Small-molecule factor D inhibitors selectively block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.
Small-molecule factor D inhibitors selectively block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.
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DOI：
10.3324/haematol.2016.153312
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发表时间：
2017-03
期刊：
影响因子：
10.1
通讯作者：
Brodsky RA
中科院分区：
文献类型：
--
作者：
Yuan X;Gavriilaki E;Thanassi JA;Yang G;Baines AC;Podos SD;Huang Y;Huang M;Brodsky RA
阵发性睡眠性血红蛋白尿症和非典型溶血性尿毒综合征是补体旁路途径过度活化的疾病，用依库珠单抗（一种针对末端补体成分C5的人源化单克隆抗体）治疗。依库珠单抗必须静脉内给药，此外，一些接受依库珠单抗治疗的阵发性睡眠性血红蛋白尿症患者出现症状性血管外溶血，表明对其他治疗方法的需求未得到满足。我们报告了两种新的小分子抑制剂的活性的替代途径成分因子D使用在体外相关的阵发性睡眠性血红蛋白尿症和非典型溶血性尿毒综合征。两种化合物均以高亲和力结合人因子D，并有效抑制其对与C3 B复合的纯化因子B的蛋白水解活性。当使用阵发性睡眠性血红蛋白尿症患者的细胞进行传统Ham试验时，D因子抑制剂在低至0.01 μM的浓度下显著降低补体介导的溶血。此外，化合物ACH-4471显著降低了阵发性睡眠性血红蛋白尿症红细胞上的C3片段沉积，表明相对于依库珠单抗，血管外溶血的可能性降低。使用最近描述的用来自非典型溶血性尿毒综合征患者的血清进行的改良Ham试验，化合物减少了旁路途径介导的对PIGA无效试剂细胞的杀伤，从而确立了它们对于补体失调旁路途径疾病的潜在效用，并验证了改良Ham试验作为用于非典型溶血性尿毒综合征的临床前药物开发的系统。最后，食蟹猴经口给予ACH-4471时，可阻断旁路途径活性。总之，小分子因子D抑制剂显示出作为补体旁路途径驱动的人类疾病的口服治疗剂的潜力，包括阵发性睡眠性血红蛋白尿症和非典型溶血性尿毒症综合征。
Paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome are diseases of excess activation of the alternative pathway of complement that are treated with eculizumab, a humanized monoclonal antibody against the terminal complement component C5. Eculizumab must be administered intravenously, and moreover some patients with paroxysmal nocturnal hemoglobinuria on eculizumab have symptomatic extravascular hemolysis, indicating an unmet need for additional therapeutic approaches. We report the activity of two novel small-molecule inhibitors of the alternative pathway component Factor D using in vitro correlates of both paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Both compounds bind human Factor D with high affinity and effectively inhibit its proteolytic activity against purified Factor B in complex with C3b. When tested using the traditional Ham test with cells from paroxysmal nocturnal hemoglobinuria patients, the Factor D inhibitors significantly reduced complement-mediated hemolysis at concentrations as low as 0.01 μM. Additionally the compound ACH-4471 significantly decreased C3 fragment deposition on paroxysmal nocturnal hemoglobinuria erythrocytes, indicating a reduced potential relative to eculizumab for extravascular hemolysis. Using the recently described modified Ham test with serum from patients with atypical hemolytic uremic syndrome, the compounds reduced the alternative pathway-mediated killing of PIGA-null reagent cells, thus establishing their potential utility for this disease of alternative pathway of complement dysregulation and validating the modified Ham test as a system for pre-clinical drug development for atypical hemolytic uremic syndrome. Finally, ACH-4471 blocked alternative pathway activity when administered orally to cynomolgus monkeys. In conclusion, the small-molecule Factor D inhibitors show potential as oral therapeutics for human diseases driven by the alternative pathway of complement, including paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.