Activin-ActRII antagonists and uses for increasing red blood cell levels
In certain aspects, the present invention provides compositions and methods for increasing red blood cell and/or hemoglobin levels in vertebrates, including rodents and primates, and particularly in humans.
1. A method for treating an anemia, the method comprising administering, to a subject in need thereof, an effective amount of a polypeptide selected from the group consisting of:
a) a polypeptide comprising an amino acid sequence at least 95% identical to SEQ ID NO:2;
b) a polypeptide comprising the amino acid sequence of SEQ ID NO:2;
c) a polypeptide comprising an amino acid sequence at least 95% identical to SEQ ID NO:3; and
d) a polypeptide comprising the amino acid sequence of SEQ ID NO:3,
and wherein the polypeptide binds to activin.
2. The method of claim 1 , wherein the polypeptide has one or more of the following characteristics:
i) binds to activin with a K D of at least 10 −7 M; and
ii) inhibits activin signaling in a cell.
3. The method of claim 1 , wherein said polypeptide is a fusion protein including, in addition to said polypeptide, one or more polypeptide portions that enhance one or more of in vivo stability, in vivo half life, uptake/administration, tissue localization or distribution, formation of protein complexes, and/or purification.
4. The method of claim 3 , wherein said fusion protein includes a polypeptide portion selected from the group consisting of: an immunoglobulin Fc domain and a serum albumin.
5. The method of claim 1 , wherein said polypeptide includes one or more modified amino acid residues selected from: a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, and an amino acid conjugated to an organic derivatizing agent.
6. The method of claim 4 , wherein said fusion protein includes an immunoglobulin Fc domain.
7. The method of claim 6 , wherein the method causes less than 15% increase in the patient's skeletal muscle mass.
8. The method of claim 6 , wherein the fusion protein is administered so as to reach a serum concentration in the patient of at least 100 ng/ml for a period of about 20 to 30 days.
9. The method of claim 6 , wherein the fusion protein is administered so as to reach a serum concentration in the patient in the range of 100 ng/ml to 1000 ng/ml.
10. The method of claim 6 , wherein the fusion protein has a serum half-life of between 15 and 30 days.
11. The method of claim 10 , wherein the fusion protein is administered to the patient no more frequently than once per week.
12. The method of claim 10 , wherein the fusion protein is administered to the patient no more frequently than once per month.
13. The method of claim 6 , wherein the fusion protein comprises an amino acid sequence at least 95% identical to SEQ ID NO: 7.
14. The method of claim 13 , wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 7.
15. The method of claim 6 , wherein the fusion protein comprises an amino acid sequence at least 95% identical to SEQ ID NO: 12.
16. The method of claim 15 , wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 12.
17. The method of claim 6 , wherein the fusion protein includes an immunoglobulin IgG1 Fc domain.
18. The method of claim 1 , wherein the polypeptide comprises an amino acid sequence at least 95% identical to SEQ ID NO:2.
19. The method of claim 18 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:2.
20. The method of claim 1 , wherein the polypeptide comprises an amino acid sequence at least 95% identical to SEQ ID NO:3.
21. The method of claim 20 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:3.
22. The method of claim 1 , wherein the anemia is associated with chronic renal disease.
23. The method of claim 1 , wherein the anemia is associated with chemotherapeutic treatment of the patient.
24. The method of claim 1 , wherein the anemia is associated with a tumor or cancer.
25. The method of claim 1 , wherein the anemia is associated with multiple myeloma.
26. The method of claim 1 , wherein the anemia is associated with lung cancer.
27. The method of claim 6 , wherein the anemia is associated with chronic renal disease.
28. The method of claim 6 , wherein the anemia is associated with chemotherapeutic treatment of the patient.
29. The method of claim 6 , wherein the anemia is associated with a tumor or cancer.
30. The method of claim 6 , wherein the anemia is associated with multiple myeloma.
31. The method of claim 6 , wherein the anemia is associated with lung cancer.
32. The method of claim 14 , wherein the anemia is associated with chronic renal disease.
33. The method of claim 14 , wherein the anemia is associated with chemotherapeutic treatment of the patient.
34. The method of claim 14 , wherein the anemia is associated with a tumor or cancer.
35. The method of claim 14 , wherein the anemia is associated with multiple myeloma.
36. The method of claim 14 , wherein the anemia is associated with lung cancer.
37. The method of claim 1 , wherein the polypeptide binds to activin A, activin B, and GDF-11.