Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer

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.

Keywords: glypican-3 (GPC3); hepatocellular carcinoma; liver cancer; monoclonal antibodies; pseudomonas exotoxin; recombinant immunotoxin.

Figure 1

Overview of immunotoxin design. (A) Representation of anti-GPC3 antibodies and their approximate binding sites. YP7 and HN3 bind to the core protein near the C-terminus and a conformational epitope that requires both the N-terminus and the C-terminus, respectively. HS20 binds directly to the heparan sulfate chains associated with GPC3; (B) Construction of HN3-PE38 and the second generation HN3-mPE24; (C) HN3 immunotoxin domains and their associated functions.