Abstract:
Dysregulated activation of the complement system is implicated in the onset or progression of several diseases. Most clinical-stage complement inhibitors target the inactive complement proteins present at high concentrations in plasma, which increases target-mediated drug disposition and necessitates high drug levels to sustain therapeutic inhibition. Furthermore, many efforts are aimed at inhibiting only terminal pathway activity, which leaves opsonin-mediated effector functions intact. We describe the discovery of SAR443809, a specific inhibitor of the alternative pathway C3/C5 convertase (C3bBb). SAR443809 selectively binds to the activated form of factor B (factor Bb) and inhibits alternative pathway activity by blocking the cleavage of C3, leaving the initiation of classical and lectin complement pathways unaffected. Ex vivo experiments with patient-derived paroxysmal nocturnal hemoglobinuria erythrocytes show that, although terminal pathway inhibition via C5 blockade can effectively inhibit hemolysis, proximal complement inhibition with SAR443809 inhibits both hemolysis and C3b deposition, abrogating the propensity for extravascular hemolysis. Finally, intravenous and subcutaneous administration of the antibody in nonhuman primates demonstrated sustained inhibition of complement activity for several weeks after injection. Overall, SAR443809 shows strong potential for treatment of alternative pathway-mediated disorders.
摘要:
补体系统的激活失调与几种疾病的发作或进展有关。大多数临床阶段的补体抑制剂靶向血浆中高浓度存在的无活性补体蛋白,这增加了靶介导的药物处置,并需要高药物水平来维持治疗抑制。此外,许多努力旨在仅抑制终末途径活性,使调理素介导的效应子功能保持完整。我们描述了SAR443809的发现,SAR443809是活性旁路C3/C5转化酶C3bBb的特异性抑制剂。SAR443809选择性结合活化形式的因子B(因子Bb),并通过阻断C3的裂解来抑制替代途径的活性,使经典和凝集素补体途径的启动不受影响。患者来源的阵发性夜间血红蛋白尿红细胞的离体实验表明,而通过C5阻断的终末途径抑制可以有效抑制溶血,用SAR443809抑制近端补体同时抑制溶血和C3b沉积,消除血管外溶血的倾向。最后,在非人灵长类动物中静脉内和皮下施用抗体证明了在注射后数周内补体活性的持续抑制.总的来说,SAR443809显示出治疗替代途径介导的疾病的强大潜力。