PRECLINICAL RADIOIMMUNOTHERAPY WITH AN INTERNALIZING MAB

使用内化 MAB 进行临床前放射免疫治疗

• 批准号: 2100646
• 负责人: RHONA N STEIN
• 金额: $ 19.74万
• 依托单位: CTR FOR MOLECULAR MEDICINE/IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-20 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2100646
• 关键词: PRECLINICAL; RADIOIMMUNOTHERAPY; INTERNALIZING; MAB

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.

抗体靶向体内肿瘤并提供还原的能力 在肿瘤负担中，已经有充分的文献记载，但是许多问题 与选择最佳放射性核素-MAB结合物有关的 保持尚未解决。 该项目的目的是检查重要 放射免疫疗法（RAIT）用于治疗癌症的变量 与mAb内部化成抗原轴承细胞的能力有关。 RS7-3G11是该项目中要使用的主要抗体，并且已经是 由于许多有希望的特征而选择。 我们的初步 结果表明RS7-3G11证明：a）高频 各种肿瘤类型，尤其是肺部的抗原表达 膀胱，乳房，宫颈，卵巢，前列腺和胃癌，带有 正常人体组织的表达有限； b）本地化的能力 动物模型中的肿瘤； c）提供肿瘤减少的能力 当结合到131i时体内负担； d）快速的能力 内部化成抗原细胞。 内在化的能力 靶细胞没有看到其他具有对方的其他mAb 积极特征，是RS7-3G11的有前途的特性 将使我们能够利用RS7-3G11在有关的比较研究中 抗体内在化在Rait中的重要性。 提案分为 旨在研究选择的评估领域 放射性核素-MAB结合物提供最佳的肿瘤活性 覆盖（a）选择放射性核素和标签技术 与抗体是否内在化的关系，（b） 评估这些偶联物和这些结合物的生物学作用 放射性核素-MAB结合物的细胞加工。 这些研究 考虑到摄取的描述和 使用使用的实体瘤的抗体分布 数学建模，我们将评估我们获得的结果是否 实验符合模型的预测。