Claims for Patent: 10,202,419

Summary for Patent: 10,202,419

Title:	Connective tissue stimulating peptides
Abstract:	Novel peptides are described which comprise an amino acid motif selected from the group consisting of \"PG\", \"GP\", \"PI\" and \"IG\" and having up to 10 amino acids upstream and/or downstream of the amino acid motif, wherein \"P\" in the motif is proline or hydroxyproline and the peptide stimulates the development, maintenance and repair of bone, cartilage and associated connective tissue. The invention further relates to pharmaceutical compositions of these peptides, as well as therapeutic and prophylactic uses of such peptides.
Inventor(s):	Sindrey; Dennis R. (Oakville, CA), Pugh; Sydney M. (Glenburnie, CA), Smith; Timothy J. N. (Kingston, CA)
Assignee:	Octane Orthobiologics Inc. (CA)
Application Number:	14/854,238
Patent Claims:	1. A method for stimulating the development, maintenance and repair of bone, cartilage and/or associated connective tissue in a mammal, the method comprising: providing a peptide comprising a peptide motif selected from the group consisting of "GPI", "PGP", "LPG", "GLP", "PIG", and "IGP" and having up to 10 amino acids upstream and/or downstream of said amino acid motif, wherein "P" in said motif is proline or hydroxyproline; and delivering the peptide to the bone, cartilage and/or associated connective tissue in a therapeutically effective amount and for a therapeutically effective time so as to stimulate the development, maintenance and repair of the bone, cartilage and/or associated connective tissue. 2. The method of claim 1, wherein said peptide is at least four amino acids in length. 3. The method of claim 1, wherein said peptide comprises an amino acid sequence represented by the formula selected from the group consisting of: X--(P.sub.1).sub.mGly(P.sub.2).sub.n, (I) (P.sub.1).sub.mGly(P.sub.2).sub.n--Z and (II) X--(P.sub.1).sub.mGly(P.sub.2).sub.n--Z; (III) wherein P.sub.1 and P.sub.2 are selected from the group consisting of proline and hydroxyproline, m=0 or 1, n=0 or 1, wherein at least one of m or n=1, and wherein m and n are independently selected; wherein formulas I, II and III comprise at least four amino acids; wherein X is selected from the group consisting of leucine, glycine-leucine, proline-isoleucine, glycine-proline-isoleucine, asparagine-glycine-leucine and proline-glycine-proline-isoleucine-glycine-proline (SEQ ID.NO.9); wherein Z is selected from the group consisting of isoleucine, arginine, isoleucine-glycine, isoleucine-glycine-proline, isoleucine-glycine-hydroxyproline, isoleucine-glycine-proline-proline (SEQ ID.NO.21), isoleucine-glycine-proline-proline-glycine (SEQ ID.NO.22), isoleucine-glycine-proline-proline-glycine-proline (SEQ ID.NO.23), isoleucine-glycine-proline-proline-glycine-proline-arginine (SEQ ID.NO.24), isoleucine-glycine-proline-proline-glycine-proline-arginine-glycine-argin- ine-threonine-glycine-aspartate-alanine (SEQ ID.NO.25) and arginine-glycine-arginine-threonine-glycine-aspartate-alanine (SEQ ID.NO.26). 4. The method of claim 3, wherein said peptide is selected from the group consisting of: NGLPGPIGP* (SEQ. ID. NO. 1); NGLPGPIG (SEQ. ID. NO.2); NGLP*GPIG (SEQ. ID. NO.3); NGLP*GPIGP* (SEQ. ID.NO.4); NGLPGP (SEQ ID.NO.5); LPGP (SEQ.ID.NO.6); PGPIG (SEQ ID.NO.7); NGLPGPIGP (SEQ.ID.NO.8); PGPIGP (SEQ ID.NO.9); PGPIGPPGPR (SEQ.ID.NO.10); GPIG (SEQ.ID.NO.11); PGPIGPPGPRGRTGDA (SEQ.ID.NO.12); GPRGRTGDA (SEQ.ID.NO.13); PGPIGPP (SEQ.ID.NO.14); PGPIGP* (SEQ.ID.NO.15); PGPI (SEQ.ID.NO.16); GLPGPIG (SEQ.ID.NO.17); GPIGP* (SEQ.ID.NO.18); GPIGP (SEQ.ID.NO.19); PIGP (SEQ.ID.NO.20) and mixtures thereof, wherein P* is hydroxyproline. 5. A method for stimulating the development, maintenance and repair of bone, cartilage and/or associated connective tissue in a mammal, the method comprising: providing a peptide comprising a peptide motif selected from the group consisting of "GPI", "LPG", "GLP", "PIG" and "IGP" and having up to 10 amino acids upstream and/or downstream of said amino acid motif, wherein "P" in said motif is proline or hydroxyproline; and releasing the peptide to bone, cartilage and/or associated connective tissue in a controlled and sustained manner so that the peptide is delivered in a therapeutically effective amount and for a therapeutically effective time in order to stimulate the development, maintenance and repair of the bone, cartilage and/or associated connective tissue. 