M281, an Anti-FcRn Antibody: Pharmacodynamics, Pharmacokinetics, and Safety Across the Full Range of IgG Reduction in a First-in-Human Study.
M281, an Anti-FcRn Antibody: Pharmacodynamics, Pharmacokinetics, and Safety Across the Full Range of IgG Reduction in a First-in-Human Study.
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DOI：
10.1002/cpt.1276
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发表时间：
2019-04
影响因子：
6.7
通讯作者：
Arroyo S
中科院分区：
文献类型：
--
作者：
Ling LE;Hillson JL;Tiessen RG;Bosje T;van Iersel MP;Nix DJ;Markowitz L;Cilfone NA;Duffner J;Streisand JB;Manning AM;Arroyo S
M281是一种完全人源性的抗新生儿Fc受体(FcRN)抗体，它能抑制FcRN介导的免疫球蛋白G(IgG)循环，以减少致病的IgG，同时保持IgG的产生。设计了一项随机、双盲、安慰剂对照的人类首例研究，对象为50名正常健康志愿者，旨在探索降低免疫球蛋白的安全性和生理性最大值。静脉注射高达60 mg/kg的单次递增剂量可引起剂量依赖性的血清免疫球蛋白G下降，所有免疫球蛋白亚类的下降趋势相似。每周多次剂量15或30 mg/kg可使免疫球蛋白≈平均下降85%，并在长达24天的时间内保持免疫球蛋白≥下降75%。M281的耐受性良好，没有严重或严重的不良事件(AEs)，中度AEs很少，感染相关AEs的发生率很低，类似于安慰剂治疗。M281药物动力学和药效学的耐受性和一致性支持进一步评估M281在致病免疫球蛋白介导的疾病中的作用。
M281 is a fully human, anti‐neonatal Fc receptor (FcRn) antibody that inhibits FcRn‐mediated immunoglobulin G (IgG) recycling to decrease pathogenic IgG while preserving IgG production. A randomized, double‐blind, placebo‐controlled, first‐in‐human study with 50 normal healthy volunteers was designed to probe safety and the physiological maximum for reduction of IgG. Intravenous infusion of single ascending doses up to 60 mg/kg induced dose‐dependent serum IgG reductions, which were similar across all IgG subclasses. Multiple weekly doses of 15 or 30 mg/kg achieved mean IgG reductions of ≈85% from baseline and maintained IgG reductions ≥75% from baseline for up to 24 days. M281 was well tolerated, with no serious or severe adverse events (AEs), few moderate AEs, and a low incidence of infection‐related AEs similar to placebo treatment. The tolerability and consistency of M281 pharmacokinetics and pharmacodynamics support further evaluation of M281 in diseases mediated by pathogenic IgG.
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