Method of treating age-related macular degeneration comprising administering a compstatin analog
The present invention features the use of compstatin and complement inhibiting analogs thereof for treating and/or preventing age related macular degeneration and other conditions involving macular degeneration, choroidal neovascularization, and/or retinal neovascularization. The invention also provides compositions comprising compstatin or a complement inhibiting analog thereof and a second therapeutic agent. The invention also provides compositions comprising compstatin or a complement inhibiting analog thereof and a gel-forming material, e.g., soluble collagen, and methods of administering the compositions.
1. A method of treating age-related macular degeneration (ARMD), comprising the step of: administering a composition comprising an effective amount of a compstatin analog to a subject suffering from ARMD.
2. The method of claim 1 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a core sequence of X′aa-Gln-Asp-Xaa-Gly (SEQ ID NO: 3), where X′aa and Xaa are selected from Trp and analogs of Trp.
3. The method of claim 1 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a core sequence of X′aa-Gln-Asp-Xaa-Gly-X″aa (SEQ ID NO: 4), where X′aa and Xaa are each independently selected from Trp and analogs of Trp and X″aa is selected from His, Ala, single methyl unbranched amino acids, Phe, Trp, and analogs of Trp.
4. The method of claim 3 , wherein the peptide has a sequence of X′aa1-X′aa2-X′aa3-X′aa-Gln-Asp-Xaa-Gly-X″aa-X″aa2-X″aa3-X″aa4-X″aa5 (SEQ ID NO: 5), and X′aa1, X′aa2, X′aa3, X″aa2, X″aa3-X″aa4, and X″aa5 are identical to the amino acids at the corresponding positions in compstatin.
5. The method of claim 1 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a sequence of X′aa1-X′aa2-X′aa3-X′aa4-Gln-Asp-Xaa-Gly-X″aa1-X″aa2-X″aa3-X″aa4-X″aa- 5 (SEQ ID NO: 5), where X′aa4 and Xaa are selected from Trp and analogs of Trp, wherein X′aa1, X′aa2, X′aa3, X″aa1, X″aa2, X″aa3, X″aa4, and X″aa5 are independently selected from among amino acids and amino acid analogs, and the peptide is cyclized via a bond between X′aa2 and X″aa4.
6. The method of claim 1 , wherein the compstatin analog is a compound that comprises a cyclic peptide having a sequence: Xaa1-Cys-Val-Xaa2-Gln-Asp-Xaa2*-Gly-Xaa3-His-Arg-Cys-Xaa4 (SEQ ID NO: 6); wherein: Xaa1 is Ile, Val, Leu, B 1 -Ile, B 1 -Val, B 1 -Leu or a dipeptide comprising Gly-Ile or B 1 -Gly-Ile, and B 1 represents a first blocking moiety; Xaa2 and Xaa2* are independently selected from Trp and analogs of Trp; Xaa3 is His, Ala or an analog of Ala, Phe, Trp, or an analog of Trp; Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, a dipeptide selected from Thr-Ala and Thr-Asn, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly, Ala, or Asn optionally is replaced by a second blocking moiety B 2 ; and the two Cys residues are joined by a disulfide bond.
7. The method of claim 6 , wherein the peptide is acetylated at the N-terminus, amidated at the C-terminus, or both acetylated at the N-terminus and amidated at the C-terminus.
8. The method of claim 6 , wherein Xaa1 is Ile, Val, Leu, Ac-Ile, Ac-Val, Ac-Leu or a dipeptide comprising Gly-Ile or Ac-Gly-Ile; Xaa2 and Xaa2* are independently selected from Trp and analogs of Trp; Xaa3 is His, Ala or an analog of Ala, Phe, Trp, or an analog of Trp; Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, a dipeptide selected from Thr-Ala and Thr-Asn, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly, Ala, or Asn optionally is replaced by —NH 2 .
9. The method of claim 6 , wherein Xaa2 is an analog of Trp having increased hydrophobic character relative to Trp.
10. The method of claim 6 , wherein Xaa2 is an analog of Trp comprising a substituted or unsubstituted bicyclic aromatic ring component or two or more substituted or unsubstituted monocyclic aromatic ring components.
11. The method of claim 1 , wherein the composition is administered intravitreally.
12. The method of claim 1 , wherein the compstatin analog is a compound that comprises a cyclic peptide comprising a cyclic portion 11 amino acids in length, wherein the sequence of the peptide is at least 50% identical to the sequence of compstatin (SEQ ID NO: 8) or to the sequence of a compstatin analog that has higher activity than compstatin.
13. The method of claim 12 , wherein the peptide comprises at least one non-standard amino acid.
14. The method of claim 13 , wherein at least one non-standard amino acid is a singly or multiply halogenated amino acid, N-alkyl amino acid, or aromatic amino acid.
15. The method of claim 1 , wherein the compstatin analog is a compound that comprises or consists of a sequence that is obtained by making 1, 2, 3, or 4 substitutions in the sequence of compstatin, wherein the peptide is cyclized via a bond between amino acids at positions that correspond to position 2 and position 12 of compstatin.
16. The method of claim 15 , wherein 1, 2, 3, or 4 amino acids in the sequence of compstatin is replaced by a non-standard amino acid.
17. The method of claim 16 , wherein at least one non-standard amino acid is a singly or multiply halogenated amino acid, N-alkyl amino acid, or aromatic amino acid.
18. The method of claim 1 , wherein the compstatin analog binds to substantially the same region of human C3 as does compstatin and has a C3 inhibitory activity at least 10-fold as great as that of compstatin.
19. The method of claim 1 , wherein the composition is locally administered to the eye or in the vicinity of the eye.