Use of GDF traps to treat anemia

• US 9,505,813 B2
• Filed: 01/25/2013
• Issued: 11/29/2016
• Est. Priority Date: 08/14/2008
• Status: Active Grant

• Current Assignee: Acceleron Pharma Inc. (Merck & Co., Inc.)
• Original Assignee: Acceleron Pharma Inc. (Merck & Co., Inc.)
• Inventors: Seehra, Jasbir, Pearsall, Robert Scott, Kumar, Ravindra
• Primary Examiner(s): Chandra, Gyan
• Application Number:
  US13/750,249
• Publication Number:
  US 20130244324A1
• Time in Patent Office: 1,404 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 38/179 for growth factors; for growth regulators
• CPC Class Codes: A61K 38/1796 for hormones for neuromediators A61K38/1787
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07K 14/47 from mammals
• CPC Class Codes: C07K 14/475 Growth factors; Growth regulators
• CPC Class Codes: C07K 14/71 for growth factors; for growth regulators
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C12N 9/12 transferring phosphorus containing groups, e.g. kinases (2.7)
• CPC Class Codes: C12Q 1/6897 involving reporter genes operably linked to promoters
• CPC Class Codes: C12Y 207/1103 Receptor protein serine/threonine kinase (2.7.11.30)

Abstract

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.

Claims

1. A method for treating anemia in a patient in need thereof, the method comprising administering to the patient an effective amount of a polypeptide comprising an amino acid sequence that is at least 90% identical to the sequence of amino acids 29-119 of SEQ ID NO:

1, wherein the polypeptide comprises an acidic amino acid at the position corresponding to position 79 of SEQ ID NO;

1, and wherein the polypeptide binds to GDF11 and/or myostatin.

2. The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to the sequence of amino acids 29-119 of SEQ ID NO:

1.

3. The method of claim 1, wherein the acidic amino acid is glutamic acid.

4. The method of claim 1, wherein the acidic amino acid is aspartic acid.

5. The method of claim 1, wherein the polypeptide comprises 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 1, wherein the polypeptide binds to GDF11.

7. The method of claim 1, wherein the polypeptide binds to myostatin.

8. The method of claim 1, wherein the patient has anemia resulting from blood loss.

9. The method of claim 1, wherein the patient has anemia that is associated with a myelodysplastic syndrome.

10. The method of claim 1, wherein the patient has anemia that is associated with kidney disease.

11. The method of claim 1, wherein the patient has anemia that is associated with chronic kidney disease.

12. The method of claim 1, wherein the patient has anemia that is associated with a tumor.

13. The method of claim 1, wherein the patient has anemia that is associated with chronic renal failure.

14. The method of claim 1, wherein the patient has anemia that is associated with acute renal failure.

15. The method of claim 1, wherein the patient has anemia that is associated with end-stage renal disease.

16. The method of claim 1, wherein the patient has anemia that is associated with chemotherapy.

17. The method of claim 1, wherein the patient has anemia that is associated with radiation therapy.

18. The method of claim 1, wherein the patient has anemia that is associated with cancer.

19. The method of claim 1, wherein the patient has anemia that is associated with a thalassemia.

20. The method of claim 1, wherein the patient has anemia that is associated with sickle-cell disease.

21. The method of claim 1, wherein the patient has undesirably low red blood cell levels and/or hemoglobin levels.

22. The method of claim 1, wherein the polypeptide binds to myostatin and GDF11.

23. The method of claim 1, wherein the polypeptide inhibits signaling by GDF11 and myostatin in a cell-based assay.

24. The method of claim 1, wherein the polypeptide inhibits signaling by GDF11 in a cell-based assay.

25. The method of claim 1, wherein the polypeptide inhibits signaling by myostatin in a cell-based assay.

26. The method of claim 1, wherein the polypeptide further comprises a constant region of an immunoglobulin.

27. The method of claim 26, wherein the constant region is derived from an IgG heavy chain.

28. The method of claim 27, wherein the constant region of an immunoglobulin is an Fc domain.

29. The method of claim 26, wherein the polypeptide forms a homodimer.

30. The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:

7.

