TSLP Inhibitors for Asthma: Current Status and Future Prospects

Thymic stromal lymphopoietin (TSLP) is an allarmin cytokine whose importance in human asthma has been repeatedly documented. Accordingly, targeting of TSLP and TSLP-mediated signalling is considered as an attractive therapeutic strategy to asthma. Tezepelumab, which is the first-in-class anti-TSLP monoclonal antibodies (mAb), is a fully human IgG2 lambda mAb that binds human TSLP, prevents interaction with its receptor and, consequently, inhibits multiple downstream inflammatory pathways. Because of the excellent results of Phase II trials, the Food and Drug Administration granted tezepelumab as a 'breakthrough' biological drug for the treatment of severe asthma. Several studies with this mAb are ongoing. CSJ117 is an Ab fragment that binds to TSLP and is delivered by inhalation but there is no published information on this biologic agent. Since new information suggests that targeting TSLP may be more likely to improve day-to-day asthma symptoms, in contrast to targeting mediators of the adaptive immune system, approaches that primarily act to ameliorate asthma exacerbations, novel approaches capable of blocking TSLP (for example, fully human single-chain fragment variables against TSLP, bifunctional drugs such as the one that combines an anti-IL-13 mAb with an anti-TSLP mAb, a fusion protein consisting of the ectodomains of TSLPR and IL-7Ra that extend into the extracellular space, also known as a TSLP-trap, fragments capable of disrupting the TSLP:TSLPR complex) are under preclinical investigation. However, some critical aspects remain to be clarified before being able to define this approach as the one that will probably better help patients suffering from severe asthma because of its holistic effects.