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

Frontiers in Immunology. 2024-08;

Xiaoliang Ding, Ling Xue, Mingjun Wang, Shengxiong Zhu, Kouzhu Zhu, Sheng Jiang, Jian Wu, Liyan Miao

Products/Services Used	Details	Operation
Catalog Antibody	Microtiter plates (Thermo, catalogue no. 446469) were coated with an anti-idiotype antibody, a mouse monoclonal antibody specific to adalimumab (GenScript, catalogue no. A01954). The bound adalimumab was then detected using biotinylated mouse anti-adalimumab antibody (GenScript, catalogue no. A01956). Horseradish peroxidase-labeled streptavidin (Solarbio, catalogue no. SE068) and 1-Step Ultra TMB-ELISA substrate solution (Thermo, catalogue no. 34028) were consecutively added to the plate to generate a chromophore, and the color development was stopped by adding a 2 N H2SO4 solution. For detection, ruthenium-labeled antihuman IgG (GenScript, catalogue no. V90401), anti-human IgM (GenScript, catalogue no. A02128) antibody, or anti-human IgA antibody (Merck, Rabbit monoclonal, catalogue no. SAB5600221) with ruthenium-labeled anti-rabbit antibody (Abcepta Biotech) was added, and the ECL signal of the plate was read on a QuickPlex SQ120 Reader (MSD).	Get A Quote

摘要

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 (R2 = 0.83, P < 0.001). Population pharmacokinetic modeling revealed a significant positive association between model-estimated individual clearance and observed ADA levels. Higher ADA levels were associated with adalimumab clearance and disease relapse in a cross-sectional cohort, suggesting a promising ADA threshold of 10 for potential clinical application. Moreover, the IgG class was the primary contributor to ADA against adalimumab and the apparent affinity exhibited an increasing trend over time, indicating a T-cell dependent mechanism for ADA elicitation by adalimumab.