31. The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:

7.

32. The method of claim 31, wherein the patient has:

a) anemia resulting from blood loss;

b) anemia that is associated with kidney disease;

c) anemia that is associated with chronic kidney disease;

d) anemia that is associated with a tumor;

e) anemia that is associated with chronic renal failure;

f) anemia that is associated with acute renal failure;

g) anemia that is associated with end-stage renal disease;

h) anemia that is associated with radiation therapy;

or

i) undesirably low red blood cell levels and/or hemoglobin levels.

33. The method of claim 31, wherein the patient has anemia that is associated with a myelodysplastic syndrome.

34. The method of claim 31, wherein the patient has anemia that is associated with chemotherapy.

35. The method of claim 31, wherein the patient has anemia that is associated with cancer.

36. The method of claim 31, wherein the patient has anemia that is associated with a thalassemia.

37. The method of claim 31, wherein the patient has anemia that is associated with sickle-cell disease.

38. The method of claim 31, wherein the acidic amino acid is glutamic acid.

39. The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 99% identical to SEQ ID NO:

7.

40. The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to SEQ ID NO:

28.

41. The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to SEQ ID NO:

28.

42. The method of claim 41, wherein the patient has:

a) anemia resulting from blood loss;

b) anemia that is associated with kidney disease;

c) anemia that is associated with chronic kidney disease;

d) anemia that is associated with a tumor;

e) anemia that is associated with chronic renal failure;

f) anemia that is associated with acute renal failure;

g) anemia that is associated with end-stage renal disease;

h) anemia that is associated with radiation therapy;

or

i) undesirably low red blood cell levels and/or hemoglobin levels.

43. The method of claim 41, wherein the patient has anemia that is associated with a myelodysplastic syndrome.

44. The method of claim 41, wherein the patient has anemia that is associated with chemotherapy.

45. The method of claim 41, wherein the patient has anemia that is associated with cancer.

46. The method of claim 41, wherein the patient has anemia that is associated with a thalassemia.

47. The method of claim 41, wherein the patient has anemia that is associated with sickle-cell disease.

48. The method of claim 41, wherein the acidic amino acid is glutamic acid.

49. The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 99% identical to SEQ ID NO:

28.

50. The method of claim 1, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:

7.

51. The method of claim 50, wherein the patient has:

a) anemia resulting from blood loss;

b) anemia that is associated with kidney disease;

c) anemia that is associated with chronic kidney disease;

d) anemia that is associated with a tumor;

e) anemia that is associated with chronic renal failure;

f) anemia that is associated with acute renal failure;

g) anemia that is associated with end-stage renal disease;

h) anemia that is associated with radiation therapy;

or

i) undesirably low red blood cell levels and/or hemoglobin levels.

52. The method of claim 50, wherein the patient has anemia that is associated with a myelodysplastic syndrome.

53. The method of claim 50, wherein the patient has anemia that is associated with chemotherapy.

54. The method of claim 50, wherein the patient has anemia that is associated with cancer.

55. The method of claim 50, wherein the patient has anemia that is associated with a thalassemia.

56. The method of claim 50, wherein the patient has anemia that is associated with sickle-cell disease.

57. The method of claim 1, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:

28.

58. The method of claim 57, wherein the patient has:

a) anemia resulting from blood loss;

b) anemia that is associated with kidney disease;

c) anemia that is associated with chronic kidney disease;

d) anemia that is associated with a tumor;

e) anemia that is associated with chronic renal failure;

f) anemia that is associated with acute renal failure;

g) anemia that is associated with end-stage renal disease;

h) anemia that is associated with radiation therapy;

or

i) undesirably low red blood cell levels and/or hemoglobin levels.

59. The method of claim 57, wherein the patient has anemia that is associated with a myelodysplastic syndrome.

60. The method of claim 57, wherein the patient has anemia that is associated with chemotherapy.

61. The method of claim 57, wherein the patient has anemia that is associated with cancer.

62. The method of claim 57, wherein the patient has anemia that is associated with a thalassemia.

63. The method of claim 57, wherein the patient has anemia that is associated with sickle-cell disease.