Dupilumab: Mechanism of action, clinical, and translational science

Abstract

Allergic disease prevalence has increased globally with the subset of type 2 inflammatory diseases playing a substantial role. Type 2 inflammatory diseases may differ in clinical presentation, but they exhibit shared pathophysiology that is targeted by the unique pharmacology of dupilumab. Dupilumab binds to the interleukin (IL)-4 receptor alpha subunit (IL-4Rα) that blocks IL-4 and IL-13 signaling, two key drivers of type 2 inflammation. Herein, we review the mechanism of action and pharmacology of dupilumab, and the clinical evidence that led to the regulatory approvals of dupilumab for the treatment of numerous type 2 inflammatory diseases: atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis.

FIGURE 1

Dupilumab mechanism of action within the type 2 inflammatory cascade. (a) Dupilumab binds to the shared IL‐4 receptor subunit alpha (IL‐4Rα) of type 1 and type 2 receptors, which are the targets of IL‐4 and IL‐13. (b) The type 1 receptor is found on monocytes, T_H0 cells, T_H2 cells, fibroblasts, eosinophils, and B cells. The type 2 receptor is found on monocytes, fibroblasts, eosinophils, activated B cells, epithelial cells, goblet cells, and smooth muscle cells. Dupilumab mitigates type 2 inflammation by inhibiting the IL‐4/IL‐13 axis, which is a primary driver of type 2 inflammation. IL‐4 stimulates the differentiation and clonal expansion of T_H2 cells, further driving production of IL‐4 and IL‐13. IL‐4 and IL‐13 promote several type 2 inflammation processes such as eosinophil trafficking to tissues, B cell isotype class switching to IgE, and fibroblast production of collagen. IL‐13 is primarily responsible for mucus production, goblet cell hyperplasia, and smooth muscle cell contractility. (c) Type 2 inflammatory disease possesses many overlapping features but still presents with tissue‐specific pathologies and differing clinical symptoms. Dupilumab is effective at treating these diseases due to their shared underlying type 2 inflammation pathways. MHC class II = major histocompatibility complex used for antigen presentation; TCR, T cell receptor; F_cεR1 = a high‐affinity IgE receptor. This is based on a series of figures from a publication by Gandhi et al.

FIGURE 2

Concentration–time profile of dupilumab given subcutaneously in healthy adult males. The figure shows a semi‐log scale plot of mean (+SD) concentrations of functional dupilumab in serum from a single ascending dose study (TDU1226; NCT01537653) of dupilumab given subcutaneously in healthy adult males from Japan. Elimination of dupilumab is nonlinear at low concentrations, but approach linear pharmacokinetics at higher concentrations as the receptor‐mediated elimination pathway is saturated. Mean values reported as LLOQ were included as zero, and the sum of the values was divided by all subjects, which was N = 6 for each dose group. The values reported as LLOQ were plotted as half the LLOQ of 0.078 mg/L for illustrative purposes. LLOQ, lower limit of quantification.