Claims for Patent: 7,528,104

Summary for Patent: 7,528,104

Title:	Peptides that bind to the erythropoietin receptor
Abstract:	The present invention relates to peptide compounds that are agonists of the erythropoietin receptor (EPO-R). The invention also relates to therapeutic methods using such peptide compounds to treat disorders associated with insufficient or defective red blood cell production. Pharmaceutical compositions, which comprise the peptide compounds of the invention, are also provided.
Inventor(s):	Holmes; Christopher P. (Saratoga, CA), Yin; Qun (Palo Alto, CA), Lalonde; Guy (Woodside, CA), Schatz; Peter J. (Cupertino, CA), Tumelty; David (Sunnyvale, CA), Palani; Balu (Cupertino, CA), Zemede; Genet (Santa Clara, CA)
Assignee:	Affymax, Inc. (Palo Alto, CA)
Application Number:	10/555,868
Patent Claims:	1. A peptide, comprising about 17 to about 40 amino acid residues in length and comprising the amino acid sequence: TABLE-US-00009 LYACHX.sub.0GPITX.sub.1VCQPLR, (SEQ ID NO:1) wherein X.sub.0 is a residue selected from the group consisting of methionine (M) and homoserine methylether (Hsm), and X.sub.1 is a residue selected from the group consisting of tryptophan (W), 1-naphthylalanine (1-nal), and 2-naphthylalanine (2-nal), wherein said peptide binds to and activates the erythropoietin receptor (EPO-R). 2. A peptide according to claim 1, wherein the N-terminal of said peptide is acetylated. 3. A peptide according to claim 1, said peptide comprising an amino acid sequence selected from the group consisting of: TABLE-US-00010 LYACHMGPITWVCQPLR; (SEQ ID NO:2) LYACHMGPIT(1-nal)VCQPLR; (SEQ ID NO:3) LYACHMGPIT(2-nal)VCQPLR; (SEQ ID NO:4) GGLYACHMGPITWVCQPLRG; (SEQ ID NO:5) GGLYACHMGPIT(1-nal)VCQPLRG; (SEQ ID NO:6) GGLYACHMGPIT(2-nal)VCQPLRG; (SEQ ID NO:7) (AcG)GLYACHMGPITWVCQPLRG; (SEQ ID NO:8) (AcG)GLYACHMGPIT(1-nal)VCQPLRG; (SEQ ID NO:9) (AcG)GLYACHMGPIT(2-nal)VCQPLRG; (SEQ ID NO:10) GGLYACHMGPITWVCQPLR(MeG); (SEQ ID NO:11) GGLYACHMGPIT(1-nal)VCQPLR(MeG); (SEQ ID NO:12) GGLYACHMGPIT(2-nal)VCQPLR(MeG); (SEQ ID NO:13) (AcG)GLYACHMGPITWVCQPLRG(MeG); (SEQ ID NO:14) (AcG)GLYACHMGPIT(1-nal)VCQPLRG(MeG); (SEQ ID NO:15) (AcG)GLYACHMGPIT(2-nal)VCQPLRG(MeG); (SEQ ID NO:16) LYACH(Hsm)GPITWVCQPLR; (SEQ ID NO:17) LYACH(Hsm)GPIT(1-nal)VCQPLR; (SEQ ID NO:18) LYACH(Hsm)GPIT(2-nal)VCQPLR; (SEQ ID NO:19) GGLYACH(Hsm)GPITWVCQPLRG; (SEQ ID NO:20) GGLYACH(Hsm)GPIT(1-nal)VCQPLRG; (SEQ ID NO:21) GGLYACH(Hsm)GPIT(2-nal)VCQPLRG; (SEQ ID NO:22) (AcG)GLYACH(Hsm)GPITWVCQPLRG; (SEQ ID NO:23) (AcG)GLYACH(Hsm)GPIT(1-nal)VCQPLRG; (SEQ ID NO:24) (AcG)GLYACH(Hsm)GPIT(2-nal)VCQPLRG; (SEQ ID NO:25) GGLYACH(Hsm)GPITWYCQPLR(MeG); (SEQ ID NO:26) GGLYACH(Hsm)GPIT(1-nal)VCQPLR(MeG); (SEQ ID NO:27) GGLYACH(Hsm)GPIT(2-nal)VCQPLR(MeG); (SEQ ID NO:28) (AcG)GLYACH(Hsm)GPITWVCQPLRG(MeG); (SEQ ID NO:29) (AcG)GLYACH(Hsm)GPIT(1-nal)VCQPLRG (SEQ ID NO:30) (MeG); and (AcG)GLYACH(Hsm)GPIT(2-nal)VCQPLRG (SEQ ID NO:31) (MeG). 4. A peptide according to claim 1, wherein the peptide is a monomer. 5. A peptide according to claim 1, wherein the peptide is a dimer. 6. A peptide according to claim 5, wherein the peptide is a homodimer. 