Claims for Patent: 8,629,109

Summary for Patent: 8,629,109

Title:	Method for promoting bone growth using activin-actriia antagonists
Abstract:	In certain aspects, the present invention provides compositions and methods for promoting bone growth and increasing bone density.
Inventor(s):	Knopf; John (Carlisle, MA), Seehra; Jasbir (Lexington, MA)
Assignee:	Acceleron Pharma Inc. (Cambridge, MA)
Application Number:	13/176,718
Patent Claims:	1. A method for treating bone fractures, comprising administering to a subject in need thereof an effective amount of a polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 2. 2. The method of claim 1, further comprising administering a second bone active-agent. 3. The method of claim 2, wherein the bone active-agent is selected from a bisphosphonate, an estrogen, a selective estrogen receptor modulator, a parathyroid hormone, a calcitonin, a calcium supplement, and a vitamin D supplement. 4. The method of claim 2, wherein the second bone active-agent is administered conjointly with the polypeptide. 5. The method of claims 4, wherein the polypeptide and the second bone active-agent are administered as a single co-formulation. 6. The method of claim 4, wherein the polypeptide and the second bone active-agent are administered simultaneously. 7. The method of claim 4, wherein the polypeptide and the second bone active-agent are administered at separate times. 8. The method of claim 1, wherein the 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, or an amino acid conjugated to a lipid moiety. 9. The method of claim 1, wherein the polypeptide is administered no more frequently than once per month. 10. The method of claim 1, wherein the polypeptide is administered no more frequently than once every three months. 11. The method of claim 1, wherein the polypeptide is administered no more frequently than once every six months. 12. The method of claim 1, wherein the polypeptide is at least 98% pure as determined by size-exclusion chromatography. 13. The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 2. 14. The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 2. 15. The method of claim 1, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 2. 16. The method of claim 1, wherein the polypeptide is glycosylated and has a glycosylation pattern identical to a glycosylation pattern obtained by expressing the polypeptide in a Chinese hamster ovary (CHO) cell line. 17. The method of claim 1, wherein the N-terminus of the polypeptide is ILGRSETQE (SEQ ID NO: 11). 18. The method of claim 1, wherein the polypeptide further comprises a domain that enhances one or more of in vivo stability, in vivo half-life, uptake/administration, tissue localization or distribution, or formation of protein complexes. 19. The method of claim 18, wherein the domain is an immunoglobulin Fc domain. 20. The method of claim 18, wherein the domain is serum albumin. 21. The method of claim 1, wherein the serum half-life of the polypeptide is greater than two weeks. 22. The method of claim 1, wherein the serum half-life of the polypeptide is 20-30 days. 23. The method of claim 1, wherein the polypeptide has one or more of the following characteristics: (i) binds to an ActRIIa ligand with a K.sub.D of at least 10.sup.-7 M; and (ii) inhibits ActRIIa signaling. 24. The method of claim 1, wherein the polypeptide is soluble. 25. The method of claim 1, wherein the polypeptide is an antagonist of activin A. 26. The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 7. 27. The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 7. 28. The method of claim 1, wherein the polypeptide comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 7. 29. The method of claim 1, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 7. 30. The method of claim 1, wherein the polypeptide binds to activin. 31. The method of claim 1, wherein the polypeptide is recombinantly expressed using a Tissue Plasminogen Activator (TPA) leader sequence. 32. The method of claim 31, wherein the TPA leader sequence comprises the amino acid sequence of SEQ ID NO:9. 33. A method for increasing bone strength, comprising administering to a subject in need thereof an effective amount of a polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 2. 34. The method of claim 33, further comprising administering a second bone active-agent. 35. The method of claim 34, wherein the bone active-agent is selected from a bisphosphonate, an estrogen, a selective estrogen receptor modulator, a parathyroid hormone, a calcitonin, a calcium supplement, and a vitamin D supplement. 36. The method of claim 34, wherein the second bone active-agent is administered conjointly with the polypeptide. 37. The method of claims 34, wherein the polypeptide and the second bone active-agent are administered as a single co-formulation. 38. The method of claim 34, wherein the polypeptide and the second bone active-agent are administered simultaneously. 39. The method of claim 34, wherein the polypeptide and the second bone active-agent are administered at separate times. 40. The method of claim 33, wherein the 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, or an amino acid conjugated to a lipid moiety. 41. The method of claim 33, wherein the polypeptide is administered no more frequently than once per month. 42. The method of claim 33, wherein the polypeptide is administered no more frequently than once every three months. 