Translational Medicine Laboratory, Rheumatic Diseases Research Center, China Medical University Hospital, Taichung, Taiwan.
College of Medicine, China Medical University, Taichung, Taiwan.
J Immunol Res. 2021 Mar 8;2021:6656121. doi: 10.1155/2021/6656121. eCollection 2021.
Anti-drug antibody (ADAb) development is associated with secondary therapeutic failure in biologic-treated rheumatoid arthritis (RA) patients. With a treat-to-target goal, we aimed to identify biomarkers for predicting ADAb development and therapeutic response in adalimumab-treated patients. Three independent cohorts were enrolled. In Cohort-1, 24 plasma samples (6 ADAb-positive and 6 ADAb-negative patients at baseline and week 24 of adalimumab therapy, respectively) were assayed with immune-related microarray containing 1,636 correctly folded functional proteins. Next, we executed statistically powered autoantibody profiling analysis of 50 samples in Cohort-2 (24 ADAb-positive and 26 ADAb-negative patients). Subsequently, immunofluorescence assay was performed on 48 samples in Cohort-3 to correlate with ADAb titers and drug levels. The biomarkers were identified for predicting ADAb development and therapeutic response using the immune-related microarray and machine learning approach. ADAb-positive patients had lower drug levels at week 24 (median = 0.024 g/ml) compared with ADAb-negative patients (median = 6.38 g/ml, < 0.001). ROC analysis based on the ADAb status revealed the top 20 autoantibodies with AUC ≥ 0.7 in differentiating both groups in Cohort-1. Analysis of Cohort-2 dataset identified a panel of 8 biomarkers (TROVE2, SSB, NDE1, ZHX2, SH3GL1, CARD9, PTPN20, and KLHL12) with 80.6% specificity, 77.4% sensitivity, and 79.0% accuracy in discriminating poor from EULAR responders. Immunofluorescence assay validated that anti-TROVE2 antibody could highly predict ADAb development and poor EULAR response (AUC 0.79 and 0.89, respectively). Multivariate regression analysis proved anti-TROVE2 antibody to be an independent predictor for developing ADAb. Immune-related protein microarray and replication analysis identified anti-TROVE2 antibody as a useful biomarker for predicting ADAb development and therapeutic response in adalimumab-treated patients.
抗药物抗体 (ADAb) 的产生与生物制剂治疗的类风湿关节炎 (RA) 患者的治疗失败有关。为了实现达标治疗的目标，我们旨在寻找预测阿达木单抗治疗患者 ADAb 产生和治疗反应的生物标志物。纳入了三个独立的队列。在队列 1 中，分别在阿达木单抗治疗基线和第 24 周时对 24 个血浆样本（6 个 ADAb 阳性和 6 个 ADAb 阴性患者）进行了检测，这些样本使用包含 1636 个正确折叠功能蛋白的免疫相关微阵列进行检测。接下来，我们对队列 2 中的 50 个样本进行了统计学上有力的自身抗体分析（24 个 ADAb 阳性和 26 个 ADAb 阴性患者）。随后，在队列 3 中对 48 个样本进行免疫荧光检测，以与 ADAb 滴度和药物水平相关联。使用免疫相关微阵列和机器学习方法，鉴定了预测 ADAb 产生和治疗反应的生物标志物。与 ADAb 阴性患者相比，ADAb 阳性患者在第 24 周时的药物水平较低（中位数=0.024μg/ml）（中位数=6.38μg/ml，<0.001）。基于 ADAb 状态的 ROC 分析显示，队列 1 中区分两组的前 20 个自身抗体的 AUC≥0.7。队列 2 数据集的分析确定了一组 8 个生物标志物（TROVE2、SSB、NDE1、ZHX2、SH3GL1、CARD9、PTPN20 和 KLHL12），在区分不良和 EULAR 应答者方面具有 80.6%的特异性、77.4%的敏感性和 79.0%的准确性。免疫荧光检测验证了抗 TROVE2 抗体可以高度预测 ADAb 的产生和不良的 EULAR 反应（AUC 分别为 0.79 和 0.89）。多元回归分析证明抗 TROVE2 抗体是产生 ADAb 的独立预测因子。免疫相关蛋白微阵列和复制分析表明，抗 TROVE2 抗体是预测阿达木单抗治疗患者 ADAb 产生和治疗反应的有用生物标志物。
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