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...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2009-01, Vol.378 (2), p.279-284
Main Authors: Nakano, Kiyotaka, Orita, Tetsuro, Nezu, Junichi, Yoshino, Takeshi, Ohizumi, Iwao, Sugimoto, Masamichi, Furugaki, Koh, Kinoshita, Yasuko, Ishiguro, Takahiro, Hamakubo, Takao, Kodama, Tatsuhiko, Aburatani, Hiroyuki, Yamada-Okabe, Hisafumi, Tsuchiya, Masayuki
Format: Article
Language:English
Subjects:
ADCC
Animals
Antibodies, Monoclonal - immunology
Antibodies, Monoclonal - isolation & purification
Antibodies, Monoclonal - therapeutic use
Antibody
Antibody-Dependent Cell Cytotoxicity
Carcinoma, Hepatocellular - drug therapy
Carcinoma, Hepatocellular - immunology
CDC
Cell Line, Tumor
CHO Cells
Cricetinae
Cricetulus
Epitope
Glypican 3
Glypicans - antagonists & inhibitors
Glypicans - immunology
Hepatocellular carcinoma
Humans
Immunodominant Epitopes - immunology
Liver Neoplasms - drug therapy
Liver Neoplasms - immunology
Mice
Neoplasm Proteins - antagonists & inhibitors
Neoplasm Proteins - immunology
Xenograft Model Antitumor Assays
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Summary: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.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2008.11.033