title: Anti-glypican 3 antibodies cause ADCC against human hepatocellular carcinoma cells.
abstract: Glypican 3 (GPC3), a GPI-anchored heparan sulfate proteoglycan, is expressed in the majority of hepatocellular carcinoma (HCC) tissues. Using MRL/lpr mice, we successfully generated a series of anti-GPC3 monoclonal antibodies (mAbs). GPC3 was partially cleaved between Arg358 and Ser359, generating a C-terminal 30-kDa fragment and an N-terminal 40-kDa fragment. All mAbs that induced antibody-dependent cellular cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC) against cells expressing GPC3 recognized the 30-kDa fragment, indicating that the C-terminal region of GPC3 serves as an epitope for mAb with ADCC and/or CDC inducing activities. Chimeric mAbs with Fc replaced by human IgG1 were created from GC33, one of the mAbs that reacted with the C-terminal 30-kDa fragment. Chimeric GC33 induced not only ADCC against GPC3-positive human HCC cells but also was efficacious against the Huh-7 human HCC xenograft. Thus, mAbs against the C-terminal 30-kDa fragment such as GC33 are useful in therapy targeting HCC.
authors.affiliation: Research Laboratories, Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Nakano
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Orita
authors.forename: Junichi
authors.initials: J
authors.lastname: Nezu
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshino
authors.forename: Iwao
authors.initials: I
authors.lastname: Ohizumi
authors.forename: Masamichi
authors.initials: M
authors.lastname: Sugimoto
authors.forename: Koh
authors.initials: K
authors.lastname: Furugaki
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kinoshita
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ishiguro
authors.forename: Takao
authors.initials: T
authors.lastname: Hamakubo
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Hisafumi
authors.initials: H
authors.lastname: Yamada-Okabe
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuchiya
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000302:isolation & purification / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D016466:CHO Cells; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000276:immunology; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D053673:Glypicans / Q000037:antagonists & inhibitors* / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; C105937:GPC3 protein, human; D053673:Glypicans; D016056:Immunodominant Epitopes; D009363:Neoplasm Proteins