Anti-glypican 3 antibodies cause ADCC against human hepatocellular carcinoma cells

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• 作者：Kiyotaka Nakano ; Tetsuro Orita ; Junichi Nezu ; Takeshi Yoshino ; Iwao Ohizumi ; Masamichi Sugimoto ; Koh Furugaki ; Yasuko Kinoshita ; Takahiro Ishiguro ; Takao Hamakubo ; Tatsuhiko Kodama ; Hiroyuki Aburatani
• 关键词：Glypican 3 ; Antibody ; ADCC ; CDC ; Hepatocellular carcinoma ; Epitope
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2009
• 出版时间：9 January 2009
• 年：2009
• 卷：378
• 期：2
• 页码：279-284
• 全文大小：343 K

文摘

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.