Gupta Paridhi, Ryman Josiah T, Jawa Vibha, Meibohm Bernd
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
EMD Serono Research and Development Institute, Billerica, MA 01821, USA.
Pharmaceutics. 2025 Jun 27;17(7):845. doi: 10.3390/pharmaceutics17070845.
The administration of human monoclonal antibodies (mAb) in preclinical pharmacokinetics and toxicology studies often triggers an immune response, leading to the formation of anti-drug antibodies (ADA). To mitigate this effect, we have recently performed and reported on studies using short-term immunosuppressive regimens to induce prolonged immune tolerance towards a human mAb, erenumab, in rats. Here, we report on the development of a semi-mechanistic modeling approach that quantitatively integrates pharmacokinetic and immunogenicity assessments from immune tolerance induction studies to provide a framework for the simulation-based evaluation of different immune induction scenarios for the maintenance of prolonged immune tolerance towards human mAbs. The integrated pharmacokinetic/pharmacodynamic (PK/PD) modeling approach combined a semi-mechanistic model of the adaptive immune system to predict ADA formation kinetics with a population pharmacokinetic model to assess the impact of the time course of the ADA magnitude on the PK of erenumab in rats. Model-derived erenumab concentration-time profiles served as input for a quantitative system pharmacology-style semi-mechanistic model of the adaptive immune system to conceptualize the ADA response as a function of the kinetics of CD4 T helper cells and T regulatory cells. The model adequately described the observed ADA magnitude-time profiles in all treatment groups and reasonably simulated the kinetics of selected immune cells responsible for ADA formation. It also successfully captured the impact of tacrolimus/sirolimus immunomodulation on ADA formation, demonstrating that the regimen effectively suppressed ADA formations and induced immune tolerance. : This work demonstrates the utility of modeling approaches to integrate pharmacokinetic and immunogenicity assessment data for the prospective planning of long-term toxicology studies to support the preclinical development of mAbs.
在临床前药代动力学和毒理学研究中，给予人源单克隆抗体（mAb）常常会引发免疫反应，导致抗药抗体（ADA）的形成。为减轻这种影响，我们最近开展并报告了相关研究，这些研究采用短期免疫抑制方案，在大鼠中诱导对人源mAb依瑞奈尤单抗产生持久的免疫耐受。在此，我们报告一种半机制建模方法的开发，该方法将免疫耐受诱导研究中的药代动力学和免疫原性评估进行定量整合，为基于模拟的不同免疫诱导方案评估提供框架，以维持对人源mAb的持久免疫耐受。这种整合的药代动力学/药效学（PK/PD）建模方法结合了适应性免疫系统的半机制模型来预测ADA形成动力学，以及群体药代动力学模型来评估ADA量的时间进程对大鼠中依瑞奈尤单抗药代动力学的影响。模型推导的依瑞奈尤单抗浓度-时间曲线作为适应性免疫系统的定量系统药理学风格半机制模型的输入，将ADA反应概念化为CD4辅助性T细胞和调节性T细胞动力学的函数。该模型充分描述了所有治疗组中观察到的ADA量-时间曲线，并合理模拟了负责ADA形成的选定免疫细胞的动力学。它还成功捕捉了他克莫司/西罗莫司免疫调节对ADA形成的影响，表明该方案有效地抑制了ADA形成并诱导了免疫耐受。这项工作证明了建模方法在整合药代动力学和免疫原性评估数据以进行长期毒理学研究前瞻性规划以支持mAb临床前开发方面的实用性。
