Claims for Patent: 5,916,870

Summary for Patent: 5,916,870

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:	09/158,220
Patent Claims:	1. 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) selected from the group consisting of hormones, cytokines, peptides and growth factors disposed in the carrier, the stimulatory factor capable of stimulating the ability of the morphogenic protein to induce tissue formation from the progenitor cell; with the proviso 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 morphogenic device 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 morphogenic device according to claim 1, wherein the morphogenic protein is an osteogenic protein. 4. The device according to any one of claims 1-3 wherein the carrier further comprises a biocompatible matrix. 5. The device according to claim 4, wherein the matrix comprises demineralized, protein-extracted, particulate, allogenic bone. 6. The device according to claim 4, wherein the matrix comprises mineral-free, delipidated Type I insoluble bone collagen particles, substantially depleted in noncollagenous protein. 7. The device according to any one of claims 1-3, wherein the morphogenic protein is an osteogenic protein that is capable of inducing the progenitor cell to form endochondral or intramembranous bone. 8. The device according to any one of claims 1-3, wherein the morphogenic protein is an osteogenic protein that is capable of inducing the progenitor cell to form cartilage. 9. The device according to any one of claims 1-3, wherein the morphogenic protein is capable of inducing the progenitor cell to form tendon/ligament-like or neural-like tissue. 10. The device 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 and COP-7. 11. The device 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. 12. The device according to any one of claims 1-3, wherein the morphogenic protein comprises OP-1. 13. The device according to claim 2, wherein the dimer is a homo- or heterodimer comprising at least one BMP-2 or OP-1 subunit. 14. The device 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. 15. The device according to claim 14, 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. 16. The device 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. 17. The device 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. 18. The device according to any one of claims 1-5, wherein the morphogenic stimulatory factor 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. 19. 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 in the mammal; and b) a composition comprising an osteogenic protein capable of inducing tissue formation when accessible to a progenitor cell and a morphogenic protein stimulatory factor (MPSF) capable of stimulating the ability of the morphogenic protein to induce tissue formation from the progenitor cell, said morphogenic Protein and MPSF disposed on the surface region in an amount sufficient to promote from a progenitor cell enhanced tissue growth between the target tissue and the device; with the proviso that when the progenitor cell is an osteoblast stimulated to form bone and the morphoaenic protein is activin, the MPSF may not be estrogen or calcitonin; when the prozenitor 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. 20. The prosthetic device according to claim 19, 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. 21. The prosthetic device according to claim 19, 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. 22. The prosthetic device according to claim 19, 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. 23. The prosthetic device according to claim 19, wherein the osteogenic protein comprises OP-1. 24. The prosthetic device according to claim 19, wherein the osteogenic protein is produced by the expression of a recombinant DNA molecule in a host cell. 25. The prosthetic device according to claim 19, 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. 26. The prosthetic device according to claim 19, wherein the morphogenic protein stimulatory factor comprises an agent that increases IGF-I bioactivity in the mammal. 27. The device according to claim 19, 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. 28. The device 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. 29. The device 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 IGF-I at a concentration from about 0.1 ng/ml to about 50 ng/ml. 30. The device according to claim 29, comprising 200 ng/ml OP-1 and 25 ng/ml of IGF-I. 31. The device 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. 32. The device according to claim 31, comprising about 200 ng/ml OP-1 and about 5 nM estradiol. 33. The device 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. 34. The device according to claim 33, comprising about 200 ng/ml OP-1 and about 500-1000 ng/ml growth hormone. 35. The device 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. 36. The device according to claim 35, comprising about 200 ng/ml OP-1 and about 0.05-5.0 nM hydrocortisone. 37. The device 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. 38. The device according to claim 37, comprising about 200 ng/ml OP-1 and about 0.05 nM insulin. 39. The device 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. 40. The device according to claim 39, comprising about 200 ng/ml OP-1 and about 25-200 nM parathyroid hormone. 41. The device 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. 42. The device according to claim 1-3, comprising about 200 ng/ml OP-1 and about 0.05-5 nM progesterone.

Details for Patent 5,916,870

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