School of Pharmacy, University of Waterloo, 10A Victoria St S, Kitchener, Ontario, N2G 1C5, Canada.
Pharm Res. 2022 Feb;39(2):239-250. doi: 10.1007/s11095-022-03177-2. Epub 2022 Feb 3.
We have hypothesized that a high concentration of circulating monocytes and macrophages may contribute to the fast weight-based clearance of monoclonal antibodies (mAbs) in young children. Exploring this hypothesis, this work uses modeling to clarify the role of monocytes and macrophages in the elimination of mAbs.
Leveraging pre-clinical data from mice, a minimal physiologically-based pharmacokinetic model was developed to characterize mAb uptake and FcRn-mediated recycling in circulating monocytes, macrophages, and endothelial cells. The model characterized IgG disposition in complex scenarios of site-specific FcRn deletion and variable endogenous IgG levels. Evaluation was performed for predicting IgG disposition with co-administration of high dose IVIG. A one-at-a-time sensitivity analysis quantified the role of relevant cellular parameters on IgG elimination in various scenarios.
The plasma AUC of mAbs was highly sensitive to endothelial cell parameters, but had near-nil sensitivity to monocyte and macrophage parameters, even in scenarios with 90% loss of FcRn expression/activity. In mice with normal FcRn expression, simulations suggest that less than 2% of an IV dose is eliminated in macrophages, while endothelial cells are predicted to dominate mAb elimination.
The model suggests that the role of monocytes and macrophages in IgG homeostasis includes extensive uptake and highly efficient FcRn-mediated protection, but not appreciable degradation when FcRn is present. Therefore, it is very unlikely that a high concentration of circulating monocytes can contribute to explaining the fast weight-based clearance of mAbs in very young children, even if FcRn expression/activity was 90% lower in children than in adults.
我们假设循环单核细胞和巨噬细胞的高浓度可能有助于年幼儿童基于体重的单克隆抗体（mAb）快速清除。为了探索这一假设，本研究利用建模来阐明单核细胞和巨噬细胞在 mAb 消除中的作用。
利用来自小鼠的临床前数据，开发了一个最小的基于生理的药代动力学模型，以描述 mAb 在循环单核细胞、巨噬细胞和内皮细胞中的摄取和 FcRn 介导的循环。该模型描述了在 FcRn 特异性缺失和可变内源性 IgG 水平的复杂情况下 IgG 的处置情况。通过评估与高剂量静脉注射免疫球蛋白（IVIG）联合给药时对 IgG 处置的预测，对模型进行了评估。逐个参数的敏感性分析量化了在各种情况下相关细胞参数对 IgG 消除的作用。
mAb 的血浆 AUC 对内皮细胞参数高度敏感，但对单核细胞和巨噬细胞参数几乎没有敏感性，即使在 FcRn 表达/活性损失 90%的情况下也是如此。在具有正常 FcRn 表达的小鼠中，模拟表明少于 IV 剂量的 2%在巨噬细胞中消除，而内皮细胞被预测为主导 mAb 消除。
该模型表明单核细胞和巨噬细胞在 IgG 动态平衡中的作用包括广泛摄取和高效的 FcRn 介导保护，但在 FcRn 存在时，不会明显降解。因此，即使儿童的 FcRn 表达/活性比成人低 90%，循环单核细胞的高浓度也不太可能有助于解释非常年幼儿童基于体重的 mAb 快速清除。
