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In situ Imaging of CAR T-cells

CAR T 细胞的原位成像

基本信息

批准号：
9274922
负责人：
CHRISTINE BROWN
金额：
$ 25.88万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
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：
2015-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9274922
关键词：
Adoptive Immunotherapy Affinity Animal Model Antibodies Antigen Targeting Antigens Armadillo Repeat B lymphoid malignancy Binding Binding Sites Biochemical CD28 gene Cell Culture Techniques Cell Therapy Cetuximab Clinic Clinical Complex Cyclic Peptides Cytotoxic T-Lymphocytes Data Development Disease ERBB2 gene Engineering Epitopes Fab Immunoglobulins Foundations Gene-Modified Goals Half-Life Image Immune response Immunotherapy In Situ In Vitro Label Malignant Neoplasms Monoclonal Antibodies Mus Names Outcome Patients Peptides Positron-Emission Tomography Protein Binding Domain Proteins Research Safety Serum Signal Transduction Site T-Lymphocyte Technology Tertiary Protein Structure Testing Therapeutic Therapeutic Monoclonal Antibodies Time Translating Transmembrane Domain Tumor Antigens antibody engineering antigen binding base cell killing cell transformation chemokine chimeric antigen receptor density extracellular human monoclonal antibodies imaging agent improved improved functioning in situ imaging in vivo in vivo imaging innovation lentivirally transduced nanoparticle neoplastic cell next generation novel novel diagnostics public health relevance receptor response small molecule targeted imaging theranostics therapy outcome trafficking tumor tumor growth uptake

项目摘要

DESCRIPTION (provided by applicant): Adoptive immunotherapy, which capitalizes on generating a potent immune response using genetically re- engineered T cells, represents a novel and powerful therapeutic approach to treat cancer and other diseases. Specifically, patient's T cells are modified to express a chimeric antigen receptor (CAR), which consists of a tumor antigen recognition domain fused to an activation sequence that triggers T cell cytotoxic and proliferative functions when tumor antigen is engaged. The tumor antigen recognition domain of the CAR is commonly a single chain variable fragment (scFv) excised from a monoclonal antibody (mAb) previously selected to recognize a tumor antigen epitope. Herein, we propose to replace the scFv domain with either a fragment antigen-binding domain (Fab) or a mAb that are engineered to bind a cyclic peptide called meditope. Incorporation of this meditope-binding site within the Fab/mAb uniquely marks the modified T cells and permits a highly specific, high affinity interaction with a meditope, an optimized, serum stable peptide that can be conjugated to small molecules including DOTA, biologics including scFvs, chemokines, etc., or nanoparticles. As such, the incorporation of the meditope interface offers the unique and timely opportunity to rapidly and independently add new functionality to CAR T cell therapy. The immediate goal of this application is to demonstrate that a meditope-enabled Fab or mAb can effectively replace the scFv within the CAR and can be used to image meditope-enabled CAR T cells in vivo. Successful demonstration of this novel interaction will set the stage to track meditope-enabled CAR T cells in patients, to correlate T cell distributions with clinical outcomes, and to add new functionality to improve this emerging and broadly applicable therapy.

描述（由申请人提供）：免疫疗法，其利用使用基因改造的T细胞产生有效的免疫应答，代表了治疗癌症和其他疾病的新的和强大的治疗方法。具体地，患者的T细胞被修饰以表达嵌合抗原受体（CAR），其由融合至激活序列的肿瘤抗原识别结构域组成，当肿瘤抗原接合时，激活序列触发T细胞细胞毒性和增殖功能。CAR的肿瘤抗原识别结构域通常是从先前选择以识别肿瘤抗原表位的单克隆抗体（mAb）切除的单链可变片段（scFv）。在本文中，我们提出用片段抗原结合结构域（Fab）或mAb替换scFv结构域，所述片段抗原结合结构域或mAb被工程化以结合称为中间位的环肽。在Fab/mAb中掺入该中间位结合位点独特地标记修饰的T细胞，并允许与中间位（一种优化的血清稳定肽）高度特异性、高亲和力相互作用，可以与包括DOTA在内的小分子、包括scFv在内的生物制剂、趋化因子等缀合，或纳米颗粒。因此，中间位界面的并入提供了独特且及时的机会，以快速且独立地为CAR T细胞疗法添加新功能。本申请的直接目标是证明中间位使能的Fab或mAb可以有效地替换CAR内的scFv，并且可以用于使中间位使能的CAR T细胞体内成像。这种新型相互作用的成功证明将为追踪患者中的中间位激活的CAR T细胞，将T细胞分布与临床结果相关联，并增加新的功能以改进这种新兴的和广泛适用的疗法。