Antibodies that bind to a portion of the VWC domain of connective tissue growth factor
The present invention relates to antibodies that bind to a portion of the Von Willebrand's factor (VWC) domain of connective tissue growth factor (CTGF). The antibodies are particularly directed to regions of CTGF involved in biological activities associated with fibrosis. The invention also relates to methods of using the antibodies to treat disorders associated with CTGF including localized and systemic fibrotic disorders including those of the lung, liver, heart, skin, and kidney.
1. An isolated antibody or fragment thereof that specifically binds to SEQ ID NO:24.
2. The antibody of claim 1 , wherein the antibody is a monoclonal antibody.
3. The antibody of claim 1 , wherein the affinity of the antibody for CTGF is at least about 10 −9 M.
4. The antibody of claim 1 , wherein the antibody is a single chain antibody.
5. The antibody of claim 1 , wherein the antibody is a humanized antibody.
6. The antibody of claim 1 , wherein the antibody is a chimeric antibody.
7. The antibody of claim 1 , wherein the antibody is a multivalent antibody.
8. The antibody of claim 1 , wherein the antibody is glycosylated.
9. The antibody of claim 1 , wherein the antibody is non-glycosylated.
10. The antibody fragment of claim 1 , wherein the fragment is selected from the group consisting of a Fab, a F(ab) 2 , and a F v fragment.
11. The antibody of claim 1 , wherein the antibody is capable of neutralizing an activity associated with CTGF.
12. The antibody of claim 11 , wherein the activity comprises cell migration.
13. The antibody of claim 11 , wherein the activity comprises production of extracellular matrix by a cell.
14. The antibody of claim 13 , wherein production of extracellular matrix is measured by expression of a protein selected from the group consisting of collagen and fibronectin.
15. The antibody of claim 11 , wherein the neutralizing is ex vivo.
16. The antibody of claim 11 , wherein the neutralizing is in vivo.
17. The antibody of claim 11 , wherein the activity is reduction in fibrosis in a subject.
18. The antibody of claim 17 , wherein the fibrosis occurs within a tissue selected from the group consisting of epithelial, endothelial, and connective tissue.
19. The antibody of claim 18 , wherein the fibrosis occurs within an organ selected from the group consisting of kidney, lung, liver, heart, eye, and skin.
20. The antibody of claim 1 , wherein the antibody modulates interaction between the CTGF polypeptide and a cell receptor, thereby neutralizing an activity associated with CTGF.
21. The antibody of claim 1 , wherein the antibody modulates interaction between the CTGF polypeptide and a secreted or membrane-associated cofactor, thereby neutralizing an activity associated with CTGF.
22. The antibody of claim 21 , wherein the cofactor is a member of the TGF-β family.
23. The antibody of claim 22 , wherein the cofactor is TGFβ-1.
24. The antibody of claim 22 , wherein the cofactor is BMP-4.
25. The antibody of claim 1 , wherein the antibody is conjugated to a cytotoxic agent or enzyme.
26. The antibody of claim 1 , wherein the antibody is detectably labeled.
27. The antibody of claim 26 , wherein the detectable label is selected from an enzyme, fluorescent moiety, chemiluminescent moiety, biotin, avidin, or radioisotope.
28. A method of neutralizing an activity associated with CTGF, the method comprising contacting an antibody of claim 1 with a CTGF polypeptide under conditions suitable for formation of a complex comprising the antibody and the CTGF polypeptide, thereby neutralizing the activity associated with CTGF.
29. The method of claim 28 , wherein the activity comprises production of extracellular matrix by a cell.
30. The method of claim 28 , wherein the antibody modulates interaction between the CTGF polypeptide and a cell receptor, thereby neutralizing an activity associated with CTGF.
31. The method of claim 28 , wherein the antibody modulates interaction between the CTGF polypeptide and a secreted or membrane-cofactor, thereby neutralizing an activity associated with CTGF.
32. The method of claim 31 , wherein the cofactor is a member of the TGF-β family.
33. The method of claim 32 , wherein the cofactor is TGFβ-1.
34. The method of claim 32 , wherein the cofactor is BMP-4.
35. The method of claim 28 , wherein the contacting is in a subject in vitro.
36. The method of claim 28 , wherein the contacting is in a subject in vivo.
37. The method of claim 36 , wherein the subject has hypertension, hyperglycemia, diabetes, congestive heart failure, arthritis, and local or systemic inflammation.
38. The method of claim 36 , wherein the subject has a CTGF-associated disorder.
39. The method of claim 38 , wherein the CTGF-associated disorder is cancer.
40. The method of claim 39 , wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia, dermatofibromas, breast cancer, breast carcinoma desmoplasia, angiolipoma, angioleimyoma, desmoplastic cancer, prostate cancer, ovarian cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, and liver cancer.
41. The method of claim 38 , wherein the CTGF-associated disorder is a fibrotic disorder.
42. The method of claim 41 , wherein the fibrotic disorder is selected from the group consisting of idiopathic pulmonary fibrosis, kidney fibrosis, glomerularsclerosis, ocular fibrosis, osteoarthritis, scleroderma, cardiac fibrosis, or liver fibrosis.
43. A medicament comprising the antibody of claim 1 for treating a subject having a CTGF-associated disorder selected from the group consisting of cancer and fibrotic disorders.
44. A medicament comprising the antibody of claim 1 for treating a subject at risk for having a CTGF-associated disorder due to a condition selected from the group consisting of hypertension, diabetes, myocardial infarction, arthritis, and inflammation.
45. A medicament comprising the antibody of claim 1 for treating a subject having a CTGF-associated disorder selected from the group consisting of diabetic nephropathy, diabetic retinopathy, and diabetic cardiovascular disease.