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A minimal physiologically based pharmacokinetic model to investigate FcRn-mediated monoclonal antibody salvage: Effects of Kon, Koff, endosome trafficking, and animal species.
mAbs ( IF 5.3 ) Pub Date : 2018-09-11 , DOI: 10.1080/19420862.2018.1506648
Brian M Maas 1 , Yanguang Cao 1
Affiliation  

Manipulation of binding affinity between monoclonal antibodies (mAbs) and the neonatal Fc receptor (FcRn) has been leveraged to extend mAb half-life; however, the steps required for success remain ambiguous and experimental observations are inconsistent. Recent models have considered the time course of endosomal transit a major contributor to the relationship between FcRn affinity and antibody half-life. Our objective was to develop a minimal physiologically based pharmacokinetic model to explain how changes in IgG-FcRn association rate constant (Kon), dissociation rate constant (Koff), and endosomal transit time [T(w)] translate to improved IgG clearance across mice, monkeys and humans. By simulating mAb clearance across physiological values of Kon, Koff, and T(w), we found that lowering Koff improves clearance only until the dissociation half-life reaches endosomal transit time. In contrast, Kon influenced clearance independently of T(w).The model was then applied to fit 66 mAb plasma profiles across species digitized from the literature, and clearance of mAb (CLIgG) and vascular fluid-phase endocytosis rate (CLup) were estimated. We found that CLIgG scaled well with body weight (allometric exponent of 0.90). After accounting for mAbs with significant FcRn binding at physiological pH, CLup was allometrically scalable (exponent 0.72). For the antibodies surveyed, Kon was more highly correlated with CLIgG across all species. The relationship between Koff and KD with CLIgG was largely inconsistent. Taken together, this model provides a parsimonious approach to evaluate endosomal transit kinetics using only mAb plasma concentrations. These findings reinforce the idea that endosomal transit kinetics should be considered when modeling FcRn salvage.



中文翻译:

研究FcRn介导的单克隆抗体拯救的基于生理的最小药物动力学模型:Kon,Koff,内体运输和动物物种的影响。

已利用单克隆抗体(mAb)与新生儿Fc受体(FcRn)之间的结合亲和力来延长mAb的半衰期。但是,成功所需的步骤仍然模棱两可,实验观察也不一致。最近的模型认为内体转运的时间过程是FcRn亲和力与抗体半衰期之间关系的主要贡献者。我们的目标是建立一个基于生理的最小药物动力学模型,以解释IgG-FcRn缔合速率常数(K on),解离速率常数(K off)和内体转运时间[ T (w)]可改善小鼠,猴子和人类的IgG清除率。通过跨K on,K offT (w)的生理值模拟mAb清除,我们发现降低K off仅在解离半衰期达到内体转运时间之前会改善清除率。相比之下,K清除率的影响与T (w)无关,然后应用该模型拟合文献数字化的物种间的66 mAb血浆谱,以及mAb的清除率(CL IgG)和血管液相内吞率(CL up)进行估算。我们发现CL IgG与体重的比例很好(异位指数为0.90)。在考虑了在生理pH下具有显着FcRn结合的mAb之后,CL up具有异速伸缩性(指数0.72)。对于所调查的抗体,在所有物种中,K onCL IgG的相关性更高。CL IgGK offK D的关系在很大程度上不一致。两者合计,该模型提供了一种仅使用mAb血浆浓度评估内体转运动力学的简化方法。这些发现强化了在建模FcRn拯救时应考虑内体转运动力学的想法。

更新日期:2018-09-11
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