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（由申请人提供）：MET或肝细胞生长因子受体是许多癌症的驱动因子和生物标志物。靶向该信号传导轴的几种激酶抑制剂和细胞外拮抗剂已在选定的MET+患者人群中证明了临床疗效。此外，MET过表达是预后不良的预测因子。因此，拟议的研究集中在以下假设：MET表达的定量分子成像将通过原发性肿瘤和转移灶中MET水平的非侵入性评估为患者分层和预后提供有效手段。需要进行临床研究来适当评估这一假设。拟议的研究旨在生成分子成像探针，以实现这种评估，同时还提供对实体瘤分子成像有益的特征的基本见解。目的：通过蛋白质工程和配体支架拓扑结构和生物物理参数的比较评估，设计用于MET的灵敏、特异性正电子发射断层扫描（PET）试剂。目的1：比较评估Gp 2、抗体、纤维连接蛋白和抗体合成配体用于PET成像的肿瘤MET表达。合成的、非激动性配体，对MET具有低纳摩尔亲和力，由三种小（5-10 kDa）蛋白质支架工程化，将用作PET成像剂。将通过PET /计算机断层扫描和切除的组织生物分布在皮下肺癌异种移植物中评价64 Cu放射性标记的配体。将在支架和突变体之间比较分子灵敏度和特异性，并与抗MET抗体进行比较。将对电极导线探针进行代谢物、免疫原性和生物物理学研究。目标二：通过调节配体生物物理学、使用临床上更好的上级放射性同位素和在更先进的小鼠模型中进行评估，增强铅探针的分子成像性能，使其向临床转化。通过使用更快速衰变的放射性同位素（68 Ga）、用于放射性同位素缀合的修饰位点和化学以及配体亲水性和电荷的调节，将增强铅成像剂。将在播散性肺癌模型中评价分子灵敏度和特异性，以准备翻译。