Intersection of biology and therapeutics: type 2 targeted therapeutics for adult asthma

Abstract

Asthma is a disease of reversible airflow obstruction characterised clinically by wheezing, shortness of breath, and coughing. Increases in airway type 2 cytokine activity, including interleukin-4 (IL-4), IL-5, and IL-13, are now established biological mechanisms in asthma. Inhaled corticosteroids have been the foundation for asthma treatment, in a large part because they decrease airway type 2 inflammation. However, inhaled or systemic corticosteroids are ineffective treatments in many patients with asthma and few treatment options exist for patients with steroid resistant asthma. Although mechanisms for corticosteroid refractory asthma are likely to be numerous, the development of a new class of biologic agents that target airway type 2 inflammation has provided a new model for treating some patients with corticosteroid refractory asthma. The objective of this Therapeutic paper is to summarise the new type 2 therapeutics, with an emphasis on the biological rationale and clinical efficacy of this new class of asthma therapeutics.

Figure 1:. ILC2s and Th2 cells are key activators of airway type-2 inflammation

The type 2 cytokines are responsible for the key pathological features of asthma, including goblet cell metaplasia, mucus plugging, bronchial hyper-reactivity, and airway eosinophilia. The type 2 immune cascade is initiated by epithelial cell exposure to environmental stimuli (ie, allergens, viruses, and pollutants). Epithelial cells secrete eotaxins that promote chemotaxis of eosinophils, basophils, and T-helper-2 (Th2) cells. (A) The role of the group 2 Innate lymphoid cell (ILC2) in driving the type 2 immune response. ILC2 cells are activated through the epithelial production of IL-33 and TSLP, and in this state secrete large amounts of type 2 cytokines (IL-4, IL-5, and IL-13). ILC2 cells induce mast cell proliferation via IL-9 and assist plasma cell class switching to immunoglobulin E (IgE) through the release of IL-4 and IL-13. (B) The role of Th2 cells as propagators of the type 2 immune response. Dendritic cells process and present antigens leading to the production of type 2 cytokines by Th2 cells. ROS=reactive oxygen species. CLC=charcot-leyden crystals. MBP=myelin basic protein. MPO=myeloperoxidase.

Figure 2:. Forest plots showing the effect size of type 2 biologic agents in patients with eosinophilic asthma

(A) Effect of biologic agents on asthma exacerbation. (B) Effect of biologic agents on forced expiratory volumes in 1 s (FEV₁). The standardised mean difference (dashed line) and 95% CI for the combined treatment effects are shown. Q2=dose every 2 weeks. Q4=dose every 4 weeks. Q8=dose every 8 weeks.