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

Abstract

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractBackground: Dupilumab, a fully human monoclonal antibody that binds IL-4Rα 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 vs IL-13 vs IL-4Rα 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 allergeninduced 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, contributes to disease pathology.

Dupilumab is effective in type 2‐high asthma patients receiving high‐dose inhaled corticosteroids at baseline

“…There are currently 5 biologic add‐on treatments for patients with uncontrolled severe asthma that target underlying type 2 inflammatory processes: dupilumab, benralizumab, reslizumab, mepolizumab, and omalizumab. As previously outlined, dupilumab blocks the shared receptor component for IL‐4/IL‐13, key and central drivers of type 2 inflammation 14‐17 . It is approved in the EU 26 as add‐on maintenance treatment in patients aged ≥12 years with severe asthma with type 2 inflammation characterized by raised blood eosinophils and/or raised FeNO levels who are inadequately controlled with a high‐dose ICS plus another medicinal product for maintenance treatment.…”

Type 2 immunity in the skin and lungs

“…The processes, however, by which eosinophils are activated are not fully established 67‐69 . In mouse models and human cell cultures, IL‐4 and IL‐13 act together as key drivers of type 2 inflammation and blocking of both of them through IL‐4Rα is superior to blocking either IL‐4 or IL‐13 alone 70 …”

EAACI Biologicals Guidelines—Recommendations for severe asthma

“…IL‐4 and IL‐13 are key cytokines in driving the initiation and the chronicity of T2 inflammation, where IL‐4 is considered an initiator of T2 immune responses and IL‐13 an effector molecule 85–89 . Dupilumab is a human IgG4 Mab that targets the IL‐4 receptor alpha chain (IL‐4Rα), common to both IL‐4R complexes: type 1 (IL‐4Rα/γc; IL‐4 specific) and type 2 (IL‐4Rα/IL‐13Rα1; IL‐4 and IL‐13 specific) 90,91 . In mice models, dual IL‐4/IL‐13 blockade prevents eosinophil infiltration into lung tissue without affecting circulating eosinophils 90 .…”