Abstract

not-yet-known not-yet-known not-yet-known unknown Background and purpose: Anaphylatoxin (C5a) plays a critical role in the pathogenesis of virus-induced acute respiratory distress syndrome (v-ARDS). However, evidence for the effect of innovative C5a inhibitor on the mortality of ARDS has been lacking. STSA1002 is a human anti-C5a antibody currently in a phase II trial for treating ARDS disease. To support its clinical development in humans, in vitro assays and in vivo studies were conducted to determine the pharmacology, preclinical characteristics and safety of this monoclonal antibody. Experimental approach: The vitro pharmacology, pharmacokinetics (PK), pharmacodynamics and toxicology of STSA1002 were firstly evaluated in cynomolgus monkeys, mouse models and health adults. Key results: In vitro experiments, we showed that STSA1002 can specifically bind to recombinant human and rhesus monkeys C5a with comparable blocking effects. Furthermore, STSA1002 remarkably blocked C5a-primed neutrophil degranulation response, dose-dependently prevented C5a-stimulated chemotaxis, continuously inhibited C5a induced up-regulation of human neutrophil CD11b and effectively decreased the levels of NETs specific biomarkers (myeloperoxidase, neutrophil elastase and proteinase 3). In vivo experiments, single intravenous administration of STSA1002 (1, 3 and 10 mg/kg) significantly improved the mortality of LPS-induced ARDS in C5a-e (hC5)1 humanized mice. In addition, PK study revealed a linear PK profile within the dose range of 5-50 mg/kg following single intravenous administration in cynomolgus monkeys. 4-week repeat-dose toxicity study in rhesus monkeys was performed to prove well safety of STSA1002. Conclusions and implications: We demonstrated, for the first time, a comprehensive preclinical characterization of STSA1002 that supports its clinical development in an immunomodulatory therapy.