RADIOIMMUNOTHERAPY WITH ALPHA AND BETA EMITTERS

使用 α 和 β 发射器进行放射免疫治疗

• 批准号: 6423087
• 负责人: DAVID A SCHEINBERG
• 金额: $ 29.18万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-21 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6423087
• 关键词: actinides; acute myelogenous leukemia; alpha radiation; antitumor antibody; beta radiation; bismuth; chronic myelogenous leukemia; clinical research; clinical trial phase I; combination cancer therapy; human subject; human therapy evaluation; laboratory mouse; neoplasm /cancer radioimmunotherapy; radionuclides; radiopharmacology; yttrium; actinides; acute myelogenous leukemia; alpha radiation; antitumor antibody; beta radiation; bismuth; chronic myelogenous leukemia; clinical research; clinical trial phase I; combination cancer therapy; human subject; human therapy evaluation; laboratory mouse; neoplasm /cancer radioimmunotherapy; radionuclides; radiopharmacology; yttrium

Although radioimmunotherapy with beta emitting radionuclides has demonstrated significant anti-cancer activity, it is severely limited by the long range of the beta particles. As a consequence, except in the radio- sensitive lymphoid cancers, major responses can not be achieved easily without dose limiting myelosuppression. In contrast, targeted alpha particle therapy with Bismuth-213 allows selective killing of single cells and small clusters of cells, but may not be effective in debulking large tumors and is also limited by its short half-life. Over the last 5 years, we have developed human therapeutic model systems for studying both alpha and beta radioimmunotherapy ranging from in vitro analyses and animal models to human clinical studies. We hypothesize that by understanding the geometry, cellular metabolism and catabolism, radiobiology and nuclear chemistry of these radioconstructs in these systems, one can design strategies to take full advantage of their unique and highly active features, while reducing their dose limiting characteristics. AIMS: 1) Explore rational combination of beta and alpha RIT. 2) Investigate in vivo alpha generators with multiple daughters, especially with regard to metabolism. 3) Develop new generator chemistry and reconstruct product purification methods. 4) Elucidate the role of targeted cell antigen density and radioconstruct specific activity in alpha RIT. Each of these issues will be addressed first in models in vitro and in vivo; next, to as great a degree as possible, these evaluations will be translated into human clinical trials.

尽管带有β发射放射性核素的放射性免疫疗法表现出显着的抗癌活性，但受Beta颗粒的远距离受到严重限制。结果，除了在射线敏感的淋巴癌中，如果没有剂量限制骨髓抑制，就无法轻易地达到主要反应。相比之下，靶向的α粒子疗法使用二晶型213进行选择性杀死单细胞和小细胞簇，但可能没有有效地杀死大型肿瘤，并且也受到其短半衰期的限制。在过去的五年中，我们开发了人类的治疗模型系统，用于研究α和β放射免疫疗法，从体外分析和动物模型到人类临床研究。我们假设，通过了解这些系统中这些放射性结构的几何形状，细胞代谢和分解代谢，放射生物学和核化学，可以设计策略以充分利用其独特和高度活跃的特征，同时降低其剂量限制特征。目的：1）探索Beta和Alpha RIT的合理组合。 2）研究具有多个女儿的体内α发电机，尤其是关于代谢。 3）开发新的发电机化学和重建产品纯化方法。 4）阐明靶向细胞抗原密度和放射性特定活性在αRIT中的作用。这些问题中的每一个都将首先在体外和体内模型中解决。接下来，为了尽可能多地，这些评估将转化为人类临床试验。