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

Nat Commun. 2015 Mar 11;6:6536. doi: 10.1038/ncomms7536.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • ADP Ribose Transferases / chemistry
  • ADP Ribose Transferases / genetics
  • ADP Ribose Transferases / immunology
  • Animals
  • Antibodies, Monoclonal / genetics
  • Antibodies, Monoclonal / immunology
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / immunology
  • Bacterial Toxins / chemistry
  • Bacterial Toxins / genetics
  • Bacterial Toxins / immunology
  • Exotoxins / chemistry
  • Exotoxins / genetics
  • Exotoxins / immunology
  • Female
  • Gene Expression
  • Glypicans / antagonists & inhibitors*
  • Glypicans / genetics
  • Glypicans / immunology
  • Hep G2 Cells
  • Hepatoblastoma / drug therapy*
  • Hepatoblastoma / genetics
  • Hepatoblastoma / immunology
  • Hepatoblastoma / pathology
  • Humans
  • Immunotoxins / chemistry
  • Immunotoxins / genetics
  • Liver / drug effects
  • Liver / immunology
  • Liver / pathology
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / immunology
  • Liver Neoplasms / pathology
  • Mice
  • Molecular Targeted Therapy
  • Protein Biosynthesis / drug effects*
  • Recombinant Fusion Proteins / administration & dosage*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Remission Induction
  • Signal Transduction
  • Single-Domain Antibodies / genetics
  • Single-Domain Antibodies / immunology
  • Tumor Burden / drug effects
  • Virulence Factors / chemistry
  • Virulence Factors / genetics
  • Virulence Factors / immunology
  • Wnt Proteins / antagonists & inhibitors*
  • Wnt Proteins / genetics
  • Wnt Proteins / immunology
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Bacterial Toxins
  • Exotoxins
  • GPC3 protein, mouse
  • Glypicans
  • Immunotoxins
  • Recombinant Fusion Proteins
  • Single-Domain Antibodies
  • Virulence Factors
  • Wnt Proteins
  • ADP Ribose Transferases
  • toxA protein, Pseudomonas aeruginosa