Journal article
Noninvasive brain cancer imaging with a bispecific antibody fragment, generated via click chemistry
Proceedings of the National Academy of Sciences - PNAS, Vol.112(41), pp.12806-12811
10/13/2015
DOI: 10.1073/pnas.1509667112
PMCID: PMC4611632
PMID: 26417085
Abstract
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 (64)Cu-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 (64)Cu-NOTA-Bs-F(ab)2. (64)Cu-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.
Details
- Title: Subtitle
- Noninvasive brain cancer imaging with a bispecific antibody fragment, generated via click chemistry
- Creators
- Haiming Luo - University of Wisconsin–MadisonReinier Hernandez - University of Wisconsin–MadisonHao Hong - University of Wisconsin–MadisonStephen A Graves - University of Wisconsin–MadisonYunan Yang - University of Wisconsin–MadisonChristopher G England - University of Wisconsin–MadisonCharles P Theuer - Tracon PharmaceuticalsRobert J Nickles - University of Wisconsin–MadisonWeibo Cai - University of Wisconsin–Madison
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.112(41), pp.12806-12811
- DOI
- 10.1073/pnas.1509667112
- PMID
- 26417085
- PMCID
- PMC4611632
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Grant note
- T32 GM008349 / NIGMS NIH HHS T32CA009206 / NCI NIH HHS T32 CA009206 / NCI NIH HHS R01 CA169365 / NCI NIH HHS 5T32GM08349 / NIGMS NIH HHS P30CA014520 / NCI NIH HHS P30 CA014520 / NCI NIH HHS 1R01CA169365 / NCI NIH HHS
- Language
- English
- Date published
- 10/13/2015
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Radiation Oncology
- Record Identifier
- 9984383899702771
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