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 the cleavage of C5 in a biological system comprising providing a polypeptide to the biological system, wherein said polypeptide comprises the amino acid sequence of SEQ ID NO: 184, wherein said polypeptide is provided at a final concentration of from about 0.1 nM to about 50 nM, and wherein cleavage of C5 is reduced by at least 50% relative to cleavage of C5 in the untreated control system.
2. The method of claim 1 , wherein hemolysis is reduced by at least 50% relative to hemolysis in said untreated control system.
3. A method of reducing hemolysis in a subject comprising administering a polypeptide at a dose sufficient to achieve plasma levels of said polypeptide of from about 0.2 mg/L (0.1 μM) to about 40 mg/L (20 wherein said polypeptide comprises the amino acid sequence of SEQ ID NO: 184, and wherein hemolysis in the subject is reduced by at least 50% relative to hemolysis levels previously observed in said subject.
4. The method of claim 3 , wherein the subject is selected from the group consisting of a human subject, a non-human primate subject, and a porcine subject.
5. The method of claim 4 , wherein said polypeptide is administered to said subject at a dose of from about 0.01 mg/kg to about 20 mg/kg.
6. The method of claim 5 , wherein said administration is carried out daily.
7. The method of claim 5 , wherein said administration is carried out weekly.
8. A method of reducing hemolysis in a subject with paroxysmal nocturnal hemoglobinuria (PNH), said method comprising administering a polypeptide to the subject at a dose of from about 0.01 mg/kg to about 20 mg/kg, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 184, and wherein administration is daily, weekly or monthly.
9. The method of claim 8 , wherein said subject has previously been treated with eculizumab.
10. The method of claim 8 , wherein said subject is also receiving treatment with eculizumab.
11. The method of claim 9 , wherein treatment with eculizumab is ineffective.
12. The method of claim 11 , wherein said polypeptide is administered at a dose of from about 0.1 mg/kg to about 10 mg/kg.
13. The method of claim 12 , wherein said polypeptide is administered daily.
14. The method of claim 12 , wherein said polypeptide is administered weekly.
15. The method of claim 12 , wherein hemolysis is reduced by at least 50% relative to hemolysis observed previously in said subject.