Methods and compositions relating to bispecific anti-CHI3L1 antibody reagents for the treatment of cancer
It is demonstrated herein that inhibitors of immune checkpoints and CHI3L1 are synergistic. Accordingly, described herein are methods and compositions relating to combinatorial therapies for cancer, e.g., comprising an inhibitor of CHI3L1; and an inhibitor of an immune checkpoint protein. In some embodiments, the CHI3L1 inhibitor can be an antibody or antibody reagent as described herein.
1. A method of treating cancer in a subject in need thereof, the method comprising administering bispecific antibody that detects and neutralizes chitinase 3-like-1 (CHI3L1) and programed death receptor 1 (PD 1) comprising:
(a) an antigen-binding portion of an anti-human PD 1 antibody; and
(b) an antigen-binding portion of an anti-human CHI3L1 antibody comprising light chain complementarity determining regions (CDRs) having the amino acid sequences of SEQ ID NOs: 4-6 and heavy chain CDRs having the amino acid sequences of SEQ ID NOs: 1-3,
wherein the cancer expresses PD-L1 and CHI3L1.
2. The method of claim 1 , wherein the bispecific antibody comprises an anti-human CHI3L1 single chain variable fragment (ScFv CHI3L1) attached to a backbone of an anti-human PD-1 antibody.
3. The method of claim 1 , wherein the bispecific antibody comprises an anti-human PD-1 single chain variable fragment (ScFv PD1) attached to a backbone of an anti-human CHI3L1 antibody.
4. The method of claim 3 , wherein the ScFv PD1 is attached to the heavy chain of the CHI3L1 antibody backbone.
5. The method of claim 3 , wherein the ScFv PD1 is attached to the light chain of the CHI3L1 antibody backbone.
6. The method of claim 3 , wherein the anti-human CHI3L1 antibody comprises a heavy chain sequence having the amino acid sequence of SEQ ID NO: 36 or a light chain sequence having the amino acid sequence of SEQ ID NO: 38.
7. The method of claim 3 , wherein the anti-human CHI3L1 antibody comprises a heavy chain sequence having the amino acid sequence of SEQ ID NO: 36 and a light chain sequence having the amino acid sequence of SEQ ID NO: 38.
8. The method of claim 3 , wherein the anti-human CHI3L1 antibody comprises a conservative substitution relative to the heavy chain sequence having the amino acid sequence of SEQ ID NO: 36 or the light chain sequence having the amino acid sequence of SEQ ID NO: 38, wherein the conservative substitution is in a sequence not comprised by a CDR.
9. The method of claim 1 , wherein the antigen-binding portion of the anti-human CHI3L1 antibody binds a CHI3L1 polypeptide at an epitope having the amino acid sequences of SEQ ID NO: 13.
10. The method of claim 1 , wherein the cancer is a primary cancer or a metastatic cancer.
11. The method of claim 1 , wherein the cancer is malignant cancer.
12. The method of claim 1 , wherein the cancer is selected from the group consisting of: prostate cancer, colon cancer, rectal cancer, ovarian cancer, kidney cancer, breast cancer, glioblastoma, melanoma, malignant melanoma, and lung cancer.
13. The method of claim 1 , wherein the subject is a subject determined to have an elevated level of CHI3L1 compared to a reference level.
14. The method of claim 13 , wherein the CHI3L1 is circulating CHI3L1.
15. The method of claim 1 , wherein the subject is a subject determined to have a level of CHI3L1 that is increased compared to a prior assessment of the level in that subject.
16. The method of claim 15 , wherein the CHI3L1 is circulating CHI3L1.