US2021047417A1PendingUtilityA1

Mica/b antibodies and methods of use

54
Assignee: CULLINAN MICA CORPPriority: Jan 25, 2018Filed: Jul 24, 2020Published: Feb 18, 2021
Est. expiryJan 25, 2038(~11.5 yrs left)· nominal 20-yr term from priority
Inventors:Neil GibsonJustin ChapmanXin Du
A61K 2039/844C07K 16/2833C07K 2317/76C07K 2317/92A61P 35/00A61P 35/02A61K 2039/505C07K 2317/732C07K 2317/51C07K 2317/73C07K 2317/565C07K 2317/515C07K 2317/56
54
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Claims

Abstract

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

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A monoclonal antibody or an antigen-binding fragment thereof, comprising a light chain variable domain (VL) comprising an amino acid sequence at least 80% identical an amino acid sequence set forth as SEQ ID NO: 7, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10. 
     
     
         2 . A monoclonal antibody or an antigen-binding fragment thereof, comprising a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical an amino acid sequence set forth as SEQ ID NO: 7, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10. 
     
     
         3 . A monoclonal antibody or an antigen-binding fragment thereof, comprising a light chain variable domain (VL) comprising an amino acid sequence at least 95% identical an amino acid sequence set forth as SEQ ID NO: 7, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10. 
     
     
         4 . A monoclonal antibody or an antigen-binding fragment thereof, comprising a light chain variable domain (VL) comprising an amino acid sequence at least 99% identical an amino acid sequence set forth as SEQ ID NO: 7, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10. 
     
     
         5 . A monoclonal antibody or an antigen-binding fragment thereof, comprising a light chain variable domain (VL) comprising an amino acid sequence 100% identical an amino acid sequence set forth as SEQ ID NO: 7, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10. 
     
     
         6 . The monoclonal antibody of any one of  claims 1 - 5 , 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         7 . The monoclonal antibody of any one of  claims 1 - 5 , wherein 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         8 . The monoclonal antibody of any one of  claims 1 - 5 , wherein 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         9 . The monoclonal antibody of any one of  claims 1 - 5 , wherein 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         10 . The monoclonal antibody of any one of  claims 1 - 5 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) comprising an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         11 . The monoclonal antibody of any one of  claims 1 - 10 , wherein the light chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified. 
     
     
         12 . The monoclonal antibody of any one of  claims 1 - 11 , wherein the heavy chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified. 
     
     
         13 . The monoclonal antibody of any one of  claims 1 - 12 , wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         14 . The monoclonal antibody of any one of  claims 1 - 13 , wherein the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         15 . The monoclonal antibody of  claim 13  or  claim 14 , wherein the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both. 
     
     
         16 . The monoclonal antibody of  claim 13  or  claim 14 , wherein the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both. 
     
     
         17 . The monoclonal antibody of any one of  claims 1 - 16 , wherein 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. 
     
     
         18 . The monoclonal antibody of any one of  claims 1 - 17 , wherein the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM. 
     
     
         19 . The monoclonal antibody of any one of  claims 1 - 18 , wherein the monoclonal antibody or fragment thereof is humanized or chimeric. 
     
     
         20 . A monoclonal antibody or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 80% identical to an amino acid sequence set forth as SEQ ID NO: 8, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9. 
     
     
         21 . A monoclonal antibody or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to an amino acid sequence set forth as SEQ ID NO: 8, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9. 
     
     
         22 . A monoclonal antibody or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 95% identical to an amino acid sequence set forth as SEQ ID NO: 8, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9. 
     
     
         23 . A monoclonal antibody or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) comprising an amino acid sequence at least 99% identical to an amino acid sequence set forth as SEQ ID NO: 8, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9. 
     
     
         24 . A monoclonal antibody or an antigen-binding fragment thereof, comprising a heavy chain variable domain (VH) comprising an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 8, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9. 
     
     
         25 . The monoclonal antibody of any one of  claims 20 - 24 , 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         26 . The monoclonal antibody of any one of  claims 20 - 24 , wherein 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         27 . The monoclonal antibody of any one of  claims 20 - 24 , wherein 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         28 . The monoclonal antibody of any one of  claims 20 - 24 , wherein 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         29 . The monoclonal antibody of any one of  claims 20 - 24 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) comprising an amino acid sequence 100% identical to an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         30 . The monoclonal antibody of any one of  claims 20 - 29 , wherein the heavy chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified. 
     
     
         31 . The monoclonal antibody of any one of  claims 20 - 30 , wherein the light chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified. 
     
