Targeted Radiotherapy of Neoplastic Meningitis using Monoclonal Antibodies Label

项目总结（见说明）： 项目1。用α粒子发射[211] At标记的单克隆抗体靶向放射治疗肿瘤性脑膜炎。 Michael Zaiutsky博士，项目负责人 肿瘤性脑膜炎（NM）的特征在于恶性肿瘤细胞在软脑膜间隙内的扩散以及沿着脑和脊柱的转移性扩散，是一种导致中位生存期仅为2-6个月的破坏性疾病。就受影响的患者数量而言，乳腺癌和肺癌是转移到软脑膜的最常见的原发部位。我们建议首先专注于乳腺癌NM的靶向放射治疗的快速翻译发展，如果成功，将相同的方法应用于肺癌。我们的策略是将联合收割机曲妥珠单抗与α粒子发射体α ^^At组合，因为这些α粒子具有比常规辐射更大的细胞毒性效力，并且在组织中具有仅几个细胞直径的范围，这些特征为NM治疗提供了重要的优势。我们寻求确定不仅用于[211]At而且用于[124] l标记曲妥珠单抗的最佳方法，以进一步进行临床研究。如果我们可以建立类似的单克隆抗体通过两种放射性卤素标记的体内行为，PET成像与[124] l-标记的曲妥珠单抗可以提供一个有价值的工具，用于确定辐射剂量，评估在神经轴内的分布，和个性化的患者治疗方案[211] At-标记的曲妥珠单抗。我们的具体目标是：1）用[211]At和[124] I标记曲妥珠单抗，使用设计为在标记的mAb内化后使肿瘤细胞内的脱卤作用最小化并使放射性截留最大化的方法; 2）在体外评价这些放射性标记的曲妥珠单抗缀合物在人乳腺癌细胞中的作用，和在具有皮下乳腺癌异种移植物的小鼠和表达HER 2的乳腺癌的无胸腺大鼠NM模型中的组织分布;（3）对NM无胸腺大鼠模型进行疗效、神经轴分布、毒性和放射剂量测定; 4）为了获得最佳[211] At-和[124] I-标记的曲妥珠单抗缀合物的FDA研究性新药许可，然后在乳腺癌NM患者中进行临床试验，5）使用相同的翻译范例确定用[211]标记帕尼单抗的最佳策略在和[124] I，并评估其作为肺癌NM患者的靶向放射治疗和诊断的潜力。

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.