6. The method according to claim 5 wherein releasing the peptide to bone, cartilage and/or associated connective tissue in a controlled and sustained manner comprises binding the peptide to a pharmaceutically acceptable carrier. 7. The method according to claim 6 wherein the peptide is bound to the carrier such that when the peptide and the carrier are implanted into a body in the vicinity of bone, cartilage and/or associated connective tissue, the peptide is released to the bone, cartilage and/or associated connective tissue in a controlled and sustained manner in a therapeutically effective amount for a period of time greater than 24 hours in order to stimulate the development, maintenance and repair of the bone, cartilage and/or associated connective tissue. 8. The method according to claim 7 wherein the period of time is selected from the group consisting of at least 48 hours, at least 1 week, at least 3 weeks, at least 6 weeks, at least 9 weeks and at least 12 weeks. 9. The method according to claim 1 wherein delivering the peptide to the bone, cartilage and/or associated connective tissues comprises binding the peptide to a pharmaceutically acceptable carrier. 10. The method according to claim 9 wherein the pharmaceutically acceptable carrier comprises a biomaterial compound. 11. The A method according to claim 6 wherein the pharmaceutically acceptable carrier comprises a biomaterial compound. 12. The method of claim 1, wherein said peptide stimulates the activity of bone cells, bone cell precursors and cells sharing lineage. 13. The method of claim 1, wherein said peptide stimulates the activity of cartilage cells, cartilage cell precursors and cells sharing lineage. 14. The method of claim 1, wherein said peptide stimulates the formation of bone. 15. The method of claim 1, wherein said peptide stimulates the formation of cartilage. 16. The method of claim 1, wherein "P" is hydroxyproline. 17. The method of claim 1, wherein said peptide is delivered to the bone, cartilage and/or associated connective tissue by linking the peptide to a chimeric peptide. 18. The method of claim 17, wherein said chimeric peptide comprises a calcium binding sequence of a protein selected from the group consisting of osteopontin, dentine matrix phosphoprotein, phosvitin, phosphohoryn, beta-casein, stratherin, matrix gla protein, riboflavin binding protein and alpha S1 casein. 19. The method of claim 18, wherein said binding sequence is selected from the group consisting of S*S* (SEQ.ID.NO.35), S*S*GS*EE (SEQ.ID.NO.36), S*S*S*EE (SEQ.ID.NO.37), S*S*S*S*S*S* (SEQ.ID.NO.38), DS*S*DS*S* (SEQ.ID.NO.39), S*LS*S*S*S* (SEQ.ID.NO.40), DS*S*EE (SEQ.ID.NO.41), DS*S*ES* (SEQ.ID.NO.42), S*MS*S*S*EE (SEQ.ID.NO.43) and S*IS*S*S*EE (SEQ.ID.NO.44) and combinations thereof, wherein S* denotes a phosphorylated serine amino acid residue. 20. The method of claim 1, further comprising assessing the stimulation by analyzing one or more criteria selected from the group consisting of bone mineral density, bone mineral content, alkaline phosphatase activity, proliferation of osteoblasts, bone nodule formation, bone nodule mineralization, chondrocyte proliferation, intracellular calcium channeling assay, collagen assay and proteoglycan assay. 21. The method of claim 1, wherein said peptide is delivered to the bone, cartilage and/or associated connective tissue by providing a composition comprising the peptide and a pharmaceutically acceptable carrier. 22. The method of claim 21, wherein said composition further comprises an agent selected from the group consisting of calcium phosphate, calcium sulfate, calcium carbonate, fibrin, hyaluronic acid, proteoglycans, calcitonin, estrogen, estradiol, prostaglandin A1, bisphosphonic acids, ipriflavones, sodium fluoride, vitamin K, bone morphogenetic proteins, fibroblast growth factor, platelet-derived growth factor, transforming growth factor, insulin-like growth factors 1 and 2, endothelin, parathyroid hormone, epidermal growth factor, leukemia inhibitory factor, osteogenin and mixtures thereof. 23. The method of claim 21, wherein the step of delivering the peptide is performed locally and/or systemically. 24. The method of claim 23, wherein systemic delivery is selected from intravenous injection, intramuscular injection, intraperitoneal injection, oral administration, enteral administration, parenteral administration, intranasal administration, pulmonary administration, topical administration, transdermal administration and combinations thereof. 