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*
-
Pseudomonas aeruginosa Exotoxin A
-
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