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      Benralizumab: From the Basic Mechanism of Action to the Potential Use in the Biological Therapy of Severe Eosinophilic Asthma

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          Abstract

          Asthma is a very frequent chronic airway disease that includes many different clinical phenotypes and inflammatory patterns. In particular, eosinophilic bronchial inflammation is often associated with allergic as well as nonallergic asthma. The most important cytokine involved in the induction, maintenance, and amplification of airway eosinophilia in asthma is interleukin-5 (IL-5), released by both T helper 2 (Th2) lymphocytes and group 2 innate lymphoid cells (ILC2). Hence, IL-5 and its receptor are suitable targets for selective biologic drugs which can play a key role in add-on treatment of severe eosinophilic asthma refractory to corticosteroids. Within such a context, the anti-IL-5 monoclonal antibodies mepolizumab and reslizumab have been developed and approved for biological therapy of uncontrolled eosinophilic asthma. In this regard, on the basis of several successful randomized controlled trials, the anti-IL-5 receptor benralizumab has also recently obtained the approval from US Food and Drug Administration (FDA).

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          Most cited references65

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          T-helper type 2-driven inflammation defines major subphenotypes of asthma.

          T-helper type 2 (Th2) inflammation, mediated by IL-4, IL-5, and IL-13, is considered the central molecular mechanism underlying asthma, and Th2 cytokines are emerging therapeutic targets. However, clinical studies increasingly suggest that asthma is heterogeneous. To determine whether this clinical heterogeneity reflects heterogeneity in underlying molecular mechanisms related to Th2 inflammation. Using microarray and polymerase chain reaction analyses of airway epithelial brushings from 42 patients with mild-to-moderate asthma and 28 healthy control subjects, we classified subjects with asthma based on high or low expression of IL-13-inducible genes. We then validated this classification and investigated its clinical implications through analyses of cytokine expression in bronchial biopsies, markers of inflammation and remodeling, responsiveness to inhaled corticosteroids, and reproducibility on repeat examination. Gene expression analyses identified two evenly sized and distinct subgroups, "Th2-high" and "Th2-low" asthma (the latter indistinguishable from control subjects). These subgroups differed significantly in expression of IL-5 and IL-13 in bronchial biopsies and in airway hyperresponsiveness, serum IgE, blood and airway eosinophilia, subepithelial fibrosis, and airway mucin gene expression (all P < 0.03). The lung function improvements expected with inhaled corticosteroids were restricted to Th2-high asthma, and Th2 markers were reproducible on repeat evaluation. Asthma can be divided into at least two distinct molecular phenotypes defined by degree of Th2 inflammation. Th2 cytokines are likely to be a relevant therapeutic target in only a subset of patients with asthma. Furthermore, current models do not adequately explain non-Th2-driven asthma, which represents a significant proportion of patients and responds poorly to current therapies.
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            Asthma

            Asthma-one of the most common chronic, non-communicable diseases in children and adults-is characterised by variable respiratory symptoms and variable airflow limitation. Asthma is a consequence of complex gene-environment interactions, with heterogeneity in clinical presentation and the type and intensity of airway inflammation and remodelling. The goal of asthma treatment is to achieve good asthma control-ie, to minimise symptom burden and risk of exacerbations. Anti-inflammatory and bronchodilator treatments are the mainstay of asthma therapy and are used in a stepwise approach. Pharmacological treatment is based on a cycle of assessment and re-evaluation of symptom control, risk factors, comorbidities, side-effects, and patient satisfaction by means of shared decisions. Asthma is classed as severe when requiring high-intensity treatment to keep it under control, or if it remains uncontrolled despite treatment. New biological therapies for treatment of severe asthma, together with developments in biomarkers, present opportunities for phenotype-specific interventions and realisation of more personalised treatment. In this Seminar, we provide a clinically focused overview of asthma, including epidemiology, pathophysiology, clinical diagnosis, asthma phenotypes, severe asthma, acute exacerbations, and clinical management of disease in adults and children older than 5 years. Emerging therapies, controversies, and uncertainties in asthma management are also discussed.
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              Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial

              Benralizumab is a humanised, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils. We aimed to assess the efficacy and safety of benralizumab as add-on therapy for patients with severe, uncontrolled asthma and elevated blood eosinophil counts.
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                Author and article information

                Contributors
                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi
                2314-6133
                2314-6141
                2018
                10 May 2018
                : 2018
                : 4839230
                Affiliations
                1Dipartimento di Scienze Mediche e Chirurgiche, Università degli Studi “Magna Græcia”, Catanzaro, Italy
                2Dipartimento di Scienze Cardio-Toraciche e Respiratorie, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy
                3Dipartimento di Medicina, Chirurgia ed Odontoiatria, Università degli Studi di Salerno, Salerno, Italy
                4Dipartimento di Scienze della Salute, Università degli Studi “Magna Græcia”, Catanzaro, Italy
                Author notes

                Academic Editor: Andrei Malinovschi

                Author information
                http://orcid.org/0000-0001-8265-3037
                http://orcid.org/0000-0001-9288-8913
                Article
                10.1155/2018/4839230
                5971345
                29862274
                12bd7bfb-6684-4a4f-a8f5-033694ef8ccd
                Copyright © 2018 Corrado Pelaia et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 February 2018
                : 4 April 2018
                Categories
                Review Article

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