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 administering a C5 inhibitor to the subject, wherein the C5 inhibitor is administered at a frequency of from about every 12 hours to about every 72 hours, wherein hemolysis in subject plasma is reduced by at least 90% during the course of administration, and wherein the C5 inhibitor comprises a polypeptide comprising the formula R 1 -Tbg-Tyr-Xaa0-Glu-R 2 , wherein:
R 1 comprises a polypeptide;
Xaa0 is selected from the group consisting of Trp, azaTrp, N-methyl Trp, 1-methyl Trp, and 3-aminomethyl Phe; and
R 2 comprises a polypeptide.
2. The method of claim 1 , wherein the C5 inhibitor is administered daily.
3. The method of claim 1 , wherein the polypeptide comprises a bridging moiety between two amino acids.
4. The method of claim 3 , wherein the R1 polypeptide comprises the formula Xaa1-Val-Glu-Arg-Xaa2-Xaa3, wherein:
Xaa1 is Cys or Lys;
Xaa2 is Phe or Ala; and
Xaa3 is Cys or Asp.
5. The method of claim 4 , wherein the polypeptide comprises a bridging moiety between Xaa1 and Xaa3.
6. The method of claim 5 , wherein the R1 polypeptide comprises the formula Xaa1-Val-Glu-Arg-Xaa2-Xaa3-Xaa4, wherein Xaa4 is selected from the group consisting of Asp, Ala, (S)-2-amino-3-(1H-tetrazol-5-yl)propanoic acid, alpha-methyl Asp, N-methyl Asp, cycloleucine, and 4-amino-tetrahydro-pyran-4-carboxylic acid.
7. The method of claim 1 , wherein the R2 polypeptide comprises the formula Tyr-Pro-Xaa5-Xaa6, wherein:
Xaa5 is selected from the group consisting of cyclohexylglycine, phenylglycine (Phg), D-Phg, and N-methyl Phg, or is absent; and
Xaa6 is selected from the group consisting of Lys, and norvaline, or is absent.
8. The method of claim 7 , wherein Xaa6 is Lys.
9. The method of claim 8 , wherein the Xaa6 Lys is conjugated with a lipid.
10. The method of claim 8 , wherein the Xaa6 Lys comprises a modified lysine residue selected from the group consisting of N-ε-palmitoyl lysine, N-ε-lauryl lysine, N-ε-capryl lysine, N-ε-caprylic lysine, N-ε-(PEG2-γ-glutamic acid-N-α-octadecanedioic acid)lysine, N-ε-(PEG24-γ-glutamic acid-N-α-hexadecanoyl)lysine, and N-ε-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl-L-lysine.
11. The method of claim 1 , wherein the polypeptide comprises an N-terminal acetyl group.
12. The method of claim 1 , wherein the polypeptide comprises a C-terminal —NH 2.
13. 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.
14. The method of claim 13 , wherein the C5 inhibitor is administered at a dose of from about 0.3 mg/kg to about 3 mg/kg.
15. 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.
16. The method of claim 15 , wherein the C5 inhibitor is administered at a dose sufficient to achieve C5 inhibitor plasma levels in the subject of about 4 μg/ml.
17. 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.
18. The method of claim 1 , wherein the subject has previously been treated with eculizumab.
19. The method of claim 18 , wherein the subject is also receiving treatment with eculizumab.
20. The method of claim 18 , wherein treatment with eculizumab is ineffective.
21. The method of claim 20 , wherein the subject has an eculizumab-resistant C5 polymorphism.