Physiologically Based Modeling of the Pharmacokinetics of "Catch-and-Release" Anti-Carcinoembryonic Antigen Monoclonal Antibodies in Colorectal Cancer Xenograft Mouse Models.
Physiologically Based Modeling of the Pharmacokinetics of "Catch-and-Release" Anti-Carcinoembryonic Antigen Monoclonal Antibodies in Colorectal Cancer Xenograft Mouse Models.
复制标题
基于生理学的结直肠癌异种移植小鼠模型中“捕获并释放”抗癌胚抗原单克隆抗体的药代动力学建模。
DOI：
10.1016/j.xphs.2018.09.037
复制
发表时间：
2019
影响因子：
3.8
通讯作者：
Balthasar,JosephP
中科院分区：
文献类型：
--
作者：
Polli,JosephRyan;Engler,FrankA;Balthasar,JosephP
具有pH敏感性靶标释放或“捕获-释放”（CAR）结合的工程化单克隆抗体（mAb）已显示出降低靶标介导的mAb消除程度、增加mAb暴露和增加剂量效力的前景。本研究开发了一种基于生理学的机械药代动力学（PBPK）模型，以评估pH敏感的CAR靶点结合对抗癌胚抗原（CEA）mAb在结直肠癌小鼠模型中分布的影响。通过将模型预测的血浆浓度-时间数据与施用T84.66（一种在pH 7.4和5.5下证明强结合的“标准”抗CEA mAb）后在荷瘤小鼠中观察到的数据进行比较，来鉴定PBPK模型。进一步的模拟评估了CAR pH依赖性结合对抗CEA mAb血浆药代动力学的影响，其中CEA亲和力随着pH降低而降低。将模拟数据与针对新型CAR mAb 10 H6观察到的数据进行比较。PBPK模型在拟合T84.66数据后提供了精确的参数估计值和出色的数据表征（中位预测误差18.4%）。模拟很好地预测了10 H6数据（中位数预测误差21.4%）。敏感性分析表明，CAR mAb处置的关键决定因素包括以下：抗原结合亲和力、酸化核内体中mAb-CEA解离的速率常数、抗原浓度和肿瘤血管反射系数。
Engineered monoclonal antibodies (mAbs) with pH-sensitive target release, or “catch-and-release” (CAR) binding, have shown promise in decreasing the extent of target-mediated mAb elimination, increasing mAb exposure, and increasing dose potency. This study developed a mechanistic physiologically based pharmacokinetic (PBPK) model to evaluate the effects of pH-sensitive CAR target binding on the disposition of anti-carcinoembryonic antigen (CEA) mAbs in mouse models of colorectal cancer. The PBPK model was qualified by comparing model-predicted plasma concentration-time data with data observed in tumor-bearing mice following the administration of T84.66, a “standard” anti-CEA mAb that demonstrates strong binding at pH 7.4 and 5.5. Further simulations evaluated the effects CAR pH-dependent binding, with decreasing CEA affinity with decreasing pH, on anti-CEA mAb plasma pharmacokinetics. Simulated data were compared with data observed for a novel CAR mAb, 10H6. The PBPK model provided precise parameter estimates, and excellent data characterization (median prediction error 18.4%) following fitting to T84.66 data. Simulations well predicted 10H6 data (median prediction error 21.4%). Sensitivity analyses demonstrated that key determinants of the disposition of CAR mAbs include the following: antigen binding affinity, the rate constant of mAb-CEA dissociation in acidified endosomes, antigen concentration, and the tumor vasculature reflection coefficient.
登录
查看更多内容
干扰素-γ对不同人结直肠肿瘤细胞中癌胚抗原表达的调节。
影响因子：
11.2
作者：
F. Guadagni;P. Witt;P. Robbins;J. Schlom;J. Greiner
通讯作者：
J. Greiner
影响因子：
3.5
作者：
Li, L;Gardner, I;Rose, R;Jamei, M
通讯作者：
Jamei, M
影响因子：
5.6
作者：
HAWKINS, RE;RUSSELL, SJ;WINTER, G
通讯作者：
WINTER, G
哺乳动物中效应细胞生物分布的基于生理学的动力学模型：对过继免疫疗法的影响。
DOI：
--
发表时间：
1996
期刊：
Cancer research.
影响因子：
--
作者：
Zhu,H;Melder,RJ;Baxter,LT;Jain,RK
通讯作者：
Jain,RK
癌胚抗原和相关抗原的单克隆抗体作为模型系统：在溶液相免疫测定中使用生物素标记的抗体和亲和素作为沉淀剂测定单克隆抗体的亲和力和特异性。
影响因子：
4.4
作者：
C. Wagener;B. Clark;K. J. Rickard;J. Shively
通讯作者：
J. Shively