In vivo imaging of T Cells using engineered antibodies and PET

使用工程抗体和 PET 对 T 细胞进行体内成像

基本信息

批准号：
8786848
负责人：
Anna M Wu
金额：
$ 19.25万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8786848
关键词：
Address Affinity Agonist Antibodies Antigens Autoimmunity B-Lymphocytes Binding Biodistribution Biological Markers Blood CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cardiovascular Diseases Cell Therapy Cell surface Cells Characteristics Chimeric Proteins Clinic Cysteine Cytosine Cytotoxic T-Lymphocytes Detection Development Diabetes Mellitus Disease Disease model Disulfides Dose Engineering Epitopes Exhibits Flow Cytometry Future Generations Goals Health Helper-Inducer T-Lymphocyte Human Hybridomas Image Imagery Immune Immune response Immune system Immunoglobulin Fragments Immunohistochemistry Immunotherapeutic agent Immunotherapy Infiltration Inflammation Injection of therapeutic agent Kinetics Label Lead Length Life Location Lymphoid Lymphoid Tissue MS4A1 gene Malignant Neoplasms Modeling Monitor Monoclonal Antibodies Mus Oligonucleotides Organ Organism Phenotype Play Positron Positron-Emission Tomography Pre-Clinical Model Process Production Proliferating Protein Engineering Proteins Protocols documentation Radioimmunoconjugate Radiolabeled Rattus Resolution Role Spleen Staging T-Lymphocyte Therapeutic Therapy Evaluation Time Tissues Tracer Wild Type Mouse Work antibody engineering base clinical application dimer drug development effective therapy fluorodeoxyglucose imaging modality immune activation immune function immunoreactivity improved in vivo in vivo imaging interest lymph nodes macrophage molecular imaging mouse model neutrophil novel pre-clinical public health relevance radiotracer research study small molecule success tool tumor

项目摘要

DESCRIPTION (provided by applicant): Inflammation and immune responses play a central role in most of the major diseases that impact human health, including cancer, cardiovascular disease, autoimmunity, neuroinflammatory processes, diabetes and other diseases. In addition, immunomodulatory therapies and adoptive cell therapies have become established as powerful therapeutic approaches in cancer. The ability monitor and distinguish immune cell subsets (e.g. T and B lymphocytes, macrophages, neutrophils, etc.) noninvasively in vivo will be invaluable to the development of effective treatments. Positron emission tomography (PET) provides highly sensitive, non- invasive and quantitative imaging, which can be combined with antibody-based probes to provide molecular imaging of tissues and cells in vivo based on cell surface phenotype. Furthermore, engineered antibody fragments (minibodies and cys-diabodies) have been developed with optimal kinetics enabling rapid in vivo targeting and clearance for imaging applications by immunoPET. In the proposed work, immunoPET will be developed to address the challenge of direct imaging of immune cell subsets. Engineered antibody fragments will be optimized for in vivo detection, imaging, and quantitation of T lymphocytes that express CD8, a marker that is a hallmark of cytotoxic T cells. Specific Aim 1 will focus on production of stable, optimized anti-CD8 minibodies and cys-diabodies derived from rat anti-mouse monoclonal antibodies. Specific Aim 2 will establish the optimal imaging agent, dose, and imaging protocol for visualization of the lymphoid organs in normal (wild-type) mice. Specific Aim 3 will focus on quantitation of T cells in normal and immune-stimulated mice to determine the parameters and limits of detection in mouse models. Once validated, immunoPET probes for CD8 T cells will be valuable tools to study immune processes in mouse models, providing a deeper understanding of immune responses in living organisms, and will open the door to broad methods for imaging and quantitating immune cell subsets in preclinical models and eventually humans.

描述（由申请人提供）：炎症和免疫反应在影响人类健康的大多数主要疾病中起着核心作用，包括癌症，心血管疾病，自身免疫性，神经炎症过程，糖尿病和其他疾病。此外，免疫调节疗法和收养细胞疗法已成为癌症强大的治疗方法。能力监测和区分免疫细胞亚群（例如，T和B淋巴细胞，巨噬细胞，中性粒细胞等）在体内无创的，对于开发有效治疗的体内将是无价的。正电子发射断层扫描（PET）提供了高度敏感，非侵入性和定量成像，可以与基于抗体的探针结合使用，以基于细胞表面表型在体内提供组织和细胞的分子成像。此外，已经开发了工程化抗体片段（小动物和CYS-二氧化碳），具有最佳动力学，从而使体内靶向和清除率可以快速地通过免疫物进行成像。在拟议的工作中，将开发免疫集来应对免疫细胞亚群直接成像的挑战。工程抗体片段将被优化，用于表达CD8的T淋巴细胞的体内检测，成像和定量，该标记是细胞毒性T细胞的标志。具体目标1将集中于生产稳定的，优化的抗CD8小动物和源自大鼠抗小鼠单克隆抗体的CYS-二刺。特定的目标2将建立正常（野生型）小鼠中淋巴机器人可视化的最佳成像剂，剂量和成像方案。特定的目标3将集中于对正常和免疫刺激的小鼠中T细胞的定量，以确定小鼠模型中检测的参数和限制。一旦经过验证，CD8 T细胞的免疫集探针将是研究小鼠模型中免疫过程的宝贵工具，对生物体中的免疫反应有了更深入的了解，并将为临床前模型和最终人类中的免疫细胞亚群的广泛方法打开广泛方法。