ANTITUMOR THERAPY WIH ANTITRANSFERRIN RECEPTOR MONOCLONAL ANTIBODIES

抗人转铁蛋白受体的单抗 在治疗癌症方面有几个潜在的应用。本NCDDG 该计划此前已开发出针对人类转铁蛋白受体的抗体 直接阻断受体功能并抑制细胞增殖 抗肿瘤药物。现在建议研究抗转铁蛋白的使用 受体单抗可通过血脑传递抗癌药物 障碍。抗转铁蛋白受体单抗选择性靶向转铁蛋白受体 脑毛细血管内皮细胞的表达及其递送 通过抗转移因子将药物和生长因子共价偶联到脑内 受体单抗已经被其他研究人员证实。缺乏一种 研究TF受体在脑毛细血管内转运的体外细胞模型 然而，内皮细胞对此的定量研究有限。 过程及所涉及的分子机理分析。 在这个NCDDG计划支持的初步研究中，一个体外脑 血管内皮细胞培养模型现已建立。具体目标 目前的提议是使用这种体外细胞培养模型来 脑毛细血管内转铁蛋白受体转运途径的研究 内皮细胞；定义所涉及的分子分选信号； 优化抗转铁蛋白受体单抗的脑毛细血管转运 并鉴定抗血管内皮细胞转铁蛋白受体的候选单抗 体内转铁蛋白受体靶向药物的临床前试验 模特。长期目标是开发更有效的治疗方法。 通过开发有效的受体介导的递送药物治疗脑恶性肿瘤 脑部的抗肿瘤药物。这一目标将通过雇佣来实现 现有的分子细胞生物学、生化和形态 以前应用于分析Tf受体在其他细胞中的交易的技术 作为传递生物活性融合的特定模型的细胞分型 蛋白质通过血脑屏障，抗人转铁蛋白的能力 受体/IL-2融合蛋白，如程序II所述 该NCDDG的靶点是从根尖面到基底外侧 将对脑毛细血管内皮细胞表面进行研究。 与NCDDG中的其他项目负责人以及NCI员工进行互动 将继续促进在以下方面开展的实验室工作过渡 把这个节目送到诊所去。

Monoclonal antibodies (mAbs) against the human transferrin (Tf) receptor have several potential applications in the treatment of cancer. This NCDDG program has previously developed antibodies against the human Tf receptor that directly block receptor function and inhibit cell proliferation as anti-tumor agents. It is now proposed to investigate the use of anti-Tf receptor mAbs to deliver anti-cancer agents across the blood-brain barrier. Targeting of anti-Tf receptor mAbs to Tf receptors selectively expressed on brain capillary endothelial cells and the delivery of covalently-coupled drugs and growth factors to the brain by anti-Tf receptor mAbs has been demonstrated by other investigators. The lack of an in vitro cell model to study Tf receptor trafficking in brain capillary endothelial cells, however, has limited quantitative studies of this process and analysis of the molecular mechanism involved. In preliminary studies supported by this NCDDG program, an in vitro brain endothelial cell culture model has now been established. The specific aims of the current proposal are to use this in vitro cell culture model to characterize Tf receptor trafficking pathways in brain capillary endothelial cells; to define the molecular sorting signals involved; to optimize transcytosis of anti-Tf receptor mAbs across brain capillary endothelial cells; and to identify candidate anti-Tf receptor mAbs for preclinical trials of drug targeting via the Tf receptor in an in vivo model. The longterm goal is to develop more effective methods of treating brain malignancies by developing effective receptor-mediated delivery of anti-tumor agents to the brain. This goal will be achieved by employing existing molecular cell biological, biochemical and morphological techniques previously applied to analyze Tf receptor trafficking in other cell typed As a specific model for delivery of biologically-active fusion proteins across the blood brain barrier, the ability of a anti-human Tf receptor/IL-2 fusion protein, constructed as described in program II of this NCDDG to be targeted from the apical surface to the basolateral surface of brain capillary endothelial cells will be investigated. Interaction with other program leaders in this NCDDG and with NCI staff will continue to facilitate the transition of laboratory work performed in this program to the clinic.