Biologics or immunotherapeutics for asthma?

Asthma is now recognised as a heterogenous inflammatory disease of the lung based on cellular infiltrates and transcriptional profiles of blood and airway cells. Four distinct subgroups have been defined, eosinophilic (T2), neutrophilic (T1), mixed eosinophilic/neutrophilic and paucigranulocytic. Patients can also be stratified at a molecular level into T2-high, T2-low and/or T1 based on their gene signatures. Current treatments for asthma have been centred on administration of steroids and/or bronchodilators for the relief of bronchoconstriction and inflammation. These treatments are not always effective and often have limited efficacy during exacerbations. Eosinophil expansion and homing to tissues, bronchoconstriction, IgE production and mucus hypersecretion (hallmark features of asthma) are regulated by the type 2 cytokines IL-4, IL-5 and IL-13, the latter of which can induce the expression of the eosinophil chemotactic factors CCL11 and CCL24. A number of new generation biologics (monoclonal antibodies) targeting pathways regulated by the T2 cytokines IL-5 and IL-4/13 (IL-4 receptor alpha) have yielded effective therapies for eosinophil induced exacerbations of severe asthma. Despite these advances, difficulties still remain in treating all exacerbations, and this may reflect the contribution of other inflammatory cells such as neutrophils to pathogenesis. This review describes the effectiveness of targeting T2 pathways, emerging approaches and identifies the potential next steps for therapeutic intervention.