Targeted Alpha-particle Therapy

靶向α粒子治疗

基本信息

批准号：
7728786
负责人：
DAVID A SCHEINBERG
金额：
$ 19.17万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7728786
关键词：
Actinium Acute leukemia Address Alpha Particles Animal Model Antibodies Antigens Beta Particle Biodistribution Biological Models Bismuth Blood Vessels Blood specimen Catabolism Cells Characteristics Chemistry Clinical Clinical Research Clinical Trials Cytarabine Cytogenetics Daughter Diffusion Diuresis Dose-Limiting Drug Kinetics Dysmyelopoietic Syndromes Elements Genotype Half-Life Human Image In Vitro Individual Investigation Kidney Knowledge Laboratories Life Lymphoid Malignant Neoplasms Metabolism Metals Methods Modeling Mus Myelosuppression Patients Phase I Clinical Trials Phase II Clinical Trials Phenotype Pre-Clinical Model Prognostic Factor Radiobiology Radiochemistry Radioimmunotherapy Radioisotopes Range Rate Residual Tumors Role Specificity Staging Surface Antigens System Testing Therapeutic Time Toxic effect Tumor Burden Tumor Debulking Tumor-Associated Vasculature Unithiol Validation concept day density design dosimetry in vivo irradiation killings leukemia man neoplastic cell novel pre-clinical response tumor

Actinium Acute leukemia Address Alpha Particles Animal Model Antibodies Antigens Beta Particle Biodistribution Biological Models Bismuth Blood Vessels Blood specimen Catabolism Cells Characteristics Chemistry Clinical Clinical Research Clinical Trials Cytarabine Cytogenetics Daughter Diffusion Diuresis Dose-Limiting Drug Kinetics Dysmyelopoietic Syndromes Elements Genotype Half-Life Human Image In Vitro Individual Investigation Kidney Knowledge Laboratories Life Lymphoid Malignant Neoplasms Metabolism Metals Methods Modeling Mus Myelosuppression Patients Phase I Clinical Trials Phase II Clinical Trials Phenotype Pre-Clinical Model Prognostic Factor Radiobiology Radiochemistry Radioimmunotherapy Radioisotopes Range Rate Residual Tumors Role Specificity Staging Surface Antigens System Testing Therapeutic Time Toxic effect Tumor Burden Tumor Debulking Tumor-Associated Vasculature Unithiol Validation concept day density design dosimetry in vivo irradiation killings leukemia man neoplastic cell novel pre-clinical response tumor

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项目摘要

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.

带有β发射放射性核素的放射免疫疗法表现出显着的抗癌活性，但受Beta颗粒的远距离，低效力和缺乏特异性的限制。结果，除了放射素敏感的淋巴癌外，如果没有剂量限制，则无法轻易获得主要反应骨髓抑制或BMT救援。作为替代方案，有针对性的α粒子疗法可以选择性杀死单细胞和小簇的细胞，但可能没有有效地降低大肿瘤。我们有开发了2种不同形式的Alpha疗法，这使我们能够问有关有关的重要问题他们的使用。靶向BI-213对于脉管系统内的靶标有用。但受到短短46分钟半寿命的限制。 AC-225原子α发电机产生的净4 alpha具有10天的半衰期，允许扩散进入较大的肿瘤，但可能会受到错误α发出子产品的毒性的限制。超过在过去的5年中，我们开发了用于研究alpha放射免疫疗法的人类治疗模型系统包括新颖的体外化学和方法，动物模型和人类临床研究。我们假设通过了解放射化学，细胞代谢和分解代谢以及这些的放射生物学这些系统中的放射性构造，可以设计临床策略，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。这将涉及阐明角色和以下关键参数的相互关系：反应率和毒性；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电机女儿级联；单细胞，脉管系统和肿瘤细胞簇几何形状。这些问题将在人类的临床中解决试验在与这些试验相关的实验室研究和临床前模型系统中。首先，我们完成我们对靶向α发射器的概念的验证，可以是急性的安全有效代理白血病（目标1）。接下来，我们第一次要求是否可以在人类中使用目标α生成器（AIM 2），，以及如何控制可能的错误的子产品毒性（AIM 3）。最后，（目标4）我们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系统了解目标α发射器和α发电机的差异，并提出最佳使用它们的策略。