Genetic Variants in C5 and Poor Response to Eculizumab
Genetic Variants in C5 and Poor Response to Eculizumab
复制标题
DOI：
10.1056/nejmoa1311084
复制
发表时间：
2014-02-13
影响因子：
158.5
通讯作者：
Kanakura, Yuzuru
中科院分区：
文献类型：
--
作者：
Nishimura, Jun-ichi;Yamamoto, Masaki;Kanakura, Yuzuru
研究背景依库珠单抗（Eculizumab）是一种人源化的单克隆抗体，其作用靶点是补体C5蛋白，可抑制与阵发性睡眠性血红蛋白尿症（PNH）相关的终末补体介导的溶血。在日本patients.MethodsWe评估了PNH患者的基因编码C5的序列，这些患者对依库珠单抗的反应良好或较差。我们还评估了C5的功能特性，因为它是编码在这些patients.ResultsOf 345日本PNH患者接受依库珠单抗，11例反应不佳。所有11个有一个单一的错义C5杂合突变，c.2654GA，这预示着多态性p.Arg885His。PNH患者中该突变的患病率（3.2%）与日本健康人群（3.5%）相似。这种多态性也在中国汉族人群中发现。一位来自阿根廷的亚裔患者，其疗效不佳，有一个非常相似的突变，c.2653CT，预测p.Arg885Cys。非突变型和突变型C5在体外均引起溶血，但只有非突变型C5与依库珠单抗结合并被依库珠单抗阻断。在体外溶血，由于nonmutant和突变C5完全封锁与使用N19-8，单克隆抗体，结合到C5上的一个不同的网站比eculizumab.ConclusionsThe功能能力的C5变异体与突变在Arg 885，连同他们的失败进行封锁eculizumab，帐户的不良反应，这种代理在携带这些突变的患者。（由Alexion Pharmaceuticals和日本厚生劳动省资助。
BackgroundEculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement-mediated hemolysis associated with paroxysmal nocturnal hemoglobinuria (PNH). The molecular basis for the poor response to eculizumab in a small population of Japanese patients is unclear.MethodsWe assessed the sequences of the gene encoding C5 in patients with PNH who had either a good or poor response to eculizumab. We also evaluated the functional properties of C5 as it was encoded in these patients.ResultsOf 345 Japanese patients with PNH who received eculizumab, 11 patients had a poor response. All 11 had a single missense C5 heterozygous mutation, c.2654GA, which predicts the polymorphism p.Arg885His. The prevalence of this mutation among the patients with PNH (3.2%) was similar to that among healthy Japanese persons (3.5%). This polymorphism was also identified in a Han Chinese population. A patient in Argentina of Asian ancestry who had a poor response had a very similar mutation, c.2653CT, which predicts p.Arg885Cys. Nonmutant and mutant C5 both caused hemolysis in vitro, but only nonmutant C5 bound to and was blocked by eculizumab. In vitro hemolysis due to nonmutant and mutant C5 was completely blocked with the use of N19-8, a monoclonal antibody that binds to a different site on C5 than does eculizumab.ConclusionsThe functional capacity of C5 variants with mutations at Arg885, together with their failure to undergo blockade by eculizumab, account for the poor response to this agent in patients who carry these mutations. (Funded by Alexion Pharmaceuticals and the Ministry of Health, Labor, and Welfare of Japan.)