期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 41, 页码 12806-12811出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1509667112
关键词
glioblastoma; bispecific antibody fragment; EGFR; CD105; positron emission tomography (PET)
资金
- University of Wisconsin-Madison
- National Institutes of Health [NIBIB/NCI 1R01CA169365, P30CA014520, 5T32GM08349, T32CA009206]
- Department of Defense [W81XWH-11-1-0644, W81XWH-11-1-0648]
- National Science Foundation [DGE-1256259]
- American Cancer Society [125246-RSG-13-099-01-CCE]
Early diagnosis remains a task of upmost importance for reducing cancer morbidity and mortality. Successful development of highly specific companion diagnostics targeting aberrant molecular pathways of cancer is needed for sensitive detection, accurate diagnosis, and opportune therapeutic intervention. Herein, we generated a bispecific immunoconjugate [denoted as Bs-F(ab)(2)] by linking two antibody Fab fragments, an anti-epidermal growth factor receptor (EGFR) Fab and an anti-CD105 Fab, via bioorthogonal click ligation of trans-cyclooctene and tetrazine. PET imaging of mice bearing U87MG (EGFR/CD105(+/+)) tumors with Cu-64-labeled Bs-F(ab)(2) revealed a significantly enhanced tumor uptake [42.9 +/- 9.5 percentage injected dose per gram (% ID/g); n = 4] and tumor-to-background ratio (tumor/muscle ratio of 120.2 +/- 44.4 at 36 h postinjection; n = 4) compared with each monospecific Fab tracer. Thus, we demonstrated that dual targeting of EGFR and CD105 provides a synergistic improvement on both affinity and specificity of Cu-64-NOTA-Bs-F(ab)(2). Cu-64-NOTA-Bs-F(ab)(2) was able to visualize small U87MG tumor nodules (<5 mm in diameter), owing to high tumor uptake (31.4 +/- 10.8% ID/g at 36 h postinjection) and a tumor/muscle ratio of 76.4 +/- 52.3, which provided excellent sensitivity for early detection. Finally, we successfully confirmed the feasibility of a ZW800-1-labeled Bs-F(ab)(2) for near-infrared fluorescence imaging and image-guided surgical resection of U87MG tumors. More importantly, our rationale can be used in the construction of other disease-targeting bispecific antibody fragments for early detection and diagnosis of small malignant lesions.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据