Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.
Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.
Transl Res. 2015 Feb;165(2):306-20. doi: 10.1016/j.trsl.2014.10.010. Epub 2014 Oct 20.
The complement inhibitor eculizumab is a humanized monoclonal antibody against C5. It was developed to specifically target cleavage of C5 thus preventing release of C5a and activation of the terminal pathway. Paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) are 2 diseases with distinctly different underlying molecular mechanisms. In PNH, progeny of hematopoietic stem cells that harbor somatic mutations lead to a population of peripheral blood cells that are deficient in complement regulators resulting in hemolysis and thrombosis. In aHUS, germline mutations in complement proteins or their regulators fail to protect the glomerular endothelium from complement activation resulting in thrombotic microangiopathy and renal failure. Critical to the development of either disease is activation of the terminal complement pathway. Understanding this step has led to the study of eculizumab as a treatment for these diseases. In clinical trials, eculizumab is proven to be effective and safe in PNH and aHUS.
补体抑制剂依库珠单抗是一种针对 C5 的人源化单克隆抗体。它被开发出来是为了专门针对 C5 的切割，从而阻止 C5a 的释放和末端途径的激活。阵发性夜间血红蛋白尿症 (PNH) 和非典型溶血尿毒症综合征 (aHUS) 是两种具有明显不同潜在分子机制的疾病。在 PNH 中，造血干细胞的后代发生体细胞突变，导致外周血细胞群缺乏补体调节剂，导致溶血和血栓形成。在 aHUS 中，补体蛋白或其调节剂的种系突变未能保护肾小球内皮免受补体激活，导致血栓性微血管病和肾衰竭。无论是哪种疾病的发展，关键都是末端补体途径的激活。对这一步骤的理解导致了对依库珠单抗作为这些疾病治疗方法的研究。在临床试验中，依库珠单抗在 PNH 和 aHUS 中的疗效和安全性已得到证实。
