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）：该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）成像受体成像受体的靶向探针。过表达的VEGF受体在肿瘤血管生成的发作和进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。但是，这些受体在处方或监测抗血管生成疗法时没有用作生物标志物，因为没有无创的方法来评估其患病率。因此，对VEGF受体的非侵入性成像可以解决未满足的临床需求，并可能导致循证选择抗血管生成治疗的患者和个性化治疗方案的设计。此外，据报道，VEGF受体在恶性生长开始时在肿瘤和连续的宿主脉管系统中过表达，因此VEGF受体成像可用于早期诊断和良性病变之间的歧视。在该项目的第一阶段，我们开发了用于近红外荧光（NIRF）和单个光子发射计算机断层扫描（SPECT）的新型探针，该探针适用于VEGF受体，适合于临床发育。对比剂对对比剂的位点特异性结合对适当设计的VEGF产生了与内皮细胞上的VEGF受体结合的探针，就像父母VEGF一样有效。我们确定我们的基于VEGF的探针经历了受体介导的内在化，并在肿瘤和宿主内皮细胞中积聚过表达VEGF受体的受体。重要的是，使用失活的基于VEGF的探针失去与VEGF受体结合的能力，我们评估了非特异性机制对探针积累肿瘤脉管系统的贡献。我们的目标成像探针基于一种新型的单链（SC）VEGF，该探针与传统的VEGF相对于传统的VEGF提供了显着改善，并具有通过二硫键链接的两个亚基。通过我们专有的人源性半胱氨酸包含标签（CYS-TAG）将对比剂特定于对比剂与SCVEGF进行特定于位置的结合，可确保成像探针的均匀性。共同，我们的I期结果为基于VEGF的探针的临床开发开发了肿瘤脉管系统中VEGF受体的选择性和特定成像的临床发展道路。在第二阶段，我们将建立基于SCVEGF的探针的安全性，开发可扩展的GLP产生共轭物，并表征这些探针的实用性，以预测/监测对VEGF受体特定抑制剂的反应以及对恶性肺病变的早期诊断。我们预计II期结果将建立基于SCVEGF的成像探针作为临床开发的可行候选者。在该项目的第二阶段中，我们将在临床前开发新的靶向探针前开发至关重要的步骤，用于特定受体的分子成像，这些探针在肿瘤脉管系统的发作和生长中起着至关重要的作用，并且是治疗性发育的主要靶标。在该项目的第一阶段获得的结果确定了1）使用新型专有技术构建目标探针的可行性，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，这些有针对性的成像探针的临床开发为基于证据的特定治疗疗法的患者选择，及时监测对抗癌疗法的反应，早期癌症诊断以及良性病变和恶性病变的歧视。