B28-18 Properties of the Il-33 Blocker, Itepekimab, Enable Greater Efficacy in an Airway Inflammation Mouse Model

Abstract Rationale IL-33 has been implicated in many inflammatory diseases. Blockade of IL-33 signaling can be achieved by binding to IL-33 and directly blocking ST2 engagement (direct blocker), or by binding to IL-33, allowing ST2 binding but preventing dimerization with IL-1RAP (indirect blocker). Itepekimab is an indirect blocker that inhibits IL-33 signaling and has shown benefit in asthma and COPD clinical studies and is currently under investigation in phase 3 in COPD. Here, we explored the relevance of directly versus indirectly blocking IL-33 signaling in vitro and in vivo. Methods Antibody binding was analyzed by surface plasmon resonance. HEK293 cell overexpressing human ST2 were used to assess human IL-33 signaling. The impact of IL-33 blockade on lung inflammation was evaluated using an intranasal IL-33 driven airway inflammation model. Results Itepekimab bound IL-33 with high affinity and prevented IL-33 dependent signaling in reporter cell lines. Once complexed with IL-33, itepekimab allowed binding of ST2 but blocked the formation of IL-33/ST2/IL-1RAP signaling complex. In contrast to a high affinity antibody that competes with ST2 binding, itepekimab complexed with IL-33 was able to bind to membrane ST2 and block signaling even when additional free IL-33 was added in vitro. In vivo, itepekimab showed greater improvement of type 2 inflammation as measured by lung eosinophilia and expression of Il4, Il13, Il9, and Mmp12 compared to a direct blocker. Conclusion This work shows a unique mechanism by which an indirect blocker has an additional mechanism of blocking IL-33 signaling and differentiates between competing and non-competing inhibitory mechanisms in vivo. This abstract is funded by: Regeneron Pharmaceuticals