Complement inhibitors for treatment of injury from intracerebral hemorrhage
View Patent ↗Methods for treating or ameliorating the damage resulting from intracerebral hemorrhage are disclosed. The methods involve administration of a complement inhibitor to inhibit C3 a or C5 a formation or activity in the affected tissue. Pharmaceutical compositions suitable for use in the methods of the invention are also provided.
1. A method for treating or reducing injury resulting from intracerebral hemorrhage in an individual, the method comprising administering a therapeutically effective amount of at least one complement inhibitor to the individual, wherein the at least one complement inhibitor reduces or prevents C3a and C5a formation or activity, thereby treating or preventing the injury resulting from intracerebral hemorrhage, and wherein the at least one complement inhibitor comprises:
(a) a C3 inhibitor, a C4 inhibitor, or a combination thereof; or
(b) a C3 inhibitor, a C3aR inhibitor, or a C4 inhibitor in combination with:
(i) a C5a inhibitor;
(ii) a C5aR inhibitor; or
(iii) a C5a inhibitor and a C5aR inhibitor.
2. The method of claim 1 , wherein the at least one complement inhibitor is a C3 inhibitor, a C3aR inhibitor, or a C4 inhibitor in combination with a C5a inhibitor or a C5aR inhibitor.
3. The method of claim 2 , wherein the C5a inhibitor or C5aR inhibitor is acetyl-Phe-[Orn-Pro-D-cyclohexylalanine-Trp-Arg] (PMX-53), PMX-53 analogs, neutrazumab, TNX-558, eculizumab, pexelizumab or ARC1905, or any combination thereof.
4. The method of claim 1 , wherein the at least one complement inhibitor is a C3 inhibitor.
5. The method of claim 4 , wherein the C3 inhibitor is compstatin, a compstatin analog, a compstatin peptidomimetic, a compstatin derivative, or any combinations thereof.
6. The method of claim 5 , wherein the C3 inhibitor comprises:
(a) Ile-Cys-Val-Val-Gln-Asp-Trp-Gly-His-His-Arg-Cys-Thr (SEQ ID NO. 1); or
(b) Xaa1-Cys-Val-Xaa2-Gln-Asp-Trp-Gly-Xaa3-His-Arg-Cys-Xaa4 (SEQ ID NO. 2); wherein Xaa1 is Ile, Val, Leu, Ac-Ile, Ac-Val, Ac-Leu or a dipeptide comprising Gly-Ile; Xaa2 is Trp or a peptidic or non-peptidic analog of Trp; Xaa3 is His, Ala, Phe or Trp; Xaa4 is L-Thr, D-Thr, Ile, Val, Gly, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly or Asn optionally is replaced by —NH 2 ; and the two Cys residues are joined by a disulfide bond; or
(c) Xaa1-Cys-Val-Xaa2-Gln-Asp-Xaa3-Gly-Xaa4-His-Arg-Cys-Xaa5 (SEQ ID NO. 3); wherein Xaa1 is Ile, Val, Leu, Ac-Ile, Ac-Val, Ac-Leu or a dipeptide comprising Gly-Ile; Xaa2 is Trp or an analog of Trp, wherein the analog of Trp has increased hydrophobic character as compared with Trp, with the proviso that, if Xaa3 is Trp, Xaa2 is the analog of Trp; Xaa3 is Trp or an analog of Trp comprising a chemical modification to its indole ring wherein the chemical modification increases the hydrogen bond potential of the indole ring; Xaa4 is His, Ala, Phe or Trp; and Xaa5 is L-Thr, D-Thr, Ile, Val, Gly, a dipeptide comprising Thr-Asn or Thr-Ala, or a tripeptide comprising Thr-Ala-Asn, wherein a carboxy terminal —OH of any of the L-Thr, D-Thr, Ile, Val, Gly or Asn optionally is replaced by —NH 2 ; and the two Cys residues are joined by a disulfide bond.
7. The method of claim 1 , wherein the at least one complement inhibitor is a C4 inhibitor.
8. The method of claim 1 , wherein the at least one complement inhibitor is administered or targeted to affected tissue.
9. The method of claim 1 , wherein the at least one complement inhibitor is administered systemically.
10. The method of claim 1 , wherein the at least one complement inhibitor is administered together or concurrently with, or sequentially before or after, at least one other agent for treatment of injury resulting from intracerebral hemorrhage.