[ Title ]
- Noninvasive brain cancer imaging with a bispecific antibody fragment, generated via click chemistry
[ Journal ]
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF
AMERICA
[ Author ]
- Luo, HM Hernandez, R Hong, H Graves, SA Yang, YN England, CG Theuer, CP Nickles, RJ Cai, WB
[ 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 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.
[ URL ]
- http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=Alerting&SrcApp=Alerting&DestApp=WOS&DestLinkType=FullRecord;UT=WOS:000363130900062