Peptide inhibitors of C3 activation as a novel strategy of complement inhibition for the treatment of paroxysmal nocturnal hemoglobinuria
Open Access
- 27 March 2014
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 123 (13), 2094-2101
- https://doi.org/10.1182/blood-2013-11-536573
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated intravascular hemolysis due to the lack of CD55 and CD59 on affected erythrocytes. The anti-C5 antibody eculizumab has proven clinically effective, but uncontrolled C3 activation due to CD55 absence may result in opsonization of erythrocytes, possibly leading to clinically meaningful extravascular hemolysis. We investigated the 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. Both compounds demonstrated dose-dependent inhibition of hemolysis with IC50 ∼4 µM and full inhibition at 6 µM. Protective levels of either Cp40 or PEG-Cp40 also efficiently prevented deposition of C3 fragments on PNH erythrocytes. We further explored the potential of both inhibitors for systemic administration and performed pharmacokinetic evaluation in nonhuman primates. A single intravenous injection of PEG-Cp40 resulted in a prolonged elimination half-life of >5 days but may potentially affect the plasma levels of C3. Despite faster elimination kinetics, saturating inhibitor concentration could be reached with unmodified Cp40 through repetitive subcutaneous administration. In 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.Keywords
This publication has 44 references indexed in Scilit:
- Long‐term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuriaBritish Journal of Haematology, 2013
- Design and development of TT30, a novel C3d-targeted C3/C5 convertase inhibitor for treatment of human complement alternative pathway–mediated diseasesBlood, 2011
- Novel analogues of the therapeutic complement inhibitor compstatin with significantly improved affinity and potencyMolecular Immunology, 2011
- Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsisBlood, 2010
- Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosisBlood, 2010
- Paroxysmal nocturnal hemoglobinuria and eculizumabHaematologica, 2010
- Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonizationHaematologica, 2010
- Structure‐kinetic relationship analysis of the therapeutic complement inhibitor compstatinJournal of Molecular Recognition, 2009
- How I treat paroxysmal nocturnal hemoglobinuriaBlood, 2009
- Factor H–mediated cell surface protection from complement is critical for the survival of PNH erythrocytesBlood, 2007