Abstract Text: Neutrophils are the most abundant immune cells in humans playing essential roles in invading pathogens and debris elimination. However, neutrophil-associated chronic inflammation has now emerged as key pathogenic mechanism in many autoimmune and chronic inflammatory diseases. Neutrophil extracellular traps (NETs) process, initially released to limit pathogen dissemination, is now recognized as a key driver of tissue fibrosis. Resolution of inflammation is elicited by pro-resolving lipids (e.g. Resolvin E1) which target GPCRs, such as ChemR23, inducing neutrophil apoptosis, and blunting neutrophil tissue recruitment. We previously reported that ChemR23 mRNA is overexpressed in human chronically inflamed tissues and demonstrated ChemR23 is expressed at the surface of neutrophils only upon inflammatory settings. We generated a novel agonist anti-ChemR23 mAb, cross-reacting with human and cynomolgus monkey, and found it induces selective inflammatory neutrophil apoptosis and potent inhibition of NETosis by both human and cynomolgus neutrophils in vitro. In vivo, we observed that the agonist anti-ChemR23 mAb accelerated the resolution of skin inflammation induced by intradermal LPS or UV-killed bacteria injection in cynomolgus monkeys, reducing erythema, limiting neutrophil skin infiltrates and decreasing neutrophil IL-8 chemokine expression in the inflamed tissue. No decrease of neutrophil count has been observed in the periphery, in accordance with the translocation of ChemR23 at the surface only upon inflammatory stimuli. Altogether, our findings show that agonist ChemR23 mAb could control neutrophil recruitment, induces local inflammatory neutrophil apoptosis, and extinguishes inflammatory NETosis. This new class of pro-resolutive mAb constitutes an innovative therapeutic approach to fill unmet needs in chronic inflammatory diseases.
