Effect of treatment with benralizumab or mepolizumab on the serum proteome in eosinophilic granulomatosis with polyangiitis

<bold>Introduction:</bold> Eosinophilic granulomatosis with polyangiitis (EGPA) is characterised by asthma, eosinophilia, and vasculitis. This study explored the effects of treatment on the proteomic signature in EGPA, utilising samples from a randomised trial. <bold>Methods:</bold> MANDARA was a randomised, double-blind study (<ext-link>NCT04157348</ext-link>) in patients with EGPA comparing benralizumab 30 mg (n=70) vs mepolizumab 300 mg (n=70) subcutaneously every 4 weeks. Serum samples at Weeks 0 (before treatment), 4, 48, and 52 were analysed for 3072 proteins using Olink^® Explore. Differential protein expression was assessed by linear regression and mixed models. Gene set enrichment analysis was performed using pathways provided by Metabase v22.3.7. <bold>Results:</bold> Sixteen pathways, including those related to eosinophil survival and chemotaxis, basophil migration, and IL-4 immune responses were modulated by benralizumab at Week 4; one pathway was down-regulated by mepolizumab at Week 4 (IL-5 signaling via JAK/STAT). By Week 48 and 52, more proteins were modulated than at Week 4, suggesting changes in the proteome that are secondary to the modulation of eosinophil-related proteins and pathways. Seven proteins (IL-5Rα, IL-5, CCL11, CCL24, CLC, PRG2, and PRG3) were differentially expressed over time between the treatments, at a false discovery rate of 5%; eosinophil granule proteins (CLC, PRG2, PRG3) decreased in both groups, and more so in the benralizumab group. <bold>Conclusion:</bold> In EGPA, treatment with benralizumab and mepolizumab modulate pathways involved in T2 inflammation, eosinophil activation, and chemotaxis. Some of these changes occur earlier with benralizumab than with mepolizumab.