Method of treating cancer by administering an antibody that binds transforming growth factor beta (TGF-beta) 1, TGF-beta 2 and TGF-beta 3
The present disclosure relates, in general, to materials and methods for antibodies specific for transforming growth factor beta (TGFβ), including TGFβ1, TGFβ2 and TGFβ3, and uses of these antibodies in the treatment of subjects having cancer, an eye disease, condition or disorder, fibrosis, including ophthalmic fibrosis or fibrosis of the eye, and other conditions or disorders related to TGFβ expression.
1. A method for treating colorectal cancer, hepatocellular carcinoma, non-small cell lung carcinoma, breast cancer, prostate cancer, pancreatic cancer, renal cancer, or fibrotic cancer, comprising the step of administering to a subject in need thereof a therapeutically effective amount of an antibody that binds transforming growth factor beta (TGFβ)1, TGFβ2 and TGFβ3 comprising:
I. (a) a heavy chain CDR1 amino acid sequence set forth in SEQ ID NO: 19;
(b) a heavy chain CDR2 amino acid sequence set forth in SEQ ID NO: 20;
(c) a heavy chain CDR3 amino acid sequence set forth in SEQ ID NO: 21;
(d) a light chain CDR1 amino acid sequence set forth in SEQ ID NO: 22;
(e) a light chain CDR2 amino acid sequence set forth in SEQ ID NO: 23; and
(f) a light chain CDR3 amino acid sequence set forth in SEQ ID NO: 24; or
II. (a) a heavy chain CDR1 amino acid sequence set forth in SEQ ID NO: 25;
(b) a heavy chain CDR2 amino acid sequence set forth in SEQ ID NO: 26;
(c) a heavy chain CDR3 amino acid sequence set forth in SEQ ID NO: 27;
(d) a light chain CDR1 amino acid sequence set forth in SEQ ID NO: 28;
(e) a light chain CDR2 amino acid sequence set forth in SEQ ID NO: 29; and
(f) a light chain CDR3 amino acid sequence set forth in SEQ ID NO: 30; or
III. (a) a heavy chain CDR1 amino acid sequence set forth in SEQ ID NO: 25;
(b) a heavy chain CDR2 amino acid sequence set forth in SEQ ID NO: 26;
(c) a heavy chain CDR3 amino acid sequence set forth in SEQ ID NO: 27;
(d) a light chain CDR1 amino acid sequence set forth in SEQ ID NO: 16;
(e) a light chain CDR2 amino acid sequence set forth in SEQ ID NO: 17; and
(f) a light chain CDR3 amino acid sequence set forth in SEQ ID NO: 18.
2. The method of claim 1 , wherein the antibody comprises
i) an amino acid sequence at least 90% identical to a heavy chain variable region amino acid sequence set out in SEQ ID NO: 6 and an amino acid sequence at least 90% identical to a light chain variable region amino acid sequence set out in SEQ ID NO: 8; or
ii) an amino acid sequence at least 90% identical to a heavy chain variable region amino acid sequence set out in SEQ ID NO: 10 and an amino acid sequence at least 90% identical to a light chain variable region amino acid sequence set out in SEQ ID NO: 12; or
iii) an amino acid sequence at least 90% identical to a heavy chain variable region amino acid sequence set out in SEQ ID NO: 10 and an amino acid sequence at least 90% identical to a light chain variable region amino acid sequence set out in SEQ ID NO: 4.
3. The method of claim 1 , wherein the antibody comprises
i) a heavy chain variable region amino acid sequence set out in SEQ ID NO: 6 and a light chain variable region amino acid sequence set out in SEQ ID NO: 8; or
ii) a heavy chain variable region amino acid sequence set forth in SEQ ID NO: 10 and a light chain variable region amino acid sequence set forth in SEQ ID NO: 12; or
iii) a heavy chain variable region amino acid sequence set forth in SEQ ID NO: 10 and a light chain variable region amino acid sequence set forth in SEQ ID NO: 4.
4. The method of claim 1 , further comprising a heavy chain constant region, wherein the heavy chain constant region is a modified or unmodified IgG, IgM, IgA, IgD, IgE, a fragment thereof, or combinations thereof.
5. The method of claim 1 , further comprising a light chain constant region wherein the light chain constant region is a modified or unmodified lambda light chain constant region, a kappa light chain constant region, a fragment thereof, or combinations thereof.
6. The method of claim 1 , in which one or more light chain framework amino acids of the antibody have been replaced with corresponding amino acid(s) from another human antibody amino acid sequence.
7. The method of claim 1 , wherein the antibody further comprises a human light chain constant region attached to said light chain variable region.
8. The method of claim 1 , wherein the antibody binds to TGFβ1 and TGFβ2 with greater affinity than TGFβ3.
9. The method of claim 1 , wherein the antibody neutralizes activity of TGFβ1 and TGFβ2 to a greater extent than TGFβ3.
10. The method of claim 1 , wherein the antibody is in a sterile pharmaceutical composition comprising the antibody and a pharmaceutically acceptable carrier.
11. The method of claim 1 , wherein the antibody or composition increases the number of natural killer (NK) cells in a tumor and/or improves NK cell cytolytic activity.
12. The method of claim 1 , wherein the antibody or composition decreases the number of regulatory T cells in a tumor and/or inhibits regulatory T cell function.
13. The method of claim 1 , wherein the antibody or composition increases the number of cytotoxic T cells (CTLs) in a tumor and/or enhances CTL function.
14. The method of claim 1 , wherein the antibody decreases the number of myeloid-derived suppressor cells (MDSC) in a tumor and/or inhibits MDSC function.
15. The method of claim 1 , wherein the antibody decreases the number of dendritic cells (DC) in a tumor and/or inhibits the tolerogenic function of dendritic cells.
16. The method of claim 1 , further comprising administering one or more additional agents.
17. The method of claim 16 , wherein the additional agent is selected from the group consisting of a chemotherapeutic agent, a cytotoxic agent, and azacitidine.
18. The method of claim 1 , wherein the antibody is in liquid form.
19. The method of claim 1 , wherein the antibody is administered at a dose of about 1 mg/kg, about 3 mg/kg or about 10 mg/kg.
20. The method of claim 19 , wherein the antibody is administered weekly, every 2 weeks, every 3 weeks, or monthly.
21. The method of claim 1 , wherein the antibody is administered at a dose of approximately 1000 mg.
22. The method of claim 20 , wherein the antibody is administered weekly, every 2 weeks, every 3 weeks, or monthly.
23. The method of claim 1 , wherein the antibody is administered intravenously or subcutaneously.
24. The method of claim 18 , wherein the antibody is reconstituted from a lyophilized formulation.