贝那利珠单抗对嗜酸性气道疾病患者血液炎症标志物的调节作用。
Modulation of blood inflammatory markers by benralizumab in patients with eosinophilic airway diseases.
机构信息
MedImmune LLC, One MedImmune Way, #4552B, Gaithersburg, MD, USA.
出版信息
Respir Res. 2019 Jan 18;20(1):14. doi: 10.1186/s12931-018-0968-8.
BACKGROUND
Benralizumab, 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.
METHODS
Serum 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.
RESULTS
Eosinophil 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.
CONCLUSIONS
Benralizumab 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 REGISTRATION
NCT01227278 and NCT01238861 .
背景
贝那鲁肽是一种人源化、去岩藻糖基化的单克隆抗体，靶向白细胞介素-5 受体α，通过增强抗体依赖性细胞介导的细胞毒性来耗竭嗜酸性粒细胞和嗜碱性粒细胞。它在中度至重度哮喘患者的临床试验中表现出疗效，在一项 IIa 期试验中，对伴有嗜酸性粒细胞炎症的慢性阻塞性肺疾病（COPD）也表现出疗效。我们通过对两项嗜酸性哮喘和嗜酸性 COPD 患者的 II 期研究中收集的治疗前后的血液炎症标志物的蛋白质组学和基因表达分析，研究了贝那鲁肽 100mg 每 8 周（前 3 剂每 4 周）皮下给药对血液的影响。
方法
在基线和治疗后 52 周（哮喘研究）或 32 周（COPD 研究）时采集血清样本进行蛋白质组学分析，采集全血进行基因表达分析。蛋白质组学分析分别针对哮喘和 COPD 的定制的 90 个和 147 个基于规则的医学分析物进行。基因表达通过 Affymetrix Human Genome U133 plus 2 阵列进行分析（~54K 个探针）。基因集变异分析（GSVA）用于确定免疫特征的转录组活性。通过 t 检验和重复测量方差分析，针对总体人群和按基线血液嗜酸性粒细胞计数（嗜酸性粒细胞高[≥300 个细胞/μL]和嗜酸性粒细胞低[<300 个细胞/μL]）分层的患者亚组，分析分析物、基因和基因特征之间的治疗相关差异。
结果
在哮喘研究中，贝那鲁肽治疗后，嗜酸性粒细胞趋化因子 eotaxin-1 和 eotaxin-2 的表达分别上调约 2.1 倍和 1.4 倍，在 COPD 研究中分别上调约 2.3 倍和 1.7 倍。在两项研究中，嗜酸性粒细胞高的患者比嗜酸性粒细胞低的患者这两种趋化因子的上调幅度更大。贝那鲁肽与表达与嗜酸性粒细胞和嗜碱性粒细胞相关的基因（如 CLC、IL-5Rα 和 PRSS33）、免疫信号复合物基因（FCER1A）、G 蛋白偶联受体基因（HRH4、ADORA3、P2RY14）和其他免疫相关基因（ALOX15 和 OLIG2）的表达显著降低（FDR<0.05）相关。嗜酸性粒细胞高的患者比嗜酸性粒细胞低的患者基因表达下调幅度更大。对免疫特征的 GSVA 表明，治疗后嗜酸性粒细胞相关特征显著减少（FDR<0.05）。
结论
贝那鲁肽具有高度选择性，调节与嗜酸性粒细胞或嗜碱性粒细胞相关的血液蛋白或基因。在嗜酸性粒细胞高与嗜酸性粒细胞低的患者中，蛋白和基因表达模式的改变最为明显。
试验注册
NCT01227278 和 NCT01238861。
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