Blocking IL-4Ra with dupilumab prevents lung inflammation in a mouse asthma model

Background: Dupilumab, an IL-4Rα binding monoclonal antibody (Ab) that inhibits IL-4 and IL-13 signaling, is approved for treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis. Aim: Describe pharmacology associated with dupilumab mechanisms of action. Methods: Dupilumab effects on lung inflammation/function were evaluated in two house dust mite (HDM)-induced humanized mouse asthma models. Mice exposed to HDM thrice-weekly for 4 weeks (acute model) or 15 weeks (chronic model) received twice-weekly dupilumab, control (CTL) Ab, or no Ab prophylactically (acute model) or therapeutically (chronic model). Results: In the acute model, dupilumab blocked lung eosinophil (eos) infiltration by 96% (19% vs 1% live cells; P<0.01 vs CTL). Similar results were observed in the chronic model (15% vs 2% live cells; P<0.05 vs CTL). In both models, dupilumab was associated with a trend toward a modest increase in blood eos compared with mice receiving CTL or no Ab. Dupilumab prevented HDM-induced lung function impairment and decreased lung expression of HDM-induced chemokines/cytokines, such as Ccl17, Cxcl1, Ccl24, IL4, and Il13. Conclusion: Dupilumab prevented lung immune cell infiltration, inflammatory cytokine/chemokine expression, and lung function impairment in humanized mouse asthma models, despite modest increases in circulating eos levels. Similar blood eos increases were observed in dupilumab-treated asthma patients, suggesting dupilumab prevents eos lung infiltration rather than eos generation and bone marrow egress. This study shows that dupilumab prevents lung function impairment and inflammation (prophylactically and therapeutically), independent of circulating eos levels.