CD11b Antibody Fragments as PET Imaging Probes for Glioma-Associated Myeloid Cells

CD11b 抗体片段作为胶质瘤相关骨髓细胞的 PET 成像探针

• 批准号: 9751856
• 负责人: Wilson Barry Edwards
• 金额: $ 23.42万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751856
• 关键词: Amino Acids; Animal Model; Animals; Antibodies; Biodistribution; Biological Markers; Blood; Brain Neoplasms; C57BL/6 Mouse; Cell Therapy; Cell physiology; Cells; Clinical; Clinical Trials; Cloning; Detection; Development; Diagnostic Imaging; Disease; Excision; Exhibits; Experimental Animal Model; Failure; Frequencies; Generations; Genes; Glioblastoma; Glioma; Goals; Human; Hybridomas; ITGAM gene; Immune; Immunoglobulin Fragments; Immunoglobulin G; Immunosuppressive Agents; Immunotherapy; Infiltration; Injections; Knock-out; Label; Lead; Link; Methods; Modeling; Molecular Weight; Monitor; Monoclonal Antibodies; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Operative Surgical Procedures; Outcome; Parents; Patients; Physiological; Positron-Emission Tomography; Pre-Clinical Model; Publishing; Radiolabeled; Resected; Sensitivity and Specificity; Splenocyte; Standardization; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Tracer; Translations; Treatment Efficacy; Tumor Immunity; Tumor Tissue; Tumor-associated macrophages; Tumor-infiltrating immune cells; cancer imaging; celecoxib; cross reactivity; disulfide bond; effective therapy; eosinophil; imaging probe; inhibitor/antagonist; innovation; mouse model; nanobodies; neuroinflammation; noninvasive diagnosis; novel; novel therapeutics; pre-clinical; preclinical study; prevent; standard of care; targeted treatment; tool; treatment response; tumor; tumor growth; tumor microenvironment; tumor progression; uptake

ABSTRACT Average survival times for glioblastoma patients remain around 15 months because of relatively few effective treatments. CD11b+ Tumor-associated myeloid cells, can account for up to 40% of the tumor mass, are well known to suppress anti-tumor immunity, and directly promote tumor growth. While significant advances have been made in the development of TAMC-targeted therapies, analysis of TAMCs requires analysis of surgically resected tumor tissue. In this R21 application we propose that development of a novel tracer, Cu-64 labeled antibody fragments, which will allow for non-invasive PET imaging of TAMCs in glioblastomas. We will therefore, test our novel hypothesis that Cu-64-labeled monobodies or diabodies derived from the m1/70 hybridoma will enable quantification TAMC infiltration into the tumor and monitoring of TAMC-targeted immunotherapies. We will first generate and test the sensitivity of our antibody fragments following injections of varying concentrations of CD11b+ mouse spleenocytes from C57BL/6j mice into CD11b-knockout C57BL/6j- background syngeneic glioma-bearing mice (Aim 1). We will then demonstrate that our novel antibody fragments can be used to monitor TAMC-targeted therapies including anti-Gr1-antibody, Celecoxib, or a CSF-1R inhibitor in the GL261 syngeneic glioma model, and a de novo glioma model (AIM 2). As the m1/70 clone can recognize both human and mouse CD11b, we believe that our preclinical studies can lead to quick translation of our findings into TAMC-targeted clinical trials in patients with glioblastoma, or in patients with other neuroinflammatory disorders. !

抽象的 由于有效的治疗方法相对较少，胶质母细胞瘤患者的平均生存时间仍维持在 15 个月左右。 治疗。 CD11b+ 肿瘤相关骨髓细胞，可占肿瘤质量的 40%，良好 已知可抑制抗肿瘤免疫，并直接促进肿瘤生长。虽然取得了重大进展 在 TAMC 靶向治疗的开发过程中，TAMC 的分析需要通过手术进行分析 切除的肿瘤组织。在此 R21 应用中，我们建议开发一种新型示踪剂，Cu-64 标记 抗体片段，这将允许对胶质母细胞瘤中的 TAMC 进行非侵入性 PET 成像。因此，我们将， 测试我们的新假设，即 Cu-64 标记的单抗体或双抗体源自 m1/70 杂交瘤 将能够量化 TAMC 浸润到肿瘤中的情况并监测 TAMC 靶向的情况 免疫疗法。我们将首先生成并测试注射后抗体片段的敏感性 将来自 C57BL/6j 小鼠的不同浓度的 CD11b+ 小鼠脾细胞转化为 CD11b 敲除 C57BL/6j- 背景同基因胶质瘤小鼠（目标 1）。然后我们将证明我们的新型抗体片段 可用于监测 TAMC 靶向治疗，包括抗 Gr1 抗体、塞来昔布或 CSF-1R 抑制剂 在 GL261 同基因神经胶质瘤模型和从头神经胶质瘤模型 (AIM 2) 中。 m1/70 克隆可以识别 无论是人类还是小鼠 CD11b，我们相信我们的临床前研究可以快速转化我们的发现 进入针对胶质母细胞瘤患者或其他神经炎症患者的 TAMC 靶向临床试验 失调。 ！