Clinical development of 18F PET tracer for imaging VEGF receptors

用于 VEGF 受体成像的 18F PET 示踪剂的临床开发

• 批准号: 8648418
• 负责人: Joseph M Backer
• 金额: $ 22.29万
• 依托单位: SIBTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8648418
• 关键词: Adverse effects; Alkynes; Angiogenesis Inhibitors; Area; Biodistribution; Biological Markers; Blood Vessels; Cancer Patient; Chemistry; Clinical; Clinical Research; Complement; Copper; Cyclic GMP; Data; Development; Drug Targeting; Failure; Goals; Image; Integrins; Lead; Ligands; Logistics; Magnetic Resonance Imaging; Mediating; Medical; Metabolic; Modeling; Monitor; Mus; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Positron-Emission Tomography; Prevalence; Production; Proteins; Radioisotopes; Radiolabeled; Reporting; Resistance; Resolution; Site; Small Business Innovation Research Grant; Specificity; Staging; Therapeutic; Time; Toxicology; Tracer; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Work; base; bevacizumab; cGMP production; clinical toxicology; commercialization; dosimetry; experience; healthy volunteer; inhibitor/antagonist; molecular imaging; mouse model; neovasculature; novel; oncology; pre-clinical; public health relevance; radiotracer; receptor; response; single photon emission computed tomography; success; triple-negative invasive breast carcinoma; tumor; tumor growth; vessel regression

The overall goal of this collaborative Fast-Track project is clinical development of a novel 18F PET tracer for molecular imaging of receptors for vascular endothelial growth factor (VEGFR). This receptor is the major anti-angiogenic drug target in oncology patients. Critically, VEGFR prevalence decreases when VEGF/VEGFR anti-angiogenic inhibitors "work", and increases when these drugs stop "working". These findings provide a rationale for VEGFR imaging for image-guided anti-angiogenic therapy. To provide for high selectivity, specificity, and VEGFR-mediated intracellular accumulation, the 18F PET tracer will be targeted by VEGFR ligand, scVEGF. The protein will be site-specifically derivatized with a strained alkyne for copper-free click- chemistry radiolabeling with 18F-PEG(4)-azide. In Phase I of this project we will select the lead scVEGF/Alkyne conjugate, optimize conditions for 18F radiolabeling, and validate the use of lead tracer for monitoring anti- angiogenic therapy in a murine model of triple negative breast cancer. In Phase II we will produce cGMP grade conjugate, undertake FDA-required toxicology and dosimetry studies, and proceed to Phase I clinical trials in healthy volunteers.

该合作快速通道项目的总体目标是临床开发一种新型药物 用于血管内皮生长因子受体分子成像的 18F PET 示踪剂 （血管内皮生长因子受体）。该受体是肿瘤患者的主要抗血管生成药物靶点。 重要的是，当使用 VEGF/VEGFR 抗血管生成抑制剂时，VEGFR 患病率会降低 “起作用”，并且当这些药物停止“起作用”时增加。这些发现提供了 VEGFR 成像用于图像引导抗血管生成治疗的基本原理。 提供高选择性、特异性和 VEGFR 介导的细胞内 积累后，18F PET 示踪剂将被 VEGFR 配体 scVEGF 靶向。这 蛋白质将用粗炔进行位点特异性衍生化，以获得无铜的点击- 用 18F-PEG(4)-叠氮化物进行化学放射性标记。 在该项目的第一阶段，我们将选择先导的 scVEGF/Akyne 结合物，优化 18F放射性标记的条件，并验证使用铅示踪剂监测抗 三阴性乳腺癌小鼠模型的血管生成治疗。在第二阶段我们将 生产 cGMP 级结合物，进行 FDA 要求的毒理学和剂量测定 研究，并在健康志愿者中进行一期临床试验。