Claims
- 1. A protein comprising a receptor antagonist multimer, wherein said receptor antagonist multimer acts as a receptor agonist.
- 2. The protein of claim 1, wherein said receptor antagonist multimer is a homodimer.
- 3. The protein of claim 1, wherein said receptor antagonist multimer is a heterodimer.
- 4. The protein of claim 1, wherein said receptor antagonist multimer comprises a prolactin receptor antagonist monomer.
- 5. The protein of claim 4, wherein said receptor antagonist multimer is a prolactin receptor antagonist homodimer.
- 6. The protein of claim 5, wherein said prolactin receptor antagonist monomer comprises an amino acid substitution at a position corresponding to 129 in hPRL.
- 7. The protein of claim 6, wherein said. prolactin receptor antagonist comprises a Gly to Arg substitution at a position corresponding to 129 in hPRL.
- 8. The protein of claim 1, wherein said receptor antagonist multimer comprises a growth hormone receptor antagonist monomer.
- 9. The protein of claim 8, wherein said receptor antagonist multimer is a growth hormone receptor antagonist homodimer.
- 10. The protein of claim 9, wherein said growth hormone receptor antagonist monomer is comprises an amino acid substitution at a position corresponding to 120 in hGH.
- 11. The protein of claim 9, wherein said growth hormone receptor antagonist monomer comprises a Gly to Arg substitution at a position corresponding to 120 in hGH.
- 12. A protein comprising a receptor agonist multimer, wherein said receptor agonist multimer has a longer half-life than its receptor agonist monomer.
- 13. The protein of claim 12, wherein said receptor agonist multimer is a homodimer.
- 14. The protein of claim 12, wherein said receptor agonist multimer is a heterodimer.
- 15. The protein of claim 12, wherein said receptor agonist multimer comprises a prolactin receptor agonist monomer.
- 16. The protein of claim 15, wherein said receptor agonist multimer is a prolactin receptor agonist homodimer.
- 17. The protein of claim 16, wherein said prolactin receptor agonist monomer is wild-type prolactin monomer.
- 18. The protein of claim 12, wherein said receptor agonist multimer comprises a growth hormone receptor agonist monomer.
- 19. The protein of claim 18, wherein said receptor agonist multimer is a growth hormone receptor antagonist homodimer.
- 20. The protein of claim 19, wherein said growth hormone receptor agonist monomer is wild-type growth hormone monomer.
- 21. The protein of claim 17 or 20, wherein said receptor agonist monomer is a human wild-type monomer.
- 22. A pharmaceutical composition comprising a therapeutically useful amount of the protein of any of claims 1-21 and a pharmaceutically suitable excipient.
- 23. A method for increasing prolactin cell signaling comprising administering to a patient an effective amount of a protein comprising a prolactin receptor binding multimer.
- 24. The method of claim 23, wherein said prolactin receptor binding multimer is a prolactin receptor antagonist multimer.
- 25. The method of claim 24, wherein said prolactin receptor antagonist multimer is a prolactin receptor antagonist homodimer.
- 26. The method of claim 25, wherein said prolactin receptor antagonist multimer comprises a hPRL-G129R monomer.
- 27. The method of claim 23, Wherein said prolactin receptor binding multimer is a prolactin receptor agonist multimer.
- 28. The method of claim 27, wherein said prolactin receptor agonist multimer is a prolactin receptor agonist homodimer.
- 29. The method of claim 28, wherein said prolactin receptor agonist multimer comprises a wt-hPRL monomer.
- 30. The method of claim 23, wherein said prolactin receptor binding multimer comprises a prolactin receptor agonist multimer and a prolactin receptor antagonist multimer
- 31. A method for increasing growth hormone cell signaling comprising administering to a patient an effective amount of a protein comprising a growth hormone receptor binding multimer.
- 32. The method of claim 31, wherein said growth hormone receptor binding multimer is a growth hormone receptor antagonist multimer.
- 33. The method of claim 32, wherein said growth hormone receptor antagonist multimer is a growth hormone receptor antagonist homodimer.
