Mechanisms of Dupilumab

Abstract

The Th2 cytokines interleukin 4 (IL-4) and IL-13 and the heterodimeric IL-4 receptor (IL-4R) complexes that they interact with play a key role in the pathogenesis of allergic disorders. Dupilumab is a humanized IgG4 monoclonal antibody 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). In this review, we detail the current state of knowledge of the different signalling pathways coupled to the IL-4R complexes and examine the possible mechanisms of Dupilumab action and survey its clinical efficacy in different allergic disorders. The development of Dupilumab and the widening spectrum of its clinical applications is relevant to the current emphasis on precision medicine approaches to the blockade of pathways involved in allergic diseases.

Keywords: IL-4R; T cells; T-reg; asthma; atopic dermatitis; dupilumab; food allergy.

Figure 1.

Signal transduction via the type I and II IL-4R complexes. IL-4R type I receptor, composed of IL-4Rα/γc heterodimers, binds IL-4 exclusively while the type II, composed of IL-4Rα/IL-13Rα1, binds both IL-4 and IL-13. Ligand binding triggers the trans-phosphorylation and activation of receptor subunit-associated JAK kinases, including JAK1/JAK3 (type I receptor) and JAK1/Tyk2 (type II receptor). JAK activation initiates a cascade of phosphorylation of specific tyrosine residues in the cytoplasmic domain of the IL-4Rα, from which emanates different signaling pathways including STAT6, IRS/PI3K/mTORC2/AKT, SHC/MAPK and Shp-1. Additional pathways implicated in receptor signaling include STAT3 activation via IL-13Ra1 and IRS2 regulation by Socs1/Ubiquitin (Ub).

Figure 2.. Signaling via the IL-4RαR576 variant.

(A) The normal wildtype allele of the IL-4Rα (Q576R) showing the activation STAT6 and TH2 induction. (B) The R576 substitution enables the binding of the adaptor GRB2 to the adjacent Y575 once the latter is phosphorylated by the JAKs, leading to MAPK activation and IL6 gene induction. This unique attribute allows signaling via the IL4Rα-R576 to induce dual activation of STAT6 and STAT3, leading to destabilization of Treg cells into a TH17 cell-like phenotype and mixed TH2/TH17 cell inflammation. Dual STAT6/STAT3 activation also results in heightened expression of CCL11, leading to exaggerated tissue eosinophilia.

Figure 3.

Potential mechanisms of action of Dupilumab in targeting the IL-4R complex. (A) Dupilumab may inhibit IL-4 binding to IL-4Rα, and/or (B) inhibit the recruitment of γc to IL-4Rα chain and/or (C) inhibit the recruitment of the IL-4Rα to IL-13Rα1.

Figure 4.

Potential sites of action of Dupilumab in inhibiting allergic inflammation. Dupilumab can act to inhibit TH2 cell differentiation, the transformation of Treg cells into ex-Treg cells in the context of allergic inflammation, and IgE production by B cells, driven by T follicular helper (TFH)- derived IL-4. It can also prevent IL-4-related vascular endothelium dysfunction. Furthermore, it can inhibit ILC2 induction via eosinophils and basophils.