Targeting alarmins in asthma- From the bench to the clinic.

Abstract

Over the past two decades, mechanistic studies of allergic and type 2 (T2)-mediated airway inflammation have led to multiple approved therapies for the treatment of moderate-to-severe asthma. The approval and availability of these monoclonal antibodies targeting immunoglobulin E, a type 2 cytokine (IL-5) and/or cytokine receptors (IL-5Rα, IL-4Rα) has been central to the progresses made in the management of moderate-to-severe asthma over this period. However, there are persistent gaps in clinician's ability to provide precise care given that many patients with type 2-high asthma do not respond to the IgE or T2 cytokine-targeting therapies and patients with type 2-low asthma have limited therapeutic options. The new frontier of precision medicine in asthma, as well as in other allergic diseases, includes the targeting of epithelium-derived cytokines, "alarmins", including TSLP, IL-25, IL-33, and their receptors. The effects of these alarmins, which can act upstream of immune cells, involve both the innate and adaptive systems and hold potential for the treatment of both type 2-high and low disease. Tezepelumab, an anti-TSLP antibody has already been approved for the treatment of severe asthma. In this review we discuss our current understanding of alarmin biology with a primary focus on allergic airway diseases. We link the mechanistic corollaries to the clinical implications and advances in drug development targeting alarmins-focusing on currently approved treatments, those under study, as well as future potential targets in the alarmin signaling pathways.