Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14260, USA.
J Pharm Sci. 2010 Mar;99(3):1582-600. doi: 10.1002/jps.21918.
Antibodies directed against tumor associated antigens are being increasingly used for detection and treatment of cancers; however, there is an incomplete understanding of the physiological determinants of antibody pharmacokinetics and tumor distribution. The purpose of this study is to (a) compare the plasma pharmacokinetics of T84.66, a monoclonal anti-CEA antibody directed against tumor associated carcinoembryonic antigen (CEA), in control and CEA expressing LS174T xenograft bearing mice, and (b) to develop a physiologically based pharmacokinetic (PBPK) model capable of integrating the influence of CEA and the IgG salvage receptor, FcRn, on T84.66 disposition. T84.66 pharmacokinetics were studied following i.v. administration (1, 10, 25 mg/kg) in control and xenograft bearing mice. In control mice, no significant differences in clearance were observed across the dose range studied. In mice bearing xenograft tumors, clearance was increased by four- to sevenfold, suggesting the presence of a "target mediated" elimination pathway. T84.66 plasma disposition was characterized with a PBPK model, and the model was applied to successfully predict antibody concentrations in tumor tissue. The PBPK model will be used to assist in the development of antibody-based targeting strategies for CEA-positive tumors.
针对肿瘤相关抗原的抗体越来越多地被用于癌症的检测和治疗；然而，人们对抗体药代动力学和肿瘤分布的生理决定因素仍不完全了解。本研究的目的是：(a)比较针对肿瘤相关癌胚抗原（CEA）的单克隆抗-CEA 抗体 T84.66 在对照和表达 CEA 的 LS174T 异种移植瘤荷瘤小鼠中的血浆药代动力学；(b)建立能够整合 CEA 和 IgG 回收受体 FcRn 对 T84.66 处置影响的基于生理学的药代动力学（PBPK）模型。在对照和异种移植瘤荷瘤小鼠中，静脉注射（1、10、25mg/kg）后研究了 T84.66 的药代动力学。在对照小鼠中，在所研究的剂量范围内未观察到清除率的显著差异。在携带异种移植瘤的小鼠中，清除率增加了四到七倍，表明存在“靶向介导”消除途径。用 PBPK 模型对 T84.66 的血浆处置进行了表征，并应用该模型成功预测了肿瘤组织中的抗体浓度。该 PBPK 模型将用于协助开发针对 CEA 阳性肿瘤的抗体靶向策略。