     
         32 . The monoclonal antibody of any one of  claims 20 - 31 , wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         33 . The monoclonal antibody of any one of  claims 20 - 32 , wherein the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         34 . The monoclonal antibody of  claim 36  or  claim 33 , wherein the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both. 
     
     
         35 . The monoclonal antibody of  claim 36  or  claim 33 , wherein the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both. 
     
     
         36 . The monoclonal antibody of any one of  claims 20 - 35 , wherein 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. 
     
     
         37 . The monoclonal antibody of any one of  claims 20 - 36 , wherein the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM. 
     
     
         38 . The monoclonal antibody of any one of  claims 20 - 37 , wherein the monoclonal antibody or fragment thereof is humanized or chimeric. 
     
     
         39 . A monoclonal antibody or an antigen-binding fragment thereof, comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 3, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10. 
     
     
         40 . A monoclonal antibody or an antigen-binding fragment thereof, comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 90% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 90% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 90% identical to SEQ ID NO: 3, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10. 
     
     
         41 . A monoclonal antibody or an antigen-binding fragment thereof, comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 95% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 95% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 95% identical to SEQ ID NO: 3, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10. 
     
     
         42 . A monoclonal antibody or an antigen-binding fragment thereof, comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 99% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 99% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 99% identical to SEQ ID NO: 3, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10. 
     
     
         43 . A monoclonal antibody or an antigen-binding fragment thereof, comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 100% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 100% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 100% identical to SEQ ID NO: 3, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10. 
     
     
         44 . The monoclonal antibody of any one of  claims 39 - 43 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 6. 
     
     
         45 . The monoclonal antibody of any one of  claims 39 - 43 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 90% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 90% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 90% identical to SEQ ID NO: 6. 
     
     
         46 . The monoclonal antibody of any one of  claims 39 - 43 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 95% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 95% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 95% identical to SEQ ID NO: 6. 
     
     
         47 . The monoclonal antibody of any one of  claims 39 - 43 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 99% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 99% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 99% identical to SEQ ID NO: 6. 
     
     
         48 . The monoclonal antibody of any one of  claims 39 - 43 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) sequence 100% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence 100% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence 100% identical to SEQ ID NO: 6. 
     
     
         49 . The monoclonal antibody of any one of  claims 39 - 48 , 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         50 . The monoclonal antibody of  claim 49 , 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         51 . The monoclonal antibody of any one of  claims 39 - 48 , 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         52 . The monoclonal antibody of  claim 51 , 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         53 . The monoclonal antibody of any one of  claims 39 - 52 , wherein the light chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified. 
     
     
         54 . The monoclonal antibody of any one of  claims 39 - 53 , wherein the heavy chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified. 
     
     
         55 . The monoclonal antibody of any one of  claims 39 - 54 , wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         56 . The monoclonal antibody of any one of  claims 39 - 55 , wherein the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         57 . The monoclonal antibody of  claim 55  or  claim 56 , wherein the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both. 
     
     
         58 . The monoclonal antibody of  claim 55  or  claim 56 , wherein the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both. 
     
     
         59 . The monoclonal antibody of any one of  claims 39 - 58 , wherein 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. 
     
     
         60 . The monoclonal antibody of any one of  claims 39 - 59 , wherein the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM. 
     
     
         61 . The monoclonal antibody of any one of  claims 39 - 60 , wherein the monoclonal antibody or fragment thereof is humanized or chimeric. 
     
     
         62 . A monoclonal antibody or an antigen-binding fragment thereof, comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 6, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9. 
     
     
         63 . A monoclonal antibody or an antigen-binding fragment thereof, comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 90% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 90% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 90% identical to SEQ ID NO: 6, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9. 
     
     
         64 . A monoclonal antibody or an antigen-binding fragment thereof, comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 95% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 95% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 95% identical to SEQ ID NO: 6, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9. 
     
     
         65 . A monoclonal antibody or an antigen-binding fragment thereof, comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 99% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 99% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 99% identical to SEQ ID NO: 6, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9. 
     
     
         66 . A monoclonal antibody or an antigen-binding fragment thereof, comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence 100% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence 100% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence 100% identical to SEQ ID NO: 6, wherein the monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain that does not have an amino acid sequence set forth as SEQ ID NO: 10, or wherein the monoclonal antibody or antigen-binding fragment thereof comprises a light chain that does not have an amino acid sequence set forth as SEQ ID NO: 9. 
     
     
         67 . The monoclonal antibody of any one of  claims 62 - 66 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 3. 
     
