Dupixent Mechanism of Action
Dupilumab is a fully human IgG4 monoclonal antibody that specifically binds to the interleukin-4 receptor alpha subunit (IL-4Rα), thereby blocking signaling from both IL-4 and IL-13 cytokines. 1
Molecular Mechanism
Dupilumab inhibits dual cytokine pathways by targeting the shared receptor component:
The drug binds to IL-4Rα, which forms heterodimers with either the common γ chain (creating the Type I IL-4 receptor) or with IL-13Rα1 (creating the Type II IL-4/IL-13 receptor) 2
By blocking IL-4Rα, dupilumab inhibits IL-4 signaling via the Type I receptor and both IL-4 and IL-13 signaling through the Type II receptor 1
This dual blockade is essential because IL-4 and IL-13 have both redundant and distinct functions in type 2 inflammation—blocking only one cytokine is insufficient to broadly inhibit type 2 inflammatory responses 3
Downstream Effects on Type 2 Inflammation
The blockade of IL-4 and IL-13 signaling disrupts multiple inflammatory cascades:
IgE synthesis: Both IL-4 and IL-13 are primarily responsible for isotype class switching of B cells to produce IgE, which dupilumab inhibits 2
Eosinophil biology: Dupilumab prevents eosinophil activation, chemotaxis, and tissue infiltration (notably affecting tissue but not circulating eosinophils) 2, 3
Mucus production: IL-4 and IL-13 drive mucus secretion from goblet cells, which is blocked by dupilumab 2
Airway remodeling: Both cytokines promote proliferation of fibroblasts and smooth muscle cells, contributing to structural changes that dupilumab prevents 2
Epithelial barrier disruption: IL-4 and IL-13 downregulate filaggrin expression in keratinocytes, compromising the epidermal barrier—a process reversed by dupilumab 2
Effects on Inflammatory Mediators
Dupilumab inhibits the release of multiple proinflammatory substances:
Blocks production of cytokines, chemokines, nitric oxide, and IgE from cells expressing IL-4Rα (including mast cells, basophils, eosinophils, macrophages, lymphocytes, epithelial cells, and goblet cells) 1
Reduces type 2-associated cytokines and chemokines such as IL-5, IL-9, IL-13, TARC, and eotaxin 2
Decreases inflammatory mediators including histamine, eicosanoids, and leukotrienes 1
Biomarker Effects
Dupilumab treatment produces measurable reductions in inflammatory biomarkers:
Fractional exhaled nitric oxide (FeNO) decreases by 24-35% within 2 weeks of treatment 1
Total IgE concentrations decline by 52% at 24 weeks and 70% at 52 weeks 1
Circulating levels of eotaxin-3, allergen-specific IgE, TARC, and periostin are reduced relative to placebo 1
Most biomarkers reach near-maximal suppression after 2 weeks of treatment, except IgE which declines more gradually 1
Role of IL-4 in T Helper 2 Differentiation
IL-4 serves as a critical differentiation factor that dupilumab blocks:
IL-4 drives T cell differentiation toward the TH2 subtype, initiating the type 2 immune response 2
IL-4 downregulates expression of cutaneous defensins and increases expression of bacterial adhesion molecules, facilitating Staphylococcus aureus colonization in atopic dermatitis—effects reversed by dupilumab 2