Local complement inhibition for treatment of complement-mediated disorders
The present invention features the local administration of complement inhibitors for treatment of complement-mediated disorders. In certain embodiments the invention features inhibiting activation of one or more locally produced complement proteins. The invention provides sustained release formulations and devices comprising a complement inhibitor and methods of use thereof.
1. A method of treating a complement-mediated disorder which is an inflammatory condition of the respiratory system comprising administering an effective amount of a compstatin analog comprising a cyclic peptide having a core sequence of X′aa-Gln-Asp-Xaa-Gly (SEQ ID NO: 3), wherein X′aa and Xaa are each independently selected from Trp and analogs of Trp, directly to the respiratory tract.
2. The method of claim 1 , wherein said compstatin analog is administered in an amount that reduces systemic complement activation by less than 20%.
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, Tip, and analogs of Trp.
4. The method of claim 1 , wherein the compstatin analog is administered by inhalation.
5. The method of claim 1 , wherein said compstatin analog is administered in an amount sufficient to inhibit complement activity attributable to at least one complement activation pathway in the respiratory tract by at least 25%.
6. The method of claim 1 , wherein said compstatin analog is administered in an amount sufficient to reduce complement activity attributable to at least one complement pathway in the respiratory tract to a level no more than twice the average level found in the respiratory tract in the absence of the inflammatory condition.
7. The method of claim 1 , wherein the inflammatory condition is mediated at least in part by a locally produced soluble complement protein, wherein the compstatin analog is administered in an amount sufficient to reduce complement activity attributable to said locally produced complement protein to a level no more than twice the average level found in the respiratory tract in the absence of the inflammatory condition.
8. The method of claim 1 , wherein said compstatin analog inhibits local activation of C3.
9. The method of claim 1 , wherein said compstatin analog inhibits cleavage of complement component C3.
10. The method of claim 1 , wherein said compstatin analog binds to complement component C3.
11. The method of claim 1 , wherein said inflammatory condition of the respiratory system is selected from the group consisting of: asthma and chronic obstructive pulmonary disease (COPD).
12. The method of claim 1 , wherein said effective amount has essentially no effect on systemic complement activation when administered to the respiratory system.
13. The method of claim 1 , wherein said compstatin analog is released from a sustained release formulation or device that releases the compstatin analog over time.
14. The method of claim 13 , wherein said sustained release formulation comprises a plurality of microparticles or nanoparticles.
15. The method of claim 13 , wherein said sustained release formulation comprises a biodegradable polymeric matrix.
16. The method of claim 1 , further comprising the step of administering a second agent effective against the inflammatory condition of the respiratory system.
17. The method of claim 1 , further comprising the step of: determining whether complement activity is aberrantly high in the respiratory tract in the subject's body.
18. A method of treating an inflammatory condition of the respiratory system comprising administering a compstatin analog comprising a cyclic peptide having a core sequence of X′aa-Gln-Asp-Xaa-Gly (SEQ ID NO: 3) wherein X′aa and Xaa are each independently selected from Trp and analogs of Trp directly to the respiratory tract, wherein said compstatin analog binds to a locally produced soluble complement protein.
19. The method of claim 18 , wherein said inflammatory condition of the respiratory system is selected from the group consisting of: asthma, COPD, allergic rhinitis, and infection-associated inflammation.
20. The method of claim 18 , wherein said compstatin analog is administered as a component of an inhalable dry powder.
21. The method of claim 18 , wherein said compstatin analog is administered as a component of an inhalable liquid aerosol.