     
         68 . The monoclonal antibody of any one of  claims 62 - 66 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 90% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 90% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 90% identical to SEQ ID NO: 3. 
     
     
         69 . The monoclonal antibody of any one of  claims 62 - 66 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 95% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 95% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 95% identical to SEQ ID NO: 3. 
     
     
         70 . The monoclonal antibody of any one of  claims 62 - 66 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 99% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 99% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 99% identical to SEQ ID NO: 3. 
     
     
         71 . The monoclonal antibody of any one of  claims 62 - 66 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) sequence 100% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence 100% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence 100% identical to SEQ ID NO: 3. 
     
     
         72 . The monoclonal antibody of any one of  claims 62 - 71 , 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         73 . The monoclonal antibody of  claim 72 , 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         74 . The monoclonal antibody of any one of  claims 62 - 71 , 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         75 . The monoclonal antibody of  claim 74 , 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         76 . The monoclonal antibody of any one of  claims 62 - 75 , wherein the heavy chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 10 are modified. 
     
     
         77 . The monoclonal antibody of any one of  claims 62 - 76 , wherein the light chain comprises an amino acid sequence wherein at least 1 to 10 amino acids of amino acid sequence set forth as SEQ ID NO: 9 are modified. 
     
     
         78 . The monoclonal antibody of any one of  claims 62 - 77 , wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         79 . The monoclonal antibody of any one of  claims 62 - 78 , wherein the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         80 . The monoclonal antibody of  claim 78  or  claim 79 , wherein the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both. 
     
     
         81 . The monoclonal antibody of  claim 78  or  claim 79 , wherein the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both. 
     
     
         82 . The monoclonal antibody of any one of  claims 62 - 81 , wherein 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. 
     
     
         83 . The monoclonal antibody of any one of  claims 62 - 82 , wherein the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM. 
     
     
         84 . The monoclonal antibody of any one of  claims 62 - 83 , wherein the monoclonal antibody or fragment thereof is humanized or chimeric. 
     
     
         85 . A pharmaceutical composition comprising: a monoclonal antibody or an antigen-binding fragment thereof according to any one of  claims 1  to  84 ; and a pharmaceutically acceptable carrier or excipient. 
     
     
         86 . A method of treating cancer in an individual in need thereof, comprising administering to the individual an effective amount of a monoclonal antibody or an antigen-binding fragment thereof comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 3. 
     
     
         87 . The method  claim 86 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 6. 
     
     
         88 . The method of any one of  claim 86  or  87 , 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         89 . The method of  claim 88 , 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         90 . The method of any one of  claim 86  or  87 , 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         91 . The method of  claim 90 , 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         92 . The method of any one of  claims 86 - 91 , wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         93 . The method of any one of  claims 86 - 92 , wherein the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         94 . The method of  claim 92  or  claim 93 , wherein the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both. 
     
     
         95 . The method of  claim 92  or  claim 93 , wherein the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both. 
     
     
         96 . The method of any one of  claims 86 - 95 , wherein 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. 
     
     
         97 . The method of any one of  claims 86 - 96 , wherein the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM. 
     
     
         98 . The method of any one of  claims 86 - 97 , wherein the monoclonal antibody or fragment thereof is humanized or chimeric. 
     
     
         99 . The method of any one of  claims 86 - 98 , wherein the monoclonal antibody or antigen binding fragment thereof reduces level of soluble MICA protein, soluble MICB protein, or both. 
     
     
         100 . The method of any one of  claims 86 - 98 , wherein the monoclonal antibody or antigen binding fragment thereof reduces shedding of soluble MICA protein, soluble MICB protein, or both. 
     
     
         101 . The method of any one of  claims 86 - 98 , wherein the monoclonal antibody or antigen binding fragment thereof inhibits shedding of soluble MICA protein, soluble MICB protein, or both. 
     
     
         102 . The method of any one of  claims 86 - 101 , wherein the cancer is hepatocellular carcinoma. 
     
     
         103 . A method of treating cancer in an individual in need thereof, comprising administering to the individual an effective amount of a monoclonal antibody or an antigen-binding fragment thereof comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 6. 
     
     
         104 . The method of  claim 103 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 3. 
     
     
         105 . The method of any one of  claim 103  or  104 , 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         106 . The method of  claim 105 , 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         107 . The method of any one of  claim 103  or  104 , 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         108 . The method of  claim 107 , 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         109 . The method of any one of  claims 103 - 108 , wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         110 . The method of any one of  claims 103 - 109 , wherein the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         111 . The method of  claim 109  or  claim 110 , wherein the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both. 
     
