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Expanding Complement Therapeutics for the Treatment of Paroxysmal Nocturnal Hemoglobinuria - PubMed

Review

Expanding Complement Therapeutics for the Treatment of Paroxysmal Nocturnal Hemoglobinuria

Dimitrios C Mastellos et al. Semin Hematol. 2018 Jul.

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is widely regarded as an archetypal complement-mediated disorder that has propelled complement drug discovery in recent decades. Its pathology is driven by chronic complement dysregulation resulting from the lack of the glycosyl phosphatidyl inositol-linked regulators DAF and CD59 on susceptible erythrocytes. This complement imbalance fuels persistent C3 activation on affected erythrocytes, which culminates in chronic complement-mediated intravascular hemolysis. The clinical application of eculizumab, a humanized anti-C5 antibody that blocks terminal pathway activation, has led to drastic improvement of therapeutic outcomes but has also unveiled hitherto elusive pathogenic mechanisms that are now known to contribute to the clinical burden of a significant proportion of patients with PNH. These emerging clinical needs have sparked a true resurgence of complement therapeutics that offer the promise of even more effective, disease-tailored therapies for PNH. Here, we review the current state of complement therapeutics with a focus on the clinical development of C3-targeted and alternative pathway-directed drug candidates for the treatment of PNH. We also discuss the relative advantages and benefits offered by each complement-targeting approach, including translational considerations that might leverage a more comprehensive clinical intervention for PNH.

Keywords: C3 inhibitors; Clinical trials; Complement therapeutics; Compstatins; Extravascular hemolysis; PNH.

Copyright © 2018 Elsevier Inc. All rights reserved.

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Conflict of interest statement

Disclosure statement

J.D.L. and A.M.R. are inventors of patents or patent applications that describe the use of complement inhibitors for therapeutic purposes, some of which are developed by Amyndas Pharmaceuticals. J.D.L. is the founder of Amyndas Pharmaceuticals, which is developing complement inhibitors, including third-generation compstatin analogues such as AMY-101, for the treatment of complement-mediated diseases. J.D.L. is also the inventor of the compstatin technology licensed to Apellis Pharmaceuticals [4(1MeW)7W, also known as POT-4 and APL-1 and PEGylated derivatives such as APL-2]. A.M.R. has received research support from Alexion, Alnylam, Rapharma and Novartis; A.M.R. has received lecture fees and serves as member of an investigator board for Alexion, Novartis and Roche. AMR is involved as an investigator in clinical trials evaluating the following agents: TT30, ALXN1210, SKY59, ACH-4471, LNP023 and AMY-101. The rest of the authors have no competing interests.

Figures

Figure 1
Figure 1. Schematic overview of the complement activation cascade illustrating targets for therapeutic modulation in PNH

Complement activation via any of the three pathways (Classical, CP, alternative, AP or lectin pathway, LP) triggers a cascade of proteolytic reactions that converge at the cleavage of the central component, C3, by short-lived enzymatic complexes, termed C3 convertases of the CP (C4b3b) or AP (C3bBb). In the absence of the GPI-linked AP regulator DAF/CD55, PNH erythrocytes undergo uncontrollable C3 opsonization that leads to C3b deposition at high surface densities. This AP-amplified opsonic turnover triggers C5 convertase activity that leads to MAC assembly on target cells. In the absence of CD59, regulation of MAC formation on PNH erythrocytes is impaired and consequently this persistent C3 opsonization culminates in chronic, MAC-mediated intravascular hemolysis, one of the cardinal clinical manifestations of PNH. In the era of eculizumab treatment, C3-mediated extravascular hemolysis of C3-opsonized PNH cells in the hepatosplenic compartment has emerged as a significant unmet clinical need for PNH patients who are suboptimal responders to anti-C5 therapy. Furthermore, a fraction of PNH patients may show incomplete response to eculizumab due to residual intravascular hemolysis which is attributed to pharmacodynamic or pharmacologic breakthrough during inhibitor dosing. These unmet needs have sparked the development of next-generation complement therapeutics that can modulate C3 or C5 activation and also target AP convertase activity (shown in callout boxes). In principle, C5 blockage results in complete abrogation of intravascular hemolysis without however affecting upstream AP dysregulation. Conceivably, the application of different anti-C5 agents (or their combination) may offer deeper terminal pathway inhibition and/or improved patient compliance through alternative dosing routes. Upstream complement intervention at the level of C3 is anticipated to afford broader inhibition of complement responses that drive PNH pathology. C3 inhibition can abrogate both intravascular and extravascular C3-mediated hemolysis while AP-targeted inhibitors can also afford broader coverage by controlling AP amplification and downstream effector generation.

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References

    1. Takeda J, Miyata T, Kawagoe K, Iida Y, Endo Y, Fujita T, et al. Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria. Cell. 1993 May 21;73(4):703–11. - PubMed
    1. Miyata T, Takeda J, Iida Y, Yamada N, Inoue N, Takahashi M, et al. The cloning of PIG-A, a component in the early step of GPI-anchor biosynthesis. Science. 1993 Feb 26;259(5099):1318–20. - PubMed
    1. Medof ME, Gottlieb A, Kinoshita T, Hall S, Silber R, Nussenzweig V, et al. Relationship between decay accelerating factor deficiency, diminished acetylcholinesterase activity, and defective terminal complement pathway restriction in paroxysmal nocturnal hemoglobinuria erythrocytes. J Clin Invest. 1987 Jul;80(1):165–74. - PMC - PubMed
    1. Risitano AM. Paroxysmal nocturnal hemoglobinuria and other complement-mediated hematological disorders. Immunobiology. 2012 Nov;217(11):1080–7. - PubMed
    1. Parker C, Omine M, Richards S, Nishimura J, Bessler M, Ware R, et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005 Dec 1;106(12):3699–709. - PMC - PubMed

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