Mechanistic prediction of first-in-human dose for bispecific CD3/EpCAM T-cell engager antibody M701, using an integrated PK/PD modeling method
Mechanistic prediction of first-in-human dose for bispecific CD3/EpCAM T-cell engager antibody M701, using an integrated PK/PD modeling method
复制标题
使用集成 PK/PD 建模方法对双特异性 CD3/EpCAM T 细胞接合抗体 M701 的首次人体剂量进行机械预测
DOI：
10.1016/j.ejps.2020.105584
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发表时间：
2021
影响因子：
4.6
通讯作者：
Tianyan Zhou
中科院分区：
文献类型：
--
作者：
Ling Song;Junsheng Xue;Jing Zhang;Si Li;Dongyang Liu;Tianyan Zhou
AimM701是治疗恶性腹水的双特异性CD3/EpCAM T细胞增殖抗体。本研究旨在预测M701的体内药代动力学（PK）特征，预测M701的细胞毒效应关系，为M701首次人体试验（FIH）设计最佳的起始剂量和有效剂量。M701的体外杀伤作用是通过与T细胞表面的CD3受体和肿瘤细胞表面的EpCAM受体结合形成的三分子突触驱动的。使用与临床全身模型参数相同的模型结构估计腹水中的人体排泄-反应（E-R）曲线。通过异速生长缩放猴PK数据预测人PK，使用二室模型表征。将人PK模型整合到基于体内突触的细胞杀伤模型中以提供人PK/PD特征。在FIH剂量设计中应用了整合的人体PK/PD模型。建议临床起始剂量和有效剂量为达到体内预期生物效应水平（MABEL）和生物活性水平的模拟人腹水药物浓度。其他方法，包括PK驱动和受体占有率计算也采用在这项研究中，以验证起始剂量prediction.ResultsIn vitroM701细胞毒性曲线下24，48，72 h孵育，以及捕获的机械突触为基础的细胞杀伤模型。根据体外模型结构和临床系统参数，获得人腹水E-R曲线。以体内MABEL和细胞毒活性水平为最大细胞毒效应的10~20%和80%。人体E-R曲线表明，在体内EC_（10）、EC_（20）和EC_（80）分别为0.56、1.26和31.6ng/mL。对于人体PK模型，使用指数0.9、1和-0.25对清除率（CL、CLd）、分布容积（Vc、Vp）和吸收率进行异速生长缩放。预测的清除率和体积分别为观测数据的0.53倍和1.19倍。在2小时腹膜内输注5和200 μ g剂量下，模拟的平均腹水M701浓度（计算为Cave_assistance = AUC τ/τ）分别为0.81和32.5 ng/mL。通过整合人体E-R曲线和腹水中的模拟PK特征，我们建议在2小时内腹腔内输注5和200 μ g作为M701 FIH研究的MABEL剂量和抑制活性剂量（PAD）。PK驱动方法预测的起始剂量为5 μ g，与PK/PD驱动方法预测的起始剂量相当。结论本研究将人PK模型整合到基于在体突触的细胞杀伤模型中，预测了人腹水PK和E-R曲线。基于目前的PK/PD综合方法，建议了双特异性T细胞增殖抗体M701的最佳临床MABEL剂量和PAD。
AimM701 is a bispecific CD3/EpCAM T-cell engager antibody to treat malignant ascites. This study aimed to predictin vivoexposure-cytotoxicity relationship and human pharmacokinetics (PK) characteristics of M701, as well as to design optimal starting dose and effective dose for M701 first-in-human (FIH) study.MethodMechanisticin vitroPK/PD model was firstly developed based onin vitrodata of M701’s cytotoxicity and binding affinities with targeting receptors. The cell killing effect of M701in vitrowas driven by tri-molecular synapse, which formed by binding drug to both CD3 receptor on T cells and EpCAM receptor on tumor cells. Human exposure-response (E-R) curve in ascites was estimated using the same model structure with clinical systemic model parameters. Human PK was predicted by allometrically scaling monkey PK data, which was characterized using a two compartment model. Human PK model was integrated intoin vivosynapse-based cell killing model to provide human PK/PD characteristics. Integrated human PK/PD model was applied in FIH dose design. Clinical starting dose and effective dose were suggested as the simulated drug concentration in human ascites that achieved the estimatedin vivominimally anticipated biological effect level (MABEL) and pharmacologically active level. Other approaches including PK-driven and receptor occupancy calculation were also employed in this study to verify the starting dose prediction.ResultsIn vitroM701 cytotoxicity curves under 24, 48, 72 h incubations were well captured by mechanistic synapse-based cell killing model. Human E-R curve in ascites was obtained based onin vitromodel structure and clinical systematic parameters. We defined 10~20% and 80% of maximum cytotoxicity effect asin vivoMABEL and pharmacologically active level. Human E-R curve indicatedin vivoEC10, EC20and EC80were 0.56, 1.26 and 31.6 ng/mL. For human PK model, clearance (CL, CLd), distribution volumes (Vc, Vp) and absorption rate were allometrically scaled using exponent of 0.9, 1 and -0.25. Predicted clearance and volume were 0.53- and 1.19-fold of observed data. Simulated average ascites M701 concentrations (calculated as Cave_ ascites= AUCτ/τ) were 0.81 and 32.5 ng/mL under dose of 5 and 200 μg within 2-hour i.p. infusion. By integrating human E-R curve and the simulated PK profile in ascites, we suggested 5 and 200 μg within 2-hour i.p. infusion as MABEL dose and pharmacologically active dose (PAD) for M701 FIH study. PK-driven approach predicted a starting dose of 5 μg, which was comparable to that predicted via PK/PD-driven approach.ConclusionsThis study predicted human ascites PK and E-R curve by integrating human PK model intoin vivosynapse-based cell killing model. Optimal clinical MABEL dose and PAD of bispecific T cell engager antibody M701 were suggested based on current integrated PK/PD approach.