PRECLINICAL RADIOIMMUNOTHERAPY WITH AN INTERNALIZING MAB

抗体在体内靶向肿瘤并提供减少肿瘤的能力。 在肿瘤负荷方面已经有很好的记录，但许多问题 关于最佳放射性核素-MAb缀合物的选择 仍然没有解决。 该项目的目的是研究重要的 放射免疫疗法（赖特）的变量用于治疗癌症， 与MAb内化到携带抗原的细胞中的能力有关。 RS7- 3G 11是本项目中使用的一抗， 由于具有许多有前途的特性而被选中。 我们的初步 结果表明，RS7- 3G 11证明：a）高频率 抗原在多种肿瘤类型，特别是肺， 膀胱癌、乳腺癌、宫颈癌、卵巢癌、前列腺癌和胃癌， 在正常人组织上的有限表达; B）定位于 c）在动物模型中提供肿瘤减少的能力; 当与131 I缀合时的体内负荷;和d）快速地 内化到携带抗原细胞中。 将自己内化为 靶细胞没有看到与许多其他单克隆抗体拥有其他 积极的特性，是RS7- 3G 11的一个有前途的特性， 将使我们能够利用RS7- 3G 11进行比较研究， 抗体内化在赖特中重要性。 该提案存在分歧 这些评价领域旨在研究 提供最佳杀肿瘤活性的放射性核素-MAb缀合物 （a）放射性核素的选择和标记技术， 与抗体是否内化的关系，和（B） 用这些缀合物评价赖特的生物学效应， 放射性核素-MAb缀合物的细胞加工。 这些研究 在设计时考虑到对吸收的描述， 实体瘤抗体的分布， 数学建模，我们将评估我们获得的结果是否 实验上符合模型的预测。

The ability of antibodies to target tumors in vivo and provide reduction in tumor burden has been well documented, but many of the issues pertaining to the selection of an optimal radionuclide-MAb conjugate remain unresolved. The aim of this project is to examine important variables of radioimmunotherapy (RAIT) for the treatment of cancer which relate to the ability of a MAb to internalize into antigen bearing cells. RS7-3G11 is the primary antibody to be used in this project, and has been selected due to a number of promising characteristics. Our preliminary results indicate that RS7-3G11 demonstrates: a) a high frequency of antigen expression on a wide variety of tumor types, especially lung, bladder, breast, cervical, ovarian, prostate, and stomach cancers, with limited expression on normal human tissue; b) the ability to localize to tumor in an animal model; c) the ability to provide reduction in tumor burden in vivo when conjugated to 131I; and d) the ability to rapidly internalize into antigen-bearing cells. The ability to internalize into target cells was not seen with many other MAbs possessing the other positive characteristics, and is a promising property of RS7-3G11 which will enable us to utilize RS7-3G11 in comparative studies on the importance of antibody internalization in RAIT. The proposal is divided into areas of evaluation which are designed to study the selection of radionuclide-MAb conjugate providing the best tumoricidal activity covering (a) choice of radionuclide and labeling technology in relationship to whether or not an antibody internalizes, and (b) evaluations of the biological effects of RAIT with these conjugates and the cellular processing of the radionuclide-MAb conjugates. These studies are designed taking into account the descriptions of the uptake and distribution of antibodies to solid tumors which have been generated using mathematical modeling, and we will assess whether the results we obtain experimentally conform to the predictions of the models.