VEGF-based Targeted Imaging of Tumor Vasculature

基于 VEGF 的肿瘤脉管系统靶向成像

• 批准号: 7271615
• 负责人: Joseph M Backer
• 金额: $ 54.52万
• 依托单位: SIBTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-08 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7271615
• 关键词: Address; Affect; Angiogenesis Inhibitors; Area; Benign; Binding; Biological Markers; Cancer Diagnostics; Characteristics; Chemistry; Clinical; Compatible; Contrast Media; Cysteine; Development; Diagnostic; Discrimination; Dose; Early Diagnosis; Endothelial Cells; Engineering; Ensure; Funding; Goals; Growth; Growth Factor; Image; Invasive; Iodination reaction; Lead; Lesion; Link; Liver; Lung; Malignant - descriptor; Mediating; Methods; Modeling; Monitor; Mus; Patient Selection; Patients; Phase; Play; Predictive Value; Preparation; Prevalence; Process; Production; Program Development; Protein Overexpression; Proteins; Range; Recombinant Vascular Endothelial Growth Factor; Relative (related person); Reporting; Role; Safety; Site; Solid; Spatial Distribution; Stress; Sulfhydryl Compounds; Technology; Therapeutic; Tumor Angiogenesis; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; base; cancer therapy; chemotherapy; design; disulfide bond; experience; imaging probe; inhibitor/antagonist; innovation; molecular imaging; monomer; new technology; novel; oncology; pre-clinical; programs; protein misfolding; receptor; receptor mediated endocytosis; response; single photon emission computed tomography; success; therapeutic target; therapy design; tumor; tumor growth; uptake

DESCRIPTION (provided by applicant): The overall goal of this project is to develop targeted probes for imaging receptors for vascular endothelial growth factor (VEGF) in tumor angiogenesis. Overexpressed VEGF receptors play the crucial role in the onset and progression of tumor angiogenesis and therefore, these receptors are the primary targets of tremendous efforts to develop inhibitors of angiogenesis. However, these receptors are not being used as biomarkers in prescribing or monitoring anti-angiogenic therapy, because there are no non-invasive methods for assessment of their prevalence. Thus, non-invasive imaging of VEGF receptors addresses unmet clinical needs and might lead to evidence-based selection of patient for anti-angiogenic therapy, and design of personalized treatment regiments. In addition, since VEGF receptors are reportedly overexpressed in tumor and contiguous host vasculature at the onset of malignant growth, VEGF receptor imaging might be used for early diagnostics and discrimination between benign and malignant lesions. In Phase I of this project we have developed novel VEGF-based probes for near-infrared fluorescent (NIRF) and single photon emission computed tomography (SPECT) imaging of VEGF receptors that are suitable for clinical development. Site-specific conjugation of contrast agents to appropriately designed VEGF yielded probes that bind to VEGF receptors on endothelial cells as effectively as parental VEGF. We established that our VEGF-based probes undergo receptor-mediated internalization and accumulate in tumor and host endothelial cells overexpressing VEGF receptors. Importantly, using inactivated VEGF-based probes that lost the ability to bind to VEGF receptors, we evaluated a contribution of non-specific mechanisms to probe accumulation in tumor vasculature. Our targeted imaging probes are based on a novel single-chain (sc) VEGF that provides fora significant improvement in expression, refolding, and purification, relative to a conventional VEGF with two subunits linked via disulfide bonds. Site-specific conjugation of contrast agents to scVEGF via our proprietary humanized cysteine containig tag (Cys-tag) ensures homogeneity of the imaging probes. Taking together, our Phase I results open the road to clinical development of VEGF-based probes for selective and specific imaging of VEGF receptors in tumor vasculature. In Phase II, we will establish safety of scVEGF-based probes, develop scalable GLP production of conjugates and characterize utility of these probes for predicting/monitoring responses to a specific inhibitor of VEGF receptors and for early diagnostic of malignant lung lesions. We expect that Phase II results will establish scVEGF-based imaging probes as viable candidates for clinical development. In Phase II of this project we will undertake crucial steps in pre-clinical development of novel targeted probes for molecular imaging of specific receptors that play crucial role in the onset and growth of tumor vasculature and are the primary targets for therapeutic development. Results obtained in the Phase I of this project established 1) feasibility of constructing targeted probes, using a novel proprietary technology, and 2) feasibility of obtaining early and dynamic information about the status of these receptors. Thus, clinical development of these targeted imaging probes open new opportunities for evidence-based selection of patients for specific therapeutic treatments, timely monitoring responses to anti-cancer therapies, for early cancer diagnostics, and discrimination between benign and malignant lesions.

描述（由申请人提供）：本项目的总体目标是开发肿瘤血管生成中血管内皮生长因子（VEGF）受体成像的靶向探针。过表达的VEGF受体在肿瘤血管生成的发生和发展中起着至关重要的作用，因此，这些受体是开发血管生成抑制剂的巨大努力的主要目标。然而，这些受体没有被用作处方或监测抗血管生成治疗的生物标志物，因为没有非侵入性方法来评估其患病率。因此，VEGF受体的非侵入性成像解决了未满足的临床需求，并可能导致基于证据的抗血管生成治疗患者的选择和个性化治疗方案的设计。此外，由于据报道VEGF受体在恶性生长开始时在肿瘤和邻近宿主脉管系统中过表达，VEGF受体成像可用于早期诊断和良性与恶性病变之间的区分。在该项目的第一阶段，我们开发了新的VEGF为基础的探针，近红外荧光（NIRF）和单光子发射计算机断层扫描（SPECT）成像的VEGF受体，适合于临床开发。造影剂与适当设计的VEGF的位点特异性偶联产生了与内皮细胞上的VEGF受体结合的探针，其与亲本VEGF一样有效。我们确定了我们的基于VEGF的探针经历受体介导的内化，并在过表达VEGF受体的肿瘤和宿主内皮细胞中积累。重要的是，使用失活的基于VEGF的探针，失去了与VEGF受体结合的能力，我们评估了非特异性机制对肿瘤血管系统中探针积累的贡献。我们的靶向成像探针是基于一种新的单链（sc）VEGF，提供了一个显着改善的表达，重折叠，和纯化，相对于传统的VEGF与两个亚基通过二硫键连接。通过我们专有的人源化含半胱氨酸标签（Cys-tag）将造影剂与scVEGF位点特异性缀合，确保成像探针的均一性。总之，我们的I期研究结果为基于VEGF的探针的临床开发开辟了道路，用于肿瘤血管系统中VEGF受体的选择性和特异性成像。在第二阶段，我们将建立安全的scVEGF为基础的探针，开发可扩展的GLP生产的共轭物和表征这些探针的效用，用于预测/监测反应的特异性抑制剂的VEGF受体和早期诊断恶性肺病变。我们预计，第二阶段的结果将建立scVEGF为基础的成像探针作为可行的候选人的临床开发。在该项目的第二阶段，我们将在临床前开发用于特异性受体分子成像的新型靶向探针方面采取关键步骤，这些受体在肿瘤血管的发生和生长中起着关键作用，并且是治疗开发的主要靶标。该项目第一阶段获得的结果确定了1）使用新的专有技术构建靶向探针的可行性，以及2）获得有关这些受体状态的早期和动态信息的可行性。因此，这些靶向成像探针的临床开发为基于证据选择患者进行特定治疗、及时监测对抗癌疗法的反应、早期癌症诊断以及区分良性和恶性病变提供了新的机会。