Abstract
Over the past 2 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 IgE, a T2 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 T2-high asthma do not respond to IgE- or T2 cytokine-targeting therapies and that patients with T2-low asthma have few therapeutic options. The new frontier of precision medicine in asthma, as well as in other allergic diseases, includes the targeting of epithelium-derived cytokines known as alarmins, including thymic stromal lymphopoietin, 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 T2-high and -low disease. Tezepelumab, an anti-thymic stromal lymphopoietin 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, with a particular focus on currently approved treatments, those under study, and future potential targets in alarmin signaling pathways.