Novel agonist monoclonal antibody targeting GPCR to decrease neutrophil accumulation and initiate resolution of chronic inflammation 2310040

Introduction Resolution of inflammation is an active process mediated by specialized receptors such GPCRs expressed on neutrophils, monocytes, and macrophages. Natural and synthetic GPCRs agonists demonstrate significant preclinical efficacy but face limitations in stability, synthesis, and receptor selectivity. Methods New antibodies were generated and characterized for high affinity and GPCR specificity. Agonist signaling and activity was assessed on cell lines and primary neutrophils and monocytes, and efficacy was evaluated in multiple clinically relevant murine models of acute and chronic inflammation. Results We developed first-in-class antibodies acting as a selective GPCR agonist for the treatment of acute and chronic inflammatory diseases with stable properties and selectivity. This therapy allows a specific agonistic signal and promotes the hallmark pro-resolving activity by limiting activation and recruitment of neutrophils and monocytes/macrophages in contrast to natural or synthetic lipids that can trigger both pro- and anti-inflammatory signals in multiple GPCRs. In an acute lung injury model, the mAb markedly inhibits neutrophils and inflammatory monocytes infiltration into inflamed tissue. In chronic models, treatment alleviates clinical severity, confirming robust therapeutic potential. Conclusion This first-in-class GPCR specific agonist mAb introduces a novel strategy to actively drive long term resolution of inflammation. Its receptor specificity, strict agonist activity and robust preclinical efficacy on neutrophils and inflammatory monocytes recruitment position it as a promising therapeutic candidate for treating acute and chronic inflammatory disorders.