Alpha-Particle Immunotherapy of Cancer

癌症的阿尔法粒子免疫疗法

• 批准号: 6932305
• 负责人: DAVID A SCHEINBERG
• 金额: $ 37.67万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-26 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6932305
• 关键词: SCID mouse; acid base balance; acidity /alkalinity; acute myelogenous leukemia; alpha radiation; antileukemic agent; antitumor antibody; beta radiation; clinical research; complement pathway; drug design /synthesis /production; drug resistance; human subject; immunoconjugates; laboratory mouse; minimal residual disease; monoclonal antibody; neoplasm /cancer immunotherapy; neoplasm /cancer pharmacology; neoplasm /cancer radionuclide therapy; paroxysmal nocturnal hemoglobinuria; radiopharmacology; recombinant proteins; tissue /cell culture

DESCRIPTION (provided by applicant): The long-term goals of this program have been to create monoclonal antibody (mAb)-based therapeutic agents for leukemias and selected cancers and to use studies in preclinical models to understand basic principles of immunotherapy and resistance to immunotherapy in order to effectively apply the concepts to other systems and into humans. On this R01, we have developed novel forms of recombinant CDR grafted humanized anti-CD33 mAb's (HUM195) and various cytotoxic antibody constructs, characterized their biology, biochemistry, radiobiology, and radiochemistry. Phase III studies of HUM195 have been successfully completed. P-glycoprotein mediated "immunological resistance" was described. Beta particle and alpha-emitting antibodies were developed, characterized and entered into human clinical trials. Targetable in vivo alpha generators were invented. Little is known about alpha therapy in vivo, and almost nothing is known about the complicated pharmacology and radiobiology of in vivo alpha generators. Initial monkey studies suggest a risk for renal toxicity at large doses of the drug. This fourth competitive grant therefore builds on several aspects of the prior work by proposing continued exploration of alpha particle and nanogenerator therapy. Initial aims are to abrogate the toxicity of daughter alpha emitting atoms produced by in vivo atomic nanogenerators. This will involve (Aim 1) understanding and then altering the pharmacology of the parent generator complexes and (Aim 2) altering the catabolism of daughter elements. Last, we will try to understand the role of cellular geometry, tumor biodistribution, and dose on alpha particle efficacy in model systems in vivo and in vitro (Aim 3). New discoveries will continue to be applied to human clinical problems in clinical trials and to other tumor systems as possible.

描述（由申请人提供）：该计划的长期目标是创建用于白血病和选定癌症的基于单克隆抗体（MAB）的治疗剂，并在临床前模型中使用研究来了解免疫疗法的基本原则为了有效地将概念应用于其他系统并将其应用于人类。在此R01上，我们开发了新型的重组CDR移植的人源化抗CD33 MAB（HUM195）和各种细胞毒性抗体构建体的形式，这些抗体构建体的特征是它们的生物学，生物化学，放射生物学和放射化学。 HUM195的III阶段研究已成功完成。描述了P-糖蛋白介导的“免疫耐药性”。开发，表征并进入人类临床试验。发明了可靶向的体内α发电机。关于体内α疗法的了解知之甚少，几乎一无所知。最初的猴子研究表明，大剂量的药物有肾脏毒性的风险。因此，这项第四次竞争赠款是基于先前工作的几个方面，它通过提出对α粒子和纳米生成剂治疗的持续探索。最初的目的是消除体内原子纳米发育仪产生的子α发射原子的毒性。这将涉及（目标1）理解，然后改变母体发生器复合物的药理学，并（目标2）改变女儿元素的分解代谢。最后，我们将尝试了解细胞几何形状，肿瘤生物分布和剂量在体内和体外模型系统中α颗粒功效的作用（AIM 3）。在临床试验和其他肿瘤系统中，新发现将继续应用于人类的临床问题。