■阿达木单抗诱导抗药物抗体(ADA)的产生,这可能导致药物浓度降低和反应丧失,带来了重大的临床挑战。然而,传统的免疫测定在敏感性和药物耐受性方面有局限性,阻碍了ADA反应的洞察力。
■这里,我们开发了一个集成的免疫分析平台,将电化学发光免疫分析与免疫磁性分离策略相结合。进行了一项涉及49例强直性脊柱炎患者的纵向队列研究,以分析ADA的动态分布,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,我们收集了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测定显示出高灵敏度(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。纵向队列的分析显示,大多数患者(44/49,90%)在治疗的前24周内出现持续性ADA。在早期免疫应答阶段的初始增加之后,ADA水平随时间趋于稳定。Further,几乎所有的受检患者(26/27,96%)被归类为NAB阳性,ADA水平与中和能力之间有很强的相关性(R2=0.83,P<0.001)。群体药代动力学建模揭示了模型估计的个体清除率与观察到的ADA水平之间的显着正相关。在横断面队列中,较高的ADA水平与阿达木单抗清除和疾病复发相关。提示有希望的ADA阈值为10,用于潜在的临床应用。此外,IgG类是ADA抗阿达木单抗的主要贡献者,表观亲和力随时间呈增加趋势,表明阿达木单抗诱导ADA的T细胞依赖性机制。
■总之,这个集成的免疫测定平台显示了对ADA进行针对生物制剂的深入分析的希望,提供对免疫原性及其临床意义的新见解。
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.