非靶向代谢组学分析揭示了与哮喘患者对美泊珠单抗和奥马珠单抗反应相关的不同代谢物

T. Nopsopon, Yulu Chen, Qingwen Chen, Craig E. Wheelock, Scott. T. Weiss, M. McGeachie, Jessica Lasky-Su, A. Akenroye
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引用次数: 0

摘要

与目前获批用于哮喘治疗的单克隆抗体反应相关的生物标志物证据有限。我们对100名开始使用甲泼尼单抗(31人)或奥马珠单抗(69人)的中重度哮喘患者治疗前的血浆样本进行了全球代谢组学分析。主要结果是治疗 12 个月内病情加重的变化。采用负二项模型评估每种代谢物与病情加重之间的关系,并对年龄、性别、体重指数、基线病情加重情况和吸入皮质类固醇的使用情况进行调整。进行了化学相似性富集分析(ChemRICH),以确定与治疗反应相关的化学亚类。甲泼尼单抗组的平均年龄为58.7岁,在开始生物治疗前的一年中出现了2.9次病情加重。奥马珠单抗组的平均年龄为48.8岁,前一年的病情恶化次数为1.5次。两种生育酚代谢物水平较高的患者使用甲泼尼单抗后病情加重的次数较多(δ-羧乙基羟基色满(CEHC)(p=2.65E-05,假发现率(FDR)=0.01)和δ-CEHC葡萄糖醛酸苷(p=2.47E-06,FDR=0.003))。在奥马珠单抗组中,六种雄激素类固醇、三种肉碱代谢物和两种胆汁酸代谢物水平较高与病情恶化程度降低有关。在富集分析中,黄嘌呤代谢物(群组 FDR=0.0006)和生育酚代谢物(群组 FDR=0.02)与麦泊珠单抗反应较差有关,而雄激素类固醇(群组 FDR=1.9E-18)、孕烯醇酮类固醇(群组 p=3.2E-07,FDR=1.4E-05)和次级胆汁酸代谢物(群组 p=0.0003,FDR=0.本研究发现了与美泊利珠单抗和奥马珠单抗反应相关的不同代谢物,其中雄激素类固醇与美泊利珠单抗和奥马珠单抗的反应相关。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Untargeted metabolomic analysis reveals different metabolites associated with response to mepolizumab and omalizumab in asthma
There is limited evidence on biomarkers associated with response to the monoclonal antibodies currently approved for asthma treatment. We sought to identify circulatory metabolites associated with response to treatment with mepolizumab or omalizumab.We conducted global metabolomic profiling of pre-treatment plasma samples from 100 patients with moderate-to-severe asthma who initiated mepolizumab (n=31) or omalizumab (n=69). The primary outcome was the change in exacerbations within 12 months of therapy. Negative binomial models were used to assess the association between each metabolite and exacerbations adjusting for age, sex, body mass index, baseline exacerbations, and inhaled corticosteroid use. Chemical Similarity Enrichment Analysis (ChemRICH) was conducted to identify chemical subclasses associated with treatment response.The mean age of the mepolizumab group was 58.7 years and 2.9 exacerbations over the year prior to initiation of biologic therapy. The mean age in the omalizumab group was 48.8 years with 1.5 exacerbations in the preceding year. Patients with higher levels of two tocopherol metabolites were associated with more exacerbations on mepolizumab (delta-carboxyethyl hydroxychroman (CEHC) (p=2.65E-05, false discovery rate (FDR=0.01) and delta-CEHC glucuronide (p=2.47E-06, FDR=0.003)). Higher levels of six androgenic steroids, three carnitine metabolites and two bile acid metabolites were associated with decreased exacerbations in the omalizumab group. In enrichment analyses, xanthine metabolites (cluster FDR=0.0006), and tocopherol metabolites (cluster FDR=0.02) were associated with worse mepolizumab response while androgenic steroids (cluster FDR=1.9E-18), pregnenolone steroids (cluster p=3.2E-07, FDR=1.4E-05), and secondary bile acid metabolites (cluster p=0.0003, FDR=0.006) were the top subclasses associated with better omalizumab response.This study identifies distinct metabolites associated with response to mepolizumab and omalizumab, with androgenic steroids associated with response to both mepolizumab and omalizumab.
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