Antibody inhibitors of GDF-8 and uses thereof
View Patent ↗The disclosure provides novel antibodies against growth and differentiation factor-8 (GDF-8), including antibody fragments, which inhibit GDF-8 activity in vitro and in vivo. The disclosure also provides methods for diagnosing, preventing, or treating degenerative disorders of muscle, bone, or insulin metabolism.
1. An isolated antibody that specifically binds to amino acids 1–50 of the polypeptide of SEQ ID NO:15, wherein the antibody reduces GDF-8 activity associated with negative regulation of muscle mass.
2. The antibody of claim 1 , wherein the antibody specifically binds to amino acids 1–25 of the polypeptide of SEQ ID NO:15.
3. The antibody of claim 1 , wherein the antibody specifically binds to the polypeptide of SEQ ID NO:8.
4. The antibody of claim 1 , wherein the antibody specifically binds to the polypeptide of SEQ ID NO:3.
5. The antibody of claim 1 , wherein the antibody recognizes the GDF-8 latent complex, GDF-8 in complex with follistatin, or GDF-8 in complex with a follistatin related protein.
6. The antibody of claim 5 , wherein the antibody recognizes the GDF-8 latent complex.
7. The antibody of claim 5 , wherein the antibody recognizes GDF-8 in complex with follistatin.
8. The antibody of claim 5 , wherein the antibody recognizes GDF-8 in complex with a follistatin related protein.
9. The antibody of claim 1 , wherein the antibody is a monoclonal antibody.
10. A pharmaceutical composition comprising the antibody of claim 1 .
11. The composition of claim 10 , further comprising a pharmaceutically acceptable excipient.
12. A diagnostic kit comprising the antibody of claim 1 .
13. The antibody of claim 1 , wherein the antibody specifically binds to the polypeptide of SEQ ID NO:15, but not to the polypeptide of SEQ ID NO:16.
14. The antibody of claim 1 , wherein the antibody is chimeric.
15. The antibody of claim 1 , wherein the antibody is a fragment chosen from a single-chain, Fab, F(ab′) 2 , and Fv antibody.
16. The antibody of claim 1 , wherein the antibody specifically binds with an affinity constant of greater than 10 6 M −1 .
17. The antibody of claim 1 , wherein the antibody specifically binds with an affinity constant of greater than 10 8 M −1 .
18. An isolated antibody that specifically binds to the polypeptide of SEQ ID NO:5, wherein the antibody reduces GDF-8 activity associated with negative regulation of muscle mass.
19. A diagnostic kit comprising the antibody of claim 18 .
20. An isolated monoclonal antibody that specifically binds to amino acids 1–50 of the polypeptide of SEQ ID NO:15, wherein the antibody has the same specificity as an antibody produced by a cell having ATCC Deposit Designation Number PTA-4236.
21. An antibody produced by the cell having ATCC Deposit Designation Number PTA-4236.
22. An isolated antibody that specifically binds to the polypeptide of SEQ ID NO:2, wherein the antibody reduces GDF-8 activity associated with negative regulation of muscle mass.
23. The antibody of claim 22 , wherein the antibody specifically binds to the polypeptide of SEQ ID NO:3.
24. An isolated antibody that specifically binds to the polypeptide of SEQ ID NO:5, wherein the antibody reduces GDF-8 activity associated with negative regulation of muscle mass.
25. The antibody of claim 24 , wherein the antibody specifically binds to the polypeptide of SEQ ID NO:18.
26. An isolated antibody having the same amino acid sequence as an antibody produced by a cell having ATCC Deposit Designation Number PTA-4236.
27. An isolated antibody that specifically binds to the polypeptide of SEQ ID NO:2, wherein the antibody comprises at least one single chain CDR chosen from amino acids 30–35 of the polypeptide of SEQ ID NO:1, amino acids 50–66 of the polypeptide of SEQ ID NO:1, and amino acids 99–102 of the polypeptide of SEQ ID NO:1.
28. An isolated antibody that specifically binds to the polypeptide of SEQ ID NO. 10, wherein the antibody binds to a mature GDF-8 protein with greater affinity than to a mature BMP-11 protein and reduces GDF-8 activity associated with negative regulation of muscle mass.
29. The antibody of claim 28 , wherein the antibody is as produced by a cell having ATCC Deposit Designation Number PTA-4236.
30. An antibody comprising a heavy chain variable region that comprises an amino acid sequence, wherein the amino acid sequence is SEQ ID NO:1, and wherein the antibody specifically binds to a mature GDF-8 protein and reduces one or more biological activities associated with the GDF-8 protein, relative to a GDF-8 protein that is not bound by the same antibody.
31. An isolated antibody that specifically binds to the polypeptide of SEQ ID NO:8, wherein the antibody comprises at least one single chain CDR chosen from amino acids 30–35 of the polypeptide of SEQ ID NO:1, amino acids 50–66 of polypeptide of SEQ ID NO:1, and amino acids 99–102 of the polypeptide of SEQ ID NO:1, and wherein the antibody reduces GDF-8 activity associated with negative regulation of muscle mass.
32. The antibody of claim 31 , wherein the antibody is a monoclonal antibody.
33. The antibody of claim 31 , wherein the antibody is chimeric.
34. The antibody of claim 31 , wherein the antibody is a fragment chosen from a single-chain, Fab, F(ab′) 2 , and Fv antibody.
35. An antibody comprising a heavy chain variable region that comprises an amino acid sequence at least 95% identical to SEQ ID NO:1, wherein the antibody comprises CDRs of the amino acids 30–35 of the polypeptide of SEQ ID NO:1, amino acids 50–66 of the polypeptide of SEQ ID NO:1, and amino acids 99–102 of the polypeptide of SEQ ID NO:1, and wherein the antibody reduces GDF-8 activity associated with negative regulation of muscle mass.