RADIOIMMUNOTHERAPY WITH ALPHA AND BETA EMITTERS

尽管使用贝塔放射性核素进行放射免疫治疗已显示出显著的抗癌活性，但它受到贝塔粒子射程较长的严重限制。因此，除了对放射敏感的淋巴癌外，如果没有剂量限制的骨髓抑制，很难实现主要的反应。相比之下，铋-213的靶向阿尔法粒子疗法允许选择性地杀死单个细胞和小簇细胞，但在清除大肿瘤方面可能并不有效，而且半衰期很短。在过去的5年里，我们开发了用于研究阿尔法和贝塔放射免疫疗法的人类治疗模型系统，范围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，人们可以设计策略，充分利用它们独特的高活性特征，同时减少它们的剂量限制特性。目的：1)探索β-RIT与α-RIT的合理结合。2)研究体内具有多个子代的阿尔法生成器，特别是关于代谢的研究。3)开发新的发生器化学，改造产品提纯方法。4)阐明靶细胞抗原密度和放射性构筑比活性在α-RIT中的作用。这些问题将首先在体外和体内模型中解决；接下来，将尽可能地将这些评估转化为人类临床试验。

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.