A two-tiered physiologically based model for dually labeled single-chain Fv-Fc antibody fragments
A two-tiered physiologically based model for dually labeled single-chain Fv-Fc antibody fragments
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DOI：
10.1158/1535-7163.mct-06-0072
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发表时间：
2006-06-01
影响因子：
5.7
通讯作者：
DiStefano, Joseph J., III
中科院分区：
文献类型：
--
作者：
Ferl, Gregory Z.;Kenanova, Vania;DiStefano, Joseph J., III
单克隆抗体（mAb）在癌症治疗中的应用越来越多，目前的工作重点是开发具有最佳生物分布特征的工程抗体，用于成像和/或放射免疫治疗。我们最近开发了单链Fv-Fc (scFv-Fc) mAb，它由单链抗体Fv片段（轻链和重链可变结构域）偶联到IgG1 Fc区域组成。将减弱与FcRn结合亲和力的点突变引入野生型scFv-Fc单抗的Fc区，产生几种新抗体，每种抗体具有不同的半衰期。在这里，我们描述了一个基于生理的两层药代动力学模型的构建，该模型能够模拟In-111和i -125标记的scFv-Fc单克隆抗体的表观生物分布，其中来自降解的In-111标记的单克隆抗体的In-111标记的代谢物倾向于被捕获在溶酶体腔室中，而来自降解的i -125标记的单克隆抗体的游离1251则通过尿路迅速消除。in -111和125 i标记的单克隆抗体的不同浓度-时间谱允许估计每个器官的降解能力，并阐明肝脏、肌肉和皮肤中累积降解对FcRn亲和力和肿瘤质量的依赖。据估计，当肿瘤很小时，肝脏约占所有降解单克隆抗体的50%。当肿瘤体积较大（约0.3 g）时，mAb在残余胴体（主要是皮肤和肌肉）中的降解率从相似的45%降至16%，因为所考虑的三种mAb变体的FcRn亲和力增加。此外，肾脏中少量单克隆抗体的消除被证明是模型与数据成功拟合的必要条件。
Monoclonal antibodies (mAb) are being used at an increasing rate in the treatment of cancer, with current efforts focused on developing engineered antibodies that exhibit optimal biodistribution profiles for imaging and/or radioimmunotherapy. We recently developed the single-chain Fv-Fc (scFv-Fc) mAb, which consists of a single-chain antibody Fv fragment (light-chain and heavy-chain variable domains) coupled to the IgG1 Fc region. Point mutations that attenuate binding affinity to FcRn were introduced into the Fc region of the wild-type scFv-Fc mAb, resulting in several new antibodies, each with a different half-life. Here, we describe the construction of a two-tiered physiologically based pharmacokinetic model capable of simulating the apparent biodistribution of both In-111- and I-125-labeled scFv-Fc mAbs, where In-111-labeled metabolites from degraded In-111-labeled mAbs tend to become trapped within the lysosomal compartment, whereas free 1 251 from degraded I-125-labeled mAbs is quickly eliminated via the urinary pathway. The different concentration-time profiles of In-111- and 125 I-labeled mAbs permits estimation of the degradation capacity of each organ and elucidates the dependence of cumulative degradation in liver, muscle, and skin on FcRn affinity and tumor mass. Liver is estimated to account for similar to 50% of all degraded mAb when tumor is small (similar to 0. 1 g) and drops to about 35% when tumor mass is larger (similar to 0.3 g). mAb degradation in residual carcass (primarily skin and muscle) decreases from similar to 45% to 16% as FcRn affinity of the three mAb variants under consideration increases. In addition, elimination of a small amount of mAb in the kidneys is shown to be required for a successful fit of model to data.