Engineered anti-TGF-β antibodies and antigen-binding fragments
Antibodies or antigen-binding fragments thereof are engineered to bind Transforming Growth Factor-β (TGFβ). TGFβ-isoform selective antibodies or antigen-binding fragments thereof may selectively bind human TGFβ1, compared to human TGFβ2 and human TGFβ3, or may selectively bind human TGFβ3, compared to human TGFβ1 and human TGFβ2. The design of the antibodies or antigen-binding fragments thereof is facilitated by a co-crystal structure of a recombinant Fab fragment of GC1008 bound to TGFβ2 and by another co-crystal structure of the scFv version of GC1008 bound to TGFβ1.
1. A method of treating breast cancer, prostate cancer, ovarian cancer, stomach cancer, renal cancer, pancreatic cancer, colorectal cancer, skin cancer, lung cancer, cervical cancer, bladder cancer, glioma, mesothelioma, leukemia, or a sarcoma in a patient in need thereof, comprising administering to the patient an antibody or antigen-binding fragment thereof, wherein the antibody comprises
a heavy chain variable domain (V H ) comprising SEQ ID NO:1 with a substitution selected from the group consisting of S30A, S30H, S30W, E74A, E74C, E74D, E74F, E74G, E74H, E74L, E74P, E74Q, E74R, E74S, E74T, E74W, and E74Y; and
a light chain variable domain (V L ) comprising SEQ ID NO:2.
2. The method of claim 1 , wherein the antibody or antigen-binding fragment further comprises a human IgG constant domain.
3. The method of claim 2 , wherein the IgG constant domain is a human IgG 4 constant domain.
4. The method of claim 3 , wherein the antibody or antigen-binding fragment further comprises a human κ constant domain.
5. The method of claim 4 , wherein the human IgG 4 constant domain comprises SEQ ID NO:3, and the human κ constant domain comprises SEQ ID NO:4.
6. The method of claim 1 , wherein the patient has breast cancer.
7. The method of claim 1 , wherein the patient has prostate cancer.
8. The method of claim 1 , wherein the patient has ovarian cancer.
9. The method of claim 1 , wherein the patient has stomach cancer.
10. The method of claim 1 , wherein the patient has renal cancer.
11. The method of claim 1 , wherein the patient has pancreatic cancer.
12. The method of claim 1 , wherein the patient has colorectal cancer.
13. The method of claim 1 , wherein the patient has skin cancer.
14. The method of claim 1 , wherein the patient has lung cancer.
15. The method of claim 1 , wherein the patient has cervical cancer.
16. The method of claim 1 , wherein the patient has bladder cancer.
17. The method of claim 1 , wherein the patient has glioma.
18. The method of claim 1 , wherein the patient has mesothelioma.
19. The method of claim 1 , wherein the patient has leukemia.
20. The method of claim 1 , wherein the patient has a sarcoma.