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Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis

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  • Wei Gao

    (Antibody Therapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Zhewei Tang

    (Antibody Therapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health
    Institute of Biomedical Sciences, School of Life Sciences, East China Normal University)

  • Yi-Fan Zhang

    (Antibody Therapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Mingqian Feng

    (Antibody Therapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

  • Min Qian

    (Institute of Biomedical Sciences, School of Life Sciences, East China Normal University)

  • Dimiter S. Dimitrov

    (Protein Interaction Group, Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute)

  • Mitchell Ho

    (Antibody Therapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health)

Abstract

Glypican-3 is a cell surface glycoprotein that associates with Wnt in liver cancer. We develop two antibodies targeting glypican-3, HN3 and YP7. The first antibody recognizes a functional epitope and inhibits Wnt signalling, whereas the second antibody recognizes a C-terminal epitope but does not inhibit Wnt signalling. Both are fused to a fragment of Pseudomonas exotoxin A (PE38) to create immunotoxins. Interestingly, the immunotoxin based on HN3 (HN3-PE38) has superior antitumor activity as compared with YP7 (YP7-PE38) both in vitro and in vivo. Intravenous administration of HN3-PE38 alone, or in combination with chemotherapy, induces regression of Hep3B and HepG2 liver tumour xenografts in mice. This study establishes glypican-3 as a promising candidate for immunotoxin-based liver cancer therapy. Our results demonstrate immunotoxin-induced tumour regression via dual mechanisms: inactivation of cancer signalling via the antibody and inhibition of protein synthesis via the toxin.

Suggested Citation

  • Wei Gao & Zhewei Tang & Yi-Fan Zhang & Mingqian Feng & Min Qian & Dimiter S. Dimitrov & Mitchell Ho, 2015. "Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis," Nature Communications, Nature, vol. 6(1), pages 1-12, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7536
    DOI: 10.1038/ncomms7536
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    Cited by:

    1. Nan Li & Alex Quan & Dan Li & Jiajia Pan & Hua Ren & Gerard Hoeltzel & Natalia Val & Dana Ashworth & Weiming Ni & Jing Zhou & Sean Mackay & Stephen M. Hewitt & Raul Cachau & Mitchell Ho, 2023. "The IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Lixue Wang & Guosheng Wang & Wenjun Mao & Yundi Chen & Md. Mofizur Rahman & Chuandong Zhu & Peter M. Prisinzano & Bo Kong & Jing Wang & Luke P. Lee & Yuan Wan, 2023. "Bioinspired engineering of fusogen and targeting moiety equipped nanovesicles," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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