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Labeling nanobodies with 18F residualizing labels for HER2 specific PET imaging

使用 18F 残留标签标记纳米抗体，用于 HER2 特异性 PET 成像

基本信息

批准号：
9057484
负责人：
GANESAN VAIDYANATHAN
金额：
$ 36.37万
依托单位：
DUKE UNIVERSITY
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：
2015-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9057484
关键词：
Accounting Adhesions Adverse effects Affinity Animal Model Antibodies Autopsy Binding Biodistribution Biological Assay Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Breast Carcinoma Catabolism Cell Line Cells Characteristics Chemistry Detection Development Diagnostic Neoplasm Staging Drug Targeting ERBB2 gene Early Diagnosis Economics Effectiveness Epidermal Growth Factor Receptor Exclusion Fab Immunoglobulins Family member Fluorescent in Situ Hybridization Fluorine Glycoproteins Goals Guanidines Half-Life Health High Pressure Liquid Chromatography Image Imaging Device Immunoglobulin G Immunohistochemistry In Vitro Kinetics Label MCF7 cell Malignant Neoplasms Medical Oncology Methods Micrometastasis Modeling Molecular Weight Monitor Mus Myocardial dysfunction Normal tissue morphology Oncogenes Patients Peptides Positron-Emission Tomography Process Property Prosthesis Proteins Radioactive Iodine Radiochemistry Radioisotopes Radiolabeled Reagent Recurrence Regimen Research Risk Role SKBR3 Signal Pathway Therapeutic Time Trastuzumab Woman Xenograft procedure accurate diagnosis analog base cancer cell cancer stem cell cell growth cost design gel electrophoresis imaging agent imaging modality immunoreactivity in vivo malignant breast neoplasm microPET migration molecular imaging molecular targeted therapies nanobodies neoplastic cell novel overexpression personalized medicine phase I trial protein degradation radiochemical radiotracer receptor research study response subcutaneous targeted treatment tumor uptake vector

项目摘要

DESCRIPTION (provided by applicant): HER2 is overexpressed in 25-30% of breast cancers and is a major contributor to tumor aggressiveness and recurrence. This has led to the development of HER2-targeted therapies such as trastuzumab, which can be effective in patients overexpressing HER2. Accurate assessment of tumor HER2 levels in real time could help personalize HER2-targeted therapy and monitor therapy response. Unlike current methods for assessing HER2 levels such as immunohistochemistry and fluorescence in situ hybridization (FISH), quantitative positron emission tomography (PET) imaging is noninvasive, can be performed repeatedly, and could provide accurate levels of HER2 in real time. Moreover, the high sensitivity of PET imaging could permit the detection of occult micrometastases and possibly HER2-expressing breast cancer stem cells. Nanobodies (Nbs) are single domain antibodies with a tenth of the molecular weight of an IgG, making them an ideal targeting vector for use in combination with the most widely utilized PET radionuclide, 18F. Conventional methods for protein labeling may result in the loss of 18F from tumor cells after a protein undergoes internalization and intracellular catabolism. We plan to extend the residualizing label (RL) approach, used successfully with radioiodine, to synthesize novel reagents designed to generate 18F-labeled catabolites that will be trapped in tumor cells after Nb internalization. Fluorine-18- labeled analogues of N-succinimidyl 4-guanidinomethyl-3-iodobenzoate (SGMIB), the best residualizing agent that we developed for radioiodination of internalizing biomolecules, will be generated. We seek to combine a new HER2 targeted 2Rs15d Nb developed by our colleague in Brussels, with a novel 18F- labeling chemistry with the goal of generating a PET imaging tool for assessing HER2 levels in breast cancer and thereby for the personalization of HER2 targeted therapy. If successful, the 18F-labeling reagents and methods that we shall develop could be applied to other proteins and peptides targeting HER2 and other internalizing receptors that are over expressed on breast cancers. We propose the following specific aims: 1. Develop prosthetic groups for 18F-labeling of Nbs based on the best Nb radioiodination residualizing agent, N-succinimidyl 4-guanidinomethyl-3-[*I] iodobenzoate ([*I]SGMIB). 2. Label Nbs with these agents and determine the characteristics of the labeled Nb conjugates. 3. Evaluate labeled Nbs in vitro using HER2-expressing breast cancer cells. 4. Evaluate labeled Nbs in vivo in mice bearing breast carcinoma xenografts.