Biological treatment in allergic disease

Advances in molecular biology alongside the accelerated development of gene and cell engineering have contributed to the development of several endotype-targeted biological therapies against chronic immune-mediated 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 (IL-4Rα; dupilumab, IL-5; mepolizumab/reslizumab,IL-5Rα; and benralizumab).2 The following points support the argument that biologicals are safe and effective in treating allergic diseases. Omalizumab is an anti-IgE humanized IgG1 monoclonal antibody(mAb) which forms complexes with soluble IgE, inhibiting binding to its high-affinity IgE-receptor (FcεRI) on effector cells, such as basophils, eosinophils and mast cells1 (Figure 1). The paucity of IgE-mediated cross-linking 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 serum-free IgE, omalizumab downregulates FcεRI expression on mast cells, basophils and dendritic cells, and IgE-CD23 interactions on B-cells,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 IL-5, inhibiting the activation and recruitment of eosinophils1 (Figure 1). Benralizumab, another humanized IgG1mAb, targets the IL-5 pathway through binding to the α subunit of the IL-5R, impeding IL-5 signal transduction1 (Figure 1). Moreover, benralizumab binds to FcγRIIIa on natural killer cells through its Fc region, depleting eosinophils through antibody-dependent cellular cytotoxicity1 (Figure 1). Anti-IL-5 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 add-on therapy demonstrate improvements in total endoscopic NPS and sinonasal symptoms, supporting their regulatory body approval for disease management in the future. Dupilumab is a humanIL-4Rα blocking IgG4mAb which inhibits the sister cytokines IL-4/IL-13 through blockade of their shared receptor subunit1 (Figure 1). IL-4 plays a key role in T2 immunity by promoting Th2 differentiation and IgE class-switching 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, T2-targeting 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 keratinocytes-derived mediators and cytokines such as thymic stromal lymphopoietic, IL-31, and IL-33, and may provide further improvements in the management of T2-mediated 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 disease-modifying immunological effect would indicate that biologicals prevent the onset or the progression of the disease, the development of associated co-morbidities, 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 biological-related remission upon discontinuation. Discontinuation of dupilumab resulted in a risk of re-initiation of AD in almost 80% of patients.10 Omalizumab cessation after 1 year of asthma treatment led to 68% relapse rate in omalizumab responders.11 For mepolizumab, one randomized, placebo-controlled trial on subcutaneous mepolizumab against placebo after long-term mepolizumab treatment in asthmatics (COMET trial) described a 59% asthma relapse and a 4–5-fold increase in blood eosinophil counts.12 Few datasets on synergies of biologicals with AIT have been reported. Omalizumab in addition to peanut, milk, multi-food, or hymenoptera immunotherapy significantly reduced the time to maintenance dose and the rate of side effects. However, it does not enhance long-term clinical outcomes or increases the rate of tolerance or sustained unresponsiveness of food AIT.13 Thus, novel approaches to mediate the dose reduction process in omalizumab facilitated oral immunotherapy are needed.14, 15 One double-blind placebo-controlled study investigated a non-marketed anti-IL-4 antibody (VAK694) in the context of a suboptimal subcutaneous grass pollen AIT. Despite some promising mechanistic findings, no additional clinical benefit to the AIT was observed. Dupilumab, approved for T2 asthma, CRSwNP and AD addresses both the IL-4 and IL-13 axis, thus potentially affecting disease progression through interfering with isotype switching and IL-13 dependent T-follicular helper cell function. However, human data from controlled trials are missing. Once omalizumab therapy is ceased if used as a monotherapy for food allergy, symptoms re-occur. Eosinophilia or eosinophil infiltration of the lung or the gastrointestinal-tract is a common phenomenon observed in patients with atopic diseases. Anti-IL5 or IL-5R targeting antibodies could have synergistic effects by abolishing this eosinophil driven inflammation on the one hand and increase safety by controlling asthma during AIT. No controlled trials are available until now. Recently increased infectious events have been reported for benralizumab in severe asthma patients, which has been linked to the presence of auto-antibodies.16 This is very interesting as this signal was absent in phase III benralizumab trials and require further consideration for future applications in vulnerable populations. Even less clinical evidence is available for a preventive or disease-modifying effect of biologicals. It is tempting to speculate on disease-modifying or preventive effects of biologicals addressing IL-4/IL-13 pathway or upstream like anti-IL-33 on very young children or even in pregnancy. However, more safety data from controlled trials are required before approaches interfering with immune pathways in childhood and very early in life (<2 years) can be considered in such vulnerable populations. In conclusion, there is no evidence that biologicals can sustainably break vicious cycles of inflammation and thereby rescind or stop the progression of the disease. Moreover, we do not have sufficient evidence to suggest a role of T2 immunity targeting biologicals to promote tolerance development to allergens when applied with or without AIT. Dr. Eiwegger reports to act as local PI for company sponsored trials by DBV and sub-investigator for Regeneron, holds grants from Innovation fund Denmark, CIHR outside the submitted work. He is Co-Investigator or scientific lead in three investigator initiated oral immunotherapy trials supported by the Food Allergy and Anaphylaxis Program SickKids and serves as associate editor for Allergy. He/his lab received unconditional/kind contributions from Macro Array Diagnostics and ALK, and he holds advisory board roles for ALK outside of the submitted work. All other authors have nothing to disclose.

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