Complement in paroxysmal nocturnal hemoglobinuria: exploiting our current knowledge to improve the treatment landscape

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder associated with an acquired deficiency in glycophosphatidylinositol-anchor biosynthesis that renders erythrocytes susceptible to complement attack. Intravascular hemolysis via the membrane attack complex is a clinical hallmark of the disease, and C5 blockade is currently the only approved treatment for PNH. However, residual anemia is an emerging observation for many PNH patients receiving anti-C5 treatment. A range of complement-targeted therapeutic approaches, encompassing surface-directed inhibition of C3 convertases, blockade of membrane attack complex assembly or C3 interception using peptidic inhibitors, has yielded promising results and offers leverage for even more effective treatment of PNH. This article discusses recent advances in this rapidly evolving field, integrating critical perspectives from preclinical PNH models and diverse complement modulation strategies with genetic insights and therapy response profiles. It also evaluates the relative efficacy, limitations and benefits afforded by C3 or C5 inhibition in the context of PNH therapeutics.

Keywords::

• C3 inhibitors
• C5 blockade
• complement therapeutics
• Cp40
• AMY-101
• eculizumab
• extravascular hemolysis
• MAC
• PNH

Acknowledgements

The authors would like to thank D McClellan for excellent editorial assistance, paid for by the authors. This work was supported by National Institutes of Health grants AI068730, AI030040, EY020633 and AI097805, a pilot grant from the Penn-CHOP Blood Center for Patient Care and Discovery, and funding from the European Union’s Seventh Framework Programme under grant agreement no. 602699 (DIREKT).

Financial & competing interests disclosure

JD Lambris and D Ricklin are inventors of patent and/or patent applications that describe the use of complement inhibitors for therapeutic purposes. JD Lambris is also the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors for clinical applications. AM Risitano acknowledges past research funding from Alexion Pharmaceuticals and consultancy with Alnylam and RA Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Complement dysregulation on paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes is driven by deficiency in glycophosphatidylinositol-linked CD55 and CD59 and is tightly intertwined with intravascular hemolysis, the main clinical manifestation of PNH.

• Anti-C5 antibody therapy (eculizumab, Soliris^®, Alexion Pharmaceuticals) has drastically changed the treatment landscape, offering PNH patients an effective therapeutic ‘handle’ for controlling intravascular hemolysis and its ensuing thrombotic complications.

• Genetic variations in complement genes (e.g., CR1, C5) have emerged as therapy-modifying factors and partly explain poor clinical responses of a subset of PNH patients to eculizumab therapy.

• Residual anemia, presumably due to C3-mediated extravascular hemolysis of surviving PNH erythrocytes, has emerged as a common clinical manifestation during eculizumab treatment, eventually limiting the hematological benefit of this treatment.

• A broad spectrum of new C5- and C3-targeted therapeutic strategies aimed at improving response rate, administration options and/or treatment costs has been developed, several of which are currently being evaluated in preclinical models or in Phase I clinical trials.

• Targeted modulation of complement activity at the C3 level emerges as an attractive alternative for effective therapeutic intervention in PNH that offers advantages over inhibition of the lytic terminal pathway (C5 level) alone.

• Engineered regulators of the C3 convertase and small synthetic C3 inhibitors have been shown to abrogate opsonization of PNH erythrocytes and downstream formation of lytic membrane attack complex, thereby preventing both intravascular and extravascular hemolysis.

• Peptidic C3 inhibitors of the compstatin family (e.g., Cp40 and the Cp40-based therapeutic AMY-101) display favorable pharmacokinetic properties, safety and inhibition profiles, thus showing great promise as potent and potentially cost-effective therapeutics for PNH.

Notes