Antibodies to TGF-β
The present invention relates to antibody molecules, in particular antibody molecules that bind Transforming Growth Factor beta (TGFβ), and uses thereof. More particularly, the invention relates to antibody molecules that bind and preferably neutralize TGFβ1, TGFβ2 and TGFβ3, so-called “pan-specific” antibody molecules, and uses of such antibody molecules. Preferred embodiments within the present invention are antibody molecules, whether whole antibody (e.g. IgG, such as IgG1 or IgG4) or antibody fragments (e.g. scFv, Fab, dAb).
1. A method of inhibiting TGFβ1, TGFβ2 or TGFβ3 signaling, comprising the step of contacting TGFβ1, TGFβ2 and TGFβ3 in vivo with an isolated specific binding member that binds to TGFβ1, TGFβ2 and TGFβ3, said binding member comprising an antigen-binding domain of an antibody, wherein the heavy chain of said antibody comprises:
an HCDR1 comprising the amino acid sequence of SEQ ID NO: 3,
an HCDR2 comprising the amino acid sequence of SEQ ID NO: 4, and
an HCDR3 comprising the amino acid sequence of SEQ ID NO: 5; and
wherein the light chain of said antibody comprises:
an LCDR1 comprising the amino acid sequence of SEQ ID NO: 8,
an LCDR2 comprising the amino acid sequence of SEQ ID NO: 9, and
an LCDR3 comprising the amino acid sequence of SEQ ID NO: 10.
2. The method of claim 1 , wherein the antibody comprises the PET1073G12 VH domain (SEQ ID NO: 2) and the PET1073G12 VL domain (SEQ ID NO: 7).
3. The method of claim 2 , wherein the antibody further comprises a human IgG4 constant region.
4. The method of claim 2 , wherein the antibody further comprises a human IgG1 constant region.
5. The method of claim 1 , wherein the isolated specific binding member comprises an isolated single chain Fv molecule comprising the PET1073G12 VH domain (SEQ ID NO: 2) and the PET1073G12 VL domain (SEQ ID NO: 7).
6. The method of claim 1 , wherein the antibody comprises the PET1073G12 VH domain (SEQ ID NO: 2).
7. The method of claim 1 , wherein the antibody comprises the PET1073G12 VL domain (SEQ ID NO: 7).
8. The method of claim 1 , wherein the antibody comprises a heavy chain comprising the PET1073G12 VH domain (SEQ ID NO: 2) and a human IgG4 constant region, and a light chain comprising the PET1073G12 VL domain (SEQ ID NO: 7) and a human κ light chain constant region.
9. The method of claim 1 , wherein the isolated specific binding member neutralizes human TGFβ1, 2 and 3.
10. The method of claim 1 , wherein said heavy chain comprises an FR4 amino acid sequence comprising the amino acid sequence in SEQ ID NO: 31.
11. The method of claim 1 , wherein the antibody comprises the PET1073G12 VH domain (SEQ ID NO: 2) with up to 5 framework mutations.
12. The method of claim 1 , wherein the antibody comprises the PET1073G12 VL domain (SEQ ID NO: 7) with up to 5 framework mutations.
13. The method of claim 1 , wherein said method inhibits TGFβ1, 2 or 3-mediated fibronectin production.
14. The method of claim 1 , wherein said method inhibits TGFβ1, 2 or 3-mediated VEGF production.
15. The method of claim 1 , wherein said method
(a) reduces TGFβ1, 2 or 3-mediated inhibition of epithelial cell proliferation;
(b) reduces TGFβ1, 2 or 3-mediated inhibition of endothelial cell proliferation; or
(c) inhibits TGFβ1, 2 or 3-mediated smooth muscle cell proliferation.
16. The method of claim 1 , wherein said method inhibits cyclosporin-induced TGFβ1, 2 or 3 activity.
17. The method of claim 1 , wherein said method increases NK cell activity.
18. The method of claim 1 , wherein said method inhibits TGFβ1, 2 or 3-mediated immunosuppression.
19. The method of claim 1 , wherein said method inhibits the growth of a TGFβ1, 2 or 3 expressing tumor.
20. The method of claim 1 , wherein said method treats a fibrotic disease.
21. The method of claim 1 , wherein said method treats a renal disease.
22. The method claim 21 , wherein the renal disease is renal fibrosis.
23. The method of claim 21 , wherein the renal disease is glomerulonephritis, nephropathy or nephrosclerosis.
24. The method of claim 21 , wherein the antibody comprises a heavy chain comprising the PET1073G12 VH domain (SEQ ID NO: 2) and a human IgG4 constant region, and a light chain comprising the PET1073G12 VL domain (SEQ ID NO: 7) and a human κ light chain constant region.
25. The method of any one of claims 13 - 23 , wherein the antibody comprises the PET1073G12 VH domain (SEQ ID NO: 2) and the PET1073G12 VL domain (SEQ ID NO: 7).