The IL-33 and IL-4Ra blocking antibodies, itepekimab and dupilumab, modulate distinct and common inflammatory mediators in asthma - mouse data

Biologics that target IL-4Ra or IL-33 pathways have demonstrated clinical efficacy in asthma and chronic obstructive pulmonary disease (COPD), highlighting the importance of IL-4, IL-13 and IL-33 in respiratory diseases. Despite this, there are limited studies that link preclinical models to human disease and evaluate disease biology in the setting of clinical trials. To address these gaps, we evaluated transcriptional, cellular and pathophysiological processes driven by IL-4/ IL-13 and IL-33 using human innate cells in vitro, a mouse model of airway inflammation and a Bronchial Allergen Challenge (BAC) in house dust mite (HDM)-sensitized individuals with mild asthma. Using the HDM mouse model of airway inflammation, we show that blockade of either IL-4Ra or IL-33 at the peak of type 2 (T2) inflammation leads to inhibition of airway inflammation and remodeling. While the combination of dupilumab and itepekimab was not additive, blockade of both IL-33 and IL-4Ra in a severe, late-phase mixed T1/T2 inflammation reduced all measured parameters. Consistent with some of these observations in mice, blocking either IL-33 or IL-4Ra in the context of T2 airway inflammation suppressed sputum gene expression in individuals with mild persistent asthma post-BAC. Overall, these results highlight that IL-33 and IL-4/IL-13 are key drivers of airway inflammation and remodeling and provide insight into the differences in targeting IL-4Ra or IL-33 pathways in asthma independently or in combination. Overall design: All mouse experiments were conducted in compliance with protocols approved by the Institutional Animal Care and Use Committee of Regeneron Pharmaceuticals. Female, 8–12-week-old mice in a hybrid 129S6/C57BL/6 background were used for all studies. For assessing dupilumab, itepekimab and combo in mice, endogenous IL-4Ra ectodomain, IL-4 and IL-33 in mice were replaced with their corresponding human sequences. Mice were exposed to house dust mite extract (HDM) intranasally three times a week for either 4, 15 or 19 weeks to induce different phases of airway inflammation. The effect of IL-33 and IL-4R-alpha blockade was assessed using Itepekimab (anti-IL-33), dupilumab (anti-IL-4Ra) or a control antibody starting prophylactically at day -3, at the peak of type 2 inflammation at 4 weeks post HDM exposure or after the onset of chronic inflammation at 11 weeks post HDM through the end of the study.