Targeted Alpha-particle Therapy

使用β发射放射性核素的放射免疫疗法已证明具有显著的抗癌活性，但 受到β粒子的长射程、低效力和缺乏特异性的限制。因此，在这方面， 除放射敏感性淋巴癌外，如果不限制剂量， 骨髓抑制或骨髓移植挽救。作为替代方案，靶向α粒子疗法允许选择性杀伤 单细胞和小细胞簇，但可能不会有效地减瘤大肿瘤。我们有 开发了两种明显不同的阿尔法疗法，这使我们能够提出重要的问题， 他们的使用。靶向Bi-213可用于脉管系统内的靶点。但受限于其短的46分钟半衰期。 Ac-225原子阿尔法发生器，产生4阿尔法净，有10天的半衰期，允许扩散 进入体积较大的肿瘤，但可能会受到来自错误的α发射子产物的毒性的限制。超过 在过去的5年里，我们开发了用于研究α放射免疫疗法的人类治疗模型系统 包括新的体外化学和方法、动物模型和人类临床研究。我们假设 通过了解放射化学、细胞代谢、代谢和放射生物学， 在这些系统中，人们可以设计临床策略，以充分利用其独特的， 高活性特征，同时降低其剂量限制特性。这将涉及阐明 以下关键参数的作用和相互关系：缓解率和毒性;肿瘤表型 和基因型;靶细胞表面抗原密度;放射性核素半衰期和发生器子级联; 单细胞、脉管系统和肿瘤细胞簇几何形状。这些问题将在人类临床中得到解决 试验，与这些试验相关的实验室研究，以及临床前模型系统。一是 完成我们的概念，有针对性的α发射体可以是安全和有效的代理人在急性 白血病（Aim 1）。接下来，我们第一次询问是否可以将靶向α发生器用于人类（目标2）， 以及如何控制可能的错误子产物毒性（目标3）。第四，（目标4）探索 在临床前模型中，是否可以使用α辐射来靶向肿瘤新生血管，使用 关于目标α发射体和α发生器的差异的知识，并提出最佳的 策略，用于其使用。

Radioimmunotherapy with beta emitting radionuclides has demonstrated significant anti-cancer activity, but is limited by the long range, low potency and lack of specificity of the beta particles. As a consequence, except in radiosensitive lymphoid cancers, major responses can not be achieved easily without dose limiting myelosuppression or BMT rescue. As an alternative, targeted alpha particle therapy allows selective killing of single cells and small clusters of cells, but may not be effective in debulking large tumors. We have developed 2 markedly different forms of alpha therapy, which allows us to ask important questions about their use. Targeted Bi-213 is useful for targets within the vasculature. but is limited by its short 46 min halflife. Ac-225 atomic alpha generators, which yield a net of 4 alphas, have 10 day half-lives, allowing diffusion into bulkier tumors, but will likely be limited by toxicity from errant alpha emitting daughter products. Over the last 5 years, we have developed human therapeutic model systems for studying alpha radioimmunotherapy including novel in vitro chemistry and methods, animal models and human clinical studies. We hypothesize that by understanding the radiochemistry, cellular metabolism and catabolism and radiobiology of these radioconstructs in these systems, one can design clinical strategies to take full advantage of their unique and highly active features, while reducing their dose limiting characteristics. This will involve elucidating the role and the interrelationships of the following key parameters: Response rates and toxicity; tumor phenotype and genotype; target cell surface antigen density; radionuclide half-life and generator daughter cascades; single-cell, vasculature and tumor cell cluster geometry. These issues will be addressed in human clinical trials, in laboratory investigations associated with these trials, and preclinical model systems. First, we complete our validation of the concept that targeted alpha emitters can be safe and effective agents in acute leukemia (Aim 1). Next, we ask for the first time if targeted alpha-generators can be used in humans (Aim 2), and how can one control the possible errant daughter product toxicities (Aim 3). Finally, (Aim 4) we explore in a preclinical model whether alpha irradiation can be used to target the tumor neovasculature, using knowledge about the differences in targeted alpha emitters and alpha-generators, and propose optimal strategies for their use.