Regeneron Pharmaceuticals, Inc., New York, NY, United States of America.
PLoS One. 2020 May 8;15(5):e0231892. doi: 10.1371/journal.pone.0231892. eCollection 2020.
Complement is a key component of the innate immune system. Inappropriate complement activation underlies the pathophysiology of a variety of diseases. Complement component 5 (C5) is a validated therapeutic target for complement-mediated diseases, but the development of new therapeutics has been limited by a paucity of preclinical models to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties of candidate therapies. The present report describes a novel humanized C5 mouse and its utility in evaluating a panel of fully human anti-C5 antibodies. Surprisingly, humanized C5 mice revealed marked differences in clearance rates amongst a panel of anti-C5 antibodies. One antibody, pozelimab (REGN3918), bound C5 and C5 variants with high affinity and potently blocked complement-mediated hemolysis in vitro. In studies conducted in both humanized C5 mice and cynomolgus monkeys, pozelimab demonstrated prolonged PK and durable suppression of hemolytic activity ex vivo. In humanized C5 mice, a switch in dosing from in-house eculizumab to pozelimab was associated with normalization of serum C5 concentrations, sustained suppression of hemolytic activity ex vivo, and no overt toxicity. Our findings demonstrate the value of humanized C5 mice in identifying new therapeutic candidates and treatment options for complement-mediated diseases.
补体是先天免疫系统的关键组成部分。不合适的补体激活是多种疾病的病理生理学基础。补体成分 5（C5）是补体介导疾病的有效治疗靶点，但由于缺乏评估候选疗法药代动力学（PK）和药效学（PD）特性的临床前模型，新疗法的开发受到限制。本报告描述了一种新型的人源化 C5 小鼠及其在评估一系列全人源抗 C5 抗体中的应用。令人惊讶的是，人源化 C5 小鼠在一组抗 C5 抗体的清除率方面显示出显著差异。一种抗体，pozelimab（REGN3918），与人 C5 和 C5 变体具有高亲和力，并能有效阻断体外补体介导的溶血。在人源化 C5 小鼠和食蟹猴中进行的研究表明，pozelimab 具有延长的 PK 和体外持久抑制溶血活性。在人源化 C5 小鼠中，从内部开发的依库珠单抗转换为 pozelimab 与血清 C5 浓度的正常化、体外溶血活性的持续抑制以及无明显毒性有关。我们的研究结果表明，人源化 C5 小鼠在鉴定补体介导疾病的新治疗候选物和治疗方案方面具有重要价值。
