Abstract 2426: Anti-Glypican3 antibody for treatment of human liver cancer

Glypican-3 (GPC3) is a member of the glypican family of heparan sulfate proteoglycans, which are linked to the cell surface through a glycosyl phosphatidyl inositol anchor. GPC3 has been reported to be highly expressed in the majority (70-100%) of HCC, and considered to play a role in the tumorigenesis of HCC. Although the molecular mechanism by which GPC3 functions in tumorigenesis has not been fully elucidated, the high prevalence in HCC has led to considerable interest in GPC3 as a diagnostic marker and therapeutic target. 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 mGC33, 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. mGC33 was efficacious even in an orthotopic model; it markedly reduced the blood alpha-fetoprotein levels of mice intrahepatically transplanted with Hep G2 cells. To develop an antibody-based immunotherapy, we generated humanized GC33 (hGC33) by complementarily determining region (CDR) grafting. hGC33 was as efficacious as mGC33 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. We also evaluated the antitumor activity of hGC33 combined with standard chemotherapy agent sorafenib. hGC33 and sorafenib combination was more potent in inhibiting tumor growth than sorafenib alone in the s.c. transplanted Hep G2 xenograft model. Administration of sorafenib alone did not change the GPC3 expression level in xenograft tumor. These suggest that this combination regimen may be clinically useful as an anti-liver cancer therapy. In careful examination of the safety of hGC33 in nonclinical studies, specific adverse findings on GPC3 expressed tissue or organs were not observed after repeated administration. Therefore hGC33 will provide a novel treatment option for liver cancer patients with GPC3-positive tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2426.