RADIOIMMUNOTHERAPY WITH ALPHA AND BETA EMITTERS

尽管使用放射核素的放射免疫疗法已显示出显著的抗癌活性，但它受到β粒子范围的严重限制。因此，除了放射敏感性淋巴细胞癌外，如果没有剂量限制的骨髓抑制，主要的反应是不容易实现的。相比之下，使用铋-213的靶向α粒子疗法可以选择性地杀死单个细胞和小细胞簇，但可能对大肿瘤的减体积无效，而且半衰期短。在过去的5年中，我们开发了用于研究α和β放射免疫治疗的人类治疗模型系统，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结构的几何结构、细胞代谢和分解代谢、放射生物学和核化学，人们可以设计出充分利用其独特和高活性特征的策略，同时降低其剂量限制特征。目的：1)探索β和α RIT的合理结合。2)研究具有多个子代的体内α产生体，特别是在代谢方面。3)开发新的发生器化学，重构产品纯化方法。4)阐明靶细胞抗原密度和放射构建特异性活性在α RIT中的作用。这些问题将首先在体外和体内模型中得到解决；接下来，在尽可能大的程度上，这些评估将转化为人体临床试验。

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.