Preclinical to Clinical Translation of Antibody-Drug Conjugates Using PK/PD Modeling: a Retrospective Analysis of Inotuzumab Ozogamicin
Preclinical to Clinical Translation of Antibody-Drug Conjugates Using PK/PD Modeling: a Retrospective Analysis of Inotuzumab Ozogamicin
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DOI：
10.1208/s12248-016-9929-7
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发表时间：
2016-09-01
期刊：
影响因子：
4.5
通讯作者：
Johnson, Theodore R.
中科院分区：
文献类型：
--
作者：
Betts, Alison M.;Haddish-Berhane, Nahor;Johnson, Theodore R.
使用基于机制的药代动力学/药效学（PK/PD）模型将inotuzumab ozogamicin（一种用于B细胞恶性肿瘤（包括非霍奇金淋巴瘤（NHL）和急性淋巴细胞白血病（ALL））的靶向CD 22的抗体-药物缀合物（ADC））从临床前转化为临床。将临床前数据整合到PK/PD模型中，该模型包括（1）表征伊妥珠单抗奥佐霉素及其释放的有效载荷N-Ac-γ-加利车霉素DMH的处置和清除的血浆PK模型，（2）描述ADC扩散到肿瘤细胞外环境中的肿瘤处置模型，（3）描述伊妥珠单抗奥佐霉素与CD 22结合、内化、细胞内N-Ac-γ-加利车霉素DMH释放的细胞模型，与DNA结合或从肿瘤细胞流出，和（4）小鼠异种移植模型中的肿瘤生长和抑制。通过纳入inotuzumab ozogamicin的人体PK和相关患者人群中临床相关的肿瘤体积、肿瘤生长速率和CD 22表达值，将临床前模型转化为临床。由此产生的随机模型预测的患者中inotuzumab ozogamicin的无进展生存期（PFS）率与观察到的临床结果相当。该模型表明，分次给药方案上级常规给药方案的ALL，但不是NHL。模拟表明，肿瘤生长是一个高度敏感的参数，并预测成功的结果。伊妥珠单抗奥佐霉素PK和N-Ac-γ-加利车霉素DMH外排也是敏感参数，被认为是比CD 22受体表达更有用的结局预测因子。总之，已开发了一种多尺度、基于机制的伊妥珠单抗奥佐米星模型，该模型可整合临床前生物测量和PK/PD数据以预测临床应答。
A mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model was used for preclinical to clinical translation of inotuzumab ozogamicin, a CD22-targeting antibody-drug conjugate (ADC) for B cell malignancies including non-Hodgkin's lymphoma (NHL) and acute lymphocytic leukemia (ALL). Preclinical data was integrated in a PK/PD model which included (1) a plasma PK model characterizing disposition and clearance of inotuzumab ozogamicin and its released payload N-Ac-gamma-calicheamicin DMH, (2) a tumor disposition model describing ADC diffusion into the tumor extracellular environment, (3) a cellular model describing inotuzumab ozogamicin binding to CD22, internalization, intracellular N-Ac-gamma-calicheamicin DMH release, binding to DNA, or efflux from the tumor cell, and (4) tumor growth and inhibition in mouse xenograft models. The preclinical model was translated to the clinic by incorporating human PK for inotuzumab ozogamicin and clinically relevant tumor volumes, tumor growth rates, and values for CD22 expression in the relevant patient populations. The resulting stochastic models predicted progression-free survival (PFS) rates for inotuzumab ozogamicin in patients comparable to the observed clinical results. The model suggested that a fractionated dosing regimen is superior to a conventional dosing regimen for ALL but not for NHL. Simulations indicated that tumor growth is a highly sensitive parameter and predictive of successful outcome. Inotuzumab ozogamicin PK and N-Ac-gamma-calicheamicin DMH efflux are also sensitive parameters and would be considered more useful predictors of outcome than CD22 receptor expression. In summary, a multiscale, mechanism-based model has been developed for inotuzumab ozogamicin, which can integrate preclinical biomeasures and PK/PD data to predict clinical response.