PLX096510

GSE140900: Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Ra antibody, is required to broadly inhibit type 2 inflammation

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

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. SOURCE: Wei Keat Lim Regeneron Pharmaceuticals