Tezepelumab
Tezepelumab is a human mAb, which binds with high affinity to TSLP, an epithelial cell-derived cytokine implicated in the pathogenesis of different phenotypes of asthma13. TSLP, a pleiotropic cytokine overexpressed in the airway epithelium of asthmatics74, exerts its effects by binding to a high-affinity heterodimeric receptor complex composed of TSLPR and IL-7Rα 13. TSLP concentrations are increased in BAL fluid of asthmatics73 and bronchial allergen challenge increases TSLP expression in the asthmatic epithelium and submucosa. Importantly, serum concentrations of TSLP are increased during asthma exacerbations182. Finally, TSLP induces the release of angiogenic and lymphangiogenic factors from HLMs60. TSLP can promote airway remodeling via the activation of human lung fibroblasts89.
The FDA has recently approved tezepelumab for the treatment of severe asthma with no phenotype or biomarker limitations. Tezepelumab is the first of a new class of biologics that antagonize an alarmin (e.g., TSLP), which plays a pivotal role in the pathogenesis of asthma13, 68. The phase II PATHWAY study showed that three different doses (70 mg, 210 mg, or 280 mg s.c. every 4 weeks) of tezepelumab reduced the number of annual exacerbation rates regardless of blood eosinophil count, with a significant increase in prebronchodilator FEV1 at 52 weeks from the start of treatment compared to the placebo group183. These results were extended in the phase III NAVIGATOR study in which tezepelumab (210 mg s.c. every 4 weeks) reduced asthma exacerbations at week 52 and significantly improved FEV1 regardless of peripheral blood eosinophils in adolescent and adult patients with severe uncontrolled asthma184 although there was a trend toward a better improvement with higher eosinophil counts in subgroup analysis.
Studies conducted in different animal models using TSLP antibodies have demonstrated that TSLP blockade reduces airway inflammation, TGF-β1 levels, hyperreactivity and airway remodeling185-188. The phase II CASCADE study evaluated the effects of tezepelumab on airway remodeling by performing bronchoscopic biopsies in moderate-to-severe asthma patients 189. Tezepelumab caused a greater reduction from baseline to the end of treatment in airway submucosal eosinophils compared to placebo. There were no other significant changes either at the level of other immune cells (neutrophils, mast cells, and T cells) and at the structural level (e.g., RBM thickness, epithelial integrity). Interestingly, tezepelumab administration was associated with lower hyperresponsiveness to mannitol inhalation compared to placebo. The latter finding was confirmed in an independent study 190. These preliminary results on the effects of tezepelumab on airway remodeling are of translational interest for several reasons. There is overwhelming evidence that fibroblasts are a source of TSLP82, 83 and there is evidence that a functional TSLP signaling axis plays a role in fibrotic lung disease83. Figure 2 schematically illustrates the mechanisms of action of different biologics and their immunological and cellular targets in the context of airway remodeling.