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Updated: Jun 27, 2026
A GPC3-targeting Bispecific Antibody, GPC3-S-Fab, with Potent Cytotoxicity
Published on: July 12, 2018
Anti-glypican 3 antibody as a potential antitumor agent for human liver cancer
Takahiro Ishiguro1, Masamichi Sugimoto, Yasuko Kinoshita
1Pharmaceutical Research Department, Chugai Pharmaceutical Co. Ltd., Kanagawa, Japan.
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 COOH-terminal 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 alpha-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 cell-mediated 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.
Insights
A new monoclonal antibody, GC33, targets glypican 3 (GPC3) in liver cancer. This antibody shows significant tumor growth inhibition and may offer a novel treatment for GPC3-positive liver tumors.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Human glypican 3 (GPC3) is a protein overexpressed in liver cancer tissues.
- Targeting GPC3 presents a potential therapeutic strategy for hepatocellular carcinoma.
Purpose of the Study:
- To develop and evaluate a monoclonal antibody (mAb) targeting GPC3 for liver cancer treatment.
- To investigate the mechanism of action, including antibody-dependent cellular cytotoxicity (ADCC).
Main Methods:
- Generation of a GPC3-specific mAb (GC33) and its humanized version (hGC33).
- Assessment of anti-tumor activity in GPC3-positive and GPC3-negative liver cancer xenograft models (s.c. and orthotopic).
- Evaluation of ADCC activity and the role of CD56+ cells in mediating the anti-tumor effects of hGC33.
Main Results:
- GC33 demonstrated significant inhibition of GPC3-expressing liver cancer xenografts (Hep G2, HuH-7) but not GPC3-negative tumors (SK-HEP-1).
- hGC33 showed comparable efficacy to GC33, with its anti-tumor activity dependent on glycosylation and ADCC.
- Depletion of CD56+ cells significantly reduced hGC33-mediated ADCC, indicating a role for natural killer (NK) cells.
Conclusions:
- The anti-tumor activity of hGC33 is primarily mediated by ADCC, with NK cell involvement being a key mechanism.
- hGC33 represents a promising novel therapeutic option for patients with GPC3-positive liver cancer.
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