Anti–Glypican 3 Antibody as a Potential Antitumor Agent for Human Liver Cancer

Abstract

Human glypican 3 (GPC3) is preferentially expressed in the tumor tissues of liver cancer patients. In this study, we obtained a monoclonal antibody (mAb) against the COOHterminal part of GPC3, which induced antibody-dependent cellular cytotoxicity (ADCC). The mAb, designated GC33, exhibited marked tumor growth inhibition of s.c. transplanted Hep G2 and HuH-7 xenografts that expressed GPC3 but did not inhibit growth of the SK-HEP-1 that was negative for GPC3. GC33 was efficacious even in an orthotopic model; it markedly reduced the blood A-fetoprotein levels of mice intrahepatically transplanted with Hep G2 cells. Humanized GC33 (hGC33) was as efficacious as GC33 against the Hep G2 xenograft, but hGC33 lacking carbohydrate moieties caused neither ADCC nor tumor growth inhibition. Depletion of CD56 + cells from human peripheral blood mononuclear cells markedly abrogated the ADCC caused by hGC33. The results show that the antitumor activity of hGC33 is mainly attributable to ADCC, and in human, natural killer cellmediated ADCC is one possible mechanism of the antitumor effects by GC33. hGC33 will provide a novel treatment option for liver cancer patients with GPC3-positive tumors. [Cancer Res 2008;68(23):9832-8]

Therapeutic Potential of Targeting Glypican-3 in Hepatocellular Carcinoma

“…Comparative studies with the parental GC33 antibody show similar results in the xenograft model. Ishiguro et al, show that, in addition to inhibiting tumor growth in an orthotopic Hep G2 xenograft model, they could dramatically reduce the expression of AFP after treatment with GC33 at a dose of 5 mg/kg [39]. Animals were inoculated with 5 × 10 6 Hep G2 cells and after 21 days were administered anti-GC33 antibody or vehicle.…”

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

“…161 Therefore, several anti-GPC3 mAbs have been produced for immunotherapy of HCC, but none of them can inhibit cell proliferation or induce apoptosis. [161][162][163][164] Feng et al 165 identified a human heavy chain variable domain antibody (HN3) targeting GPC3 by phage display technology and proved that HN3 could recognize a unique conformational epitope in the GPC3 core protein with high affinity. The HN3 inhibits cell growth in several hepatoma cell models in vitro and significantly inhibits the growth of HCC tumor-bearing node mice in vivo.…”

Novel Therapeutic Targets for Hepatocellular Carcinoma Treatment

“…The therapeutic monoclonal antibody against GPC3 has been developed which could induce antibody-dependent HCC cytotoxicity. Targeting GPC3 is able to inhibit tumor growth of HCC cell line xenograft (Ishiguro et al, 2008). Study also showed the concomitant treatment with GPC3 monoclonal antibody and sorafenib was more potent in preventing tumor growth than sorafenib alone in the HepG2 xenograft model (Ishiguro et al, 2008).…”

“…Targeting GPC3 is able to inhibit tumor growth of HCC cell line xenograft (Ishiguro et al, 2008). Study also showed the concomitant treatment with GPC3 monoclonal antibody and sorafenib was more potent in preventing tumor growth than sorafenib alone in the HepG2 xenograft model (Ishiguro et al, 2008). It is likely that targeting GPC3 could provide great clinical benefit during HCC management.…”