MIC-binding antibodies and methods of use thereof
View Patent ↗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.
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.
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, 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 , 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.
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 , 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.
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. 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 .
16. The method of claim 15 , wherein the cell is an MIC positive epithelial tumor cell or a MIC positive cell of a hematopoietic malignancy.
17. 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 .
18. The method of claim 17 , wherein the cell is a MIC positive epithelial tumor cell or a MIC positive cell of a hematopoietic malignancy.
19. 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.
20. A cDNA encoding an antibody or antigen-binding portion thereof of claim 1 .