The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria
The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria
复制标题
DOI：
10.1182/blood.2019003399
复制
发表时间：
2020-03-19
期刊：
影响因子：
20.3
通讯作者：
de Latour, Regis Peffault
中科院分区：
文献类型：
--
作者：
Roeth, Alexander;Nishimura, Jun-ichi;de Latour, Regis Peffault
抑制补体C5是临床症状明显的阵发性睡眠性血红蛋白尿(PNH)患者的标准治疗方案。终末补体途径的持续和完全抑制以及C5的高血清浓度给药物开发带来了挑战，导致了仅静脉注射的治疗选择。Crovalimab是一种连续的单抗回收技术，其抗体被设计用于在符合C5抑制的疾病中延长自我给药的小容量皮下剂量。一项由3部分组成的开放标签适应1/2期试验被用来评估健康志愿者(第1部分)、补体阻断治疗(第2部分)和C5抑制剂治疗(第3部分)PNH患者的安全性、药代动力学、药效学和探索性疗效。第二部分(n=10)和第三部分(n=19)包括29名患者。Crovalimab浓度超过预先指定的100微克/毫升水平，并导致治疗初治和C5抑制剂预治疗的PNH患者完全和持续的终末补体途径抑制。溶血活性和游离C5水平被抑制在临床相关阈值以下(脂质体分析
Complement C5 inhibition is the standard of care (SoC) for patients with paroxysmal nocturnal hemoglobinuria (PNH) with significant clinical symptoms. Constant and complete suppression of the terminal complement pathway and the high serum concentration of C5 pose challenges to drug development that result in IV-only treatment options. Crovalimab, a sequential monoclonal antibody recycling technology antibody was engineered for extended self-administered subcutaneous dosing of small volumes in diseases amenable for C5 inhibition. A 3-part open-label adaptive phase 1/2 trial was conducted to assess safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy in healthy volunteers (part 1), as well as in complement blockade-naive (part 2) and C5 inhibitor-treated (part 3) PNH patients. Twenty-nine patients were included in part 2 (n = 10) and part 3 (n = 19). Crovalimab concentrations exceeded the prespecified 100-mu g/mL level and resulted in complete and sustained terminal complement pathway inhibition in treatment-naive and C5 inhibitor-pretreated PNH patients. Hemolytic activity and free C5 levels were suppressed below clinically relevant thresholds (liposome assay