Molecular targeted therapies for asthma : current management and future directions

Abstract

 The development of molecular targeted therapy for asthma was initiated from inhibiting IgE or IL-5 signaling, which activates effector function cells, including mast cells or eosinophils. To date in 2017, anti-IgE omalizumab and anti-IL-5 antibody mepolizumab is clinically available in Japan. United States Food and Drug Administration has already approved another anti-IL-5 antibody, reslizumab. In addition, clinical efficacy of anti-IL-5Rα antibody benralizumab, which is reported to have ADCC (antibody-dependent cell-mediated cytotoxicity) activity, has been proved in two phase 3 studies. IL-13 in addition to IL-5, is an important cytokine derived from Th2 cells and type 2 innate lymphoid cells. Anti IL-4Rα antibody, which inhibits both IL-4 and IL-13 signaling, is more promising than antibodies targeting only IL-13. Those antibodies are in phase 2b or 3 trials.

 More recently, the strategies targeting Th2 differentiation or activation including CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) inhibitor, TSLP (thymic stromal lymphopoietin) antibody, and TLR (Toll-like receptor) ligands are under investigation. The position of those molecules is more upstream of allergic airway inflammation. But clinical trials concerning those molecules are still in phase 1 or 2, and further investigations showing the additive effect on ICS are required.

 Anti-IL-5 should be used only for eosinophilic asthma based on previous studies. As molecular targeted therapies should be tailored to the endotypes, further refinement of specific biomarkers is needed for optimal treatment.