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Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria

An Erratum to this article was published on 01 December 2007

This article has been updated

Abstract

The complement system provides critical immunoprotective and immunoregulatory functions but uncontrolled complement activation can lead to severe pathology. In the rare hemolytic disease paroxysmal nocturnal hemoglobinuria (PNH), somatic mutations result in a deficiency of glycosylphosphatidylinositol-linked surface proteins, including the terminal complement inhibitor CD59, on hematopoietic stem cells. In a dysfunctional bone marrow background, these mutated progenitor blood cells expand and populate the periphery. Deficiency of CD59 on PNH red blood cells results in chronic complement-mediated intravascular hemolysis, a process central to the morbidity and mortality of PNH. A recently developed, humanized monoclonal antibody directed against complement component C5, eculizumab (Soliris; Alexion Pharmaceuticals Inc., Cheshire, CT, USA), blocks the proinflammatory and cytolytic effects of terminal complement activation. The recent approval of eculizumab as a first-in-class complement inhibitor for the treatment of PNH validates the concept of complement inhibition as an effective therapy and provides rationale for investigation of other indications in which complement plays a role.

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Figure 1: Targeted blockade of complement protein C5.
Figure 2: Engineering of eculizumab to reduce immunogenicity and eliminate effector functions.
Figure 3: Terminal complement deposition on the surface of PNH RBCs results in chronic hemolysis and serious clinical morbidities.
Figure 4: Reduction in hemolysis during treatment with eculizumab.
Figure 5: Eculizumab in PNH development timeline.

Change history

  • 12 December 2007

    In the version of this article initially published, on p.1258, 2nd paragraph, the incorrect eculizumab serum concentrations appear to reach steady state and the incorrect accumulation ratio (Racc) for eculizumab were given. The correct sentence is “Eculizumab serum concentrations appear to reach steady state after ~57 days. At steady state, the eculizumab accumulation ratio (Racc) was calculated to be 1.075.” In addition, in Figure 5, in the PDF version only, the word “assessment” was cut off the bottom of the box beginning “September 2006”. The final sentence should read “BLA and MAA submitted to FDA and EMEA, respectively; receive accelerated assessment.” And in Table 1, the heading “Units of packed RBCs transfused/patient/month” now appears in a separate row. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

The authors wish to acknowledge the Alexion research team for their involvement in the identification and characterization of eculizumab, the Alexion clinical and drug development teams for the eculizumab clinical program, the clinicians and patients for their participation in the trials, and Kerry Quinn-Senger and Rebecca Baker for assistance with the preparation of this manuscript.

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Correspondence to Russell P Rother.

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R.P.R., S.A.R. and L.B. are employees of Alexion Pharmaceuticals, Inc. and have equity ownership in the company. They have assigned to Alexion Pharmaceuticals their inventions made as employees and have received no royalties from the company for these inventions. C.F.M. is a former employee of Alexion and is a consultant for the company. R.A.B. is a consultant for Alexion and has received lecture fees from the company.

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Rother, R., Rollins, S., Mojcik, C. et al. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol 25, 1256–1264 (2007). https://doi.org/10.1038/nbt1344

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