NEW BCAS FOR RADIOIMMUNOTHERAPY WITH RADIOMETALS

用于放射性金属放射免疫治疗的新型 BCAS

• 批准号: 2633869
• 负责人: DONALD J. BUCHSBAUM
• 金额: $ 19.33万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-01 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2633869
• 关键词: athymic mouse; chelating agents; chemical synthesis; colon neoplasms; drug metabolism; drug screening /evaluation; heavy metals; hydroxamate; immunoconjugates; laboratory rabbit; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer radionuclide therapy; pharmacokinetics; radiochemistry; radionuclides; radiopharmacology

The overall goal of this project is to develop new bifunctional chelating agents (BCAs) for the radiolabeling of monoclonal antibodies (MAbs) with radiometals other than 90Y for radioimmunotherapy in animal studies and ultimately clinically. We are proposing to study in this application a novel family of BCAs for radiolabeling of MAb CC49. The MAb CC49 is a well characterized reagent reactive with human adenocarcinomas and is being used in clinical phase and phase Il localization and therapy trials by us and other investigators. Therefore, the animal studies proposed in this application will elucidate the therapeutic efficacy, stability and other characteristics of BCA radiometal labeled conjugates, with the long term goal of their use in human clinical therapy trials. The specific aims are 1) To optimize the ability of trisuccin, a new hydroxamic acid based BCA to bind various radioactive metals to monoclonal antibodies for radioimmunoimaging and radioimmunotherapy, 2) To expand this "family" of hydroxamic acid-based BCAs to provide alternative or improved radioisotope linking strategies, 3) To radiolabel the MAb CC49 with 99mTc, 186Re and 67Cu using trisuccin and other hydroxamic acid-based BCAs, 4) To characterize the immunoreactivity, the in vitro and in vivo stability of hydroxamic acid chelated monoclonal antibodies labeled with the above radioisotopes. 5) To compare the tumor localization and biodistribution of radioisotopes linked to MAb CC49 via hydroxamic acid BCAs versus 99mTc and 186Re-MAG2-GABA-labeled CC49, and 6) To compare radioimmunotherapy effects of radiolabeled CC49 when radioisotopes are linked by hydroxamic acid based BCAs versus 99mTc and 186Re-MAG2-GABA- labeled CC49. Standard analytical and biochemical techniques will be used to demonstrate the purity of the hydroxamic acid compounds synthesized. Stability and pharmacokinetic studies will be carried out in rabbits. The biodistribution and therapy studies will be carried out in athymic nude mice bearing subcutaneous human colon cancer xenografts. The eventual goal of this project is to produce a better radioimmunotherapeutic agent for treatment of human malignancies.

本项目的总体目标是开发新型双功能螯合剂 单克隆抗体（MAb）放射性标记试剂（BCA）， 在动物研究中用于放射免疫治疗的放射性金属（90 Y除外）， 最终临床上。 我们建议在本申请中研究一种 用于放射性标记MAb CC 49的新的BCA家族。MAb CC 49是一种 与人腺癌反应的充分表征的试剂， 用于临床阶段和II期定位和治疗试验 我们和其他调查员因此， 本申请将阐明治疗效果、稳定性和 BCA放射性金属标记缀合物的其他特征， 它们在人类临床治疗试验中使用的长期目标。 具体 目的是：1）优化新的异羟肟酸三琥珀酸的合成能力 基于BCA将各种放射性金属与单克隆抗体结合， 放射免疫成像和放射免疫治疗，2）为了扩大这个“家庭”， 基于异羟肟酸的BCA以提供替代的或改进的 放射性同位素连接策略，3）用放射性同位素标记MAb CC 49， 99 mTc、186 Re和67 Cu使用三琥珀酰亚胺和其他异羟肟酸基 4）为了表征免疫反应性，在体外和体内 标记的异羟肟酸螯合单克隆抗体的稳定性 上述放射性同位素。5)为了比较肿瘤定位和 通过异羟肟酸与单克隆抗体CC 49连接的放射性同位素的生物分布 BCAs与99 mTc和186 Re-MAG 2-GABA标记的CC 49，以及6）比较 放射性同位素标记的CC 49的放射免疫治疗效果 与99 mTc和186 Re-MAG 2-GABA-连接的异羟肟酸基BCAs， 编号为CC 49将使用标准分析和生化技术 以证明合成的异羟肟酸化合物的纯度。 将在家兔中进行稳定性和药代动力学研究。的 生物分布和治疗研究将在无胸腺裸鼠中进行 携带皮下人结肠癌异种移植物的小鼠。最终 本项目的目标是生产更好的放射免疫制剂 用于治疗人类恶性肿瘤。