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引用次数: 0
摘要
背景和目的：目前，尚无可用的方法来预测嵌合抗原受体-T（CAR-T）细胞的首次人源化（FIH）剂量。这项工作的目的是根据小鼠的不同剂量预测 CAR-T 细胞的 FIH 剂量：本研究评估了六种预测 CAR-T 细胞 FIH 剂量的缩放方法。这些方法包括基于体重的固定指数（如 1.0 和 0.75）、使用指数 0.33 的人体等效剂量 (HED)、两种改进的 HED 方法（如使用动物总剂量（代替每公斤体重）和体表面积代替体重）、使用指数 0.33 的动物总剂量以及根据生理参数得出的生理因子。本研究预测了六种 CAR-T 细胞的 FIH 剂量。将预测的人体剂量与美国 FDA 推荐的四种 CAR-T 细胞产品的人体剂量进行了比较，其余两种 CAR-T 细胞则采用了文献数据：结果表明，两种改进的 HED 方法和生理因素是预测 CAR-T 细胞 FIH 剂量的最佳和可靠的方法：结论：所提出的方法简单、预测准确，可在电子表格中使用。
Prediction of First-in-Human Dose of Chimeric Antigen Receptor-T (CAR-T) Cells from Mice.
BACKGROUND AND OBJECTIVE: Currently, there is no available method for the prediction of first-in-human (FIH) dose for chimeric antigen receptor-T (CAR-T) cells. The objective of this work was to predict the FIH dose of CAR-T cells from different doses given to mice.
Methods: In this study, six scaling methods were evaluated for the prediction of FIH dose for CAR-T cells. The methods were body weight-based fixed exponents such as 1.0 and 0.75, human equivalent dose (HED) using exponents 0.33, two modified HED methods such as using total animal dose (in place of per kg basis) and body surface area in place of body weight using total animal dose with exponent 0.33 and a physiological factor derived from physiological parameters. The FIH doses of six CAR-T cells were predicted in this study. The predicted human doses were compared with the recommended human dose by the US-FDA for four CAR-T cell products, and the literature data were used for the remaining two CAR-T cells.
Results: The results indicated that the two modified HED methods and physiological factor are the best and reliable methods for the prediction of FIH dose for CAR-T cells.
Conclusions: The proposed methods are simple and accurate in their predictive power and can be used on a spreadsheet.
期刊介绍：
Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences.
Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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