GeNeuro SA, Chemin Pré-Fleuri, Plan-les-Ouates, Geneva, Switzerland; Department of Pharmacology, University of Pretoria, Pretoria, South Africa.
GeNeuro SA, Chemin Pré-Fleuri, Plan-les-Ouates, Geneva, Switzerland.
Clin Ther. 2019 Sep;41(9):1737-1746. doi: 10.1016/j.clinthera.2019.05.020. Epub 2019 Jul 13.
Temelimab/GNbAC1 is a humanized immunoglobulin G4 monoclonal antibody antagonist of the human endogenous retrovirus W envelope protein, which is associated with multiple sclerosis (MS) pathophysiology and possibly with other autoimmune disorders. Human endogenous retrovirus W envelope protein is expressed in the central nervous system of patients with MS, and sufficient amount of temelimab must reach the target. The safety of very high dosages of temelimab should be tested to support further clinical trials in MS.
This randomized, placebo-controlled, dose-escalation study evaluated the safety and pharmacokinetic profile of temelimab in 24 healthy volunteers after a single intravenous infusion at doses of 36, 60, 85, and 110 mg/kg administered sequentially.
Temelimab was well tolerated, with no particular adverse drug reactions at any dose. The maximal dose of 110 mg/kg could be administered, and no antidrug antibodies were induced. After administration of 36-110 mg/kg, mean temelimab C increased from 859 to 2450 μg/mL, and AUC values increased from 319,900 to 1,030,000 μg·h/mL. There was an approximate dose-proportional increase in exposure, similar to observations at lower doses.
The favorable data in terms of safety and pharmacokinetic variables support temelimab use at high doses in future MS trials to optimally neutralize the temelimab target in the central nervous system. ClinicalTrials.gov identifier: NCT03574428.
Temelimab/GNbAC1 是一种人源化免疫球蛋白 G4 单克隆抗体拮抗剂，针对人类内源性逆转录病毒 W 包膜蛋白，与多发性硬化症（MS）病理生理学有关，可能与其他自身免疫性疾病有关。人类内源性逆转录病毒 W 包膜蛋白在 MS 患者的中枢神经系统中表达，必须有足够量的 temelimab 到达靶标。应该测试非常高剂量的 temelimab 的安全性，以支持 MS 进一步的临床试验。
这项随机、安慰剂对照、剂量递增研究评估了 Temelimab 在 24 名健康志愿者中的安全性和药代动力学特征，这些志愿者在单剂量静脉输注 36、60、85 和 110mg/kg 后，按顺序给药。
Temelimab 耐受性良好，任何剂量均无特殊药物不良反应。可以给予最大剂量 110mg/kg，并且没有诱导出抗药物抗体。在给予 36-110mg/kg 后，平均 Temelimab C 从 859μg/mL 增加到 2450μg/mL，AUC 值从 319900μg·h/mL 增加到 1030000μg·h/mL。暴露量呈近似剂量比例增加，与较低剂量的观察结果相似。
在安全性和药代动力学变量方面的有利数据支持在未来的 MS 试验中使用高剂量的 Temelimab，以在中枢神经系统中最佳地中和 Temelimab 靶标。临床试验标识符：NCT03574428。