- 34. The method of claim 33, wherein said growth hormone receptor antagonist multimer comprises a hPGH-G120R monomer.
- 35. The method of claim 31, wherein said growth hormone receptor binding multimer is a growth hormone receptor agonist multimer.
- 36. The method of claim 35, wherein said growth hormone receptor agonist multimer is a growth hormone receptor agonist homodimer.
- 37. The method of claim 36, wherein said growth hormone receptor agonist multimer comprises a wt-hGH monomer.
- 38. The method of claim 31, wherein said growth hormone receptor binding multimer comprises a growth hormone receptor agonist multimer and a growth hormone receptor antagonist multimer
- 39. Method of treating a disease, disorder or condition comprising administering to a patient an effective amount of a protein comprising a receptor antagonist multimer.
- 40. The method of claim 39, wherein said receptor antagonist multimer comprises a prolactin receptor antagonist monomer.
- 41. The method of 40, wherein said prolactin receptor antagonist monomer comprises an amino acid substitution at a position corresponding to 129 in hPRL.
- 42. The method of claim 41, wherein said prolactin receptor antagonist monomer is hPRL-G129R monomer.
- 43. The method of claim 42, wherein said receptor antagonist multimer is a hPRL-G129R homodimer.
- 44. The method of claim 39, wherein said receptor antagonist multimer comprises a growth hormone receptor antagonist monomer.
- 45. The method of 44, wherein said growth hormone receptor antagonist monomer comprises an amino acid substitution at a position corresponding to 120 in hGH.
- 46. The method of claim 45, wherein said growth hormone receptor antagonist monomer is a hGH-G120R monomer.
- 47. The method of claim 46, wherein said receptor antagonist multimer is a hGH-G120R homodimer.
- 48. The method of any one of claims 39-42, wherein said disease, disorder or condition is selected from the group consisting of immunodepression, supplementing ovarian stimulation for in vitro fertilization and restoring normal sperm in infertile men.
- 49. The method of any one of claims 44-47, wherein said. disease, disorder or condition is selected from the group consisting of dwarfism, osteoporosis, congestive heart failure, frailty associated with aging, obesity, accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing, accelerating recovery of burn patients, accelerating recovery of patients having undergone major surgery, improving muscle strength, mobility, maintenance of skin thickness, maintenance of metabolic homeostasis and maintenance of renal homeostasis
- 50. Method of treating a disease, disorder or condition comprising administering to a patient an effective amount of a protein comprising a receptor agonist multimer.
- 51. The method of claim 50, wherein said receptor agonist multimer comprises a prolactin receptor agonist monomer.
- 52. The method of 51, wherein said prolactin receptor agonist monomer is wt-hPRL.
- 53. The method of claim 52, wherein said receptor agonist multimer is a wt-hPRL homodimer.
- 54. The method of claim 50, wherein said receptor agonist multimer comprises a growth hormone receptor antagonist monomer.
- 55. The method of 54, wherein said growth hormone receptor agonist monomer comprises wt-hGH monomer.
- 56. The method of claim 55, wherein said receptor agonist multimer is a wt-hGH homodimer.
- 57. The method of any one of claims 51-53, wherein said disease, disorder or condition is selected from the group consisting of immunodepression, supplementing ovarian stimulation for in vitro fertilization and restoring normal sperm in infertile men.
- 58. The method of any one of claims 54-56, wherein said disease, disorder or condition is selected from the group consisting of dwarfism, osteoporosis, congestive heart failure, frailty associated with aging, obesity, accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing, accelerating recovery of burn patients, accelerating recovery of patients having undergone major surgery, improving muscle strength, mobility, maintenance of skin thickness, maintenance of metabolic homeostasis and maintenance of renal homeostasis.
- 59. A method of treating a disease, disorder or condition comprising administering to a patient an effective amount of a protein comprising a receptor binding multimer, wherein said receptor binding multimer comprises a receptor antagonist monomer and a receptor agonist monomer.
