Targeted delivery of Lu-177 to tumor vasculature

描述(由申请人提供)： 我们的目标是开发一种靶向抗癌的177Lu放射治疗剂，通过受体介导的肿瘤血管内皮细胞摄取定位于肿瘤。由于β辐射(最大深度为1.5 mm)，177Lu放射性药物预计对宿主内皮细胞和周围肿瘤细胞具有细胞毒性，但对周围健康组织不具有细胞毒性。此外，靶向破坏肿瘤血管可使摄取区域以外的肿瘤区域饥饿，进一步放大所提议的放射性药物的细胞毒性效应。为了实现177Lu在肿瘤血管系统中的选择性积聚，我们将其靶向于血管内皮生长因子(VEGFR)的受体。这些受体在肿瘤血管系统中过度表达，它们在肿瘤血管生成中的关键作用被开发选择性抑制VEGFR活性的药物的巨大驱动力所强调。尽管靶向VEGFR的意义源于它们在肿瘤血管生成中的作用，但到目前为止，“抑制方法”只取得了一定的成功。批准的抗血管生成药物(阿瓦斯丁、苏尼替尼、索拉非尼)与既定的化疗或放射治疗相结合，只能在一小群不可预测的患者中延长几个月的生命。由于这些问题，我们提出了一种不同的方法来进行VEGFR靶向治疗。我们建议使用VEGFR来靶向传递治疗性放射性核素，而不是抑制这些受体。我们假设，破坏肿瘤血管和旁观者杀伤肿瘤细胞的组合将提供比单独抑制VEGFR更大的治疗效果。为了靶向肿瘤血管，我们将使用专利的VEGFR配体，这是我们公司开发的一种工程单链(Sc)血管内皮生长因子。根据我们已发表的数据，可以用聚乙二醇化的螯合剂对单链血管内皮生长因子进行定点衍生化，以实现血管内皮生长因子受体介导的显像和治疗性放射性核素向肿瘤血管系统的传递。我们的初步结果表明，这种偶联物可以用177Lu标记到足以在肿瘤模型中发挥治疗效果的特定放射性。此外，这些研究还指出了优化scVEGF/177Lu放射性药物化学设计的几条途径。在该项目的第一阶段，我们建议优化scVEGF/177Lu的组成，计算优化后的scVEGF/177Lu的剂量学，并进行单剂量或分步剂量治疗方案的初步测试。这些都是关键任务，因为任何潜在的放射治疗剂的生存能力都取决于其治疗窗口，即其治疗效果和非特异性放射毒性之间的平衡。在该项目的第二阶段，我们将在乳腺癌转移模型和难以治疗的肝癌、胰腺癌和脑癌模型中测试优化的scVEGF/177Lu。第二个主要的第二阶段任务将是开发在第一阶段优化的scVEGF结合物的GMP生产：开发一种靶向放射治疗剂，将177Lu输送到肿瘤血管。我们预计这种治疗剂将被肿瘤内皮细胞内化，并对这些细胞和周围的肿瘤细胞具有细胞毒作用。在本项目的第一阶段，我们将优化靶向放射治疗剂，建立其放射毒性和治疗效果的小鼠乳腺癌模型。第一阶段的研究结果将为第二阶段靶向放射治疗药物的临床开发提供合理的依据。

DESCRIPTION (provided by applicant): Our goal is to develop a targeted anti-cancer 177Lu radiotherapeutic agent that localizes to a tumor via receptor- mediated uptake by endothelial cells in the tumor vasculature. Due to beta emission (1.5 mm max depth) 177Lu radiopharmaceutical is expected to be cytotoxic to the host endothelial cells and to surrounding tumor cells, but not to surrounding healthy tissue. In addition, targeted destruction of tumor vasculature can bring starvation to tumor areas outside of uptake areas, further amplifying the cytotoxic effects of the proposed radiopharmaceutical. To achieve selective accumulation of 177Lu in the tumor vasculature, we will target it to the receptors for vascular endothelial growth factor (VEGFR). These receptors are overexpressed in tumor vasculature and their critical role in tumor angiogenesis is underscored by the massive drive to develop drugs that selectively inhibit VEGFR activity. Although the significance of targeting VEGFR stems from their role in tumor angiogenesis, the "inhibition approach" has, so far, only achieved a modest success. Approved anti-angiogenic drugs (Avastin, Sunitinib, Sorafenib) in combination with established chemo- or radiotherapy prolong life only for several months in a small and unpredictable set of patients. Because of these issues, we propose a different approach to VEGFR- targeted therapy. Instead of inhibiting these receptors, we propose to use VEGFR for targeted delivery of therapeutic radionuclides. We hypothesize that combination of destruction of tumor vasculature and bystander killing of tumor cells will provide for a significantly larger therapeutic effect than VEGFR inhibition alone. For the targeting of 177Lu to the tumor vasculature, we will use a proprietary VEGFR ligand, an engineered single-chain (sc) VEGF developed in our company. According to our published data, scVEGF can be site- specifically derivatized with PEGylated chelators for VEGF receptor mediated delivery of imaging and therapeutic radionuclides to tumor vasculature. Our preliminary results indicate that such conjugates can be radiolabeled with 177Lu to a specific radioactivity that is sufficient for therapeutic efficacy in tumor models. Furthermore, these studies indicated several pathways to optimize the chemical design of scVEGF/177Lu radiopharmaceutical. In Phase I of this project we propose to optimize the composition of scVEGF/177Lu, calculate the dosimetry of optimized scVEGF/177Lu, and perform an initial test of single or divided dose treatment regimens. These are the critical tasks because the viability of any potential radiotherapeutic agent is determined by its therapeutic window, the balance between its therapeutic efficacy and non-specific radiotoxicity. In Phase II of the project we will test optimized scVEGF/177Lu in metastatic models of breast cancer and models of poorly treatable liver, pancreatic, and brain cancer. The second major Phase II task will be the development of GMP production of scVEGF conjugate optimized in Phase I. PUBLIC HEALTH RELEVANCE: The developing a targeted radiotherapeutic agent for delivery of 177Lu to tumor vasculature. We expect that this therapeutic agent will be internalized by tumor endothelial cells and will be cytotoxic to such cells and surrounding tumor cells. In Phase I of this project, we will optimize targeted radiotherapeutic agent, establish its radiotoxicity and therapeutic efficacy mouse model of breast cancer. The results of Phase I will provide a rational basis for clinical development of targeted radiotherapeutic agent in Phase II.