Multimeric ligands with enhanced stability
View Patent ↗The present invention provides compositions and methods for making multimeric proteins to increase stability over their monomer. For example, more stable growth hormone and prolactin receptor agonists are provided.
1. A protein comprising a receptor antagonist dimer,
wherein said receptor antagonist dimer (i) is a receptor agonist and (ii) comprises a first monomer and a second monomer;
wherein said first monomer is a wild-type human prolactin (hPRL) monomer that comprises an amino acid substitution at a position corresponding to 129 in hPRL, and said second monomer is selected from the group consisting of a wild-type human prolactin (hPRL) monomer that comprises an amino acid substitution at a position corresponding to 129 in hPRL, and a wild-type human growth hormone (hGH) monomer that comprises an amino acid substitution at a position corresponding to 120 in hGH.
2. The protein of claim 1 , wherein said receptor antagonist dimer is a homodimer.
3. The protein of claim 1 , wherein said first monomer comprises a Gly to Arg substitution at a position corresponding to 129 in hPRL.
4. A pharmaceutical composition comprising the protein of claim 1 and a pharmaceutically acceptable carrier.
5. The protein of claim 1 , wherein said second monomer is a wild-type human growth hormone (hGH) monomer that comprises an amino acid substitution at a position corresponding to 120 in hGH.
6. The protein of claim 5 , wherein said first monomer comprises a Gly to Arg substitution at a position corresponding to 129 in hPRL.
7. The protein of claim 1 , wherein said amino acid substitution in said first monomer consists of a bulky side chain amino acid at position 129.
8. A protein comprising a receptor antagonist dimer,
wherein said receptor antagonist dimer (i) is a receptor agonist and
(ii) comprises a first monomer and a second monomer;
wherein said first monomer is a wild-type human growth hormone (hGH) monomer that comprises an amino acid substitution at a position corresponding to 120 in hGH, and said second monomer is selected from the group consisting of a wild-type human prolactin (hPRL) monomer that comprises an amino acid substitution at a position corresponding to 129 in hPRL, and a wild-type human growth hormone (hGH) monomer that comprises an amino acid substitution at a position corresponding to 120 in hGH.
9. The protein of claim 8 , wherein said receptor antagonist dimer is a homodimer.
10. The protein of claim 9 , wherein said first monomer comprises a Gly to Arg substitution at a position corresponding to 120 in hGH.
11. The protein of claim 8 , wherein said amino acid substitution in said first monomer consists of a bulky side chain amino acid at position 120.