PRECLINICAL RADIOIMMUNOTHERAPY WITH AN INTERNALIZING MAB

抗体在体内靶向肿瘤并提供减量的能力 在肿瘤负担方面已经有了很好的记录，但许多问题 用于修饰或说明最佳放射性核素-MAb结合物的选择 仍然悬而未决。这个项目的目的是检查重要的 放射免疫治疗(RAIT)在癌症治疗中的变量 与单抗内化成携带抗原的细胞的能力有关。 RS7-3G11是该项目中使用的主要抗体，已被 由于许多有希望的特征而被选中。我们的预赛 结果表明，RS7-3G11表现出：a)高频率 抗原在多种肿瘤类型上的表达，尤其是肺癌， 膀胱癌、乳腺癌、宫颈癌、卵巢癌、前列腺癌和胃癌 在正常人体组织上的有限表达；b)定位于 动物模型中的肿瘤；c)提供肿瘤减少的能力 与131I结合时在体内的负担；以及d)快速 内化为携带抗原的细胞。能够内化为 靶细胞与许多其他拥有另一种单抗的单抗不同 正特性，是RS7-3G11的一个很有前途的特性，它 将使我们能够利用RS7-3G11进行比较研究 抗体内化在RAIT中的重要性。这项提议意见不一。 进入评估领域，旨在研究 具有最佳杀瘤活性的放射性核素-单抗结合物 覆盖(A)放射性核素的选择和标记技术 与抗体是否内化的关系，以及(B) 用这些结合物评价RAIT的生物学效应 放射性核素-单抗结合物的细胞处理。这些研究 在设计时考虑到对摄取和 抗实体瘤抗体的分布 数学建模，我们将评估我们所获得的结果 在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.