Hepatocyte growth factor fragments that function as potent met receptor agonists and antagonists
The NK1 fragment of hepatocyte growth factor (HGF) binds to and activates the Met receptor, a transmembrane receptor tyrosine kinase that plays a critical role in embryonic development and organ formation. The instant application discloses NK1 variant polypeptides which act as agonists or antagonists of HGF. Further disclosed are covalently linked NK1 variant polypeptides. Many of the disclosed variant polypeptides possess improved stability characteristics.
1. A variant of human Hepatocyte Growth Factor (hHGF, SEQ ID NO: 1) having amino acid substitutions:
K62E, N127D/A/K/R, K137R, K170E, and N193D.
2. The variant according to claim 1 , wherein said variant is an antagonist of Met.
3. The variant according to claim 1 , wherein said variant is an agonist of Met.
4. The variant according to claim 1 , wherein said variant is conjugated to a member selected from the group consisting of a detectable moiety, a water-soluble polymer, a water-insoluble polymer, a therapeutic moiety, a targeting moiety and a combination thereof.
5. A pharmaceutical formulation comprising a variant according to claim 1 , wherein said variant is in combination with a pharmaceutically acceptable carrier.
6. A variant of human Hepatocyte Growth Factor (hHGF, SEQ ID NO: 1) according to claim 1 further comprising amino acid substitutions at one or more of positions 64, 77, 95, 125, 130, 132, 142, 148, 154, and 173.
7. The variant according to claim 1 , wherein said variant is conjugated to a diagnostic imaging agent.
8. A variant of human Hepatocyte Growth Factor (hHGF, SEQ ID NO: 1) comprising a sequence selected from the group consisting of SEQ ID NOs: 2-22, wherein said variant is conjugated to a diagnostic imaging agent.
9. A pharmaceutical formulation comprising a variant according to claim 8 , wherein said variant is in combination with a pharmaceutically acceptable carrier.
10. A variant of human Hepatocyte Growth Factor (hHGF, SEQ ID NO: 1) having amino acid substitutions K62E, Q95R, I125T, N127D/A/K/R, I130V, K132N/R, K137R, K170E, Q173R, and N193D.
11. A variant of human Hepatocyte Growth Factor (hHGF, SEQ ID NO: 1) according to claim 10 further comprising amino acid substitutions at one or more of positions 64, 77, 142, 148, and 154.
12. A pharmaceutical formulation comprising a variant according to claim 10 , wherein said variant is in combination with a pharmaceutically acceptable carrier.
13. A variant of human Hepatocyte Growth Factor (hHGF, SEQ ID NO: 1) having amino acid substitutions K62E, Q95R, K132N, K137R, K170E, Q173R, and N193D.
14. A variant of human Hepatocyte Growth Factor (hHGF, SEQ ID NO: 1) according to claim 13 further comprising amino acid substitutions at one or more of positions 64, 77, 125, 127, 130, 142, 148, and 154.
15. A pharmaceutical formulation comprising a variant according to claim 13 , wherein said variant is in combination with a pharmaceutically acceptable carrier.
16. A variant of human Hepatocyte Growth Factor (hHGF, SEQ ID NO: 1) having amino acid substitutions K62E, Q95R, N127D/A/K/R, K132N/R, K137R, K170E, Q173R, and N193D.
17. A variant of human Hepatocyte Growth Factor (hHGF, SEQ ID NO: 1) according to claim 16 further comprising amino acid substitutions at one or more of positions 64, 77, 125, 130, 142, 148, and 154.
18. A pharmaceutical formulation comprising a variant according to claim 16 , wherein said variant is in combination with a pharmaceutically acceptable carrier.
19. A variant of human Hepatocyte Growth Factor (hHGF, SEQ ID NO: 1) comprising a sequence selected form the group consisting of SEQ ID NOs: 2-22.
20. A pharmaceutical formulation comprising a variant according to claim 19 , wherein said variant is in combination with a pharmaceutically acceptable carrier.