Perspective abstract
Nature Biotechnology 25, 1256 - 1264 (2007)
Published online: 7 November 2007 | doi:10.1038/nbt1344
There is an Erratum (December 2007) associated with this Perspective.
Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria
Russell P Rother1, Scott A Rollins1, Christopher F Mojcik1, Robert A Brodsky2 & Leonard Bell1
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.
- Alexion Pharmaceuticals, Inc., 352 Knotter Drive, Cheshire, Connecticut 06410, USA.
- Johns Hopkins University School of Medicine, Division of Hematology, 720 Rutland Avenue, Ross Building Room 1025, Baltimore, Maryland 21205, USA.
Correspondence to: Russell P Rother1 e-mail: rotherr@alxn.com
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