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Toxins 2016, 8(10), 274; doi:10.3390/toxins8100274

Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Academic Editors: Tomas Girbes and David J. Fitzgerald
Received: 11 May 2016 / Revised: 13 September 2016 / Accepted: 14 September 2016 / Published: 22 September 2016
(This article belongs to the Collection Immunotoxins 2016)
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Abstract

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, yet no effective therapeutics exist. This review provides an overview of the recent development of recombinant immunotoxins for the treatment of glypican-3 (GPC3) expressing HCC. GPC3 is a cell surface heparan sulfate proteoglycan that is overexpressed in HCC, but is absent from normal adult human tissues. Treatment of HCC with anti-GPC3 immunotoxins represents a new therapeutic option. Using phage display and hybridoma technologies, three high affinity antibodies (HN3, HS20 and YP7) have been generated against GPC3. Two of these antibodies (HN3 and HS20) have demonstrated the ability to inhibit Wnt/Yap signaling, leading to a reduction in liver cancer cell proliferation. By combining the HN3 antibody capable of inhibiting Wnt/Yap signaling with the protein synthesis inhibitory domain of the Pseudomonas exotoxin, a recombinant immunotoxin that exhibits a dual inhibitory mechanism was generated. This immunotoxin was found to be highly effective in the treatment of human HCCs in mouse xenograft models. Engineering of the toxin fragment to reduce the level of immunogenicity is currently being explored. The development of immunotoxins provides opportunities for novel liver cancer therapies. View Full-Text
Keywords: recombinant immunotoxin; glypican-3 (GPC3); hepatocellular carcinoma; liver cancer; monoclonal antibodies; pseudomonas exotoxin recombinant immunotoxin; glypican-3 (GPC3); hepatocellular carcinoma; liver cancer; monoclonal antibodies; pseudomonas exotoxin
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Fleming, B.D.; Ho, M. Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer. Toxins 2016, 8, 274.

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