title: Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis.
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.
authors.affiliation: Antibody Therapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.affiliation: 1] Antibody Therapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA [2] Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200062, China.
authors.forename: Zhewei
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Antibody Therapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Zhang
authors.affiliation: Antibody Therapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Mingqian
authors.initials: M
authors.lastname: Feng
authors.affiliation: Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200062, China.
authors.forename: Min
authors.initials: M
authors.lastname: Qian
authors.affiliation: Protein Interaction Group, Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA.
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
authors.affiliation: Antibody Therapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Ho
mesh_terms: D036002:ADP Ribose Transferases / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D001427:Bacterial Toxins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D005098:Exotoxins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D005260:Female; D015870:Gene Expression; D053673:Glypicans / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D056945:Hep G2 Cells; D018197:Hepatoblastoma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D000922:Immunotoxins / Q000737:chemistry / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D014176:Protein Biosynthesis / Q000187:drug effects*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D012074:Remission Induction; D015398:Signal Transduction; D061905:Single-Domain Antibodies / Q000235:genetics / Q000276:immunology; D047368:Tumor Burden / Q000187:drug effects; D037521:Virulence Factors / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D023041:Xenograft Model Antitumor Assays; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D005098:Exotoxins; D053673:Glypicans; D000922:Immunotoxins; D011993:Recombinant Fusion Proteins; D061905:Single-Domain Antibodies; D037521:Virulence Factors; D051153:Wnt Proteins; D000097668:Pseudomonas aeruginosa Exotoxin A; C000602440:GPC3 protein, mouse