43. The method of claim 33, wherein the polypeptide is administered no more frequently than once every six months. 44. The method of claim 33, wherein the polypeptide is at least 98% pure as determined by size-exclusion chromatography. 45. The method of claim 33, wherein the polypeptide comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 2. 46. The method of claim 33, wherein the polypeptide comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 2. 47. The method of claim 33, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 2. 48. The method of claim 33, wherein the polypeptide is glycosylated and has a glycosylation pattern identical to a glycosylation pattern obtained by expressing the polypeptide in a Chinese hamster ovary (CHO) cell line. 49. The method of claim 33, wherein the N-terminus of the polypeptide is ILGRSETQE (SEQ ID NO: 11). 50. The method of claim 33, wherein the polypeptide further comprises a domain that enhances one or more of in vivo stability, in vivo half-life, uptake/administration, tissue localization or distribution, or formation of protein complexes. 51. The method of claim 50, wherein the domain is an immunoglobulin Fc domain. 52. The method of claim 50, wherein the domain is serum albumin. 53. The method of claim 33, wherein the serum half-life of the polypeptide is greater than two weeks. 54. The method of claim 33, wherein the serum half-life of the polypeptide is 20-30 days. 55. The method of claim 33, wherein the polypeptide has one or more of the following characteristics: (i) binds to an ActRIIa ligand with a K.sub.D of at least 10.sup.-7 M; and (ii) inhibits ActRIIa signaling. 56. The method of claim 33, wherein the polypeptide is soluble. 57. The method of claim 33, wherein the polypeptide binds to activin. 58. The method of claim 33, wherein the polypeptide is an antagonist of activin A. 59. The method of claim 33, wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 7. 60. The method of claim 33, wherein the polypeptide comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 7. 61. The method of claim 33, wherein the polypeptide comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 7. 62. The method of claim 33, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 7. 63. The method of claim 33, wherein the polypeptide is recombinantly expressed using a Tissue Plasminogen Activator (TPA) leader sequence. 64. The method of claim 63, wherein the TPA leader sequence comprises the amino acid sequence of SEQ ID NO:9. 65. A method for increasing bone mineral density comprising administering to a subject in need thereof an effective amount of a polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 2. 66. The method of claim 65, further comprising administering a second bone active-agent. 67. The method of claim 66, wherein the bone-active agent is selected from a bisphosphonate, an estrogen, a selective estrogen receptor modulator, a parathyroid hormone, a calcitonin, a calcium supplement, and a vitamin D supplement. 68. The method of claim 66, wherein the second bone active-agent is administered conjointly with the polypeptide. 69. The method of claims 66, wherein the polypeptide and the second bone active-agent are administered as a single co-formulation. 70. The method of claim 66, wherein the polypeptide and the second bone active-agent are administered simultaneously. 71. The method of claim 66, wherein the polypeptide and the second bone active-agent are administered at separate times. 72. The method of claim 65, wherein the 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, or an amino acid conjugated to a lipid moiety. 73. The method of claim 65, wherein the polypeptide is administered no more frequently than once per month. 74. The method of claim 65, wherein the polypeptide is administered no more frequently than once every three months. 75. The method of claim 65, wherein the polypeptide is administered no more frequently than once every six months. 76. The method of claim 65, wherein the polypeptide is at least 98% pure as determined by size-exclusion chromatography. 77. The method of claim 65, wherein the polypeptide comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 2. 78. The method of claim 65, wherein the polypeptide comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 2. 79. The method of claim 65, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 2. 80. The method of claim 65, wherein the polypeptide is glycosylated and has a glycosylation pattern identical to a glycosylation pattern obtained by expressing the polypeptide in a Chinese hamster ovary (CHO) cell line. 81. The method of claim 65, wherein the N-terminus of the polypeptide is ILGRSETQE (SEQ ID NO: 11). 82. The method of claim 65, wherein the polypeptide further comprises a domain that enhances one or more of in vivo stability, in vivo half-life, uptake/administration, tissue localization or distribution, or formation of protein complexes. 83. The method of claim 82, wherein the domain is an immunoglobulin Fc domain. 84. The method of claim 82, wherein the domain is serum albumin. 85. The method of claim 65, wherein the serum half-life of the polypeptide is greater than two weeks. 86. The method of claim 65, wherein the serum half-life of the polypeptide is 20-30 days. 87. The method of claim 65, wherein the polypeptide has one or more of the following characteristics: (i) binds to an ActRIIa ligand with a K.sub.D of at least 10.sup.