7. A peptide according to claim 1, further comprising one or more water soluble polymers covalently bound to the peptide. 8. A peptide according to claim 7, wherein the water soluble polymer is polyethylene glycol (PEG). 9. A peptide according to claim 8, wherein said PEG comprises a linear unbranched molecule having a molecular weight of about 500 to about 60,000 Daltons. 10. A peptide according to claim 9, wherein the PEG has a molecular weight of less than about 20,000 Daltons. 11. A peptide according to claim 9, wherein the PEG has a molecular weight of about 20,000 to about 60,000 Daltons. 12. A peptide according to claim 9, wherein the PEG has a molecular weight of about 20,000 to about 40,000 Daltons. 13. A peptide according to claim 9, wherein two PEG moieities are covalently bound to the peptide, each of said PEG comprising a linear unbranched molecule. 14. A peptide according to claim 13, wherein each of said PEG has a molecular weight of about 20,000 to about 30,000 Daltons. 15. A peptide dimer, comprising: (a) a first peptide chain; (b) a second peptide chain; and (c) a linking moiety connecting said first and second peptide chains, wherein at least one of said first peptide chain and said second peptide chain comprises about 17 to about 40 amino acid residues in length and comprises the amino acid sequence: TABLE-US-00011 LYACHX.sub.0GPITX.sub.iVCQPLR, (SEQ ID NO:1) wherein X.sub.0 is a residue selected from the group consisting of methionine (M) and homoserine methylether (Hsm), and X.sub.1 is a residue selected from the group consisting of tryptophan (W), 1-naphthylalanine (1-nal), and 2-naphthylalanine (2-nal), wherein said peptide dimer binds to and activates the erythropoietin receptor (EPO-R). 16. A peptide dimer according to claim 15, wherein at least one of said first peptide chain and said second peptide chain comprises an amino acid sequence selected from the group consisting of: TABLE-US-00012 LYACHMGPITWVCQPLR; (SEQ ID NO:2) LYACHMGPIT(1-nal)VCQPLR; (SEQ ID NO:3) LYACHMGPIT(2-nal)VCQPLR; (SEQ ID NO:4) GGLYACHMGPITWVCQPLRG; (SEQ ID NO:5) GGLYACHMGPIT(1-nal)VCQPLRG; (SEQ ID NO:6) GGLYACHMGPIT(2-nal)VCQPLRG; (SEQ ID NO:7) (AcG)GLYACHMGPITWVCQPLRG; (SEQ ID NO:8) (AcG)GLYACHMGPIT(1-nal)VCQPLRG; (SEQ ID NO:9) (AcG)GLYACHMGPIT(2-nal)VCQPLRG; (SEQ ID NO:10) GGLYACHMGPITWVCQPLR(MeG); (SEQ ID NO:11) GGLYACHMGPIT(1-nal)VCQPLR(MeG); (SEQ ID NO:12) GGLYACHMGPIT(2-nal)VCQPLR(MeG); (SEQ ID NO:13) (AcG)GLYACHMGPITWVCQPLRG(MeG); (SEQ ID NO:14) (AcG)GLYACHMGPIT(1-nal)VCQPLRG(MeG); (SEQ ID NO:15) (AcG)GLYACHMGPIT(2-nal)VCQPLRG(MeG); (SEQ ID NO:16) LYACH(Hsm)GPITWVCQPLR; (SEQ ID NO:17) LYACH(Hsm)GPIT(1-nal)VCQPLR; (SEQ ID NO:18) LYACH(Hsm)GPIT(2-nal)VCQPLR; (SEQ ID NO:19) GGLYACH(Hsm)GPITWVCQPLRG; (SEQ ID NO:20) GGLYACH(Hsm)GPIT(1-nal)VCQPLRG; (SEQ ID NO:21) GGLYACH(Hsm)GPIT(2-nal)VCQPLRG; (SEQ ID NO:22) (AcG)GLYACH(Hsm)GPITWVCQPLRG; (SEQ ID NO:23) (AcG)GLYACH(Hsm)GPIT(1-nal)VCQPLRG; (SEQ ID NO:24) (AcG)GLYACH(Hsm)GPIT(2-nal)VCQPLRG; (SEQ ID NO:25) GGLYACH(Hsm)GPITWVCQPLR(MeG); (SEQ ID NO:26) GGLYACH(Hsm)GPIT(1-nal)VCQPLR(MeG); (SEQ ID NO:27) GGLYACH(Hsm)GPIT(2-nal)VCQPLR(MeG); (SEQ ID NO:28) (AcG)GLYACH(Hsm)GPITWYCQPLRG(MeG); (SEQ ID NO:29) (AcG)GLYACH(Hsm)GPIT(1-nal)VCQPLRG (SEQ ID NO:30) (MeG); and (AcG)GLYACH(Hsm)GPIT(2-nal)VCQPLRG (SEQ ID NO:31) (MeG). 