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  • [Proc Natl Acad Sci U S A] Noninvasive brain cancer imaging with a bispecific antibody fragment, generated via click chemistry.

    위스콘신대 메디슨 / Cai W*

  • 출처
    Proc Natl Acad Sci U S A
  • 등재일
    2015 Oct 13
  • 저널이슈번호
    112(41):12806-11. doi: 10.1073/pnas.1509667112. Epub 2015 Sep 28.
  • 내용

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    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. 

     

    Author information

    Luo H1, Hernandez R2, Hong H1, Graves SA2, Yang Y1, England CG2, Theuer CP3, Nickles RJ2, Cai W4.

    1Department of Radiology, University of Wisconsin-Madison, Madison, WI 53705;

    2Department of Medical Physics, University of Wisconsin-Madison, Madison, WI 53705;

    3TRACON Pharmaceuticals, Inc., San Diego, CA 92122;

    4Department of Radiology, University of Wisconsin-Madison, Madison, WI 53705; Department of Medical Physics, University of Wisconsin-Madison, Madison, WI 53705; Materials Science Program, University of Wisconsin-Madison, Madison, WI 53705; University of Wisconsin Carbone Cancer Center, Madison, WI 53705 wcai@uwhealth.org. 

  • 키워드
    http://www.ncbi.nlm.nih.gov/pubmed/?term=Noninvasive+brain+cancer+imaging+with+a+bispecific+antibody+fragment%2C+generated+via+click+chemistry.
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