Tezepelumab: A Potential New Biological Therapy for Severe Refractory Asthma

Abstract

Thymic stromal lymphopoietin (TSLP) is an innate cytokine, belonging to the group of alarmins, which plays a key pathogenic role in asthma by acting as an upstream activator of cellular and molecular pathways leading to type 2 (T2-high) airway inflammation. Released from airway epithelial cells upon tissue damage induced by several noxious agents including allergens, viruses, bacteria, and airborne pollutants, TSLP activates dendritic cells and group 2 innate lymphoid cells involved in the pathobiology of T2-high asthma. Tezepelumab is a fully human monoclonal antibody that binds to TSLP, thereby preventing its interaction with the TSLP receptor complex. Preliminary results of randomized clinical trials suggest that tezepelumab is characterized by a good safety and efficacy profile in patients with severe, uncontrolled asthma.

Monoclonal Antibodies Targeting Alarmins: A New Perspective for Biological Therapies of Severe Asthma

“…Other cellular elements belonging to the innate immune system, whose functions are affected by TSLP, include basophils and mast cells ( Figure 1 ) [ 20 ]. At the level of basophils, TSLP induces cell differentiation, stimulates histamine release, promotes cytokine production, and up-regulates the expression of the basophil activation marker CD203c [ 29 , 49 ].…”

“…Finally, the partial therapeutic activity of currently licensed biologics is limited to type 2 asthma, thereby not interfering with the pathogenic mechanisms underlying T2-low disease [ 17 , 19 ]. Therefore, the potential usefulness of anti-alarmins should be also tested in patients with non-type 2 asthma, given the important pathobiologic role played by TSLP in neutrophilic airway inflammation [ 20 ].…”

“…Because of their relevant pathogenic functions, alarmins represent suitable molecular targets for emerging biological therapies of asthma [ 15 , 16 , 17 , 18 , 19 , 20 ]. In particular, neutralization of alarmins via specific antibodies potentially provides an effective therapeutic strategy capable of interfering at a very upstream level with the complex immunopathologic cascades leading to type 2 asthma.…”

“…In fact, this approach can impact more broadly on asthma pathobiology with respect to current downstream therapies targeting circumscribed pathways mediated by single cytokines (IL-4, IL-5, and IL-13) or receptors (IL-4 receptor and IL-5 receptor) [ 21 ]. Among anti-alarmins, the most studied anti-TSLP monoclonal antibody in clinical trials is tezepelumab [ 20 , 22 , 23 ]; some anti-IL-33 antibodies are under investigation, whereas no anti-IL-25 drug has entered clinical evaluation so far [ 18 ]. In this regard, it is noteworthy that anti-alarmins could induce effective therapeutic benefits for patients with uncontrolled T2-high asthma by lowering disease exacerbations, as well as by improving symptom control, lung function, quality of life, and oral corticosteroid (OCS) dependence [ 18 , 20 ].…”

“…Among anti-alarmins, the most studied anti-TSLP monoclonal antibody in clinical trials is tezepelumab [ 20 , 22 , 23 ]; some anti-IL-33 antibodies are under investigation, whereas no anti-IL-25 drug has entered clinical evaluation so far [ 18 ]. In this regard, it is noteworthy that anti-alarmins could induce effective therapeutic benefits for patients with uncontrolled T2-high asthma by lowering disease exacerbations, as well as by improving symptom control, lung function, quality of life, and oral corticosteroid (OCS) dependence [ 18 , 20 ]. Furthermore, tezepelumab should also be evaluated in patients with difficult-to-treat T2-low asthma.…”