17. A peptide dimer according to claim 15, wherein the linking moiety comprises the formula: --NH--R.sub.3--NH-- wherein R.sub.3 is a lower (C.sub.1-6) alkylene. 18. A peptide dimer according to claim 17, wherein the linking moiety is a lysine residue. 19. A peptide dimer according to claim 15, wherein the linking moiety comprises the formula: --CO--(CH.sub.2).sub.n--X--(CH.sub.2).sub.m--CO-- wherein n is an integer from 0 to 10, m is an integer from 1 to 10, X is selected from the group consisting of O, S, N(CH.sub.2).sub.pNR.sub.1, NCO(CH.sub.2).sub.pNR.sub.1, and CHNR.sub.1, R.sub.1 is selected from the group consisting of H, Boc, and Cbz, and p is an integer from 1 to 10. 20. A peptide dimer according to claim 19, wherein n and m are each 1, X is NCO(CH.sub.2).sub.pNR.sub.1, p is 2, and R.sub.1 is H. 21. A peptide dimer according to claim 15, further comprising a water soluble polymer. 22. A peptide dimer according to claim 21, wherein the water soluble polymer is covalently bound to the linker moiety. 23. A peptide dimer according to claim 15, further comprising a spacer moiety. 24. A peptide dimer according to claim 23, wherein the spacer moiety comprises the formula: --NH--(CH.sub.2).sub..alpha.--[O--(CH.sub.2).sub..beta.].sub..gamma.--O.s- ub..delta.--(CH.sub.2).sub..epsilon.--Y-- wherein .alpha., .beta., and .epsilon. are each integers whose values are independently selected from 1 to 6, .delta. is 0 or 1, .gamma. is an integer selected from 0 to 10, and Y is selected from the group consisting of NH or CO, provided that .beta. is 2 when .gamma. is greater than 1. 25. A peptide dimer according to claim 24 wherein each of .alpha., .beta., and .gamma. is 2, Each of .gamma. and .delta. is 1, and Y is NH. 26. A peptide dimer according to claim 23, further comprising one or more water soluble polymers. 27. A peptide dimer according to claim 26, wherein the water soluble polymer is covalently bound to the spacer moiety. 28. A peptide dimer according to claim 21 or 26, wherein the water soluble polymer is polyethylene glycol (PEG). 29. A peptide dimer according to claim 28, wherein the PEG is a linear unbranched PEG having a molecular weight of about 500 to about 60,000 Daltons. 30. A peptide dimer according to claim 29, wherein the PEG has a molecular weight of about 500 to less than about 20,000 Daltons. 31. A peptide dimer according to claim 29, wherein the PEG has a molecular weight of about 20,000 to 60,000 Daltons. 32. A peptide dimer according to claim 31, wherein the PEG has a molecular weight of about 20,000 to about 40,000 Daltons. 33. A peptide according to claim 28, wherein two PEG moieities are covalently bound to the peptide, each of said PEG comprising a linear unbranched molecule. 34. A peptide according to claim 33, wherein each of said PEG has a molecular weight of about 20,000 to about 30,000 Daltons. 35. A pharmaceutical composition comprising: (i) a peptide of about 17 to a bout 40 amino acid residues in length, and comprising the amino acid sequence: TABLE-US-00013 LYACHX.sub.0GPITX.sub.1VCQPLR, (SEQ ID NO:1) wherein X.sub.0 is a residue selected from the group consisting of methionine (M) and homoserine methylether (Hsm), and X.sub.1 is a residue selected from the group consisting of tryptophan (W), 1-naphthylalanine (1-nal), and 2-naphthylalanine (2-nal); and (ii) a pharmaceutically acceptable carrier. 