Mic-binding antibodies and methods of use thereof

Abstract

The technology described herein relates to antibodies and/or polypeptides which bind to MIC and inhibit MIC shedding. Methods of using such antibodies and/or polypeptides for the treatment of cancer are also described herein.

What is claimed: 
     
         1 . An isolated antibody or antigen-binding portion thereof that specifically binds a MIC polypeptide, said antibody or antigen-binding portion thereof comprising heavy and light chain complementarity determining regions (CDRs):
 (a) a light chain CDR1 having the amino acid sequence of SEQ ID NO: 2;   (b) a light chain CDR2 having the amino acid sequence of SEQ ID NO: 3;   (c) a light chain CDR3 having the amino acid sequence of SEQ ID NO: 4;   (d) a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 5;   (e) a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 6; and   (f) a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 7 or a conservative substitution variant of one or more of (a)-(e).   
     
     
         2 . The isolated antibody or antigen-binding portion thereof of  claim 1 , which inhibits MIC shedding. 
     
     
         3 . The isolated antibody or antigen-binding portion thereof of  claim 1 , which when bound to MIC on the surface of a cell, does not decrease recognition of MIC by natural killer (NK) cells by more than 10%. 
     
     
         4 . A pharmaceutical composition comprising an antibody or antigen-binding portion thereof of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         5 . The isolated antibody or antigen-binding portion thereof of  claim 1 , wherein the antibody or polypeptide is selected from the group consisting of:
 an immunoglobulin molecule, a monoclonal antibody, a chimeric antibody, a CDR-grafted antibody, a humanized antibody, a Fab, a Fab′, a F(ab′)2, a Fv, a disulfide linked Fv, a scFv, a single domain antibody, a diabody, a multispecific antibody, a dual specific antibody, an anti-idiotypic antibody, and a bispecific antibody.   
     
     
         6 . The isolated antibody or antigen-binding portion thereof of  claim 1 , which comprises an scFV comprising the amino acid sequence of SEQ ID NO: 8. 
     
     
         7 . An isolated antibody or antigen-binding portion thereof that specifically binds an epitope comprising the amino acid sequence NGTYQT (SEQ ID NO: 01) in a MIC polypeptide, said antibody or antigen-binding portion thereof comprising heavy chain CDRs having the amino acid sequences of SEQ ID NO: 5, 6 and 7 or a conservative substitution variant of such amino acid sequence, said antibody or antigen-binding portion thereof inhibiting MIC shedding. 
     
     
         8 . The isolated antibody or antigen-binding portion thereof of  claim 7 , which comprises light chain CDRs having the amino acid sequences of SEQ ID NOs 2, 3, and 4 or a conservative substitution variant of such amino acid sequence. 
     
     
         9 . The isolated antibody or antigen-binding portion thereof of  claim 7 , which comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 09. 
     
     
         10 . The isolated antibody or antigen-binding portion thereof of  claim 7 , which comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10. 
     
     
         11 . An isolated antibody or antigen-binding portion thereof that specifically binds an epitope comprising the amino acid sequence NGTYQT (SEQ ID NO: 01) in a MIC polypeptide, said antibody or antigen-binding portion thereof comprising light chain CDRs having the amino acid sequences of SEQ ID NO: 2, 3 and 4 or a conservative substitution variant of such amino acid sequence, said antibody or antigen-binding portion thereof inhibiting MIC shedding. 
     
     
         12 . The isolated antibody or antigen-binding portion thereof of  claim 11 , which comprises heavy chain CDRs having the amino acid sequences of SEQ ID NO: 5, 6 and 7 or a conservative substitution variant of such amino acid sequence. 
     
     
         13 . The isolated antibody or antigen-binding portion thereof of  claim 11 , which comprises a light chain comprising the amino acid sequence of SEQ ID NO: 10. 
     
     
         14 . The isolated antibody or antigen-binding portion thereof of  claim 11 , which comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 09. 
     
     
         15 . An isolated antibody or antigen-binding portion thereof that competes with an antibody of  claim 1  for binding to an epitope comprising the amino acid sequence NGTYQT (SEQ ID NO: 01) in a MIC polypeptide. 
     
     
         16 . A method of inhibiting MIC shedding by a cell, the method comprising contacting the cell with an antibody antigen-binding portion thereof of  claim 1 . 
     
     
         17 . The method of  claim 16 , wherein the cell is an MIC positive epithelial tumor cell or a MIC positive cell of a hematopoietic malignancy. 
     
     
         18 . A method of increasing surface MIC expression on a tumor cell, the method comprising contacting the cell with an antibody antigen-binding portion thereof of  claim 1 . 
     
     
         19 . The method of  claim 18 , wherein the cell is a MIC positive epithelial tumor cell or a MIC positive cell of a hematopoietic malignancy. 
     
     
         20 . A method of treating a MIC positive epithelial cell tumor or a MIC positive hematopoietic malignancy in a subject, the method comprising administering an antibody or antigen binding portion thereof of  claim 1  to the subject. 
     
     
         21 . A nucleic acid encoding an antibody or antigen-binding portion thereof of  claim 1 .