First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody
First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody
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DOI：
10.1111/ajt.15661
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发表时间：
2019-12-06
影响因子：
8.8
通讯作者：
Gergely, Peter
中科院分区：
文献类型：
--
作者：
Espie, Pascal;He, YanLing;Gergely, Peter
Iscalimab是一种完全人源性、CD 40通路阻断性、非消耗性单克隆抗体，正在开发作为免疫抑制剂。我们描述了一项首次在健康受试者和类风湿性关节炎患者中进行的人体、随机、双盲、安慰剂对照研究，旨在研究iscaliumab的安全性、耐受性、药代动力学和药效学。健康受试者（n = 56）接受单次静脉注射iscalumab（0.03、0.1、0.3、1或3 mg/kg）或皮下注射iscalumab（3 mg/kg）或安慰剂。风湿性关节炎患者（n = 20）接受单剂量静脉内iscalimab（10或30 mg/kg）或安慰剂。Iscalimab表现出靶向介导的药物分布，导致剂量依赖性和非线性药代动力学。在血浆浓度>0.3-0.4 μ g/mL时，观察到全血B细胞上的完全（>= 90%）CD 40受体占有率。在接受3 mg/kg iscalimab的受试者中，对锁眼帽贝血蓝蛋白的抗体反应被短暂抑制。iscaliumab对CD 40的占据阻止了全血中B细胞上离体人rCD 154诱导的CD 69表达。所有剂量总体上安全且耐受性良好，任何安全性参数均无临床相关变化，包括无血栓栓塞事件证据。Iscalimab似乎是一种很有前途的CD 40-CD 154共刺激通路阻断剂，可能用于移植和其他自身免疫性疾病。
Iscalimab is a fully human, CD40 pathway blocking, nondepleting monoclonal antibody being developed as an immunosuppressive agent. We describe a first-in-human, randomized, double-blind, placebo-controlled study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of iscalimab in healthy subjects and rheumatoid arthritis patients. Healthy subjects (n = 56) received single doses of intravenous iscalimab (0.03, 0.1, 0.3, 1, or 3 mg/kg), or subcutaneous iscalimab (3 mg/kg), or placebo. Rheumatoid arthritis patients (n = 20) received single doses of intravenous iscalimab (10 or 30 mg/kg) or placebo. Iscalimab exhibited target-mediated drug disposition resulting in dose-dependent and nonlinear pharmacokinetics. Complete (>= 90%) CD40 receptor occupancy on whole blood B cells was observed at plasma concentrations >0.3-0.4 mu g/mL. In subjects receiving 3 mg/kg iscalimab, antibody responses to keyhole limpet hemocyanin were transiently suppressed. CD40 occupancy by iscalimab prevented ex vivo human rCD154-induced expression of CD69 on B cells in whole blood. All doses were generally safe and well tolerated, with no clinically relevant changes in any safety parameters, including no evidence of thromboembolic events. Iscalimab appears to be a promising blocker of the CD40-CD154 costimulatory pathway with potential use in transplantation and other autoimmune diseases.