Claims for Patent: 5,948,428

Summary for Patent: 5,948,428

Title:	Compositions and therapeutic methods using morphogenic proteins and stimulatory factors
Abstract:	The present invention provides pharmaceutical compositions comprising a morphogenic protein stimulatory factor (MPSF) for improving the tissue inductive activity of morphogenic proteins, particularly those belonging to the BMP protein family. Methods for improving the tissue inductive activity of a morphogenic protein in a mammal using those compositions are provided. This invention also provides implantable morphogenic devices comprising a morphogenic protein and a MPSF disposed within a carrier, that are capable of inducing tissue formation in allogeneic and xenogeneic implants. Methods for inducing local tissue formation from a progenitor cell in a mammal using those devices are also provided. A method for accelerating allograft repair in a mammal using morphogenic devices is provided. This invention also provides a prosthetic device comprising a prosthesis coated with a morphogenic protein and a MPSF, and a method for promoting in vivo integration of an implantable prosthetic device to enhance the bond strength between the prosthesis and the existing target tissue at the joining site. Methods of treating tissue degenerative conditions in a mammal using the pharmaceutical compositions are also provided.
Inventor(s):	Lee; John C. (San Antonio, TX), Yeh; Lee-Chuan C. (San Antonio, TX)
Assignee:	Stryker Corporation (Kalamazoo, MI)
Application Number:	08/761,468
Patent Claims:	1. A pharmaceutical composition for inducing tissue formation in a mammal, comprising: a) a morphogenic protein capable of inducing tissue formation when accessible to a progenitor cell in the mammal; b) a morphogenic protein stimulatory factor (MPSF) capable of stimulating the ability of the morphogenic protein to induce tissue formation from the progenitor cell; and c) a pharmaceutically acceptable carrier; wherein the MPSF is selected from the group consisting of hormones, cytokines, peptides and growth factors; and provided that when the progenitor cell is an osteoblast stimulated to form bone and the morphogenic protein is activin, the MPSF may not be estrogen or calcitonin; when the progenitor cell is an osteoblast stimulated to form bone and the morphogenic protein is a BMP homodimer or TGF-.beta., the MPSF may not be FGF, IGF-II, PDGF, estrogen, calcitonin, or vitamin D; when the progenitor cell is an osteoblast stimulated to form bone or cartilage and the morphogenic protein is a BMP homodimer, the MPSF may not be TGF-.beta.; and when the progenitor cell is an osteoblast stimulated to form bone and the morphogenic protein is a homodimer of BMP-2 or BMP-3, the MPSF may not be parathyroid hormone. 2. The composition according to claim 1, wherein the morphogenic protein comprises a pair of subunits disulfide bonded to produce a dimeric species and wherein at least one of the subunits comprises a polypeptide belonging to the BMP protein family. 3. The composition according to claim 1, wherein the morphogenic protein is an osteogenic protein. 4. The composition according to any one of claims 1-3, wherein the morphogenic protein stimulatory factor comprises an agent that increases IGF-I bioactivity in the mammal. 5. The composition according to claim 4, wherein the agent that increases IGF-I bioactivity in the mammal is an altered form of IGF-I. 6. The composition according to claim 5, wherein the altered form of IGF-I is a truncated IGF-I molecule which has a decreased affinity for IGFBPs in the mammal compared to normal IGF-I. 7. The composition according to claim 6, wherein the altered form of IGF-I is des (1-3) IGF-I. 8. The composition according to any one of claims 1-3, wherein the morphogenic protein stimulatory factor is present in an amount capable of synergistically stimulating the ability of the morphogenic protein to induce tissue formation in the mammal. 9. The composition according to any one of claims 1-3, wherein the morphogenic protein comprises a polypeptide selected from the group consisting of: BMP-2, BMP-4, BMP-5, BMP-6, BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, and BMP-13, COP-5, COP-7. 10. The composition according to any one of claims 1-3, wherein the morphogenic protein comprises a polypeptide selected from the group consisting of OP-1, BMP-2, BMP-4 and BMP-6. 11. The composition according to any one of claims 1-3, wherein the morphogenic protein comprises a polypeptide selected from the group consisting of OP-1, BMP-5 and BMP-6. 12. The composition according to any one of claims 1-3, wherein the morphogenic protein comprises OP-1. 13. The composition according to any one of claims 1-3, wherein the morphogenic protein is present at a concentration of at least about 1 ng/ml, and the morphogenic protein stimulatory factor is present at a concentration of at least about 0.01 ng/ml. 14. The composition according to claim 12, wherein the morphogenic protein comprises OP-1 at a concentration of from about 1 ng/ml to about 500 ng/ml and the morphogenic protein stimulatory factor comprises IGF-I or an altered form of IGF-I at a concentration of from about 0.1 ng/ml to about 50 ng/ml. 15. The composition according to claim 14, comprising 200 ng/ml of OP-1. 