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 hemolysis in a subject, the method comprising administration of a C5 inhibitor to the subject, wherein:
the C5 inhibitor is a polypeptide comprising an amino acid sequence corresponding to amino acid residues 9-12 of SEQ ID NO: 192,
the C5 inhibitor is administered at a frequency of from about every 12 hours to about every 72 hours, and
wherein hemolysis in subject plasma is reduced by at least 90% during the course of administration.
2. The method of claim 1 , wherein the C5 inhibitor is administered daily.
3. The method of claim 1 , wherein the C5 inhibitor is a polypeptide.
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 7 , 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 7 , wherein the polypeptide comprises SEQ ID NO: 184.
11. The method of claim 7 , wherein the polypeptide comprises SEQ ID NO: 194.
12. The method of claim 1 , wherein the C5 inhibitor is administered at a dose of from about 0.01 mg/kg to about 20 mg/kg.
13. The method of claim 12 , wherein the C5 inhibitor is administered at a dose of from about 0.3 mg/kg to about 3 mg/kg.
14. The method of claim 1 , wherein the C5 inhibitor is administered at a dose sufficient to achieve C5 inhibitor plasma levels in the subject of from about 2 μg/ml to about 20 μg/ml.
15. The method of claim 14 , wherein the C5 inhibitor is administered at a dose sufficient to achieve C5 inhibitor plasma levels in the subject of about 4 μg/ml.
16. The method of claim 1 , wherein the subject has a disease, disorder, or condition wherein C5 cleavage leads to progression of the disease, disorder, or condition.
17. The method of claim 16 , wherein the disease, disorder, or condition comprises paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, or myasthenia gravis.
18. The method of claim 1 , wherein the subject has PNH.
19. The method of claim 1 , wherein the subject has previously been treated with eculizumab.
20. The method of claim 19 , wherein the subject is also receiving treatment with eculizumab.
21. The method of claim 19 , wherein treatment with eculizumab is ineffective.
22. The method of claim 21 , wherein the subject has an eculizumab-resistant C5 polymorphism.