随机I期试验结果显示,empasiprubart对经典途径和凝集素补体途径具有安全和可持续的抑制作用

IF 15.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Inge Van de Walle, Laura Bracke, Heidi Gytz Olesen, Tonke van Bragt, Stéphanie Cadour, Phillip De Decker, Giorgia Ciurlia, Erwin Pannecoucke, Emma K. Persson, Olivier Van de Steen, Xinghong Leng, Gregers Rom Andersen, Domenica Gandini, C. Erik Hack
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引用次数: 0

摘要

经典和凝集素补体途径的激活有助于几种人类疾病。Empasiprubart是一种人源化循环单克隆抗体,通过与补体因子2 (C2)的CCP2结构域结合来抑制这两种途径,补体因子2 (C2)是一种依赖于Ca2+和ph的相互作用。在这里,我们解决了Empasiprubart与C2络合的晶体结构,提供了其Ca2+依赖性的分子基础,并报告了一项随机、双盲、安慰剂对照试验,以评估安全性和耐受性(主要目标)以及药代动力学。在78名健康受试者(NCT04532125)中,empasiprubart的药效学和免疫原性(次要目标)。单次静脉注射(IV)剂量的empasiprubart可降低99%的循环C2水平,并且剂量依赖性地抑制经典途径和凝集素途径。多次静脉注射empasiprubart会加强游离C2水平的降低,这种情况一直持续到研究结束时41周。这种延长的减少符合empasiprubart消除半衰期(70-88天)。单次和多次递增剂量的empasiprubart通常是安全且耐受性良好的。总的来说,我们的研究结果揭示了empasiprubart的原子细节机制,并证明它是一种用于补体介导疾病的一流抗c2治疗抗体。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Randomized phase I trial outcomes show safe and sustainable inhibition of classical and lectin complement pathways by empasiprubart

Randomized phase I trial outcomes show safe and sustainable inhibition of classical and lectin complement pathways by empasiprubart

Activation of classical and lectin complement pathways contributes to several human diseases. Empasiprubart is a humanized recycling monoclonal antibody that inhibits both pathways by binding to the CCP2 domain of complement factor 2 (C2), an interaction that is dependent on both Ca2+ and pH. Here, we resolve the crystal structure of empasiprubart complexed with C2, providing the molecular basis of its Ca2+ dependency, and report a randomized, double-blind, placebo-controlled trial to assess the safety and tolerability (primary objectives) in addition to pharmacokinetics, pharmacodynamics, and immunogenicity (secondary objectives) of empasiprubart in 78 healthy participants (NCT04532125). A single intravenous (IV) dose of empasiprubart reduces circulating C2 levels by up to 99% and dose-dependently inhibits the classical and lectin pathways. Multiple IV empasiprubart doses reinforce reductions in free C2 levels, which persist until the endpoint of the study at 41 weeks. This prolonged reduction is in line with the empasiprubart elimination half-life (70–88 days). Single and multiple ascending doses of empasiprubart are generally safe and well tolerated. Overall, our results reveal in atomic detail the mechanism of empasiprubart and demonstrate that it is a first-in-class anti-C2 therapeutic antibody for use in complement-mediated diseases.

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来源期刊
Nature Communications
Nature Communications Biological Science Disciplines-
CiteScore
24.90
自引率
2.40%
发文量
6928
审稿时长
3.7 months
期刊介绍: Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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