Ser Asn Leu Asn Thr Tyr Leu Tyr 1 5 10 15 <210> 18 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 18 Tyr Ile Ser Pro Gly Gly Asp Tyr Ile Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 19 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 19 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Leu Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ile Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Phe Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys 100 105 110 Arg <210> 20 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 20 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Pro Gly Gly Asp Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Thr Asp Arg Arg His Tyr Gly Ser Tyr Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 21 <211> 219 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 21 Asp Ile Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly 1 5 10 15 Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser 20 25 30 Asn Leu Asn Thr Tyr Leu Tyr Trp Phe Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Gln Ile Leu Ile Tyr Arg Met Ser Asn Leu Ala Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Ala Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln His 85 90 95 Leu Glu Tyr Pro Phe Thr Phe Gly Pro Gly Thr Lys Leu Glu Ile Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 22 <211> 450 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 22 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Ala Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Pro Gly Gly Asp Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Thr Asp Arg Arg His Tyr Gly Ser Tyr Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly 450 <210> 23 <211> 234 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 23 Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Thr Leu Ser 20 25 30 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Gly 35 40 45 Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 50 55 60 Lys Leu Leu Ile Gln Tyr Thr Ser Leu Leu His Ser Gly Val Pro Ser 65 70 75 80 Arg Phe Ser Gly Ser Gly Ser Gly Thr Glu Tyr Thr Leu Thr Ile Ser 85 90 95 Ser Leu Gln Pro Asp Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr Ser 100 105 110 Lys Phe Pro Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 115 120 125 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 130 135 140 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 145 150 155 160 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 165 170 175 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 180 185 190 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 195 200 205 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 210 215 220 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 <210> 24 <211> 234 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 24 Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro 1 5 10 15 Gly Ser Thr Gly Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser 20 25 30 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Gly 35 40 45 Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 50 55 60 Lys Leu Leu Ile Gln Tyr Thr Ser Leu Leu His Ser Gly Val Pro Ser 65 70 75 80 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Thr Leu Thr Ile Ser 85 90 95 Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Tyr Ser 100 105 110 Lys Phe Pro Arg Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 115 120 125 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 130 135 140 Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 145 150 155 160 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 165 170 175 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 180 185 190 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 195 200 205 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 210 215 220 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 <210> 25 <211> 471 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 25 Met Asp Pro Lys Gly Ser Leu Ser Trp Arg Ile Leu Leu Phe Leu Ser 1 5 10 15 Leu Ala Phe Glu Leu Ser Tyr Gly Gln Ile Gln Leu Val Gln Ser Gly 20 25 30 Ser Glu Leu Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 35 40 45 Phe Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala 50 55 60 Pro Gly Gln Gly Leu Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly 65 70 75 80 Glu Pro Thr Tyr Ala Gln Gly Phe Thr Gly Arg Phe Val Phe Ser Leu 85 90 95 Glu Thr Ser Val Ser Thr Ala Tyr Leu Gln Ile Ser Ser Leu Lys Ala 100 105 110 Glu Asp Thr Ala Val Tyr Phe Cys Ala Arg Asn Tyr Gly Asn Tyr Leu 115 120 125 Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 130 135 140 Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 145 150 155 160 Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro 165 170 175 Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 180 185 190 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 195 200 205 Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile 210 215 220 Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val 225 230 235 240 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 245 250 255 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 260 265 270 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 275 280 285 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 290 295 300 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 305 310 315 320 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 325 330 335 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 340 345 350 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 355 360 365 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 370 375 380 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 385 390 395 400 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 405 410 415 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 420 425 430 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 435 440 445 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 450 455 460 Ser Leu Ser Leu Ser Pro Gly 465 470 <210> 26 <211> 471 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 26 Met Asp Pro Lys Gly Ser Leu Ser Trp Arg Ile Leu Leu Phe Leu Ser 1 5 10 15 Leu Ala Phe Glu Leu Ser Tyr Gly Gln Ile Gln Leu Val Gln Ser Gly 20 25 30 Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala 35 40 45 Phe Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn Trp Val Lys Gln Ala 50 55 60 Pro Gly Gln Gly Leu Lys Trp Met Gly Trp Ile Asn Thr Tyr Thr Gly 65 70 75 80 Glu Pro Thr Tyr Ala Asp Asp Phe Lys Gly Arg Val Thr Phe Thr Leu 85 90 95 Glu Thr Ser Ile Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser 100 105 110 Asp Asp Thr Ala Val Tyr Phe Cys Ala Arg Asn Tyr Gly Asn Tyr Leu 115 120 125 Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser 130 135 140 Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr 145 150 155 160 Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro 165 170 175 Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val 180 185 190 His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser 195 200 205 Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile 210 215 220 Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val 225 230 235 240 Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala 245 250 255 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro 260 265 270 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val 275 280 285 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val 290 295 300 Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln 305 310 315 320 Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln 325 330 335 Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 340 345 350 Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 355 360 365 Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr 370 375 380 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser 385 390 395 400 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr 405 410 415 Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr 420 425 430 Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe 435 440 445 Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys 450 455 460 Ser Leu Ser Leu Ser Pro Gly 465 470 <210> 27 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 27 Asp Ile Gln Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Thr Ile Ser Cys Ser Ala Ser Gln Gly Ile Ser Asn Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly Thr Leu Lys Leu Leu Ile 35 40 45 Gln Tyr Thr Ser Leu Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Tyr Ser Leu Thr Ile Ser Asn Leu Glu Pro 65 70 75 80 Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Tyr Ser Lys Phe Pro Arg 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 28 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic polypeptide <400> 28 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Ser Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Phe Gly Tyr Thr Phe Thr Asn Tyr 20 25 30 Gly Met Asn Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met 35 40 45 Gly Trp Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn His Leu Lys Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Arg Asn Tyr Gly Asn Tyr Leu Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Thr Leu Thr Val Ser Ser 115 <210> 29 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 29 Ser Ala Ser Gln Gly Ile Ser Asn Tyr Leu Asn 1 5 10 <210> 30 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 30 Thr Ser Leu Leu His Ser Gly 1 5 <210> 31 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 31 Gln Gln Tyr Ser Lys Phe Pro Arg Thr 1 5 <210> 32 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 32 Gly Tyr Thr Phe Thr Asn Tyr Gly Met Asn 1 5 10 <210> 33 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 33 Ile Asn Thr Tyr Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys Gly 1 5 10 15 <210> 34 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Description of Artificial Sequence: Synthetic peptide <400> 34 Asn Tyr Gly Asn Tyr Leu Phe Asp Tyr 1 5