16. A morphogenic device for implantation in a mammal, the device comprising: a) an implantable biocompatible carrier, b) a morphogenic protein disposed in the carrier, the morphogenic protein capable of inducing tissue formation when accessible to a progenitor cell, and c) a morphogenic protein stimulatory factor (MPSF) disposed in the carrier, the MPSF capable of stimulating the ability of the morphogenic protein to induce tissue formation from the progenitor cell; wherein the MPSF is selected from the group consisting of hormones, cytokines, peptides and growth factors; and provided that when the progenitor cell is an osteoblast stimulated to form bone and the morphogenic protein is activin, the MPSF may not be estrogen or calcitonin; when the progenitor cell is an osteoblast stimulated to form bone and the morphogenic protein is a BMP homodimer or TGF-.beta., the MPSF may not be FGF, IGF-II, PDGF, estrogen or calcitonin, or vitamin D; when the progenitor cell is an osteoblast stimulated to form bone or cartilage and the morphogenic protein is a BMP homodimer, the MPSF may not be TGF-.beta.; and when the progenitor cell is an osteoblast stimulated to form bone and the morphogenic protein is a homodimer of BMP-2 or BMP-3, the MPSF may not be parathyroid hormone. 17. The morphogenic device according to claim 16, wherein the morphogenic protein comprises a pair of subunits disulfide bonded to produce a dimeric species, and wherein at least one of the subunits comprises a polypeptide belonging to the BMP protein family. 18. The morphogenic device according to claim 16, wherein the morphogenic protein is an osteogenic protein. 19. The device according to any one of claims 16-18, wherein the morphogenic protein stimulatory factor comprises an agent that increases IGF-I bioactivity in the mammal. 20. The device according to any one of claims 16-18, wherein the carrier further comprises a biocompatible matrix. 21. The device according to claim 20, wherein the matrix comprises demineralized, protein-extracted, particulate, allogenic bone. 22. The device according to claim 20, wherein the matrix comprises mineral-free, delipidated Type I insoluble bone collagen particles, substantially depleted in noncollagenous protein. 23. The device according to any one of claims 16-18, wherein the morphogenic protein comprises a polypeptide selected from the group consisting of: BMP-2, BMP-4, BMP-5, BMP-6, BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, and BMP-13, COP-5 and COP-7. 24. The device according to any one of claims 16-18, wherein the morphogenic protein comprises a polypeptide selected from the group consisting of OP-1, BMP-2, BMP-4 and BMP-6. 25. The device according to any one of claims 16-18, wherein the morphogenic protein comprises a polypeptide selected from the group consisting of OP-1, BMP-5 and BMP-6. 26. The device according to any one of claims 16-18, wherein the morphogenic protein comprises OP-1. 27. The device according to any one of claims 16-18, wherein the morphogenic protein is present at a concentration of at least about 1 ng/ml, and the morphogenic protein stimulatory factor is present at a concentration of at least about 0.01 ng/ml. 28. The device according to claim 19, wherein the morphogenic protein comprises OP-1 at a concentration of from about 1 ng/ml to about 500 ng/ml and the morphogenic protein stimulatory factor comprises IGF-I or an altered form of IGF-I at a concentration of from about 0.1 ng/ml to about 50 ng/ml. 29. The device according to claim 28, wherein the morphogenic protein comprises OP-1 at a concentration of 200 ng/ml. 30. A method for improving the tissue inductive activity of a morphogenic protein on a mammalian progenitor cell comprising the step of coadministering to the cell a morphogenic protein stimulatory factor which comprises an agent that increases IGF-1 bioactivity. 31. The method according to claim 30, wherein the agent that increases IGF-I bioactivity in the mammal is an altered form of IGF-I. 32. The method according to claim 31, wherein the altered form of IGF-I is a truncated IGF-I molecule which has a decreased affinity for IGFBPs in the mammal compared to normal IGF-I. 33. The method according to claim 32, wherein the altered form of IGF-I is des (1-3) IGF-I. 34. The method according to claim 30, wherein the morphogenic protein comprises a disulfide bonded dimeric species comprising a polypeptide selected from the group consisting of OP-1, BMP-5 and BMP-6. 35. The composition according to claim 3, wherein the osteogenic protein is capable of inducing the progenitor cell to form endochondral or intramembranous bone. 36. The composition according to any one of claims 1-3, wherein the morphogenic protein is capable of inducing the progenitor cell to form cartilage, tendon/ligament-like tissue or neural-like tissue. 