Molecular PET Imaging of MET with Small Protein Ligands

小蛋白质配体 MET 的分子 PET 成像

• 批准号: 8890455
• 负责人: Benjamin Hackel
• 金额: $ 18.55万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8890455
• 关键词: Affinity; Antibodies; Biodistribution; Biological Markers; Biophysics; Blood; Cancer Model; Cell Survival; Characteristics; Charge; Chemistry; Clinical; Clinical Research; Development; Early Diagnosis; Engineering; Enhancing Antibodies; Epitopes; Evaluation; Evolution; Extravasation; Fibronectins; Future; Growth; Hepatocyte Growth Factor; Human; Image; Immunohistochemistry; Kinetics; Knowledge; Lead; Left; Ligands; Location; Magnetism; Malignant Neoplasms; Malignant neoplasm of lung; Metabolic; Molecular; Monoclonal Antibodies; Mus; Mutagenesis; Neoplasm Metastasis; Patients; Penetration; Performance; Physiological; Positron; Positron-Emission Tomography; Preparation; Primary Neoplasm; Protein Engineering; Proteins; Proto-Oncogene Protein c-met; Radioisotopes; Radiolabeled; Receptor Protein-Tyrosine Kinases; Relative (related person); Research; Role; Scaffolding Protein; Sensitivity and Specificity; Signal Transduction; Site; Solid Neoplasm; Specificity; Stratification; Surface; Tissues; Tracer; Translations; Tyrosine Kinase Inhibitor; X-Ray Computed Tomography; Xenograft Model; Xenograft procedure; Yeasts; angiogenesis; base; biophysical analysis; biophysical properties; clinical efficacy; comparative; cross reactivity; design; directed evolution; empowered; extracellular; hydrophilicity; imaging agent; imaging probe; immunogenicity; improved; in vivo; insight; kinase inhibitor; longitudinal positron emission tomography; molecular imaging; mouse model; mutant; novel; outcome forecast; overexpression; patient population; public health relevance; radiotracer; scaffold; subcutaneous; targeted treatment; tumor; tumor xenograft

 DESCRIPTION (provided by applicant): MET, or hepatocyte growth factor receptor is a driver and biomarker of numerous cancers. Several kinase inhibitors and extracellular antagonists targeting this signaling axis have demonstrated clinical efficacy in select MET+ patient populations. Moreover, MET overexpression is a predictor of poor prognosis. Thus, the proposed research is centered on the following hypothesis: quantitative molecular imaging of MET expression will provide an efficient means for patient stratification and prognosis by non-invasive assessment of MET levels in primary tumors and metastases. Clinical studies will be needed to appropriately evaluate this hypothesis. The proposed research is designed to generate the molecular imaging probes to enable this assessment while also providing fundamental insight into the characteristics that benefit molecular imaging of solid tumors. Objective: Engineer a sensitive, specific positron emission tomography (PET) agent for MET through protein engineering and comparative evaluation of ligand scaffold topology and biophysical parameters. Aim 1: Comparatively evaluate Gp2, affibody, fibronectin, and antibody synthetic ligands for PET imaging of MET expression in cancer. Synthetic, non-agonistic ligands, with low nanomolar affinities to MET, engineered from three small (5-10 kDa) protein scaffolds will be used as PET imaging agents. 64Cu- radiolabeled ligands will be evaluated in subcutaneous lung cancer xenografts by PET / computed tomography and excised tissue biodistribution. Molecular sensitivity and specificity will be compared across scaffolds and mutants as well as compared to an anti-MET antibody. Metabolite, immunogenicity, and biophysical studies will be performed on lead probes. Aim 2: Enhance the molecular imaging performance of lead probes towards clinical translation through modulation of ligand biophysics, use of a clinically superior radioisotope, and assessment in a more advanced mouse model. Lead imaging agents will be enhanced through the use of a more rapidly decaying radioisotope (68Ga), modified sites and chemistries for radioisotope conjugation, and modulation of ligand hydrophilicity and charge. Molecular sensitivity and specificity will be evaluated in a disseminated lung cancer model in preparation for translation.

 描述(申请人提供)：MET，或肝细胞生长因子受体，是多种癌症的驱动因素和生物标志物。针对这一信号轴的几种激酶抑制剂和细胞外拮抗剂已经在精选的MET+患者群体中证明了临床疗效。此外，MET过度表达是预后不良的预测指标。因此，本研究围绕以下假设展开：通过对原发肿瘤和转移瘤中MET水平的非侵入性评估，MET表达的定量分子成像将为患者分层和预后提供有效的手段。需要临床研究来适当地评估这一假说。这项拟议的研究旨在产生分子成像探针，以实现这一评估，同时还提供对有利于实体肿瘤分子成像的特征的基本见解。目的：通过蛋白质工程和对配体支架拓扑结构和生物物理参数的比较评价，设计出一种灵敏、特异的MET正电子发射断层扫描(PET)试剂。目的1：比较评价GP2、亲和体、纤维连接蛋白和抗体合成配体在肿瘤MET表达的PET显像中的作用。由三个小的(5-10 kDa)蛋白质支架制成的具有低纳米分子亲和力的合成的非激动型配体将被用作PET显像剂。64铜标记的配体将通过PET/计算机断层扫描和切除的组织生物分布来评估皮下肺癌移植瘤。分子敏感性和特异性将在支架和突变体之间进行比较，并与抗MET抗体进行比较。将在铅探针上进行代谢物、免疫原性和生物物理研究。目的2：通过调节配体生物物理，使用临床上最好的放射性同位素，以及在更先进的小鼠模型中进行评估，提高铅探针的分子成像性能，使其适用于临床。铅显像剂将通过使用衰变更快的放射性同位素(68Ga)、用于放射性同位素偶联的修饰位置和化学物质以及调节配体亲水性和电荷来增强。分子敏感性和特异性将在播散性肺癌模型中进行评估，为翻译做准备。