Targeted delivery of Lu-177 to tumor vasculature

将 Lu-177 靶向递送至肿瘤脉管系统

• 批准号: 7745604
• 负责人: Joseph M Backer
• 金额: $ 28.64万
• 依托单位: SIBTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-24 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7745604
• 关键词: Angiogenesis Inhibition; Angiogenesis Inhibitors; Area; Avastin; BAY 54-9085; Biodistribution; Bolus Infusion; Breast Cancer Model; Breast Carcinoma; Cells; Chelating Agents; Chemicals; Clinical; Data; Development; Dose; Endocytosis; Endothelial Cells; Engineering; Equilibrium; Evaluation; FDA approved; Goals; Growth Factor Inhibition; Image; Injection of therapeutic agent; Length; Life; Ligands; Liver; Luciferases; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Modeling; Mus; Neoplasm Metastasis; Pancreas; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Positron-Emission Tomography; Process; Production; Publishing; Radiation; Radiation therapy; Radioactivity; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Reporting; Residual Tumors; Role; Schedule; Signal Transduction; Site; Starvation; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Tissues; Tracer; Treatment Efficacy; Treatment Protocols; Tumor Angiogenesis; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; base; cellular engineering; chemotherapy; cold temperature; cytotoxic; design; dosimetry; effective therapy; efficacy testing; in vivo; killings; malignant breast neoplasm; mouse model; neoplastic cell; novel; overexpression; public health relevance; radiotracer; receptor; research study; stem; success; targeted delivery; tumor; uptake; vector

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.

描述（由申请人提供）： 我们的目标是开发一种靶向抗癌177 Lu放射治疗剂，其通过肿瘤血管系统中内皮细胞的受体介导的摄取定位于肿瘤。由于β发射（1.5 mm最大深度），预计177 Lu放射性药物对宿主内皮细胞和周围肿瘤细胞具有细胞毒性，但对周围健康组织无细胞毒性。此外，肿瘤脉管系统的靶向破坏可以使摄取区域之外的肿瘤区域饥饿，进一步放大所提出的放射性药物的细胞毒性作用。为了实现177 Lu在肿瘤血管系统中的选择性积累，我们将其靶向血管内皮生长因子（VEGFR）的受体。这些受体在肿瘤血管系统中过表达，并且它们在肿瘤血管生成中的关键作用通过开发选择性抑制VEGFR活性的药物的大规模驱动而得到强调。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”仅取得了适度的成功。批准的抗血管生成药物（阿瓦斯丁，舒尼替尼，索拉非尼）与既定的化疗或放疗联合使用只能延长一小部分不可预测患者的生命数月。由于这些问题，我们提出了一种不同的方法来VEGFR靶向治疗。而不是抑制这些受体，我们建议使用VEGFR治疗放射性核素的靶向输送。我们假设，肿瘤血管的破坏和肿瘤细胞的旁观者杀伤的组合将提供比单独的VEGFR抑制显著更大的治疗效果。为了将177 Lu靶向肿瘤血管，我们将使用专有的VEGFR配体，即我们公司开发的工程化单链（sc）VEGF。根据我们公开的数据，scVEGF可以用PEG化螯合剂位点特异性衍生化，用于VEGF受体介导的成像和治疗性放射性核素向肿瘤脉管系统的递送。我们的初步结果表明，这种共轭物可以用177 Lu放射性标记到足以在肿瘤模型中获得治疗效果的特定放射性。此外，这些研究指出了优化scVEGF/177 Lu放射性药物的化学设计的几种途径。在该项目的I期，我们建议优化scVEGF/177 Lu的组成，计算优化的scVEGF/177 Lu的剂量学，并进行单次或分次剂量治疗方案的初始测试。这些都是关键的任务，因为任何潜在的放射治疗剂的可行性是由其治疗窗口，其治疗效果和非特异性放射毒性之间的平衡决定的。在该项目的第二阶段，我们将在乳腺癌转移模型和难治性肝癌、胰腺癌和脑癌模型中测试优化的scVEGF/177 Lu。第二个主要的II期任务是开发在I期优化的scVEGF缀合物的GMP生产。公共卫生相关性：开发用于将177 Lu输送到肿瘤血管系统的靶向放射治疗剂。我们预期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性。本项目I期将优化靶向放射治疗剂，建立其放射毒性和疗效的乳腺癌小鼠模型。I期研究结果将为II期靶向放射治疗药物的临床开发提供合理依据。