ANTITUMOR THERAPY WIH ANTITRANSFERRIN RECEPTOR MONOCLONAL ANTIBODIES

抗人转铁蛋白（Tf）受体的单克隆抗体（mAb） 在癌症治疗中有几个潜在的应用。这个NCDDG 该项目先前已经开发出了针对人类Tf受体的抗体 直接阻断受体功能并抑制细胞增殖， 抗肿瘤剂。现在建议研究使用抗Tf 受体单克隆抗体递送抗癌剂穿过血脑 屏障抗转铁蛋白受体单克隆抗体选择性靶向转铁蛋白受体的研究 表达在脑毛细血管内皮细胞上， 共价偶联药物和生长因子通过抗Tf作用于脑 受体单克隆抗体已被其他研究人员证明。缺乏一个 转铁蛋白受体在脑毛细血管内转运体外细胞模型 然而，内皮细胞对此的定量研究有限。 过程和分子机制的分析。 在NCDDG项目支持的初步研究中， 内皮细胞培养模型现已建立。具体目标 目前的建议是使用这种体外细胞培养模型， 表征脑毛细血管中Tf受体运输途径 内皮细胞;定义所涉及的分子分选信号; 优化抗Tf受体单克隆抗体穿过脑毛细血管的转胞吞作用 内皮细胞;并鉴定候选抗Tf受体mAb， 通过体内Tf受体靶向药物的临床前试验 模型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， 抗肿瘤药物这一目标将通过采用 现有的分子细胞生物学、生物化学和形态学 以前应用于分析其他细胞中Tf受体运输的技术 细胞分型作为递送生物活性融合的特定模型 蛋白质穿过血脑屏障，抗人转铁蛋白的能力 受体/IL-2融合蛋白，如在程序II中所述构建， 该NCDDG从顶面到基底外侧靶向 将研究脑毛细血管内皮细胞的表面。 与本NCDDG的其他项目负责人和NCI工作人员的互动 将继续促进实验室工作在 把这个项目带到诊所

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.