TY - JOUR
T1 - A novel anti-human HB-EGF monoclonal antibody with multiple antitumor mechanisms against ovarian cancer cells
AU - Miyamoto, Shingo
AU - Iwamoto, Ryo
AU - Furuya, Akiko
AU - Takahashi, Kumiko
AU - Sasaki, Yuka
AU - Ando, Hiroshi
AU - Yotsumoto, Fusanori
AU - Yoneda, Tomoko
AU - Hamaoka, Miki
AU - Yagi, Hiroshi
AU - Murakami, Takuya
AU - Hori, Sayaka
AU - Shitara, Kenya
AU - Mekada, Eisuke
PY - 2011/11/1
Y1 - 2011/11/1
N2 - Purpose: Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is a member of the EGF family and plays a pivotal role in tumor progression in ovarian cancer. We developed an anti-HB-EGF monoclonal antibody (mAb) and investigated its antitumor activities in vitro and in vivo to evaluate its potential as a therapeutic antibody against ovarian cancer. Experimental Design: We prepared mAbs from HB-EGF null mice immunized with recombinant human soluble HB-EGF and evaluated their binding and neutralizing activity against HB-EGF. Next, we generated a mouse-human chimeric antibody and examined its in vitro and in vivo antitumor activities. Results: Two murine anti-HB-EGF mAbs were developed, and one of them, KM3566, was revealed to have a high binding reactivity for membrane-anchored HB-EGF (pro-HB-EGF) expressed on the cell surface, as well as neutralizing activity against growth promoting activity of soluble HB-EGF. The mouse-human chimeric counterpart for KM3566 (cKM3566) induced dose-dependent antibody-dependent cellular cytotoxicity (ADCC) against cancer cells expressing HB-EGF in vitro, and significantly inhibited tumor growth in severe combined immunodeficient mice inoculated with MCAS or ES-2 human ovarian cancer cells. Conclusions: A novel anti-HB-EGF chimeric antibody, cKM3566, with two antitumor mechanisms, neutralization and ADCC, exhibits potent in vivo antitumor activity. These results indicate that cKM3566 is a promising antiovarian cancer therapeutic antibody.
AB - Purpose: Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is a member of the EGF family and plays a pivotal role in tumor progression in ovarian cancer. We developed an anti-HB-EGF monoclonal antibody (mAb) and investigated its antitumor activities in vitro and in vivo to evaluate its potential as a therapeutic antibody against ovarian cancer. Experimental Design: We prepared mAbs from HB-EGF null mice immunized with recombinant human soluble HB-EGF and evaluated their binding and neutralizing activity against HB-EGF. Next, we generated a mouse-human chimeric antibody and examined its in vitro and in vivo antitumor activities. Results: Two murine anti-HB-EGF mAbs were developed, and one of them, KM3566, was revealed to have a high binding reactivity for membrane-anchored HB-EGF (pro-HB-EGF) expressed on the cell surface, as well as neutralizing activity against growth promoting activity of soluble HB-EGF. The mouse-human chimeric counterpart for KM3566 (cKM3566) induced dose-dependent antibody-dependent cellular cytotoxicity (ADCC) against cancer cells expressing HB-EGF in vitro, and significantly inhibited tumor growth in severe combined immunodeficient mice inoculated with MCAS or ES-2 human ovarian cancer cells. Conclusions: A novel anti-HB-EGF chimeric antibody, cKM3566, with two antitumor mechanisms, neutralization and ADCC, exhibits potent in vivo antitumor activity. These results indicate that cKM3566 is a promising antiovarian cancer therapeutic antibody.
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U2 - 10.1158/1078-0432.CCR-11-1029
DO - 10.1158/1078-0432.CCR-11-1029
M3 - Article
C2 - 21918176
AN - SCOPUS:80455140254
SN - 1078-0432
VL - 17
SP - 6733
EP - 6741
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -
