Biologic Therapies Targeting Type 2 Signaling in Atopic Dermatitis: A Comparative Review of Structural and Thermodynamic Differences in Mechanism of Action

Atopic dermatitis (AD) is a chronic skin disease characterized by heterogeneous clinical morphology, immune dysregulation, and disease burden. A key component of the immune dysregulation in AD occurs through type 2 immunity, with elevations in IL-4 and IL-13. Multiple other cytokines contribute to both acute and chronic states of AD, including IL-31, IL-22, IFN-γ, and thymic stromal lymphopoietin. Several biologic therapies targeting type 2 cytokine (IL-4 and IL-13) signaling through distinct mechanisms of action (MOAs) have been developed, with more expected in the future, including with multivalency. Although biologics targeting the IL-4/IL-13 pathway have good overall efficacy for AD, variable individual patient responses to different biologics have been observed. This review analyzes and addresses the function of biologic therapies for AD from a fresh molecular perspective. It describes the structural and thermodynamic properties of IL-4/IL-13 signaling and how these properties inform MOA differences between the AD biologics dupilumab, tralokinumab, lebrikizumab, and rademikibart and translates the molecular science into potential clinical implications of these MOA differences. The fundamental conclusion is that each of the biologics currently in clinical use for treating AD function very uniquely by disrupting the assembly of the cytokine-receptor signaling complex at different energetic steps.