The anti-IL-33 antibody, itepekimab, potently blocks airway inflammation post a single dose in mice

<bold>Introduction:</bold> Blockade of IL-33 using itepekimab, a high affinity fully human IgG4 monoclonal antibody, has shown benefit in early asthma and COPD clinical studies. Here, we performed pharmacokinetic (PK) and pharmacodynamic (PD) assessment of itepekimab in a house dust mite (HDM)-driven lung inflammation mouse model. <bold>Results:</bold> Itepekimab doses ranging from 25mg/kg down to 1mg/kg potently blocked type 2 (T2) airway inflammation in mice, measured by lung eosinophilia and production of IL-4, IL-5, IL-13, and type 1/type 17 (T1/17) airway inflammation measured by lung neutrophilia, and production of MPO, IL-1b, TNF-a and MCP-1. Consistently, 1mg/kg of itepekimab was sufficient to improve consolidation, airway mucus plugging, expression of pro-fibrotic genes in the lung and prevented progression to severe disease. Interestingly, itepekimab exhibited a similar PK profile to an isotype control in HDM challenged IL-33 humanized mice, suggesting low target mediated clearance for itepkimab. When dosed at 1mg/kg, itepekimab was detectable in circulation of HDM challenged mice for more than 60 days (>2 months) post mAb exposure, suggesting a half-life consistent with an IgG4 antibody. Notably, in the context of ongoing HDM exposure, a single 1mg/kg dose of itepekimab subdued lung inflammation 2 months post-treatment, resulting in reduction of cytokine/chemokine expression and immune cell activation in the airway. <bold>Conclusion:</bold> Taken together, these results highlight that itepekimab is a potent blocker of IL-33 at doses as low as 1mg/kg, resulting in reduction of T1/T17 and T2 airway inflammation as well as lung remodeling in a chronic progressive lung inflammation mouse model.