Dynamics and implications of anti-drug antibodies against adalimumab using ultra-sensitive and highly drug-tolerant assays

作者：Xiaoliang Ding, Ling Xue, Mingjun Wang, S. Zhu, Kouzhu Zhu, Sheng Jiang, Jian Wu, Liyan Miao · 发表于：Frontiers in Immunology · 年份：2024 · DOI：10.3389/fimmu.2024.1429544 · 被引用次数：9 · 研究领域：Spondyloarthritis Studies and Treatments、Cancer Immunotherapy and Biomarkers、Rheumatoid Arthritis Research and Therapies

Background Adalimumab induces the production of anti-drug antibodies (ADA) that may lead to reduced drug concentration and loss-of-response, posing significant clinical challenges. However, traditional immunoassays have limitations in terms of sensitivity and drug-tolerance, hindering the insights of ADA response. Methods Herein, we developed an integrated immunoassay platform combining the electrochemiluminescence immunoassay with immunomagnetic separation strategy. A longitudinal cohort study involving 49 patients with ankylosing spondylitis was carried out to analyze the dynamic profiles of ADA and to investigate the impact of ADA on adalimumab pharmacokinetics using a population pharmacokinetic model. Additionally, cross-sectional data from 12 patients were collected to validate the correlation between ADA levels and disease relapse. Results The ADA assay demonstrated high sensitivity (0.4 ng/mL) and drug-tolerance (100 μg/mL), while the neutralizing antibodies (NAB) assay showed a sensitivity of 100 ng/mL and drug-tolerance of 20 μg/mL. Analysis of the longitudinal cohort revealed that a majority of patients (44/49, 90%) developed persistent ADA within the first 24 weeks of treatment. ADA levels tended to plateau over time after an initial increase during the early immune response phase. Further, nearly all of the tested patients (26/27, 96%) were classified as NAB positive, with a strong correlation between ADA levels and neutralization capacity (R 2 = 0.83, P < ...