Targeted Radiotherapy of Neoplastic Meningitis using Monoclonal Antibodies Label

项目总结(见说明)： 项目1：使用α粒子发射标记的单抗进行肿瘤脑膜炎的定向放射治疗[211]at。迈克尔·扎伊茨基博士，项目负责人 肿瘤性脑膜炎(NM)是一种导致中位生存期仅为2-6个月的疾病，其特征是恶性肿瘤细胞在软脑膜间隙内扩散，并沿大脑和脊柱转移。就受影响的患者数量而言，乳腺癌和肺癌是最常见的转移到软脑膜的原发部位。我们建议最初专注于针对乳腺癌NM的靶向放射治疗的快速翻译开发，如果成功，将同样的方法应用于肺癌。我们的策略是将曲妥珠单抗与a粒子发射器相结合，因为这些a粒子具有比传统辐射更大的细胞毒性效果，并且在组织中的范围只有几个细胞直径，这一特点为NM治疗提供了重要的优势。我们寻求确定曲妥珠单抗的最佳标记方法，不仅为[211]AT，也为[124]L走向临床研究。如果我们能够建立通过两种放射性卤素标记的单抗在体内的相似行为，[124]L标记的曲妥珠单抗的正电子发射计算机断层扫描可以为确定辐射剂量学、评估神经轴内的分布和个性化患者的治疗方案提供一个有价值的工具。我们的具体目标是：1)用[211]At和[124]L标记曲妥珠单抗，旨在最大限度地减少脱卤化和最大限度地将放射性捕获到肿瘤细胞内；2)评估这些放射性标记的曲妥珠单抗结合物在体外人乳腺癌细胞中的组织分布，以及在皮下移植乳腺癌小鼠和表达HER2的裸鼠NM模型中的组织分布；3)确定这些放射性标记的曲妥珠单抗在裸鼠NM模型中的治疗效果、神经轴分布、毒性和辐射剂量学；4)为获得FDA最好的[211]At和[124]L标记的曲妥珠单抗结合物的研究新药许可，然后在乳腺癌NM患者中进行临床试验；5)使用相同的翻译范式确定[211]At和[124]I标记Panitumab的最佳策略，并评估它们作为肺癌NM靶向放射治疗和诊断的可能性。

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.