     
         112 . The method of  claim 109  or  claim 110 , wherein the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both. 
     
     
         113 . The method of any one of  claims 103 - 112 , wherein 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. 
     
     
         114 . The method of any one of  claims 103 - 113 , wherein the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM. 
     
     
         115 . The method of any one of  claims 103 - 114 , wherein the monoclonal antibody or fragment thereof is humanized or chimeric. 
     
     
         116 . The method of any one of  claims 103 - 115 , wherein the monoclonal antibody or antigen binding fragment thereof reduces level of soluble MICA protein, soluble MICB protein, or both. 
     
     
         117 . The method of any one of  claims 103 - 115 , wherein the monoclonal antibody or antigen binding fragment thereof reduces shedding of soluble MICA protein, soluble MICB protein, or both. 
     
     
         118 . The method of any one of  claims 103 - 115 , wherein the monoclonal antibody or antigen binding fragment thereof inhibits shedding of soluble MICA protein, soluble MICB protein, or both. 
     
     
         119 . The method of any one of  claims 103 - 118 , wherein the cancer is hepatocellular carcinoma. 
     
     
         120 . 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 an antigen-binding fragment thereof comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 3. 
     
     
         121 . The method  claim 120 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 6. 
     
     
         122 . The method of any one of  claim 120  or  121 , 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         123 . The method of  claim 122 , 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         124 . The method of any one of  claim 120  or  121 , 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         125 . The method of  claim 124 , 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         126 . The method of any one of  claims 120 - 125 , wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         127 . The method of any one of  claims 120 - 126 , wherein the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         128 . The method of  claim 126  or  claim 127 , wherein the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both. 
     
     
         129 . The method of  claim 126  or  claim 127 , wherein the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both. 
     
     
         130 . The method of any one of  claims 120 - 129 , wherein 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. 
     
     
         131 . The method of any one of  claims 120 - 130 , wherein the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM. 
     
     
         132 . The method of any one of  claims 120 - 131 , wherein the monoclonal antibody or fragment thereof is humanized or chimeric. 
     
     
         133 . The method of any one of  claims 120 - 132 , wherein the monoclonal antibody or antigen binding fragment thereof reduces level of soluble MICA protein, soluble MICB protein, or both. 
     
     
         134 . The method of any one of  claims 120 - 132 , wherein the monoclonal antibody or antigen binding fragment thereof reduces shedding of soluble MICA protein, soluble MICB protein, or both. 
     
     
         135 . The method of any one of  claims 120 - 132 , wherein the monoclonal antibody or antigen binding fragment thereof inhibits shedding of soluble MICA protein, soluble MICB protein, or both. 
     
     
         136 . 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 an antigen-binding fragment thereof comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 6. 
     
     
         137 . The method of  claim 136 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 3. 
     
     
         138 . The method of any one of  claim 136  or  137 , 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         139 . The method of  claim 138 , 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         140 . The method of any one of  claim 136  or  137 , 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         141 . The method of  claim 140 , 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         142 . The method of any one of  claims 136 - 141 , wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         143 . The method of any one of  claims 136 - 142 , wherein the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         144 . The method of  claim 142  or  claim 143 , wherein the MICA protein is membrane-bound MICA protein, soluble MICA protein, or both. 
     
     
         145 . The method of  claim 142  or  claim 143 , wherein the MICB protein is membrane-bound MICB protein, soluble MICB protein, or both. 
     
     
         146 . The method of any one of  claims 136 - 145 , wherein 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. 
     
     
         147 . The method of any one of  claims 136 - 146 , wherein the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM. 
     
     
         148 . The method of any one of  claims 136 - 147 , wherein the monoclonal antibody or fragment thereof is humanized or chimeric. 
     
     
         149 . The method of any one of  claims 136 - 148 , wherein the monoclonal antibody or antigen binding fragment thereof reduces level of soluble MICA protein, soluble MICB protein, or both. 
     
     
         150 . The method of any one of  claims 136 - 148 , wherein the monoclonal antibody or antigen binding fragment thereof reduces shedding of soluble MICA protein, soluble MICB protein, or both. 
     
     
         151 . The method of any one of  claims 136 - 148 , wherein the monoclonal antibody or antigen binding fragment thereof inhibits shedding of soluble MICA protein, soluble MICB protein, or both. 
     
     
         152 . A method of reducing level of soluble MICA protein, soluble MICB protein, or both in an individual in need thereof, comprising administering to the individual an effective amount of a monoclonal antibody or an antigen-binding fragment thereof comprising at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 3. 
     
