Role of biologics in severe eosinophilic asthma - focus on reslizumab

Abstract

Within the context of the heterogeneous phenotypic stratification of asthmatic population, many patients are characterized by moderate-to-severe eosinophilic asthma, not adequately controlled by relatively high dosages of inhaled and even oral corticosteroids. Therefore, these subjects can obtain significant therapeutic benefits by additional biologic treatments targeting interleukin-5 (IL-5), given the key pathogenic role played by this cytokine in maturation, activation, proliferation, and survival of eosinophils. In particular, reslizumab is a humanized anti-IL-5 monoclonal antibody that has been found to be an effective and safe add-on therapy, capable of decreasing asthma exacerbations and significantly improving disease control and lung function in patients experiencing persistent allergic or nonallergic eosinophilic asthma, despite the regular use of moderate-to-high doses of inhaled corticosteroids. These important therapeutic effects of reslizumab, demonstrated by several controlled clinical trials, have led to the recent approval by US Food and Drug Administration of its use, together with other antiasthma medications, for the maintenance treatment of patients suffering from severe uncontrolled asthma.

Keywords: IL-5; Janus kinases; MAPK; chronic obstructive pulmonary disease; eosinophilic asthma; reslizumab.

Figure 1

Molecular mechanisms and signaling pathways activated by IL-5 in eosinophils. Notes: Binding of IL-5 to the α subunit of its receptor (IL-5Rα) induces the assembly of a dimeric receptor complex consisting of both α and βc subunits. The subsequent activation of several signaling pathways, including JAK/STAT, MAPK, PI3K, and NF-κB, is responsible for transcription of genes involved in eosinophil differentiation, degranulation, survival, proliferation, chemotaxis, and adhesion. Abbreviations: IL-5, interleukin-5; JAK, Janus kinases; STAT, signal transducers and activators of transcription; PI3K, phosphoinositide 3-kinase; MAPK, mitogen-activated protein kinases.

Figure 2

Anti-IL-5/IL-5R biologic therapies. Notes: Monoclonal antibodies aimed to inhibit eosinophil functions include mepolizumab and reslizumab, which bind to and neutralize IL-5, as well as benralizumab, which targets and blocks IL-5Rα. Abbreviation: IL-5, interleukin-5.