Soluble MIC neutralizing monoclonal antibody for treating cancer
Disclosed are compositions and methods relating to antibodies that bind soluble Major Histocompatibility Complex class I chain-related (sMIC). Specifically, disclosed are antibodies designed or selected to inhibit sMIC (e.g. to neutralize sMIC) shed from MIC+ tumors. Further disclosed are methods of using the antibodies for the treatment of MIC-positive cancers.
1. An isolated antibody or antigen-binding portion thereof that specifically binds to a sMIC polypeptide comprising heavy and light chain complementarity determining regions (CDRs):
a. a light chain CDR1 having the amino acid sequence of SEQ ID NO: 9;
b. a light chain CDR2 having the amino acid sequence of SEQ ID NO: 10;
c. a light chain CDR3 having the amino acid sequence of SEQ ID NO: 11;
d. a heavy chain CDR1 having the amino acid sequence of SEQ ID NO: 12;
e. a heavy chain CDR2 having the amino acid sequence of SEQ ID NO: 13; and
f. a heavy chain CDR3 having the amino acid sequence of SEQ ID NO: 14.
2. The antibody or antigen-binding portion thereof of claim 1 , wherein the antibody or antigen-binding portion thereof 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 diabody, a multispecific antibody, a dual specific antibody, an anti-idiotypic antibody, and a bispecific antibody.
3. A pharmaceutical composition comprising an antibody or antigen-binding portion thereof of claim 1 and a pharmaceutically acceptable carrier.
4. A nucleic acid encoding an antibody or antigen-binding portion thereof of claim 1 .
5. The nucleic acid of claim 4 , wherein one or more of the nucleic acid sequences encoding the CDRs of the antibody or antigen-binding portion thereof are selected from the group consisting of SEQ ID NOs: 1-6.
6. The nucleic acid of claim 4 , wherein the nucleic acid sequences encoding the CDRs of the antibody or antigen-binding portion thereof are SEQ ID NOs: 1-6.
7. The nucleic acid of claim 4 , wherein the nucleic acid is a cDNA.
8. A method of inhibiting sMIC, the method comprising contacting a cell with or administering to a subject an antibody or antigen-binding portion thereof of claim 1 .
9. A method of treating a MIC-positive cancer in a subject in need thereof, the method comprising administering an effective amount of a pharmaceutical composition of claim 3 to the subject.
10. The method of claim 9 , wherein the MIC-positive cancer is an epithelial cell tumor.
11. The method of claim 9 , wherein the MIC-positive cancer is a hematopoietic malignancy.
12. The method of claim 9 , further comprising administering an additional immunotherapy.
13. The antibody or antigen-binding portion thereof of claim 1 , comprising a light chain having the sequence of SEQ ID NO: 7.
14. The antibody or antigen-binding portion thereof of claim 13 , further comprising a conservative substitution in a sequence not comprised by a CDR.
15. The antibody or antigen-binding portion thereof of claim 1 , comprising a heavy chain having the sequence of SEQ ID NO: 8.
16. The antibody or antigen-binding portion thereof of claim 15 , further comprising a conservative substitution in a sequence not comprised by a CDR.