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

摘要 胶质母细胞瘤患者的平均生存时间保持在15个月左右，因为有效率相对较低。 治疗。CD11b+肿瘤相关髓系细胞，可占肿瘤质量的40%，表现良好 已知能抑制抗肿瘤免疫，并直接促进肿瘤生长。虽然取得了重大进展， 在TAMC靶向治疗的开发中取得了进展，TAMC的分析需要手术分析 切除肿瘤组织。在R21应用中，我们建议开发一种新型示踪剂，铜-标记 抗体片段，这将允许对胶质母细胞瘤的TAMCs进行非侵入性PET成像。因此，我们将， 检验我们的新假设，即铜-标记的单体或双胞体来自M1/70杂交瘤 将能够量化TAMC向肿瘤的渗透并监测TAMC靶向 免疫疗法。我们将在注射后首先产生并测试抗体片段的敏感性。 不同浓度CD11b+小鼠脾细胞在CD11b基因敲除C57BL/6J小鼠体内的表达 背景同基因胶质瘤荷瘤小鼠(目标1)。然后我们将展示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同基因胶质瘤模型和新生胶质瘤模型(AIM 2)中。正如M1/70克隆人所认识到的那样 人类和小鼠的CD11b，我们相信我们的临床前研究可以快速翻译我们的发现 在胶质母细胞瘤患者或其他神经炎性疾病患者中进行TAMC靶向临床试验 精神错乱。 好了！

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. !