Comparative Insights on IL-5 Targeting with Mepolizumab and Benralizumab: Enhancing EGPA Treatment Strategies

Abstract

Eosinophilic granulomatosis with polyangiitis (EGPA) is a necrotizing vasculitis characterized by extravascular granulomas and eosinophilia in both blood and tissues. Eosinophils, which play a critical role in the pathophysiology of EGPA, require interleukin (IL)-5 for maturation in the bone marrow and migration to tissues. Glucocorticoids and immunosuppressants have been the cornerstone of treatment; however, their side effects have imposed a significant burden on many patients. Mepolizumab, an antibody that binds to and neutralizes IL-5, demonstrated efficacy in controlling disease activity in EGPA in the MIRRA trial conducted in 2017. In 2024, benralizumab, an IL-5 receptor alpha antagonist, was shown to be non-inferior to mepolizumab in efficacy against EGPA in the MANDARA trial. Both drugs were originally used for severe asthma and have benefited EGPA by reducing eosinophil counts. Due to differences in pharmacological structure and pharmacokinetics, the degree of eosinophil suppression varies between the two agents, and recent studies suggest that they may also affect inflammatory and homeostatic eosinophils differently. This review summarizes the latest insights into the pathophysiology of EGPA, highlights the similarities and differences between the two drugs, and discusses future treatment strategies for EGPA based on current clinical unmet needs, including drug selection.

Keywords: benralizumab; eosinophil; eosinophilic granulomatosis with polyangiitis; interleukin-5; mepolizumab.

Figure 1

Skin biopsy findings with hematoxylin and eosin staining. (A) Eosinophilic infiltration is observed not only around the blood vessels (arrowhead) but also extensively within the collagen fibers and interstitial tissue (arrows). (B) Eosinophil-predominant inflammatory cell infiltration is evident within the vascular wall.

Figure 2

The role of IL-5 in the pathophysiology of EGPA. Interleukin-5 (IL-5) promotes eosinophil differentiation and maturation in the bone marrow and facilitates its migration into peripheral blood. In peripheral blood, excessive eosinophils can contribute to eosinophil-induced ischemia. Recent studies suggest that upon migrating into tissues, eosinophils become activated by IL-5 and other stimuli, leading to the induction of eosinophil extracellular trap cell death (EETosis). This process results in the release of galectin-10 and eosinophil granules, driving eosinophilic inflammation and tissue damage. Moreover, EETosis has been implicated in immunothrombosis formation, further contributing to EGPA pathogenesis.

Figure 3

Differences in the mechanisms of action of mepolizumab and benralizumab on eosinophils. Mepolizumab is a humanized monoclonal antibody with high affinity and specificity for Interleukin-5 (IL-5). It inhibits the binding of IL-5 to its receptor on eosinophils, thereby suppressing eosinophil proliferation. Benralizumab, a humanized monoclonal antibody, binds specifically to IL-5 receptor α via its Fab fragment, blocking the interaction between IL-5 and its receptor. The Fc region of benralizumab interacts with FcγRIIIa receptors on natural killer (NK) cells, promoting antibody-dependent cellular cytotoxicity (ADCC) by facilitating the release of apoptosis-inducing proteins such as granzymes and perforin. Additionally, benralizumab enhances antibody-dependent cellular phagocytosis (ADCP) via FcγRIIIa on macrophages. Activated NK cells release interferon-γ, stimulating tumor necrosis factor (TNF)-α secretion from macrophages. TNF-α binds to TNF receptor 1 (TNFR1) expressed on eosinophils, inducing eosinophil apoptosis and consequently enhancing ADCP.

Figure 4

Hypothesis for the preferable selection of mepolizumab and benralizumab in EGPA treatment. Mepolizumab, unlike benralizumab, might be more effective in patients currently receiving ISs, where NK cell dysfunction is anticipated. Furthermore, mepolizumab may reduce inflammatory eosinophils while preserving homeostatic eosinophils, potentially maintaining immune homeostasis and promoting GC reduction. Conversely, benralizumab might rapidly reduce eosinophil counts in cases with extremely high levels. It may also reduce GC dependency in patients who are particularly concerned about GC-related side effects.