-7 M; and (ii) inhibits ActRIIa signaling. 88. The method of claim 65, wherein the polypeptide is soluble. 89. The method of claim 65, wherein the polypeptide binds to activin. 90. The method of claim 65, wherein the polypeptide is an antagonist of activin A. 91. The method of claim 65, wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 7. 92. The method of claim 65, wherein the polypeptide comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 7. 93. The method of claim 65, wherein the polypeptide comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 7. 94. The method of claim 65, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 7. 95. The method of claim 65, wherein the polypeptide is recombinantly expressed using a Tissue Plasminogen Activator (TPA) leader sequence. 96. The method of claim 95, wherein the TPA leader sequence comprises the amino acid sequence of SEQ ID NO:9. 97. A method for treating a bone-related disorder, comprising administering to a subject in need thereof an effective amount of a polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 2, wherein the bone-related disorder is associated with low bone density or decreased bone strength. 98. The method of claim 97, wherein the bone-related disorder is selected from osteoporosis, hypogonadal bone loss, tumor-induced bone loss, cancer therapy-induced bone loss, bony metastases, hyperparathyroidism, Cushing's disease, thyrotoxicosis, chronic diarrheal state or malabsorption, renal tubular acidosis, anorexia nervosa, and Paget's disease. 99. The method of claim 97, further comprising administering a second bone active-agent. 100. The method of claim 99, wherein the bone active-agent is selected from a bisphosphonate, an estrogen, a selective estrogen receptor modulator, a parathyroid hormone, a calcitonin, a calcium supplement, and a vitamin D supplement. 101. The method of claim 99, wherein the second bone active-agent is administered conjointly with the polypeptide. 102. The method of claims 99, wherein the polypeptide and the second bone active-agent are administered as a single co-formulation. 103. The method of claim 99, wherein the polypeptide and the second bone active-agent are administered simultaneously. 104. The method of claim 99, wherein the polypeptide and the second bone active-agent are administered at separate times. 105. The method of claim 97, wherein the 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, or an amino acid conjugated to a lipid moiety. 106. The method of claim 97, wherein the polypeptide is administered no more frequently than once per month. 107. The method of claim 97, wherein the polypeptide is administered no more frequently than once every three months. 108. The method of claim 97, wherein the polypeptide is administered no more frequently than once every six months. 109. The method of claim 97, wherein the polypeptide is at least 98% pure as determined by size-exclusion chromatography. 110. The method of claim 97, wherein the polypeptide comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 2. 111. The method of claim 97, wherein the polypeptide comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 2. 112. The method of claim 97, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 2. 113. The method of claim 97, wherein the polypeptide is glycosylated and has a glycosylation pattern identical to a glycosylation pattern obtained by expressing the polypeptide in a Chinese hamster ovary (CHO) cell line. 114. The method of claim 97, wherein the N-terminus of the polypeptide is ILGRSETQE (SEQ ID NO: 11). 115. The method of claim 97, wherein the polypeptide further comprises a domain that enhances one or more of in vivo stability, in vivo half-life, uptake/administration, tissue localization or distribution, or formation of protein complexes. 116. The method of claim 115, wherein the domain is an immunoglobulin Fc domain. 117. The method of claim 115, wherein the domain is serum albumin. 118. The method of claim 97, wherein the serum half-life of the polypeptide is greater than two weeks. 119. The method of claim 97, wherein the serum half-life of the polypeptide is 20-30 days. 120. The method of claim 97, wherein the polypeptide has one or more of the following characteristics: (i) binds to an ActRIIa ligand with a K.sub.D of at least 10.sup.-7 M; and (ii) inhibits ActRIIa signaling. 121. The method of claim 97, wherein the polypeptide is soluble. 122. The method of claim 97, wherein the polypeptide binds to activin. 123. The method of claim 97, wherein the polypeptide is an antagonist of activin A. 124. The method of claim 97, wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 7. 125. The method of claim 97, wherein the polypeptide comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 7. 126. The method of claim 97, wherein the polypeptide comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 7. 127. The method of claim 97, wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 7. 128. The method of claim 97, wherein the polypeptide is recombinantly expressed using a Tissue Plasminogen Activator (TPA) leader sequence. 129. The method of claim 128, wherein the TPA leader sequence comprises the amino acid sequence of SEQ ID NO:9.

Details for Patent 8,629,109

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2025-11-23