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.