title: Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria.
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.
authors.affiliation: Alexion Pharmaceuticals, Inc., 352 Knotter Drive, Cheshire, Connecticut 06410, USA. rother@alxn.com
authors.forename: Russell P
authors.initials: RP
authors.lastname: Rother
authors.forename: Scott A
authors.initials: SA
authors.lastname: Rollins
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Mojcik
authors.forename: Robert A
authors.initials: RA
authors.lastname: Brodsky
authors.forename: Leonard
authors.initials: L
authors.lastname: Bell
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics* / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D002986:Clinical Trials as Topic; D003182:Complement C5 / Q000037:antagonists & inhibitors* / Q000502:physiology; D051056:Complement Inactivating Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D017277:Drug Approval; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006457:Hemoglobinuria, Paroxysmal / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D051379:Mice; D015202:Protein Engineering
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003182:Complement C5; D051056:Complement Inactivating Agents; C481642:eculizumab