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.

符合尼比布的使命，以支持“新生物医学成像和生物工程技术和设备从根本上改善了检测，治疗和预防疾病，“该提案的总体目标是开发新的磁共振成像（MRI）无电离辐射的抗体靶向成像的方法。作为精确医学方法的一部分患者护理，基于抗体的靶向疗法已成为治疗癌症和他们的申请在其他疾病中有希望。除了治疗的使用外，为了诊断目的，正在探索哪些抗体识别和结合抗原。特别是抗体 - 有针对性的成像技术可以在诊断，患者风险分层，目标选择中起重要作用疗法，评估对治疗的反应以及对不良影响的预测。而抗体靶向剂由于几乎每种成像方式都创建了大多数人由于使用放射性和/或光学问题相对方式的高灵敏度。以抗体为目标的MRI策略的发展已经由于MRI的固有敏感性以及强大的MR对比剂的毒性固有较低的灵敏度，因此成功较低。使用外部预磁的分子开发所谓的超极化（HP）13C MRI 在四个数量级的顺序上产生信号增强。使用代谢活性化合物通过测量两种注射剂，可以实时观察体内代谢过程和下游代谢产品。直接标记和过度化抗体可能是可行的，但是在典型浓度下，信号将非常弱，并且由于快速而可能会损失极化在抗体达到目标之前放松。在这里，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扩增因子的技术催化。通过将外源酶尿素酶与针对特定抗原的抗体联系起来，并使用HP 13C- 尿素作为底物，可以通过检测来成像无背景信号的抗体位置代谢产物13CO2和13C双碳酸盐。我们将通过将尿素链接到一个针对人表皮生长因子受体2（HER2）抗原的抗体作为HER2的过表达已在20％的乳腺癌（BCA）患者中鉴定出来，也是对化学疗法和马疗法。具体而言，我们将首先评估目标特异性和信号 BCA细胞培养物中尿素酶 - 抗体偶联物的强度（AIM 1），然后评估安全性和在鼠BCA模型中，该技术对体内成像的功效（AIM 2）。尽管该建议的重点是在BCA模型中成像HER2表达，但成像方法可以应用于将独特抗原作为靶标的癌症或其他疾病。