In Vivo Pharmacodynamic Method to Assess Complement C5a Receptor Antagonist Efficacy
In Vivo Pharmacodynamic Method to Assess Complement C5a Receptor Antagonist Efficacy
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DOI：
10.1021/acsptsci.1c00227
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发表时间：
2021-12-21
影响因子：
--
通讯作者：
Woodru, Trent M.
中科院分区：
文献类型：
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作者：
Cui, Cedric S.;Kumar, Vinod;Woodru, Trent M.
The complement C5a receptor 1 (C5aR1) has been studied as a potential therapeutic target for autoimmune and inflammatory diseases, with several drug candidates identified. Understanding the pharmacokinetics and pharmacodynamics of a drug candidate is a crucial preclinical step that allows for a greater understanding of a compound's in vivo biodistribution and target engagement to assist in clinical dose selection and dosing frequency. However, few in vivo pharmacodynamic methods have been described for C5a inhibitors. In this study, we, therefore, developed a complete in vivo pharmacodynamic assay in mice and applied this method to the peptide-based C5aR1 antagonists PMX53 and JPE-1375. Intravenous administration of recombinant mouse C5a induced rapid neutrophil mobilization and plasma TNF elevation over a 60 min period. By using C5a receptor-deficient mice, we demonstrated that this response was driven primarily through C5aR1. We next identified using this model that both PMX53 and JPE-1375 have similar in vivo working doses that can inhibit C5aR1-mediated neutrophilia and cytokine production in a dose as low as 1 mg/kg following intravenous injection. However, the in vivo active duration for PMX53 lasted for up to 6 h, significantly longer than that for JPE-1375 (