36. A pharmaceutical composition according to claim 35, wherein the peptide comprises an amino acid sequence selected from the group consisting of: TABLE-US-00014 LYACHMGPITWVCQPLR; (SEQ ID NO:2) LYACHMGPIT(1-nal)VCQPLR; (SEQ ID NO:3) LYACHMGPIT(2-nal)VCQPLR; (SEQ ID NO:4) GGLYACHMGPITWVCQPLRG; (SEQ ID NO:5) GGLYACHMGPIT(1-nal)VCQPLRG; (SEQ ID NO:6) GGLYACHMGPIT(2-nal)VCQPLRG; (SEQ ID NO:7) (AcG)GLYACHMGPITWVCQPLRG; (SEQ ID NO:8) (AcG)GLYACHMGPIT(1-nal)VCQPLRG; (SEQ ID NO:9) (AcG)GLYACHMGPIT(2-nal)VCQPLRG; (SEQ ID NO:10) GGLYACHMGPITWVCQPLR(MeG); (SEQ ID NO:11) GGLYACHMGPIT(1-nal)VCQPLR(MeG); (SEQ ID NO:12) GGLYACHMGPIT(2-nal)VCQPLR(MeG); (SEQ ID NO:13) (AcG)GLYACHMGPITWVCQPLRG(MeG); (SEQ ID NO:14) (AcG)GLYACHMGPIT(1-nal)VCQPLRG(MeG); (SEQ ID NO:15) (AcG)GLYACHMGPIT(2-nal)VCQPLRG(MeG); (SEQ ID NO:16) LYACH(Hsm)GPITWVCQPLR; (SEQ ID NO:17) LYACH(Hsm)GPIT(1-nal)VCQPLR; (SEQ ID NO:18) LYACH(Hsm)GPIT(2-nal)VCQPLR; (SEQ ID NO:19) GGLYACH(Hsm)GPITWVCQPLRG; (SEQ ID NO:20) GGLYACH(Hsm)GPIT(1-nal)VCQPLRG; (SEQ ID NO:21) GGLYACH(Hsm)GPIT(2-nal)VCQPLRG; (SEQ ID NO:22) (AcG)GLYACH(Hsm)GPITWVCQPLRG; (SEQ ID NO:23) (AcG)GLYACH(Hsm)GPIT(1-nal)VCQPLRG; (SEQ ID NO:24) (AcG)GLYACH(Hsm)GPIT(2-nal)VCQPLRG; (SEQ ID NO:25) GGLYACH(Hsm)GPITWVCQPLR(MeG); (SEQ ID NO:26) GGLYACH(Hsm)GPIT(1-nal)VCQPLR(MeG); (SEQ ID NO:27) GGLYACH(Hsm)GPIT(2-nal)VCQPLR(MeG); (SEQ ID NO:28) (AcG)GLYACH(Hsm)GPITWVCQPLRG(MeG); (SEQ ID NO:29) (AcG)GLYACH(Hsm)GPIT(1-nal)VCQPLRG (SEQ ID NO:30) (MeG); and (AcG)GLYACH(Hsm)GPIT(2-nal)VCQPLRG (SEQ ID NO:31) (MeG). 37. A pharmaceutical composition according to claim 35, wherein the peptide is a monomer. 38. A pharmaceutical composition according to claim 35, wherein the peptide is a dimer. 39. A pharmaceutical composition according to claim 38, wherein the peptide is a homodimer. 40. A pharmaceutical composition according to claim 35, wherein one or more water soluble polymers is covalently bound to the peptide. 41. A pharmaceutical composition according to claim 40, wherein the water soluble polymer is polyethylene glycol (PEG). 42. A pharmaceutical composition according to claim 41, wherein the PEG is a linear unbranched PEG having a molecular weight of about 500 to about 60,000 Daltons. 43. A pharmaceutical composition according to claim 42, wherein the PEG has a molecular weight of about 500 to less than about 20,000 Daltons. 44. A pharmaceutical composition according to claim 42, wherein the PEG has a molecular weight of about 20,000 to about 60,000 Daltons. 45. A pharmaceutical composition according to claim 44, wherein the PEG has a molecular weight of about 20,000 to about 40,000 Daltons. 46. A pharmaceutical composition according to claim 41, wherein two PEG moieties are covalently bound to the peptide, each of said PEG comprising a linear unbranched molecule. 47. A pharmaceutical composition according to claim 46, wherein each of said PEG has a molecular weight of about 20,000 to 30,000 Daltons.