Lessons learned from clinical trials of thymic stromal lymphopoietin (TSLP) inhibition.

Abstract

Type 2 (T2) immune-mediated epithelial-driven diseases are characterized by dysregulated immune responses at epithelial barrier surfaces. A key mediator of these diseases is thymic stromal lymphopoietin (TSLP), an epithelial cytokine that acts as a regulator of both T2 and non-T2 inflammation. TSLP activates dendritic cells and other immune cells, promoting the release of proinflammatory cytokines, including interleukin (IL)-4, IL-5, and IL-13. Given its central role in initiating and amplifying T2 inflammation, TSLP has emerged as a promising therapeutic target in multiple epithelial-driven inflammatory diseases. Tezepelumab is a human monoclonal antibody that selectively blocks TSLP from interacting with its receptor complex, thereby interrupting this inflammatory cascade, and its study in various disease states has clarified the clinical importance of TSLP-driven inflammation. In this review, we examine preclinical and clinical evidence and enumerate the lessons learned to date regarding the role of TSLP in sustaining select T2 inflammatory diseases-specifically asthma, chronic rhinosinusitis with nasal polyps, chronic obstructive pulmonary disease, allergic rhinitis, atopic dermatitis, and chronic spontaneous urticaria. Tezepelumab is currently the only approved anti-TSLP therapy. Other TSLP-targeting agents, including ecleralimab, SHR-1905, bosakitug, verekitug, sunakiment, TAVO101, ocankitug, HBM9378, MG-ZG122, GB-0895, and solrikitug, are in clinical development.