Tezepelumab reduces the expression of MUC5AC in patients with asthma

<bold>Title:</bold> Tezepelumab reduces the expression of MUC5AC in patients with asthma <bold>Introduction:</bold> Asthma is characterized by airway inflammation and excessive mucus production, contributing to airway obstruction. Mucus hypersecretion has been linked to overexpression of MUC5AC, which is augmented by T2 inflammation and may lead to more viscoelastic, adhesive mucus. Tezepelumab (a monoclonal antibody targeting TSLP) has been shown to reduce mucus plugging in patients with asthma. We hypothesized that blocking TSLP signalling reduces MUC5AC expression. <bold>Methods:</bold> These exploratory analyses were conducted on samples from the UPSTREAM study. RNA sequencing was performed on bronchial brushings obtained from patients with asthma before and after receiving tezepelumab (n=12) or placebo (n=13) treatment for 12 weeks. We investigated changes in the expression of a priori selected genes related to mucus secretion. <bold>Results:</bold> The expression of TSLP showed a trend towards being reduced in the group receiving tezepelumab (P=0.06) but not in placebo. The expression of MUC5AC and EGFR was significantly reduced in the tezepelumab group (P=0.04 and P=0.02, respectively), while no effect was seen on MUC5B, MUC5AC/MUC5B ratio or SPDEF. At baseline, MUC5AC expression was related to FeNO (r=0.47, P=0.006) and EGFR expression (r=0.36, P=0.04), but not to blood eosinophil count (r=0.28, P=0.12). Notably, treatment-related changes in MUC5AC expression were similar in patients regardless of FeNO or blood eosinophils. <bold>Conclusion:</bold> Anti-TSLP treatment reduces the expression of MUC5AC independent of T2-biomarker status, possibly through a downregulation of the EGFR pathway. This could mechanistically explain how tezepelumab reduces mucus plugging.