Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Ra antibody, is required to broadly inhibit type 2 inflammation

Background: Dupilumab, a fully human monoclonal antibody that binds IL-4Ra and inhibits signaling of both IL-4 and IL-13, has shown efficacy across multiple diseases with underlying type 2 signatures and is approved for treatment of asthma, atopic dermatitis and chronic sinusitis with nasal polyposis. We sought to provide a comprehensive analysis of the redundant and distinct roles of IL-4 and IL-13 in type 2 inflammation and report dupilumab mechanisms of action. Methods: Using primary cell assays and a mouse model of house dust mite induced asthma, we compared IL-4 versus IL-13 versus IL-4Ra blockers. Results: Intranasal administration of either IL-4 or IL-13 confers an asthma-like phenotype in mice by inducing immune cell lung infiltration, including eosinophils, increasing cytokine/chemokine expression and mucus production, thus demonstrating redundant functions of these cytokines. We further teased out their respective contributions using human in vitro culture systems. Then, in a mouse asthma model by comparing in head to head studies, either IL-4 or IL-13 inhibition to dual IL-4/IL-13 inhibition, we demonstrate that blockade of both IL-4 and IL-13 is required to broadly block type 2 inflammation, which translates to protection from allergen-induced lung function impairment. Notably, only dual IL-4/IL-13 blockade prevented eosinophil infiltration into lung tissue without affecting circulating eosinophils, demonstrating that tissue, but not circulating eosinophils contribute to disease pathology. Conclusions: Overall, these data support IL-4 and IL-13 as key drivers of type 2 inflammation, and help provide insight into the therapeutic mechanism of dupilumab, a dual IL-4/IL-13 blocker, in multiple type 2 diseases. [1] Bone marrow-derived human mast cells were treated with IL4 or IL13 at 100nM for 24 hours, primed with Fel d 1-specific IgE for 18 hours, and activated with Fel d 1 antigen for 4h. Samples were analyzed for RNA expression profiling of chemokine/cytokine-related genes (NGS). [2] Il4rahu/hu Il4hu/hu mice were exposed intranasally to 50 μg house dust mite (HDM) 3 times per week for 4 consecutive weeks. HDM-exposed mice either received no antibody treatment, or twice-weekly subcutaneous injections of IL4Ra Ab (dupilumab), IL4 Ab, mouse IL13Ra2-Fc or a corresponding isotype control antibody (human IgG4 and mouse IgG2a) starting 3 days before the first HDM exposure. At the end of the studies, mice were sacrificed, and lungs were harvested for RNA expression profiling of chemokine/cytokine-related genes (NGS).