Biological treatment in allergic disease

Abstract

Advances in molecular biology alongside the accelerated development of gene and cell engineering have contributed to the development of several endotypetargeted biological therapies against chronic immunemediated allergic diseases. Conventional therapies for asthma, chronic rhinosinusitis with polyposis (CRSwNP), chronic spontaneous urticarial, and atopic dermatitis (AD) are not without limitations, and as such the advent of biological therapies have provided a promising alternative treatment option. Biologicals have proven efficacious in the treatment of refractory chronic spontaneous urticaria, asthma, AD, CRSwNP, and there is increasing evidence for their utility in treating food allergy.1– 3 Biologicals are applied and investigated for the most urgent need: acute treatment, symptom control, and reduction of steroid usage. Currently, there are five approved biologicals for allergic disease management, targeted against IgE (omalizumab), type 2 (T2) cytokines, and cytokine receptors (IL4Rα; dupilumab, IL5; mepolizumab/reslizumab,IL5Rα; and benralizumab).2 The following points support the argument that biologicals are safe and effective in treating allergic diseases. Omalizumab is an antiIgE humanized IgG1 monoclonal antibody(mAb) which forms complexes with soluble IgE, inhibiting binding to its highaffinity IgEreceptor (FcεRI) on effector cells, such as basophils, eosinophils and mast cells1 (Figure 1). The paucity of IgEmediated crosslinking of allergen reduces effector cell activation and the subsequent release of immune mediators such as histamine, responsible for driving the salient symptoms of atopic disease. Moreover, through reducing serumfree IgE, omalizumab downregulates FcεRI expression on mast cells, basophils and dendritic cells, and IgECD23 interactions on Bcells,1 in turn downregulating IgE synthesis and T helper 2 (Th2) cell differentiation (Figure 1). Data from two phase III clinical trials demonstrates that omalizumab reduces disease exacerbations by ~55% in severe asthma patients4 and leads to significant improvements in mean nasal polyp scores (NPS) and nasal congestion scores (NCS) in CRSwNP patients compared to placebo.5 Moreover, omalizumab significantly improves patient quality of life compared to conventional therapies in severe asthma,6 CRSwNP,5 and chronic spontaneous urticaria7 for which it is authorized. Mepolizumab and reslizumab are humanized IgG1 and IgG4mAbs, respectively, which bind directly to IL5, inhibiting the activation and recruitment of eosinophils1 (Figure 1). Benralizumab, another humanized IgG1mAb, targets the IL5 pathway through binding to the α subunit of the IL5R, impeding IL5 signal transduction1 (Figure 1). Moreover, benralizumab binds to FcγRIIIa on natural killer cells through its Fc region, depleting eosinophils through antibodydependent cellular cytotoxicity1 (Figure 1). AntiIL5 biologics demonstrate the most efficacy against allergies characterized by eosinophilia, such as severe eosinophilic asthma and CRSwNP. Systematic reviews have demonstrated that mepolizumab, reslizumab, and benralizumab reduce asthma incidence rate ratios by 0.49, 0.46, and 0.53, respectively, and report that mepolizumab and benralizumab reduce required daily oral corticosteroid dose.6 Moreover, preliminary data from phase III trials have reported that severe CRSwNP patients treated with mepolizumab (SYNAPSE: NCT03085797) or benralizumab (OSTRO: NCT03401229) as an addon therapy demonstrate improvements in total endoscopic NPS and sinonasal symptoms, supporting their regulatory body approval for disease management in the future. Dupilumab is a humanIL4Rα blocking IgG4mAb which inhibits the sister cytokines IL4/IL13 through blockade of their shared receptor subunit1 (Figure 1). IL4 plays a key role in T2 immunity by promoting Th2 differentiation and IgE classswitching in B cells (Figure 1). Originally approved for the treatment of AD, dupilumab significantly improved symptom scores including Eczema Area Severity Index and itch Numeric Rating Scale scores during phase III clinicals.8 Dupilumabis also authorized for the treatment of severe asthma1,6 and severe CRSwNP.9 Therefore, T2targeting biologicals have greatly improved treatment efficacy compared to conventional therapies in asthma, CRSwNP, chronic spontaneous urticaria and AD. Novel biologicals are in development at a rapid pace, including epithelial and keratinocytesderived mediators and cytokines such as thymic stromal lymphopoietic, IL31, and IL33, and may provide further improvements in the management of T2mediated diseases in the future. The following points support the argument that biologicals do not prevent or modify progression of allergic diseases upon discontinuation. A positive diseasemodifying immunological effect would indicate that biologicals prevent the onset or the progression of the disease, the development of associated comorbidities, support tolerance development by allergen immunotherapy (AIT) or create a persistent beneficial effect after cessation of the treatment. Few datasets address the issue of revision or sustainability of a biologicalrelated remission upon discontinuation. Discontinuation