Engineered antibody fragments for PET imaging of immunotherapeutic targets in gliomas

用于神经胶质瘤免疫治疗靶点 PET 成像的工程化抗体片段

基本信息

批准号：
10459345
负责人：
Wilson Barry Edwards
金额：
$ 52.89万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2020-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10459345
关键词：
Adult Antibodies Antigens Biological Monitoring Biomedical Technology Cancer Etiology Cell Therapy Cell surface Cells Cellular immunotherapy Chelating Agents Chemistry Child Childhood Clinical Research Data Development Diagnostic Imaging Effectiveness Enrollment Excision Future Glioma Goals Health Histologic Human ITGAM gene Imaging Techniques Immune Targeting Immunoglobulin Fragments Immunologics Immunosuppression Immunotherapeutic agent Immunotherapy Label Magnetic Resonance Imaging Malignant Glioma Mediating Mission Modeling Molecular Monitor Mus Myeloid Cells Myeloid-derived suppressor cells National Institute of Biomedical Imaging and Bioengineering Outcomes Research Patients Population Positron-Emission Tomography Primary Brain Neoplasms Process Prognosis Public Health Publishing Radiation therapy Radioimmunoconjugate Radiolabeled Research Specimen Survival Rate T-Cell Activation T-Lymphocyte Testing Time Tracer Translating Treatment Cost Treatment Side Effects Tumor Antigens Tumor Tissue Tumor-associated macrophages United States National Institutes of Health Ursidae Family Work antibody engineering base chemotherapy childhood cancer mortality clinical decision-making clinically relevant cross reactivity epigenetic therapy imaging approach imaging biomarker imaging probe immunotherapy trials improved ineffective therapies molecular imaging non-invasive imaging noninvasive diagnosis novel patient response patient stratification personalized medicine pre-clinical precision medicine preclinical study prevent radiotracer recruit response serial imaging standard of care survival prediction targeted imaging time interval tool treatment response tumor tumor microenvironment unnecessary treatment uptake

项目摘要

PROJECT SUMMARY/ABSTRACT There are no effective non-invasive diagnostic imaging approaches to accurately stratify and monitor immunotherapy in adults and children with glioma. PET imaging, utilizing radiolabeled antibody fragments, minibodies (Mb), or diabodies (Db), stably chelated to radiometals, is a promising option for the safe and effective direct quantification of cell surface markers in glioma patients that reflect dynamic immunological processes that bear directly on immunotherapeutic effectiveness. However, development of PET for molecular imaging of markers to guide immunotherapy is in its nascent stage. The long-term goal of this application is to translate effective antibody fragment-based radiotracers for non-invasive diagnostic imaging before and during immunotherapy to meaningfully impact clinical decision making for patients on immunotherapies. The overall objective of this application is to validate radiotracer compositions for unique situations in monitoring immunotherapies in patient-relevant murine glioma models. The rationale for the proposed research is that non- invasive diagnostic imaging with radiotracers quantifying an important immune target, activated T-cells, and immunosuppressive cells to prevent and shorten the duration of ineffective therapies. The central hypothesis is that radiolabeled CD11b, EphA2, and CD69, antibody-based PET tracers can effectively guide immunotherapies for malignant gliomas. In Aim 1, CD11b will be quantified in glioma models by PET with Cu-64-labeled anti- CD11b Mb/Db to quantify immunosuppressive tumor-associated myeloid cells (TAMC) before and during TAMC- targeted immunotherapies. In Aim 2 preclinical PET will be employed to quantify EphA2 expression levels in gliomas. EphA2, a highly relevant clinical immunotherapy target, will serve as a “proof of principle” antigen, and provide a base to develop comprehensive antigen-PET strategies. Standard uptake values (SUV) of Cu-64- labeled anti-EphA2 Mb/Db will be used to quantify EphA2 levels on glioma cells in syngeneic orthotopic models with a range of EphA2 levels and identify glioma-bearing mice that will respond to immunotherapies. In Aim 3, responses to glioma immunotherapy will be assessed by CD69 PET with Cu-64-labeled anti-CD69 Mb/Db to quantify T-cell activation and predict survival rates of glioma-bearing mice following T-cell-mediated immunotherapies. The use of robust imaging probe chemistry, adult and pediatric murine glioma models, and immunotherapy approaches, will validate novel human/mouse cross-reactive Mb/Db for their translational capacity. If successful, this proposal will radically change the way gliomas are stratified and monitored on immunotherapy trials, using real-time molecular PET imaging to determine which subjects to enroll and when to stop or continue therapy. Outcomes from this research will greatly improve response rates to immunotherapy while reducing unnecessary treatment-related side effects, ineffective and costly treatments, in an era of precision medicine with increased treatment options.

项目摘要/摘要没有有效的非侵入性诊断成像方法可以准确分层和监测成人和神经胶质瘤儿童的免疫疗法。宠物成像，利用放射性标记的抗体片段，稳定地选择辐射量的迷你基（MB）或糖尿病（dB）是安全有效的承诺选择直接定量神经胶质瘤患者的细胞表面标记，反映了动态免疫学过程直接承受免疫治疗效果。但是，开发用于分子成像的PET的开发引导免疫疗法的标记处于其新生阶段。该应用程序的长期目标是翻译有效的抗体碎片基于基于抗侵袭性诊断成像之前和期间的抗体片段免疫疗法有意义地影响患者对免疫疗法的临床决策。总体此应用的目的是验证用于监测的独特情况的radiotracer组成与患者相关的鼠神经胶质瘤模型中的免疫疗法。拟议研究的理由是非使用放射性示例量化重要的免疫靶标，激活的T细胞和侵入性诊断成像免疫抑制细胞可预防和缩短无效疗法的持续时间。中心假设是那个放射标记的CD11b，EPHA2和CD69，基于抗体的PET示踪剂可以有效地引导免疫疗法对于恶性神经胶质瘤。在AIM 1中，CD11b将通过PET中的Cu-64标记抗 - CD11b Mb/dB在TAMC-之前和期间定量免疫抑制肿瘤相关的髓样细胞（TAMC）靶向免疫疗法。在AIM 2中，将聘请临床前宠物来量化EPHA2表达水平神经胶质瘤。 EPHA2是一个高度相关的临床免疫疗法靶标，将作为“原则证明”抗原，并且提供一个制定全面的抗原-PET策略的基础。 CU-64-的标准吸收值（SUV）标记的抗EPHA2 MB/dB将用于量化同步原位模型中神经胶质瘤细胞上的EPHA2水平具有一系列EPHA2水平，并鉴定出对免疫疗法反应的含有神经胶质瘤的小鼠。在AIM 3中， CD69 PET用CU-64标记的抗CD69 MB/DB评估对神经胶质瘤免疫疗法的反应量化T细胞激活并预测伴有神经胶质瘤小鼠的存活率后T细胞介导免疫疗法。使用可靠的成像探针化学，成人和小儿鼠神经胶质瘤模型以及免疫疗法方法将验证新型的人/小鼠交叉反应性MB/dB的翻译容量。如果成功，该提案将从根本上改变对神经胶质瘤的分层和监控方式免疫疗法试验，使用实时分子PET成像来确定要注册的受试者以及何时停止或继续治疗。这项研究的结果将大大提高对免疫疗法的反应率在减少不必要的治疗副作用，无效和昂贵的治疗时，精密药物，具有增加的治疗选择。