37. The composition according to claim 2, wherein the dimer is a homo- or heterodimer comprising at least one BMP-2, or OP-1 (BMP-7) subunit. 38. The composition according to any one of claims 1-3, wherein the morphogenic protein is produced by the expression of a recombinant DNA molecule in a host cell. 39. The composition according to any one of claims 1-3, wherein the morphogenic protein stimulatory factor comprises at least one compound selected from the group consisting of: insulin-like growth factor I (IGF-I), estradiol, fibroblast growth factor (FGF), growth hormone (GH), growth and differentiation factor (GDF), hydrocortisone (HC), insulin, progesterone, parathyroid hormone (PTH), vitamin D, retinoic acid and IL-6. 40. The composition according to any one of claims 1-3, wherein the morphogenic protein comprises OP-1 at a concentration of from about 1 ng/ml to about 500 ng/ml and the morphogenic protein stimulatory factor comprises estradiol at a concentration of from about 0.05 nM to about 1000 nM. 41. The composition according to any one of claims 1-3, wherein the morphogenic protein comprises OP-1 at a concentration of from about 1 ng/ml to about 500 ng/ml and the morphogenic protein stimulatory factor comprises growth hormone at a concentration of from about 5 ng/ml to about 1000 ng/ml. 42. The composition according to any one of claims 1-3, wherein the morphogenic protein comprises OP-1 at a concentration of from about 1 ng/ml to about 500 ng/ml and the morphogenic protein stimulatory factor comprises hydrocortisone at a concentration of from about 0.05 nM to about 5.0 nM. 43. The composition according to any one of claims 1-3, wherein the morphogenic protein comprises OP-1 at a concentration of from about 1 ng/ml to about 500 ng/ml and the morphogenic protein stimulatory factor comprises insulin at a concentration of from about 0.01 nM to about 1000 nM. 44. The composition according to any one of claims 1-3, wherein the morphogenic protein comprises OP-1 at a concentration of from about 1 ng/ml to about 500 ng/ml and the morphogenic protein stimulatory factor comprises parathyroid hormone at a concentration of from about 10 nM to about 1000 nM. 45. The composition according to any one of claims 1-3, wherein the morphogenic protein comprises OP-1 at a concentration of from about 1 ng/ml to about 500 ng/ml and the morphogenic protein stimulatory factor comprises progesterone at a concentration of from about 0.05 nM to about 1000 nM. 46. The device according to claim 18, wherein the osteogenic protein is capable of inducing the progenitor cell to form endochondral or intramembranous bone. 47. The device according to any one of claims 16-18, wherein the morphogenic protein is capable of inducing the progenitor cell to form cartilage, tendon/ligament-like or neural-like tissue. 48. The device according to claim 17, wherein the dimer is a homo- or heterodimer comprising at least one BMP-2 or OP-1 subunit. 49. The device according to any one of claims 16-18, wherein the morphogenic protein is produced by the expression of a recombinant DNA molecule in a host cell. 50. The device according to claim 49, wherein the morphogenic protein comprises at least one subunit comprising an amino acid sequence sufficiently duplicative of the amino sequence of COP-5 or COP-7 such that the species is capable of inducing tissue formation in a mammal when disposed in the carrier and implanted in the mammal. 51. The device according to any one of claims 16-18, wherein the morphogenic protein stimulatory factor comprises at least one compound selected from the group consisting of: insulin-like growth factor I (IGF-I), estradiol, fibroblast growth factor (FGF), growth hormone (GH), growth and differentiation factor (GDF), hydrocortisone (HC), insulin, progesterone, parathyroid hormone (PTH), vitamin D, retinoic acid and IL-6. 52. The device according to any one of claims 16-18, comprising a composition according to any one of claims 4-8, 14-15 or 40-45. 53. The device according to claim 46, wherein the MPSF is immobilized. 54. The device according to claim 28, wherein the IGF-I or the altered form of IGF-I is immobilized. 55. An implantable prosthetic device for repairing orthopedic defects, injuries or anomalies in a mammal, comprising: a) a prosthetic implant having a surface region implantable adjacent to a target tissue comprising a progenitor cell in the mammal; and b) a composition comprising an osteogenic protein and a morphogenic protein stimulatory factor (MPSF) disposed on the surface region in an amount sufficient to promote enhanced tissue growth into the surface; wherein the MPSF is selected from the group consisting of hormones, cytokines, peptides and growth factors; and provided that when the progenitor cell is an osteoblast stimulated to form bone and the morphogenic protein is activin, the MPSF may not be estrogen or calcitonin; when the progenitor cell is an osteoblast stimulated to form bone and the morphogenic protein is a BMP homodimer or TGF-.beta., the MPSF may not be FGF, IGF-II, PDGF, estrogen, calcitonin, or vitamin D; when the progenitor cell is an osteoblast stimulated to form bone or cartilage and the morphogenic protein is a BMP homodimer, the MPSF may not be TGF-.beta.; and when the progenitor cell is an osteoblast stimulated to form bone and the morphogenic protein is a homodimer of BMP-2 or BMP-3, the MPSF may not be parathyroid hormone. 