Targeted Radiotherapy of Neoplastic Meningitis using Monoclonal Antibodies Label

使用单克隆抗体标签进行肿瘤性脑膜炎的靶向放射治疗

基本信息

批准号：
8236380
负责人：
Michael Rod Zalutsky
金额：
$ 34.48万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-11 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8236380
关键词：
Adverse effects Affect Alpha Particles Antibodies Behavior Brain Breast Carcinoma Caliber Cancer Patient Cells Central Nervous System Neoplasms Cerebrospinal Fluid Characteristics Clinical Clinical Trials Conduct Clinical Trials Data Development Diagnostic Disease Doctor of Philosophy Drug or chemical Tissue Distribution ERBB2 gene Effectiveness Human Immunotoxins In Vitro Instruction Investigational Drugs Investigational Therapies Label Leptomeninges Lymphoma Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of lung Metastatic Neoplasm to the Leptomeninges Methodology Methods Modeling Monoclonal Antibodies Mus Neoplasm Metastasis Neurocognitive Normal tissue morphology Nude Rats Patients Positron-Emission Tomography Quality of life Radiation Radiation therapy Radioactive Radioactivity Radioimmunotherapy Radioisotopes Radiolabeled Radiometry Research Roche brand of trastuzumab Site Solid Neoplasm Targeted Radiotherapy Therapeutic Tissues Toxic effect Trastuzumab Treatment Efficacy Treatment Protocols Vaccines Vertebral column Xenograft procedure base cancer site chemotherapy cytotoxic cytotoxicity dehalogenation design effective therapy in vivo leukemia lung Carcinoma malignant breast neoplasm neoplastic cell outcome forecast panitumumab particle radiotracer subcutaneous tool

项目摘要

PROJECT SUMMARY (See instructions): Project 1. Targeted Radiotherapy of Neoplastic Meningitis using Monoclonal Antibodies Labeled with Alpha Particle Emitting [211] At. Michael Zaiutsky, Ph.D., Project Leader Neoplastic meningitis (NM), characterized by the dissemination of malignant tumor cells within the leptomeningeal space and metastatic spread along the brain and spine, is a devestating disease resulting in a median survival of only 2-6 months. In terms of number of patients affected, breast and lung carcinoma are the most common primary sites that metastasize to the leptomeninges. We propose to focus initially on the rapid translational development of a targeted radiotherapeutic for breast carcinoma NM and if successful, apply the same approach to lung carcinoma. Our strategy is to combine trastuzumab with the a-particle emitter ^^^At because these a-particles have a greater cytotoxic effectiveness than conventional radiation and have a range in tissue of only a few cell diameters, characteristics that offer important advantages for NM treatment. We seek to determine the best method for labeling trastuzumab not only for[211]At but also for [124] l to move fonward to clinical investigation. If we can establish similar in vivo behavior for mAb labeled via the two radiohalogens, PET imaging with [124] l-labeled trastuzumab could provide a valuable tool for determining radiation dosimetry, evaluating distribution within the neuroaxis, and individualizing patient treatment protocols for [211]At-labeled trastuzumab. Our Specific Aims are: 1) To label trastuzumab with [211]At and [124] l using methodologies designed to minimize dehalogenation and maximize entrapment of radioactivity within tumor cells after labeled mAb internalization; 2) to evaluate these radiolabeled trastuzumab conjugates in human breast carcinoma cells in vitro, and tissue distribution in mice with subcutaneous breast carcinoma xenografts and in an athymic rat NM model of HER2 expressing breast carcinoma; 3) to determine the therapeutic efficacy, neuroaxis distribution, toxicity, and radiation dosimetry in athymic rat models of NM; 4) To obtain FDA Investigational New Drug permits for the best [211] At- and [124] l-labeled trastuzumab conjugates, and then to conduct clinical trials in patients with breast carcinoma NM and 5) Using the same translational paradigm determine the best strategy for labeling panitumumab with [211]At and [124] I and evaluate their potential as targeted radiotherapeutics and diagnostics for patients with lung carcinoma NM.

项目摘要（请参阅说明）：项目1。使用标记为α颗粒发射的单克隆抗体[211] AT的单克隆抗体对肿瘤性脑膜炎的靶向放疗。迈克尔·扎伊特斯基（Michael Zaiutsky）博士，项目负责人肿瘤性脑膜炎（NM），其特征是在脑膜空间内传播恶性肿瘤细胞，沿着大脑和脊柱传播转移性，是一种偏斜的疾病，导致中位生存期仅为2-6个月。就受影响的患者数量而言，乳腺癌和肺癌是转移到瘦素的最常见的主要部位。我们建议最初将重点放在针对乳腺癌的靶向放射性疗法的快速转化发展上，如果成功，请在肺癌中采用相同的方法。我们的策略是将曲妥珠单抗与A颗粒发射器相结合，因为这些A颗粒的细胞毒性有效性比常规辐射具有更大的细胞毒性有效性，并且仅在几个细胞直径的组织中具有范围，这为NM处理提供了重要的优势。我们试图确定不仅为[211]的曲妥珠单抗标记的最佳方法，还为[124] l进行临床研究。如果我们可以通过两种放射性糖原标记的MAB建立类似的体内行为，则使用[124] L标记的曲妥珠单抗的PET成像可以提供一个有价值的工具，用于确定辐射剂量剂量法，评估神经志中的分布，并在[211]固定的Trastuzumab中对患者治疗方案进行个性化治疗方案。我们的具体目的是：1）使用旨在最大程度地减少去盐化并最大化肿瘤内部肿瘤细胞中的放射性诱捕的方法，将曲妥珠单抗标记为[211]和[124] L； 2）评估这些放射性标记的曲妥珠单抗结合物在人类乳腺癌细胞中的体外和皮下乳腺癌的小鼠中的组织分布以及在表达乳腺癌的HER2的无胸腺大鼠NM模型中； 3）确定NM的无菌大鼠模型中的治疗功效，神经Xis分布，毒性和辐射剂量测定； 4）获得FDA研究的最佳[211] AT-和[124] L标记的曲妥珠单抗结合物，然后在乳腺癌NM和5）中进行临床试验，并使用相同的翻译范式进行了相同的翻译范式，以确定与[211]和[211]和评估[124]和评估[211]和[124]的最佳策略，并且NM肺癌。