Journal ArticleDOI
Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria
TLDR
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.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.read more
Citations
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Journal ArticleDOI
Terminal Complement Inhibitor Eculizumab in Atypical Hemolytic–Uremic Syndrome
Ch. Legendre,Christoph Licht,Petra Muus,Laurence Greenbaum,Sunil Babu,C. Bedrosian,C. Bingham,David J. Cohen,Y. Delmas,Kenneth W. Douglas,Frank Eitner,Thorsten Feldkamp,Denis Fouque,Richard R. Furman,Osama Gaber,Maria Herthelius,Maryvonne Hourmant,Diana Karpman,Yvon Lebranchu,Christophe Mariat,Jan Menne,Bruno Moulin,Jens Nürnberger,Masayo Ogawa,Giuseppe Remuzzi,T. Richard,Rebecca Sberro-Soussan,B. Severino,Neil S. Sheerin,Antonella Trivelli,L.B. Zimmerhackl,Timothy H.J. Goodship,Chantal Loirat +32 more
TL;DR: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome and was also associated with improvement in health-related quality of life.
Journal ArticleDOI
Complement System Part I - Molecular Mechanisms of Activation and Regulation
Nicolas S. Merle,Nicolas S. Merle,Nicolas S. Merle,Sarah E. Church,Sarah E. Church,Sarah E. Church,Véronique Frémeaux-Bacchi,Lubka T. Roumenina,Lubka T. Roumenina,Lubka T. Roumenina +9 more
TL;DR: This article will review the mechanisms of activation of alternative, classical, and lectin pathways, the formation of C3 and C5 convertases, the action of anaphylatoxins, and the membrane-attack-complex, and discuss the importance of structure–function relationships.
Journal ArticleDOI
Therapeutic antibodies for autoimmunity and inflammation
Andrew C. Chan,Paul Carter +1 more
TL;DR: How key insights obtained from the development of therapeutic antibodies complemented by newer antibody engineering technologies are delivering a second generation of therapeutic antibody with promise for greater clinical efficacy and safety is reviewed.
Journal ArticleDOI
Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies
TL;DR: A number of important issues require further study, including the appropriate duration of treatment according to an individual's genetic background and medical history, the optimal strategy to prevent post-transplantation recurrence of aHUS and a cost–efficacy analysis.
Journal ArticleDOI
Paroxysmal nocturnal hemoglobinuria.
TL;DR: Bone marrow transplantation remains the only cure for PNH but should be reserved for patients with suboptimal response to eculizumab, a first-in-class monoclonal antibody that inhibits terminal complement.
References
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