Modulation of blood inflammatory markers by benralizumab in patients with eosinophilic airway diseases

Abstract

BackgroundBenralizumab, a humanized, afucosylated, monoclonal antibody that targets interleukin-5 receptor α, depletes eosinophils and basophils by enhanced antibody-dependent cell-mediated cytotoxicity. It demonstrated efficacy for patients with moderate to severe asthma and, in a Phase IIa trial, for chronic obstructive pulmonary disease (COPD) with eosinophilic inflammation. We investigated effects of benralizumab 100\u2009mg every 8\u2009weeks (first three doses every 4\u2009weeks) subcutaneous on blood inflammatory markers through proteomic and gene-expression analyses collected during two Phase II studies of patients with eosinophilic asthma and eosinophilic COPD.MethodsSerum samples for proteomic analysis and whole blood for gene expression analysis were collected at baseline and 52\u2009weeks (asthma study) or 32\u2009weeks (COPD study) post-treatment. Proteomic analyses were conducted on a custom set of 90 and 147 Rules-Based Medicine analytes for asthma and COPD, respectively. Gene expression was profiled by Affymetrix Human Genome U133 plus 2 arrays (~\u200954\u2009K probes). Gene set variation analysis (GSVA) was used to determine transcriptomic activity of immune signatures. Treatment-related differences between analytes, genes, and gene signatures were analyzed for the overall population and for patient subgroups stratified by baseline blood eosinophil count (eosinophil-high [≥300 cells/μL] and eosinophil-low [<\u2009300 cells/μL]) via t-test and repeated measures analysis of variance.ResultsEosinophil chemokines eotaxin-1 and eotaxin-2 were significantly upregulated (false discovery rate [FDR] <\u20090.05) by approximately 2.1- and 1.4-fold in the asthma study and by 2.3- and 1.7-fold in the COPD study following benralizumab treatment. Magnitude of upregulation of these two chemokines was greater for eosinophil-high patients than eosinophil-low patients in both studies. Benralizumab was associated with significant reductions (FDR\u2009<\u20090.05) in expression of genes associated with eosinophils and basophils, such as CLC, IL-5Rα, and PRSS33; immune-signaling complex genes (FCER1A); G-protein–coupled receptor genes (HRH4, ADORA3, P2RY14); and further immune-related genes (ALOX15 and OLIG2). The magnitude of downregulation of gene expression was greater for eosinophil-high than eosinophil-low patients. GSVA on immune signatures indicated significant treatment reductions (FDR\u2009<\u20090.05) in eosinophil-associated signatures.ConclusionsBenralizumab is highly selective, modulating blood proteins or genes associated with eosinophils or basophils. Modulated protein and gene expression patterns are most prominently altered in eosinophil-high vs. eosinophil-low patients.Trial registrationNCT01227278 and NCT01238861.