56. The prosthetic device according to claim 55, wherein the osteogenic protein is produced by the expression of a recombinant DNA molecule in a host cell. 57. The prosthetic device according to claim 55, wherein the morphogenic protein stimulatory factor comprises at least one compound selected from the group consisting of: insulin-like growth factor I (IGF-I), estradiol, fibroblast growth factor (FGF), growth hormone (GH), growth and differentiation factor (GDF), hydrocortisone (HC), insulin, progesterone, parathyroid hormone (PTH), vitamin D, retinoic acid and IL-6. 58. The prosthetic device according to claim 55, wherein the morphogenic protein stimulatory factor comprises an agent that increases IGF-I bioactivity in the mammal. 59. The prosthetic device according to claim 55, wherein the morphogenic protein stimulatory factor is present in an amount capable of synergistically stimulating the ability of the morphogenic protein to induce tissue formation in the mammal. 60. The prosthetic device according to claim 55, wherein the morphogenic protein stimulatory factor comprises an agent that increases IGF-I bioactivity in the mammal. 61. The prosthetic device according to claim 60, wherein the agent that increases IGF-I bioactivity in the mammal is an altered form of IGF-I. 62. The prosthetic device according to claim 61, wherein the altered form of IGF-I is a truncated IGF-I molecule which has a decreased affinity for IGFBPs in the mammal compared to normal IGF-I. 63. The prosthetic device according to claim 62, wherein the altered form of IGF-I is des (1-3) IGF-I. 64. The prosthetic device according to claim 55, wherein the morphogenic protein stimulatory factor is present in an amount capable of synergistically stimulating the ability of the morphogenic protein to induce tissue formation in the mammal. 65. The prosthetic device according to claim 55, wherein the osteogenic protein is capable of inducing the progenitor cell to form a tissue selected from the group consisting of endochondral bone, intramembranous bone, cartilage, tendon/ligament-like tissue and neural tissue. 66. The prosthetic device according to claim 55, wherein the osteogenic protein comprises a polypeptide selected from the group consisting of: BMP-2, BMP-4, BMP-5, BMP-6, OP-1 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, and BMP-13, COP-5 and COP-7. 67. The prosthetic device according to claim 55, wherein the osteogenic protein comprises a disulfide bonded dimeric species comprising a polypeptide selected from the group consisting of OP-1, BMP-2, BMP-4 and BMP-6. 68. The prosthetic device according to claim 55, wherein the osteogenic protein comprises a disulfide bonded dimeric species comprising a polypeptide selected from the group consisting of OP-1, BMP-5 and BMP-6. 69. The prosthetic device according to claim 55, wherein the osteogenic protein comprises OP-1. 70. A method for inducing local tissue formation from a progenitor cell in a mammal comprising the step of implanting in the mammal a morphogenic device according to any one of claims 19-29 and 46-54 at a locus accessible to at least one progenitor cell of the mammal. 71. The method according to claim 70, wherein the locus is a jaw bone for use in periodontal or dental recontructive procedures. 72. The method according to claim 70, wherein the locus is a bone defect selected from the group consisting of a fracture, a non-union fracture a fusion and a bony void. 73. The method according to claim 70, wherein the locus is a joint for use in cartilage and soft tissue repair. 74. The method according to claim 70, wherein the locus is nervous system-associated tissue for use in neural regeneration and repair. 75. A method of accelerating allograft repair and incorporation in a mammal, comprising the step of implanting at a locus in need of replacement bone a matrix-comprising device according to any one of claims 19-29 and 46-54. 76. The method according to claim 75, wherein the matrix of the device comprises allogenic bone. 77. A method of promoting in vivo integration into a target tissue of a mammal an implantable prosthetic device, the method comprising the steps of: a) providing on a surface of the prosthetic device a composition according to any one of claims 1-15 and 35-46, and b) implanting the device in a mammal at a locus where the target tissue and the surface of the prosthetic device are maintained at least partially in contact for a time sufficient to permit enhanced tissue growth between the target tissue and the device. 78. A method of treating a tissue degenerative condition in a mammal comprising the step of administering a pharmaceutical composition according to any one of claims 1-15 and 35-45.

Details for Patent 5,948,428

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2015-12-12