Novel Therapeutic Targets for the Treatment of Atopic Dermatitis

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease that significantly impacts quality of life. The pathogenesis of AD is a complex combination of skin barrier dysfunction, type II immune response, and pruritus. Progress in the understanding of the immunological mechanisms of AD has led to the recognition of multiple novel therapeutic targets. For systemic therapy, new biologic agents that target IL-13, IL-22, IL-33, the IL-23/IL-17 axis, and OX40-OX40L are being developed. Binding of type II cytokines to their receptors activates Janus kinase (JAK) and its downstream signal, namely signal transduction and activator of transcription (STAT). JAK inhibitors block the activation of the JAK-STAT pathway, thereby blocking the signaling pathways mediated by type II cytokines. In addition to oral JAK inhibitors, histamine H4 receptor antagonists are under investigation as small-molecule compounds. For topical therapy, JAK inhibitors, aryl hydrocarbon receptor modulators, and phosphodiesterase-4 inhibitors are being approved. Microbiome modulation is also being examined for the treatment of AD. This review outlines current and future directions for novel therapies of AD that are currently being investigated in clinical trials, focusing on their mechanisms of action and efficacy. This supports the accumulation of data on advanced treatments for AD in the new era of precision medicine.

Keywords: atopic dermatitis; biologic; small-molecule inhibitor.

Figure 1

Novel therapeutic biologic targets in the pathogenesis of AD. Scratch injury induced by pruritis and allergens produce TSLP, IL-25, and IL-33, which are cytokines classified as alarmins, in keratinocytes. When these act on ILC2, they induce the production of IL-5 and IL-13, resulting in differentiation and proliferation that is prone toward Th2. This pathway is enhanced via OX40L-OX40 interaction between dendritic cells and T cells. Th2-cell-derived IL-4 and IL-13 produce skin barrier dysfunction in keratinocytes, which enhances scratch injury-induced and allergen-induced cell damage. In addition to the Th2 immune response, IL-17 from Th17 cells and IL-22 from Th22 cells induce acanthosis in the epidermis, which contributes to the formation of intractable lichenified AD skin lesions. CB326 and BSI-045: anti-TSLP Ab. Telazorimab and rocatinlimab: anti-OX40 Ab. KY1005: anti-OX40L antibody. CM310, CBP201, and dupilumab: anti-IL4Rα antibody. Tralokinumab and lebrikizumab: anti-IL-13 Ab. Nemolizumab: anti-IL-31 Ab. KLP-716: anti-oncostatin M receptorβ Ab. Spesolimab: anti-IL-36 receptor Ab. Fezakinumab: anti-IL-22 Ab.