Anti-IL-5 Pathway Agents in Eosinophilic-Associated Disorders Across the Lifespan

Abstract

Monoclonal antibodies targeting interleukin (IL)-5 pathways have revolutionized the treatment expectations for eosinophilic-associated conditions, particularly in patients with respiratory involvement. Mepolizumab (IL-5 antagonist monoclonal antibody), benralizumab (IL-5 receptor blocker monoclonal antibody), and reslizumab (IL-5 antagonist monoclonal antibody) have collectively contributed to the overall improvement of the disease burden in various conditions. Eosinophilic asthma currently boasts the most robust evidence across all age groups: all three biologics are approved for adults (aged ≥18 years); mepolizumab is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) also in children (aged ≥ 6 years), while bernalizumab was recently approved by the FDA for patients aged ≥6 years in the USA. In chronic rhinosinusitis with nasal polyps, subcutaneous mepolizumab is the only anti-IL-5 therapy approved so far and can be used in adult patients (aged ≥18 years). For eosinophilic esophagitis, conflicting evidence surrounds both mepolizumab, reslizumab, and benralizumab, leading to non-approval of these agents by the FDA/EMA. Recently, mepolizumab was approved for eosinophilic granulomatosis with polyangiitis patients aged ≥6 years or older and for hypereosinophilic syndrome adult patients. A phase III trial proving noninferiority of benralizumab versus mepolizumab in eosinophilic granulomatosis with polyangiitis has been recently published, while evidence on reslizumab is scant. Overall, current evidence on anti-IL-5 biologics for eosinophilic-associated disorders is mostly focused on adults, whereas data for individuals aged under 18 years and over 65 years are scarce, resulting in a lack of evidence, particularly regarding efficacy, for the use of anti-IL-5 agents in these specific patient populations. This review addresses high-quality evidence from randomized controlled trials and real-world post-marketing studies regarding the use of anti-IL-5 therapies for eosinophilic-associated disorders across all age groups, spanning childhood, adulthood, and older age.

Fig. 1

Eosinophilic-associated disorders and eosinophil blood levels. Single-organ disease has usually (but not always) lower circulating eosinophil levels than systemic diseases. Accordingly, the combination of two or more single organ disease, as the explanatory cases of asthma with comorbidities (e.g., asthma complicated by chronic rhinosinusitis with nasal polyposis [CRSwNP]) which is reported in the figures, has usually higher circulating eosinophil levels than single-organ disease (e.g., asthma or CRSwNP alone), but usually lower than systemic diseases, as eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome (HES). EOE eosinophilic esophagitis. Part of the figure was created with BioRender.com

Fig. 2

Interleukin-5 (IL-5) and biological agents interfering with the IL-5 pathway (anti-IL-5 agents), thus negatively modulating the growth, survival, recruitment in inflamed tissues and function of eosinophils. Activated CD4 type 2 T helper lymphocytes produce IL-5. Innate lymphoid cells 2 (ILC2) cells are another relevant source of IL-5; these cells are activated by alarmins (thymic stromal lymphopoietin, IL-33, and IL-25) produced by surrounding cells, as epithelial cells for airways, in response to various triggers. Epithelial cells, in the context of eosinophilic inflammation, could also produce IL-5. Interleukin-5 is a crucial mediator responsible for eosinophilopoiesis, eosinophil survival, and activation. Mepolizumab, reslizumab, and bernalizumab target eosinophils through the targeting of IL-5 pathway. There is another monoclonal antibody with an anti-IL-5 effect named depemokimab, which is currently under development (not reported in the figure, since not licensed yet). Th2 T-helper 2. Part of the figure was created with BioRender.com

Fig. 3

Clinical development of mepolizumab. Here are reported the more relevant clinical trials for mepolizumab for eosinophilic asthma, chronic rhinosinusitis with nasal polyps (CRwNP), eosinophilic esophagitis (EoE), eosinophilic granulomatosis with polyangiitis (EGPA), and hypereosinophilic syndrome (HES). Mepolizumab is presently licensed for asthma, CRSwNP, EGPA, and HES

Fig. 4

Clinical development of benralizumab. Here are reported the more relevant clinical trials for benralizumab for eosinophilic asthma, chronic rhinosinusitis with nasal polyps (CRwNP), eosinophilic esophagitis (EoE), eosinophilic granulomatosis with polyangiitis (EGPA), and hypereosinophilic syndrome (HES). Bernalizumab is presently licensed for asthma

Fig. 5

Clinical development of reslizumab. Here are reported the more relevant clinical trials for reslizumab for eosinophilic asthma, chronic rhinosinusitis with nasal polyps (CRwNP), eosinophilic esophagitis (EoE), eosinophilic granulomatosis with polyangiitis (EGPA), and hypereosinophilic syndrome (HES). Reslizumab is presently licensed for asthma