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

Highlights:

• 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.