Enzyme-enabled hyperpolarized 13C MRI for antibody-targeted imaging

用于抗体靶向成像的酶超极化 13C MRI

基本信息

批准号：
10055495
负责人：
Joseph Pao Yung Kao
金额：
$ 42.49万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-21 至 2024-03-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10055495
关键词：
Adverse effects Ammonia Animal Model Animals Antibodies Antibody Specificity Antigens Bacteria Bicarbonates Binding Biological Assay Biomedical Engineering Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Catalysis Cell Culture Techniques Cell Line Cells Clinical Trials Complement Contrast Media Coupled Detection Development Devices Diagnosis Diagnostic Disease EGFR Protein Overexpression Enzymes Epidermal Growth Factor Receptor Goals Growth Hormonal Human Image Imaging Techniques Ionizing radiation Label Link Location MCF7 cell Magnetic Resonance Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Malignant Neoplasms Measurement Measures Metabolic Metabolism Methods Mission Modality Monitor Mus National Institute of Biomedical Imaging and Bioengineering Normal tissue morphology Nuclear Optics Parents Patient Care Patient risk Patients Perfusion Physiologic Monitoring Plants Play Positron-Emission Tomography Pre-Clinical Model Prediction of Response to Therapy Predictive Factor Radioactive Radionuclide Imaging Relaxation Research Research Support Risk stratification Role Safety Selection for Treatments Signal Transduction Specificity System Techniques Therapeutic Uses Therapy Evaluation Time Toxic effect Urea Urease antibody conjugate antigen binding base bioimaging cancer therapy cell type chemotherapy clinical translation disorder prevention enzyme substrate experimental study imaging approach imaging modality improved in vivo in vivo Model in vivo imaging interest malignant breast neoplasm metabolic imaging novel optical imaging overexpression precision medicine receptor research and development response single photon emission computed tomography targeted agent targeted imaging targeted treatment tool treatment response tumor tumor xenograft virtual

项目摘要

In keeping with the mission of NIBIB to support research and development of “new biomedical imaging and bioengineering techniques and devices to fundamentally improve the detection, treatment, and prevention of disease,” the overarching goal of this proposal is to develop a novel magnetic resonance imaging (MRI)-based method for antibody-targeted imaging without ionizing radiation. As part of the precision medicine approach to patient care, antibody-based targeted therapies have become an important tool for the treatment of cancer and their application holds promise in other diseases. In addition to their therapeutic use, the high specificity with which antibodies recognize and bind antigens is being exploited for diagnostic purposes. In particular, antibody- targeted imaging techniques can play important roles in diagnosis, patient risk stratification, selection of targeted therapies, evaluation of response to therapy and prediction of adverse effects. While antibody-targeted agents have been created for nearly every imaging modality the majority utilize radioactive and/or optical probes due to the high sensitivity of the respective modality. The development of antibody-targeted MRI strategies has been less successful due to the inherently low sensitivity of MRI coupled with the toxicity of strong MR contrast agents. The development of so-called hyperpolarized (HP) 13C MRI using externally pre-magnetized molecules produces signal enhancement on the order of four orders of magnitude. Using metabolically active compounds permits real-time observation of metabolic processes in vivo through measurement of both the injected agent and downstream metabolic products. Directly labeling and hyperpolarizing an antibody may be feasible, but the signal would be very weak at typical concentrations, and the polarization would likely be lost due to the fast relaxation before the antibodies reach their target. Here we propose to develop a new antibody-targeted MRI technique that leverages the multiple signal amplification factors inherent in both HP 13C MRI and enzyme catalysis. By linking the exogenous enzyme urease to an antibody targeting a specific antigen and using HP 13C- urea as the substrate the location of the antibody can be imaged without background signal through the detection of the metabolic products 13CO2 and 13C-bicarbonate. We will evaluate the method by linking urease to an antibody that targets the human epidermal growth factor receptor 2 (HER2) antigen as overexpression of HER2 has been identified in 20% of breast cancer (BCa) patients and is also a predictive factor of response to chemotherapy and hormonal treatment. Specifically, we will first evaluate the targeting specificity and the signal strength of the urease-antibody conjugate in BCa cell cultures (Aim 1) followed by evaluating the safety and efficacy of the technique for in vivo imaging in a murine BCa model (Aim 2). Although this proposal is focused on imaging HER2 expression in a BCa model the imaging approach can be applied to any cancers or other diseases that present unique antigens as a target.

秉承 NIBIB 的使命，支持“新生物医学成像和生物工程技术和设备，从根本上改善疾病的检测、治疗和预防该提案的总体目标是开发一种新型的基于磁共振成像（MRI）的方法无需电离辐射的抗体靶向成像方法作为精准医学方法的一部分。患者护理、基于抗体的靶向治疗已成为治疗癌症和癌症的重要工具它们的应用除了治疗用途外，还具有高特异性。哪些抗体识别并结合抗原被用于诊断目的。靶向成像技术可以在诊断、患者风险分层、靶向治疗选择等方面发挥重要作用。治疗、评估治疗反应和预测抗体靶向药物。几乎每种成像方式都已创建，大多数使用放射性和/或光学探头，因为抗体靶向 MRI 策略的开发已取得了较高的灵敏度。由于 MRI 固有的低灵敏度以及强 MR 对比剂的毒性，不太成功。使用外部预磁化分子开发所谓的超极化 (HP) 13C MRI 使用代谢活性化合物产生四个数量级的信号增强。通过测量注射剂可以实时观察体内代谢过程直接标记和超极化抗体可能是可行的，但在典型浓度下信号将非常弱，并且由于快速，偏振可能会丢失在此，我们建议开发一种新的抗体靶向 MRI。利用 HP 13C MRI 和酶固有的多个信号放大因子的技术通过将外源酶脲酶与针对特定抗原的抗体连接并使用 HP 13C- 进行催化。以尿素为底物，通过检测可在无背景信号的情况下对抗体的位置进行成像我们将通过将脲酶与 13C-碳酸氢盐连接来评估该方法。靶向人表皮生长因子受体 2 (HER2) 抗原（HER2 过度表达）的抗体已在 20% 的乳腺癌 (BCa) 患者中发现，也是对乳腺癌治疗反应的预测因素具体来说，我们将首先评估靶向特异性和信号。脲酶-抗体缀合物在 BCa 细胞培养物中的强度（目标 1），然后评估安全性和该技术在小鼠 BCa 模型中体内成像的功效（目标 2）。尽管该提案的重点是 BCa 模型中 HER2 表达的成像，但成像方法可以可应用于以独特抗原为靶标的任何癌症或其他疾病。