- 60. A method of making a receptor agonist comprising designing a cDNA encoding a receptor antagonist multimer which links the C terminus of the first receptor antagonist monomer with the N terminus of the second receptor antagonist monomer.
- 61. A method of making a receptor agonist comprising designing a cDNA encoding a receptor agonist multimer which links the C terminus of the first receptor agonist monomer with the N terminus of the second receptor agonist monomer.
- 62. A method of making a receptor agonist comprising designing a cDNA encoding a receptor binding multimer which links the C terminus of the first receptor agonist monomer with the N terminus of the second receptor antagonist monomer.
- 63. A method of making a receptor agonist comprising designing a cDNA encoding a receptor binding multimer which links the C terminus of the first receptor antagonist monomer with the N terminus of the second receptor agonist monomer.
- 64. The method of claim 60, wherein said first and second receptor antagonist monomers are selected from the group consisting of a prolactin receptor antagonist monomer and a growth hormone receptor antagonist monomer.
- 65. The method of claim 61, wherein said first and second receptor agonist monomers are selected from the group consisting of a prolactin receptor agonist monomer and a growth hormone receptor agonist monomer.
- 66. The method of claim 60, wherein said first receptor antagonist monomer is selected from the group consisting of a prolactin receptor antagonist monomer and a growth hormone receptor antagonist monomer.
- 67. The method of claim 61, wherein said first receptor agonist monomer is selected from the group consisting of a prolactin receptor agonist monomer and a growth hormone receptor agonist monomer.
- 68. The method of claim 62, wherein said first receptor agonist monomer is selected from the group consisting of a prolactin receptor agonist monomer and a growth hormone receptor agonist monomer.
- 69. The method of claim 63, wherein said second receptor antagonist monomer is selected from the group consisting of a prolactin receptor antagonist monomer and a growth hormone receptor antagonist monomer.
- 70. A DNA construct comprising the nucleotide sequence of the receptor antagonist multimer.
- 71. A DNA construct comprising the nucleotide sequence of the receptor agonist multimer.
- 72. A DNA construct comprising the nucleotide sequence of the receptor binding multimer, wherein said receptor binding multimer comprises a receptor agonist monomer and a receptor antagonist monomer.
- 73. A method of increasing protein stability comprising making a receptor antagonist multimer.
- 74. A method of increasing protein stability comprising making a receptor agonist multimer.
- 75. A method of increasing protein stability comprising making a receptor binding multimer, wherein said receptor binding multimer comprises a receptor agonist monomer and a receptor antagonist monomer.
- 76. The. method of claim 75, wherein said receptor agonist monomer is selected from the group consisting of a prolactin receptor agonist monomer and a growth hormone receptor agonist monomer.
- 77. The method of claim 75, wherein said receptor antagonist monomer is selected from the group consisting of a prolactin receptor antagonist monomer and a growth hormone receptor antagonist monomer.
- 78. The method of claim 73 or 74, wherein said protein is prolactin.
- 79. The method of claim 78, wherein said receptor antagonist multimer or receptor agonist multimer is a homodimer.
- 80. The method of claim 79, wherein said receptor antagonist homodimer is a hPRL-G129R homodimer.
- 81. The method of claim 79, wherein said receptor agonist homodimer is a wild-type hPRL homodimer.
- 82. The method of claim 73 or 74, wherein said protein is growth hormone.
- 83. The method of claim 82, wherein said receptor antagonist multimer or receptor agonist multimer is a homodimer.
- 84. The method of claim 83, wherein said receptor antagonist homodimer is a hGH-G120R homodimer.
- 85. The method of claim 83, wherein said receptor agonist homodimer is a wild-type hGH homodimer.
STATEMENT OF SUPPORT
[0001] Supported in part by the Endowment Fund of the Greenville Hospital System and Grants (DAMD17-99-1-9129, DAMD17-01-1-0207, NIH/NCI 1R21CA87093).
Provisional Applications (1)
|
Number |
Date |
Country |
|
60374137 |
Apr 2002 |
US |