     
         153 . The method  claim 152 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 6. 
     
     
         154 . The method of any one of  claim 152  or  153 , 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         155 . The method of  claim 154 , 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         156 . The method of any one of  claim 152  or  153 , 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         157 . The method of  claim 156 , 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         158 . The method of any one of  claims 152 - 157 , wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         159 . The method of any one of  claims 152 - 158 , wherein the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         160 . The method of  claim 158  or  claim 159 , wherein the MICA protein is soluble MICA protein. 
     
     
         161 . The method of  claim 158  or  claim 159 , wherein the MICB protein is soluble MICB protein. 
     
     
         162 . The method of any one of  claims 152 - 161 , wherein 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. 
     
     
         163 . The method of any one of  claims 152 - 162 , wherein the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM. 
     
     
         164 . The method of any one of  claims 152 - 163 , wherein the monoclonal antibody or fragment thereof is humanized or chimeric. 
     
     
         165 . The method of any one of  claims 152 - 164 , wherein the monoclonal antibody or antigen-binding fragment thereof reduces or inhibits shedding of soluble MICA protein, soluble MICB protein, or both, thereby reducing level of soluble MICA protein, soluble MICB protein, or both in the individual. 
     
     
         166 . The method of any one of  claims 152 - 165 , wherein the individual has a cancer characterized by elevated levels of soluble MICA protein, soluble MICB protein, or both. 
     
     
         167 . The method of  claim 166 , wherein the cancer is hepatocellular carcinoma. 
     
     
         168 . A method of reducing level of soluble MICA protein, soluble MICB protein, or both in an individual in need thereof, comprising administering to the individual an effective amount of a monoclonal antibody or an antigen-binding fragment thereof comprising at least one of a heavy chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 6. 
     
     
         169 . The method of  claim 168 , wherein the monoclonal antibody or antigen-binding fragment thereof comprises at least one of a light chain complementarity determining region 1 (CDR1) sequence at least 80% identical to SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) sequence at least 80% identical to SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) sequence at least 80% identical to SEQ ID NO: 3. 
     
     
         170 . The method of any one of  claim 168  or  169 , 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         171 . The method of  claim 170 , 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         172 . The method of any one of  claim 168  or  169 , 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 an amino acid sequence set forth as SEQ ID NO: 7. 
     
     
         173 . The method of  claim 172 , 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 an amino acid sequence set forth as SEQ ID NO: 8. 
     
     
         174 . The method of any one of  claims 168 - 173 , wherein the monoclonal antibody or antigen-binding fragment thereof specifically binds to a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         175 . The method of any one of  claims 168 - 174 , wherein the monoclonal antibody or antigen-binding fragment thereof binds to an alpha-3 domain of a MICA protein, a MICB protein, or both MICA and MICB protein. 
     
     
         176 . The method of  claim 174  or  claim 175 , wherein the MICA protein is soluble MICA protein. 
     
     
         177 . The method of  claim 174  or  claim 175 , wherein the MICB protein is soluble MICB protein. 
     
     
         178 . The method of any one of  claims 168 - 177 , wherein 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. 
     
     
         179 . The method of any one of  claims 168 - 178 , wherein the monoclonal antibody or antigen-binding fragment thereof is an IgG or IgM. 
     
     
         180 . The method of any one of  claims 168 - 179 , wherein the monoclonal antibody or fragment thereof is humanized or chimeric. 
     
     
         181 . The method of any one of  claims 168 - 180 , wherein the monoclonal antibody or antigen-binding fragment thereof reduces or inhibits shedding of soluble MICA protein, soluble MICB protein, or both, thereby reducing level of soluble MICA protein, soluble MICB protein, or both in the individual. 
     
     
         182 . The method of any one of  claims 168 - 181 , wherein the individual has a cancer characterized by elevated levels of soluble MICA protein, soluble MICB protein, or both. 
     
     
         183 . The method of  claim 182 , wherein the cancer is hepatocellular carcinoma. 
     
     
         184 . A monoclonal antibody or an antigen-binding fragment thereof according to any one of  claims 1  to  84  for use in treating cancer in an individual in need thereof 
     
     
         185 . A monoclonal antibody according to any one of  claims 1  to  84  for use in preparation of a medicament for treating cancer in an individual in need thereof 
     
     
         186 . The monoclonal antibody for use according to  claim 184  or  claim 185 , wherein the cancer is hepatocellular carcinoma.

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