A mechanistic compartmental model for total antibody uptake in tumors.
A mechanistic compartmental model for total antibody uptake in tumors.
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DOI：
10.1016/j.jtbi.2012.08.034
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发表时间：
2012-12-07
影响因子：
2
通讯作者：
Wittrup, K. Dane
中科院分区：
文献类型：
--
作者：
Thurber, Greg M.;Wittrup, K. Dane
抗体正在开发中，用于治疗各种癌症，如淋巴瘤、结肠癌和乳腺癌。这类药物更大功效的主要限制是体内分布差。抗体的定位发生缓慢，通常治疗量不足，并且在整个肿瘤中不均匀分布。虽然单个血管周围的微分布对于许多治疗是重要的，但是定位于肿瘤中的抗体的总量对于许多应用是至关重要的，例如成像、用抗体药物缀合物确定治疗指数以及放射免疫治疗中的给药。对于成像和预先靶向的治疗策略，摄取的时间过程对于确定何时拍摄图像或递送第二试剂至关重要。我们在这里提出了一个简单的抗体摄取和保留的机制模型，捕获的主要速率，确定肿瘤内的抗体浓度的时间过程，包括剂量，亲和力，血浆清除率，目标表达，内化，渗透性和血管化。由于许多参数是已知的或可以在体外估计，该模型可以近似肿瘤中抗体浓度的时间过程，以帮助实验设计，数据解释和改善定位的策略。
Antibodies are under development to treat a variety of cancers, such as lymphomas, colon, and breast cancer. A major limitation to greater efficacy for this class of drugs is poor distribution in vivo. Localization of antibodies occurs slowly, often in insufficient therapeutic amounts, and distributes heterogeneously throughout the tumor. While the microdistribution around individual vessels is important for many therapies, the total amount of antibody localized in the tumor is paramount for many applications such as imaging, determining the therapeutic index with antibody drug conjugates, and dosing in radioimmunotherapy. With imaging and pretargeted therapeutic strategies, the time course of uptake is critical in determining when to take an image or deliver a secondary reagent. We present here a simple mechanistic model of antibody uptake and retention that captures the major rates that determine the time course of antibody concentration within a tumor including dose, affinity, plasma clearance, target expression, internalization, permeability, and vascularization. Since many of the parameters are known or can be estimated in vitro, this model can approximate the time course of antibody concentration in tumors to aid in experimental design, data interpretation, and strategies to improve localization.
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影响因子：
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