Claims

1. A method for producing a human ovarian tumor comprising administering to a mammalian subject the present invention a method for producing a human ovarian tumor comprising administering to a mammalian subject the present invention a method for producing a human ovarian tumor comprising administering to a mammalian subject the present invention a method for producing a human ovarian tumor comprising administering to a mammalian subject the present invention a light chain variable domain (VL) comprising the amino acid sequence set forth as SEQ ID NO: 15 and a heavy chain variable domain (VH) comprising the amino acid sequence set forth as SEQ ID NO: 16; or a light chain variable domain (VL) comprising the amino acid sequence set forth as SEQ ID NO: 19 and a heavy chain variable domain (VH) comprising the amino acid sequence set forth as SEQ ID NO: 20; A monoclonal antibody or antigen-binding fragment thereof.

2. The monoclonal antibody or antigen-binding fragment thereof of claim 1, wherein the monoclonal antibody comprises a light chain comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO:

24.

3. The monoclonal antibody or antigen-binding fragment thereof of claim 1 or 2, wherein the monoclonal antibody comprises a heavy chain comprising an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO: 22, SEQ ID NO: 25, or SEQ ID NO:

26.

4. The monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, wherein the monoclonal antibody binds to the alpha-3 domain of the MICA protein, the MICB protein, or both the MICA and MICB proteins.

5. The monoclonal antibody or antigen-binding fragment thereof may be a whole immunoglobulin, scFv, Fab, F(ab') 2 or a disulfide-linked Fv, or the monoclonal antibody or antigen-binding fragment thereof is an IgG or an IgM; or the monoclonal antibody or antigen-binding fragment thereof is humanized or chimeric; A monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1 to 4.

6. A pharmaceutical composition comprising the monoclonal antibody or antigen-binding fragment thereof according to any one of claims 1 to 5 and a pharmaceutically acceptable carrier or excipient.

7. A pharmaceutical composition for reducing the level of soluble MICA protein, soluble MICB protein, or both in an individual, comprising the monoclonal antibody or antigen-binding fragment thereof of any one of claims 1 to 5 or the pharmaceutical composition of claim 6.

Images