Anti-glypican 3 antibody as a potential antitumor agent for human liver cancer.
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.
Ishiguro
Takahiro
T
Pharmaceutical Research Department, Chugai Pharmaceutical Co. Ltd., Kanagawa, Japan.
Sugimoto
Masamichi
M
Kinoshita
Yasuko
Y
Miyazaki
Yoko
Y
Nakano
Kiyotaka
K
Tsunoda
Hiroyuki
H
Sugo
Izumi
I
Ohizumi
Iwao
I
Aburatani
Hiroyuki
H
Hamakubo
Takao
T
Kodama
Tatsuhiko
T
Tsuchiya
Masayuki
M
Yamada-Okabe
Hisafumi
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity; D000951:Antigens, Neoplasm / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001557:Benzenesulfonates / Q000008:administration & dosage; D048708:Cell Growth Processes / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000008:administration & dosage; D053673:Glypicans / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D001557:Benzenesulfonates; C105937:GPC3 protein, human; D053673:Glypicans; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D004317:Doxorubicin; D000077157:Sorafenib