Anti-TGF-β antibodies and their use
The invention provides an improved pan-TGF-β antibody for treatment of conditions that are mediated by TGF-β, including autoimmune diseases, fibrotic conditions, and cancers. Also provided are methods and uses of the antibody in conjunction with other immunomodulatory agents such as an anti-PD-1 antibody.
1. A method of inhibiting TGF-β signal transduction in a patient in need thereof, comprising administering to the patient a therapeutic amount of an isolated monoclonal antibody, wherein the antibody binds to human TGF-β1, TGF-β2, and TGF-β3 and comprises the heavy chain complementarity-determining regions (CDR) 1-3 in SEQ ID NO:1 and the light chain CDR1-3 in SEQ ID NO:2, and wherein the antibody comprises a human IgG 4 constant region having a proline at position 228 (EU numbering).
2. The method of claim 1 , wherein the patient has cancer.
3. The method of claim 2 , wherein the cancer is selected from the group consisting of melanoma, lung cancer, cutaneous squamous cell carcinoma, colorectal cancer, breast cancer, ovarian cancer, head and neck cancer, hepatocellular carcinoma, urothelial cancer, and renal cell carcinoma.
4. The method of claim 2 , wherein the cancer is characterized by overexpression of one or more of smooth muscle α2 actin (ACTA2), vimentin (VIM), matrix Gla protein (MGP), and ZW10 interacting kinetochore protein (ZWINT).
5. The method of claim 2 , wherein the cancer is a mesenchymal tumor.
6. The method of claim 2 , wherein the antibody alleviates an immunosuppressive tumor microenvironment in a cancer tissue in the patient.
7. The method of claim 1 , wherein the antibody comprises a heavy chain variable domain (V H ) amino acid sequence corresponding to residues 1-120 of SEQ ID NO:1 and a light chain variable domain (V L ) amino acid sequence corresponding to residues 1-108 of SEQ ID NO:2.
8. The method of claim 7 , wherein the antibody comprises a heavy chain amino acid sequence set forth in SEQ ID NO:1 and a light chain amino acid sequence set forth in SEQ ID NO:2.
9. A method of treating cancer or increasing an immune response in a patient in need thereof, comprising administering to the patient (1) a therapeutically effective amount of an isolated monoclonal antibody, and (2) a therapeutically effective amount of an inhibitor of an immune checkpoint protein, wherein the antibody binds to human TGF-β1, TGF-β2, and TGF-β3 and comprises the heavy chain complementarity-determining regions (CDR) 1-3 in SEQ ID NO:1 and the light chain CDR1-3 in SEQ ID NO:2, and wherein the antibody comprises a human IgG 4 constant region having a proline at position 228 (EU numbering).
10. The method of claim 9 , wherein the immune checkpoint protein is PD-1, PD-L1, or PD-L2.
11. The method of claim 10 , wherein the inhibitor of the immune checkpoint protein is an anti-PD-1 antibody.
12. The method of claim 11 , wherein the anti-PD-1 antibody comprises:
a) the heavy chain CDR1-3 in SEQ ID NO:5 and the light chain CDR1-3 in SEQ ID NO:6;
b) a V H amino acid sequence corresponding to residues 1-117 of SEQ ID NO:5 and a V L amino acid sequence corresponding to residues 1-107 of SEQ ID NO:6; or
c) a heavy chain amino acid sequence set forth in SEQ ID NO:5 and a light chain amino acid sequence set forth in SEQ ID NO:6.
13. The method of claim 12 , wherein the anti-TGF-β antibody comprises a heavy chain amino acid sequence set forth in SEQ ID NO:1 and a light chain amino acid sequence set forth in SEQ ID NO:2.
14. The method of claim 9 , wherein the cancer is refractory to anti-PD-1 or anti-PD-L1 antibody treatment.
15. The method of claim 9 , wherein the cancer is advanced or metastatic melanoma, or cutaneous squamous cell carcinoma.
16. The method of claim 9 , wherein the cancer is a mesenchymal subtype of a solid tumor.
17. The method of claim 9 , wherein the cancer is characterized by overexpression of one or more of smooth muscle α2 actin (ACTA2), vimentin (VIM), matrix Gla protein (MGP), and ZW10 interacting kinetochore protein (ZWINT).
18. The method of claim 9 , wherein the cancer is selected from the group consisting of melanoma, lung cancer, cutaneous squamous cell carcinoma, colorectal cancer, breast cancer, ovarian cancer, head and neck cancer, hepatocellular carcinoma, urothelial cancer, and renal cell carcinoma.
19. The method of claim 9 , wherein the antibody comprises a heavy chain variable domain (V H ) amino acid sequence corresponding to residues 1-120 of SEQ ID NO:1 and a light chain variable domain (V L ) amino acid sequence corresponding to residues 1-108 of SEQ ID NO:2.
20. The method of claim 19 , wherein the antibody comprises a heavy chain amino acid sequence set forth in SEQ ID NO:1 and a light chain amino acid sequence set forth in SEQ ID NO:2.
21. A method of treating cancer in a patient in need thereof, comprising administering to the patient (1) a therapeutically effective amount of an isolated monoclonal antibody, and (2) a therapeutically effective amount of an antibody to PD-1 or PD-L1, wherein the isolated monoclonal antibody comprises a heavy chain amino acid sequence set forth in SEQ ID NO:1 and a light chain amino acid sequence set forth in SEQ ID NO:2.
22. The method of claim 21 , wherein the cancer is refractory to anti-PD-1 or anti-PD-L1 antibody treatment.
23. The method of claim 21 , wherein the antibody to PD-1 or PD-L1 is an antibody to PD-1 comprising a heavy chain amino acid sequence set forth in SEQ ID NO:5 and a light chain amino acid sequence set forth in SEQ ID NO:6.
24. The method of claim 21 , wherein the cancer is advanced or metastatic melanoma, or cutaneous squamous cell carcinoma.
25. The method of claim 21 , wherein the cancer is a mesenchymal subtype of a solid tumor.
26. The method of claim 21 , wherein the cancer is colorectal cancer.
27. The method of claim 21 , wherein the cancer is urothelial cancer.
28. The method of claim 21 , wherein the cancer is non-small cell lung cancer.
29. The method of claim 21 , wherein the cancer is hepatocellular carcinoma.
30. The method of claim 21 , wherein the cancer is ovarian cancer.
31. The method of claim 21 , wherein the cancer is cervical cancer.
32. The method of claim 21 , wherein the cancer is pancreatic cancer.
33. The method of claim 21 , wherein the cancer is prostate cancer.