Integrated Pharmacokinetic/Pharmacodynamic Model of a Bispecific CD3xCD123 DART Molecule in Nonhuman Primates: Evaluation of Activity and Impact of Immunogenicity
Integrated Pharmacokinetic/Pharmacodynamic Model of a Bispecific CD3xCD123 DART Molecule in Nonhuman Primates: Evaluation of Activity and Impact of Immunogenicity
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DOI：
10.1158/1078-0432.ccr-17-2265
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发表时间：
2018-06-01
影响因子：
11.5
通讯作者：
Mager, Donald E.
中科院分区：
文献类型：
--
作者：
Campagne, Olivia;Delmas, Audrey;Mager, Donald E.
目的：Flotetuzumab（MGD 006或S80880）是一种双特异性分子，可识别CD 3和CD 123膜蛋白，重定向T细胞以杀死表达CD 123的细胞，用于治疗急性髓性白血病。在本研究中，我们开发了一个数学模型来表征MGD 006的剂量-反应关系，并评估其免疫原性对食蟹猴的影响。实验设计：32只动物通过静脉输注接受多次递增剂量（100-300-600- 1，000 ng/kg/天），每周连续4天。该模型反映了MGD 006与CD 3和CD 123受体的顺序结合。MGD 006/CD 3复合物的形成与进行运输的总T细胞相关，而三分子复合物的形成导致T细胞活化和克隆扩增。活化的T细胞用于驱动外周CD 123阳性细胞的耗竭。抗药抗体的产生与MGD 006的处置相关，作为消除途径。通过预测接受连续7天输注的8只猴中MGD 006的活性来检验模型验证。结果：MGD 006分布以及总T细胞和CD 123阳性细胞谱得到了良好表征。抗药抗体的发展导致T细胞运输的抑制，但没有系统地消除CD 123阳性细胞耗竭。由于在第一个周期中产生的活化T细胞的自我增殖，靶细胞耗竭在药物消除后可能持续存在。该模型通过7天输注给药方案进行了外部验证。结论：为MGD 006开发了一个转化模型，该模型将T细胞活化和扩增作为药理学活性的关键驱动因素，并为正在进行的临床研究中的给药策略提供了一个机制定量平台。(C)2018年AACR。
Purpose: Flotetuzumab (MGD006 or S80880) is a bispecific molecule that recognizes CD3 and CD123 membrane proteins, redirecting T cells to kill CD123-expressing cells for the treatment of acute myeloid leukemia. In this study, we developed a mathematical model to characterize MGD006 exposure-response relationships and to assess the impact of its immunogenicity in cynomolgus monkeys.Experimental Design: Thirty-two animals received multiple escalating doses (100-300-600-1,000 ng/kg/day) via intravenous infusion continuously 4 days a week. The model reflects sequential binding of MGD006 to CD3 and CD123 receptors. Formation of the MGD006/CD3 complex was connected to total T cells undergoing trafficking, whereas the formation of the trimolecular complex results in T-cell activation and clonal expansion. Activated T cells were used to drive the peripheral depletion of CD123positive cells. Anti-drug antibody development was linked to MGD006 disposition as an elimination pathway. Model validation was tested by predicting the activity of MGD006 in eight monkeys receiving continuous 7-day infusions.Results: MGD006 disposition and total T-cell and CD123positive cell profiles were well characterized. Anti-drug antibody development led to the suppression of T-cell trafficking but did not systematically abolish CD123-positive cell depletion. Target cell depletion could persist after drug elimination owing to the self-proliferation of activated T cells generated during the first cycles. The model was externally validated with the 7-day infusion dosing schedule.Conclusions: A translational model was developed for MGD006 that features T-cell activation and expansion as a key driver of pharmacologic activity and provides a mechanistic quantitative platform to inform dosing strategies in ongoing clinical studies. (C) 2018 AACR.