Biologics in severe asthma: a state-of-the-art review

Abstract

Asthma is considered severe if it remains uncontrolled despite optimal conventional therapy, characterised by poor symptom control, frequent exacerbations and increased exposure to systemic corticosteroids. This has a significant impact on morbidity, mortality and healthcare resource utilisation. Recent advances in the understanding of asthma heterogeneity and immunopathogenesis have helped delineate precise disease pathways. The discovery of these pivotal pathways has led to the development of highly effective biologic therapies. Currently available asthma biologics target immunoglobulin E, interleukin (IL)-5/IL-5Rα, IL-4Rα and thymic stromal lymphopoietin. Identification of specific asthma phenotypes, utilising easily measurable biomarkers, has paved the way towards personalised and precision asthma management. Biologic therapies play a significant role in reducing exacerbations, hospitalisations and the need for maintenance systemic steroids, while also improving the quality of life in patients with severe asthma. The evidence for their clinical efficacy comes from randomised controlled trials (RCTs), extension studies, metanalyses and real-world data. This review synthesises findings from early, pivotal RCTs and subsequent studies following the approval of biologics for severe asthma. The safety and efficacy data from these studies, completed in a variety of settings, provide practical perspectives on their application and enhance their generalisability.

FIGURE 1

Severe asthma immunopathogenesis in type 2 (T2)-high asthma and the specific targets of biologic therapies. In the T2-high pathway, on exposure to allergens, pollutants or microbes, the airway epithelium releases alarmins such as interleukin (IL)-33, IL-25 and thymic stromal lymphopoietin (TSLP). The dendritic cells (DCs) present these aeroallergens to naïve CD4⁺ T-cells (Th₀), which promotes their differentiation into Th₂ cells. IL-4 plays a key role in this differentiation. The Th₂ cells, along with type 2 innate lymphoid cells (ILC2), produce high levels of type 2 cytokines such as IL-4, IL5 and IL-13. Besides promoting the differentiation of Th₀ to Th₂, IL-4, along with IL-13, plays a major role in driving IgE isotype switching in B-lymphocytes. IgE then binds to the high-affinity receptors (FcεRI) on the surface of mast cells and basophils. On re-exposure to the same allergens, these interact with the IgE and induces the mast cells/basophils to release histamines, leukotrienes and prostaglandins resulting in bronchoconstriction. Omalizumab inhibits the binding of IgE to the high-affinity receptors on mast cells/basophils. IL-5 stimulates proliferation, differentiation and activation of eosinophils. Activated eosinophils release leukotrienes and toxic granules, which leads to airway inflammation, tissue damage and acute asthma flare. Three biologics, mepolizumab, reslizumab and benralizumab, target the IL-5 pathway. Besides its important role in recruiting eosinophils along with IL-4, IL-13 induces nitric oxide synthase, elicits mucus hypersecretion and stimulates airway smooth muscle contraction. Dupilumab inhibits the IL-4 and IL-13 signalling pathways. Inflammation in T2-low asthma is neutrophilic or absent (pauci-granulocytic). The alarmins TSLP and IL-33 may contribute to airway hyperresponsiveness in T2-low asthma. Tezepelumab inhibits the TSLP and the downstream inflammatory cascade. Created with BioRender.com.

FIGURE 2

Mechanism of action of the biologics targeting interleukin (IL)-5 pathway. Mepolizumab and reslizumab are monoclonal antibodies that target the ligand IL-5. Benralizumab binds to the anti-IL5Rα (alpha subunit of IL-5 receptor) subunit. In addition to blocking the effects of IL-5, benralizumab also binds to the FcγRIIIα receptor for IgG expressed on natural killer (NK) cells, macrophages and neutrophils, and induces eosinophil apoptosis via antibody-dependent cell-mediated cytotoxicity (ADCC). ab: antibody. Created with BioRender.com.

FIGURE 3

Signal transduction via interleukin (IL)-4R complexes and mechanism of action of dupilumab. IL-4 or IL-13 binds to the receptors as shown and activates the Janus family protein kinases (JAKs). JAK activation initiates a cascade of phosphorylation leading to activation of the signal transducer and activator of transcription 6 (STAT6) signalling pathway and pro-inflammatory gene expression. Dupilumab is a monoclonal antibody that inhibits both IL-4 and IL-13 signalling by binding to the IL-4Rα subunit shared by IL-4 and IL-13 receptor complexes. IL-4Ra/γc: alpha subunit of IL-4R receptor pairing with γc chain to form a heterodimeric complex receptor and binds IL-4 exclusively; IL-13Ra1/IL-4Ra: alpha subunit of IL-4R pairing with alpha 1 subunit of IL-13 receptor to form a IL-13- and IL-4-binding heterodimeric complex. Created with BioRender.com.