Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China.
Institute for Interdisciplinary Drug Research and Translational Sciences, Soochow University, Suzhou, China.
Front Immunol. 2024 Aug 22;15:1429544. doi: 10.3389/fimmu.2024.1429544. eCollection 2024.
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.
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.
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 = 0.83, < 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.
In summary, this integrated immunoassay platform shows promise for in-depth analysis of ADA against biologics, offering fresh insights into immunogenicity and its clinical implications.
阿达木单抗会诱导产生抗药物抗体（ADA），这可能导致药物浓度降低和应答丧失，带来重大的临床挑战。然而，传统的免疫分析在灵敏度和药物耐受性方面存在局限性，阻碍了对 ADA 应答的深入了解。
在此，我们开发了一种将电化学发光免疫分析与免疫磁分离策略相结合的集成免疫分析平台。对 49 例强直性脊柱炎患者进行了一项纵向队列研究，以分析 ADA 的动态谱，并使用群体药代动力学模型研究 ADA 对阿达木单抗药代动力学的影响。此外，还收集了 12 例患者的横断面数据，以验证 ADA 水平与疾病复发之间的相关性。
ADA 分析显示出高灵敏度（0.4ng/ml）和药物耐受性（100μg/ml），而中和抗体（NAB）分析显示灵敏度为 100ng/ml，药物耐受性为 20μg/ml。对纵向队列的分析表明，大多数患者（44/49，90%）在治疗的前 24 周内持续产生 ADA。ADA 水平在早期免疫应答阶段初始增加后，随着时间的推移趋于稳定。此外，几乎所有接受测试的患者（26/27，96%）均被归类为 NAB 阳性，ADA 水平与中和能力之间存在很强的相关性（R=0.83，<0.001）。群体药代动力学模型显示，模型估计的个体清除率与观察到的 ADA 水平之间存在显著正相关。较高的 ADA 水平与阿达木单抗清除率和疾病复发相关，在一个横断面队列中，表明有希望将 ADA 阈值设定为 10 用于潜在的临床应用。此外，IgG 类是针对阿达木单抗的 ADA 的主要贡献者，表观亲和力随时间呈上升趋势，表明 ADA 由阿达木单抗引发是一种 T 细胞依赖的机制。
总之，该集成免疫分析平台有望深入分析针对生物制剂的 ADA，为免疫原性及其临床意义提供新的见解。
