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 mg every 8 weeks (first three doses every 4 weeks) 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 weeks (asthma study) or 32 weeks (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 (~ 54 K 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 [< 300 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] < 0.05) 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 < 0.05) 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 < 0.05) 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.Electronic supplementary materialThe online version of this article (10.1186/s12931-018-0968-8) contains supplementary material, which is available to authorized users.

Sputum and blood transcriptomics characterisation of the inhaled PDE4 inhibitor CHF6001 on top of triple therapy in patients with chronic bronchitis

“…Furthermore, both doses also led to significant upregulation of the gene coding for the anti-inflammatory interleukin 10 receptor (IL-10RB) [15] and of the suppressor of cytokine signalling 3 (SOCS3) [22], and significantly modulated genes toward a positive regulation of the vitamin D pathway [23][24][25][26][27] (upregulation of VDR, RXR, DHCR7) and toward a negative regulation of oxidative stress [23,28,29] (upregulation of SESN2, HP, CYGB and downregulation of ATG7, CD1B, NCF1), Th2 cytokine production [23,30] (upregulation of SCGB1A1 and TNFRSF21), B cells activation/proliferation [23,31] (upregulation of SAMSN1, INPP5D) and significant downregulation of the eosinophil major basic protein (PRG2) [32]. With both doses, genes associated with eosinophils and basophils were significantly downregulated (CLC, OLIG1, OLIG2 and PRSS33) [33]. Treatment with the highest dose also significantly downregulated genes coding for the pro-inflammatory and mucus producer mitogen-activated protein kinase 13 (MAPK13) [23,34], the cytotoxicity natural killer cell triggering receptor NCR3 [23], significantly upregulated the metalloproteinase inhibitor TIMP1 [23,35] and the neutrophil elastase inhibitor SER-PINB1 [36], and significantly modulated genes toward positive regulation of ciliary function (IFT88, DNAI2, DNAI1) [23,37,38].…”

“…In addition, differentially regulated genes, pathways, biological processes and molecular functions were considered significant only upon correction for multiplicity (pFDR< 0.05). Few previous studies have investigated gene expression by microarray in blood after treatment of COPD patients with anti-inflammatory agents [33,55,56] and most of them did not correct for multiplicity [55,56]. One study evaluated the effect of azithromycin by microarray both in blood and sputum of COPD patients, although the analyses were not corrected for placebo [57].…”

Granulocyte-targeted therapies for airway diseases

“…Benralizumab, was tested in patients with eosinophilic COPD (ClinicalTrials.gov Identifier: NCT01227278) administered every 4 weeks (Q4W) (weeks 1, 4 and 8), and then Q8W (weeks 16, 24, 32, 40 and 48). It was observed that genes related to basophil or eosinophil, such as the serine protease PRSS33 were downregulated by benralizumab [143]. SB010, a GATA3-specific DNAzyme, was tested in COPD patients with sputum eosinophilia (DRKS00006087), in which patients inhaled SB010 for 28 days.…”

Immunoactive preparations and regulatory responses in the respiratory tract: potential for clinical application in chronic inflammatory airway diseases

“…Current treatment guidelines for chronic inflammatory airway diseases all rely to a greater or lesser extent on antiinflammatory therapeutics, particularly corticosteroids, as well as infection control when necessary [10][11][12]. Next-generation monoclonal therapies have shown promise in COPD, asthma, CRS, and AR [13][14][15][16]. However, these therapies remain expensive and beyond the reach of developing countries where the majority of the world's population reside and where the prevalence of allergic respiratory disease is likely to rise alongside increasing urbanization [2,17].…”