Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria

  • For effect of the peptidic C3 inhibitor, compstatin Cp40, and its long-acting form (polyethylene glycol [PEG]-Cp40) on hemolysis and opsonization of PNH erythrocytes in an established in vitro system:
    1. Both compounds demonstrate dose-dependent inhibition of hemolysis with IC50 ∼4 µM and full inhibition at 6 µM.
    2. Protective levels of either Cp40 or PEG-Cp40 efficiently prevent deposition of C3 fragments on PNH erythrocytes.
  • For potential of both inhibitors for systemic administration and performed pharmacokinetic evaluation in nonhuman primates:
    1. A single intravenous injection of PEG-Cp40 results in a prolonged elimination half-life of >5 days but may potentially affect the plasma levels of C3.
    2. Despite faster elimination kinetics, saturating inhibitor concentration could be reached with unmodified Cp40 through repetitive subcutaneous administration.
  • Conclusion: Peptide inhibitors of C3 activation effectively prevent hemolysis and C3 opsonization of PNH erythrocytes, and are excellent, and potentially cost-effective, candidates for further clinical investigation.
Author and source information

Authors: Risitano AM, Ricklin D, Huang Y, Reis ES, Chen H, Ricci P, Lin Z, Pascariello C, Raia M, Sica M, Del Vecchio L, Pane F, Lupu F, Notaro R, Resuello RR, DeAngelis RA, Lambris JD.
Reference: Blood. 2014 Mar 27;123(13):2094-101. doi: 10.1182/blood-2013-11-536573. Epub 2014 Feb 4.