Modulators of complement activity
The present invention provides polypeptide modulators of complement activity, including cyclic polypeptide modulators. Also provided are methods of utilizing such modulators as therapeutics.
1. A method of reducing complement activity associated with coagulation, the method comprising reducing C5 cleavage, by contacting a C5 system with a polypeptide comprising amino acid residues 9-12 of SEQ ID NO: 192.
2. The method of claim 1 , wherein the complement activity is associated with a coagulation pathway component.
3. The method of claim 2 , wherein the coagulation pathway component comprises one or more of tissue factor, FXa, FIXa, FXIa, thrombin, and plasmin.
4. The method of claim 1 , wherein the polypeptide comprises from about 10 to about 18 amino acids.
5. The method of claim 1 , wherein the polypeptide comprises a cyclic loop.
6. The method of claim 1 , wherein the polypeptide comprises an amino acid sequence with at least 80% sequence identity to the amino acid sequence of SEQ ID NO: 192.
7. The method of claim 6 , wherein the polypeptide comprises a C-terminal lysine, wherein the C-terminal lysine is conjugated with a lipid.
8. The method of claim 6 , wherein the polypeptide is conjugated with a hydrophilic polymer.
9. The method of claim 8 , wherein the hydrophilic polymer comprises polyethylene glycol.
10. The method of claim 6 , wherein the polypeptide comprises SEQ ID NO: 184.
11. The method of claim 6 , wherein the polypeptide comprises SEQ ID NO: 194.
12. A method of reducing complement activity in a subject, wherein the complement activity is associated with coagulation, the method comprising administering a polypeptide to the subject, thereby reducing complement activity in the subject, wherein the polypeptide comprises amino acid residues 9-12 of SEQ ID NO: 192.
13. The method of claim 12 , wherein the polypeptide is administered at a dose of from about 0.01 mg/kg to about 20 mg/kg.
14. The method of claim 12 , wherein the polypeptide is administered at a dose sufficient to achieve polypeptide plasma levels in the subject of from about 2 μg/ml to about 20 μg/ml.
15. The method of claim 12 , wherein the subject has a disease, disorder, or condition wherein complement activity leads to progression of the disease, disorder, or condition.
16. The method of claim 15 , wherein the disease, disorder, or condition comprises thrombosis.
17. The method of claim 15 , wherein the disease, disorder, or condition comprises paroxysmal nocturnal hemoglobinuria (PNH) or atypical hemolytic uremic syndrome.
18. The method of claim 12 , wherein the complement activity is associated with a coagulation pathway component.
19. The method of claim 18 , wherein the coagulation pathway component comprises one or more of tissue factor, FXa, FIXa, FXIa, thrombin, and plasmin.
20. The method of claim 12 , wherein the polypeptide comprises SEQ ID NO: 194.