Molecular PET Imaging of MET with Small Protein Ligands

小蛋白质配体 MET 的分子 PET 成像

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：MET或肝细胞生长因子受体是众多癌症的驱动器和生物标志物。针对该信号轴的几种激酶抑制剂和细胞外拮抗剂在某些MET+患者种群中表现出临床效率。此外，MET过表达是预后不良的预测指标。这是拟议的研究以以下假设为中心：MET表达的定量分子成像将通过对原发性肿瘤和转移酶中MET水平的非侵入性评估来为患者分层和预后提供有效的手段。将需要适当评估这一假设。拟议的研究旨在产生分子成像问题，以实现这一评估，同时还提供了对有利于实体瘤分子成像的特征的基本见解。目的：工程师通过蛋白质工程和配体支架拓扑和生物物理参数的比较评估MET的敏感，特定的正电子发射断层扫描（PET）代理。 AIM 1：用于癌症中MET表达的PET成像的相对评估的GP2，Affibody，纤维蛋白和抗体合成配体。从三个小（5-10 kDa）蛋白质支架设计的纳摩尔亲和力低的合成，非阳性配体将用作宠物成像剂。 64cu-放射性标记的配体将通过宠物 /计算机断层扫描和出色的组织生物分布在皮下肺癌Xenographics中评估。与抗MET抗体相比，将比较跨支架和突变体的分子敏感性和特异性。代谢物，免疫原性和生物物理研究将在铅问题上进行。 AIM 2：通过调节配体生物物理学，使用临床上较高的放射性同位素以及在更先进的小鼠模型中评估，通过调节配体生物物理学来提高铅问题对临床翻译的分子成像性能。通过使用更快速腐烂的放射性同位素（68GA），改良的位点和化学剂，用于放射性同位素共轭以及配体亲水性和电荷的调节，将增强铅成像剂。分子敏感性和特异性将在传播的肺癌模型中评估，以准备翻译。