25. The method of claim 23, wherein local delivery comprises injection or use with an implant. 26. The method of claim 25, wherein said peptide is delivered to the bone, cartilage and/or associated connective tissue by providing a coating for the peptide, or by filling or dispersing the peptide within a matrix of said implant. 27. The method of claim 26, wherein said peptide is delivered to the bone, cartilage and/or associated connective tissue by combining the peptide with a granular or powdered biomaterial compound. 28. The method of claim 1, wherein said peptide is delivered to the bone, cartilage and/or associated connective tissue by combining the peptide with a biocompatible and/or biodegradable polymer. 29. The method of claim 1, wherein said peptide is selected from the group consisting of NGLPGPIGP* (SEQ. ID. NO. 1); NGLPGPIG (SEQ. ID. NO.2); NGLP*GPIG (SEQ. ID. NO.3); NGLP*GPIGP* (SEQ. ID.NO.4); NGLPGP (SEQ ID.NO.5); LPGP (SEQ.ID.NO.6); PGPIG (SEQ ID.NO.7); NGLPGPIGP (SEQ.ID.NO.8); PGPIGP (SEQ ID.NO.9); PGPIGPPGPR (SEQ.ID.NO.10); GPIG (SEQ.ID.NO.11); PGPIGPPGPRGRTGDA (SEQ.ID.NO.12); GPRGRTGDA (SEQ.ID.NO.13); PGPIGPP (SEQ.ID.NO.14); PGPIGP* (SEQ.ID.NO.15); PGPI (SEQ.ID.NO.16); GLPGPIG (SEQ.ID.NO.17); GPIGP* (SEQ.ID.NO.18); GPIGP (SEQ.ID.NO.19); PIGP (SEQ.ID.NO.20) and mixtures thereof. 30. The method of claim 5, wherein said peptide stimulates the activity of bone cells, bone cell precursors and cells sharing lineage. 31. The method of claim 5, wherein said peptide stimulates the activity of cartilage cells, cartilage cell precursors and cells sharing lineage. 32. The method of claim 5, wherein said peptide stimulates the development, maintenance and repair of bone, cartilage and associated connective tissue. 33. The method of claim 5, wherein said peptide is at least four amino acids in length. 34. The method of claim 5, wherein said peptide is released to the bone, cartilage and/or associated connective tissue by linking the peptide to a chimeric peptide. 35. The method of claim 34, wherein said chimeric peptide comprises a calcium binding sequence of a protein selected from the group consisting of osteopontin, dentine matrix phosphoprotein, phosvitin, phosphohoryn, beta-casein, stratherin, matrix gla protein, riboflavin binding protein and alpha S1 casein. 36. The method of claim 35, wherein said binding sequence is selected from the group consisting of S*S* (SEQ.ID.NO.35), S*S*GS*EE (SEQ.ID.NO.36), S*S*S*EE (SEQ.ID.NO.37), S*S*S*S*S*S* (SEQ.ID.NO.38), DS*S*DS*S* (SEQ.ID.NO.39), S*LS*S*S*S* (SEQ.ID.NO.40), DS*S*EE (SEQ.ID.NO.41), DS*S*ES* (SEQ.ID.NO.42), S*MS*S*S*EE (SEQ.ID.NO.43) and S*IS*S*S*EE (SEQ.ID.NO.44) and combinations thereof, wherein S* denotes a phosphorylated serine amino acid residue. 37. The method of claim 5, further comprising assessing the stimulation by analyzing one or more criteria selected from the group consisting of bone mineral density, bone mineral content, alkaline phosphatase activity, proliferation of osteoblasts, bone nodule formation, bone nodule mineralization, chondrocyte proliferation, intracellular calcium channeling assay, collagen assay and proteoglycan assay. 38. The method of claim 5 wherein said peptide is selected from the group consisting of: NGLPGPIGP* (SEQ. ID. NO. 1); NGLPGPIG (SEQ. ID. NO.2); NGLP*GPIG (SEQ. ID. NO.3); NGLP*GPIGP* (SEQ. ID.NO.4); NGLPGP (SEQ ID.NO.5); LPGP (SEQ.ID.NO.6); PGPIG (SEQ ID.NO.7); NGLPGPIGP (SEQ.ID.NO.8); PGPIGP (SEQ ID.NO.9); PGPIGPPGPR (SEQ.ID.NO.10); GPIG (SEQ.ID.NO.11); PGPIGPPGPRGRTGDA (SEQ.ID.NO.12); GPRGRTGDA (SEQ.ID.NO.13); PGPIGPP (SEQ.ID.NO.14); PGPIGP* (SEQ.ID.NO.15); PGPI (SEQ.ID.NO.16); GLPGPIG (SEQ.ID.NO.17); GPIGP* (SEQ.ID.NO.18); GPIGP (SEQ.ID.NO.19); and PIGP (SEQ.ID.NO.20). 39. The method of claim 38, wherein the peptide has the sequence NGLPGPIGP* (SEQ. ID. NO.1). 40. The method of claim 39, wherein the peptide further comprises S*S*S*EE (SEQ.ID.NO.37). 41. The method of claim 38, wherein the peptide has the sequence PGPIG (SEQ ID.NO.7). 42. The method of claim 38, wherein the peptide has the sequence GPIG (SEQ.ID.NO.11). 43. The method of claim 38, wherein the peptide has the sequence PGPIGP* (SEQ.ID.NO.15). 44. The method of claim 38, wherein the peptide has the sequence PGPIGPPGPRGRTGDA (SEQ.ID.NO.12).

Details for Patent 10,202,419

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2022-05-03