Tezepelumab: redefining TSLP blockade in severe asthma through mechanistic precision and translational pharmacology

Approximately 40%-50% of patients prescribed GINA Step 4-5 ICS/LABA therapy remain inadequately controlled, and existing biologics are restricted by phenotypic eligibility criteria that exclude the substantial type 2-low patient population. Thymic stromal lymphopoietin (TSLP) is an epithelial-derived alarmin cytokine that functions as a key upstream orchestrator of both type 2 and non-type 2 inflammatory pathways in asthma pathogenesis. Tezepelumab, a human monoclonal antibody targeting TSLP, represents the first biologic approved for severe asthma without phenotype- or biomarker-restricted eligibility, including type 2-low disease, with the caveat that the magnitude of benefit is somewhat smaller in T2-low patients. This review provides a comprehensive analysis of tezepelumab's molecular pharmacology, structural basis of target engagement, clinical pharmacokinetic/pharmacodynamic profile, pivotal clinical trial evidence, safety data, and regulatory positioning. We systematically evaluate tezepelumab's mechanistic rationale, therapeutic efficacy, biomarker correlations, and real-world implementation considerations, including pharmacoeconomic and access barriers. Furthermore, we critically discuss the current limitations of clinical trial evidence, population selection biases, real-world applicability concerns, and the need for long-term outcome data. Future research directions encompassing predictive biomarker development, expansion into non-asthma indications, real-world evidence generation, and advanced mechanistic studies are outlined. Tezepelumab exemplifies precision respiratory medicine by targeting upstream inflammatory cascades and establishes a paradigm for next-generation asthma therapeutics.