Efficacy and Potential Positioning of Tezepelumab in the Treatment of Severe Asthma

Abstract

The excellent results for monoclonal antibodies in the treatment of severe uncontrolled asthma (SUCA) represent a milestone in current treatment of asthmatic disorders. Remaining, however, are several subsidiary areas for improvement in which new biologics are expected to make a decisive contribution. These biologics include tezepelumab, a monoclonal antibody that blocks thymic stromal lymphopoietin (TSLP). TSLP is an epithelial-release cytokine (alarmin) that plays a key role in initiating both the innate (group 2 innate lymphoid cell (ILC) pathway) and the acquired (T helper 2 (Th2) pathway) immune responses by activating the type 2 (T2) asthma inflammatory pathway through both. It is also thought that it may additionally intervene in the neutrophilic non-T2 inflammatory pathway (via interaction with ILC3 and interleukin-17). Six clinical trials that included 2187 patients with uncontrolled asthma, with 2 or more exacerbations in the previous year, on medium/high-dose inhaled corticosteroids and at least 1 other controller, have demonstrated - irrespective of T2 endotype (and possibly also non-T2 endotype) - the efficacy and safety of tezepelumab, as it significantly reduces exacerbations (61.7%-66%) and bronchial hyperresponsiveness, and improves lung function, disease control, and quality of life. Tezepelumab could be indicated for the treatment of patients with, independently of the T2 phenotype (eosinophilic and non-eosinophilic), and may even be the only biologic available for treatment of non-T2 SUCA.

Keywords: Alarmin; Phenotype; Thymic stromal lymphopoietin; Uncontrolled asthma.

Fig. 1

Adapted from Domingo. The figure, which may explain clinical results, shows how adaptive immunity (via Th2) is activated by allergens, resulting in synthesized IgE, which enters the medium to bind to effector cells. The right part of the figure shows how damage produced in the bronchial ciliated epithelium causes alarmins to be released that activate ILC2 and NKT cells. In both cases, the ILs typical of T2 asthma (IL-4, IL-5, and IL-13) are synthesized and released. Note how TSLP exerts APC control. TSLP also appears to have some effect on activation of ILC3 belonging to the non-T2 pathway.

Fig. 2

Adapted from Varricchi et al. The figure shows how TSLP is produced from a bronchial ciliated epithelium damaged by triggering factors. Once produced and released into the medium, this positively charged TSLP binds to TSLPR. Signalling only occurs when TSLP binds to IL-7Rα.