Immunology Section, Canterbury Health Laboratories, Christchurch, New Zealand.
Department of Hematology, University of Otago, Christchurch, New Zealand.
Ther Drug Monit. 2024 Oct 1;46(5):619-626. doi: 10.1097/FTD.0000000000001200. Epub 2024 Apr 9.
Detecting antidrug antibodies (ADAs) against infliximab or adalimumab is useful for therapeutic drug monitoring. Various ADA detection methods exist, and antibody titer is an output in some algorithms. Homogenous mobility shift assay (HMSA) measures relative ADA concentration and determines drug-ADA complex size in vitro. However, the relevance of complex size determination in drug monitoring remains unclear. Hence, the association between complex size, ADA concentration, and sample detectable neutralizing activity was evaluated.
Sera from infliximab-treated and adalimumab-treated patients who tested positive for ADA in the National Screening Service were analyzed using 3 ADA assays. HMSA determined the relative ADA concentrations and complex sizes, competitive ligand-binding assay evaluated the sample neutralizing capacity, and enzyme-linked immunosorbent assay detected immunoglobulin (Ig)G4 ADA.
Most ADA-positive samples (>80%) formed drug-ADA dimer complexes, whereas 17% had dimer and multimer complexes, and 3% had multimeric complexes. Multimer presence had 100% positive predictive value for detectable neutralizing activity. ADA concentration and detectable neutralizing activity were moderately correlated (r = 0.65) in adalimumab-treated patients and strongly correlated (r = 0.81) in infliximab-treated patients. In adalimumab-treated patients, multimer presence was a stronger predictor of neutralizing activity than ADA concentration was, but not in infliximab-treated patients. However, in infliximab-treated patient samples, multimer presence revealed a distinct subset with high ADA concentrations, neutralizing activity, and IgG4 ADA.
Multimers detected using HMSA had a strong positive predictive value for competitive ligand-binding assay detectable neutralizing activity. Multimeric IgG4-containing ADA-drug complexes revealed a distinct subset of infliximab-treated patient samples, whose clinical relevance merits further investigation.
检测英夫利昔单抗或阿达木单抗的抗药物抗体（ADA）对于治疗药物监测很有用。存在各种 ADA 检测方法，并且在一些算法中抗体滴度是一个输出。均相迁移率变动分析（HMSA）测量相对 ADA 浓度并在体外确定药物-ADA 复合物的大小。然而，在药物监测中复合物大小确定的相关性尚不清楚。因此，评估了复合物大小、ADA 浓度和样品可检测中和活性之间的关系。
使用 3 种 ADA 检测方法分析在国家筛选服务中检测到 ADA 呈阳性的英夫利昔单抗和阿达木单抗治疗患者的血清。HMSA 确定相对 ADA 浓度和复合物大小，竞争配体结合测定评估样品中和能力，酶联免疫吸附测定检测免疫球蛋白（Ig）G4 ADA。
大多数 ADA 阳性样品（>80%）形成药物-ADA 二聚体复合物，而 17%的样品具有二聚体和多聚体复合物，3%的样品具有多聚体复合物。多聚体的存在对可检测中和活性具有 100%的阳性预测值。ADA 浓度和可检测中和活性在阿达木单抗治疗患者中呈中度相关（r = 0.65），在英夫利昔单抗治疗患者中呈强相关（r = 0.81）。在阿达木单抗治疗患者中，多聚体的存在比 ADA 浓度更能预测中和活性，但在英夫利昔单抗治疗患者中则不然。然而，在英夫利昔单抗治疗患者的样本中，多聚体的存在揭示了一个具有高 ADA 浓度、中和活性和 IgG4 ADA 的独特亚组。
HMSA 检测到的多聚体对竞争配体结合测定可检测中和活性具有很强的阳性预测值。含有多聚体 IgG4 的 ADA-药物复合物揭示了一个独特的英夫利昔单抗治疗患者样本亚组，其临床相关性值得进一步研究。
