Anti-glypican 3 antibodies cause ADCC against human hepatocellular carcinoma cells.
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.
Nakano
Kiyotaka
K
Research Laboratories, Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
Orita
Tetsuro
T
Nezu
Junichi
J
Yoshino
Takeshi
T
Ohizumi
Iwao
I
Sugimoto
Masamichi
M
Furugaki
Koh
K
Kinoshita
Yasuko
Y
Ishiguro
Takahiro
T
Hamakubo
Takao
T
Kodama
Tatsuhiko
T
Aburatani
Hiroyuki
H
Yamada-Okabe
Hisafumi
H
Tsuchiya
Masayuki
M
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
D000911:Antibodies, Monoclonal; C105937:GPC3 protein, human; D053673:Glypicans; D016056:Immunodominant Epitopes; D009363:Neoplasm Proteins