A Novel Anti-Human HB-EGF Monoclonal Antibody with Multiple Antitumor Mechanisms against Ovarian Cancer Cells

• Published in: Clinical cancer research 2011-11, Vol.17 (21), p.6733-6741
• Main Authors: MIYAMOTO, Shingo, IWAMOTO, Ryo, MURAKAMI, Takuya, HORI, Sayaka, SHITARA, Kenya, MEKADA, Eisuke, FURUYA, Akiko, TAKAHASHI, Kumiko, SASAKI, Yuka, ANDO, Hiroshi, YOTSUMOTO, Fusanori, YONEDA, Tomoko, HAMAOKA, Miki, YAGI, Hiroshi
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - isolation & purification; Antibodies, Monoclonal - pharmacology; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - pharmacology; Antibody Specificity; Antibody-dependent cell-mediated cytotoxicity; Antineoplastic agents; Antitumor activity; Biological and medical sciences; Cell surface; Cercopithecus aethiops; CHO Cells; Cricetinae; Cricetulus; Cytotoxicity; Epidermal growth factor; Female; Female genital diseases; Gynecology. Andrology. Obstetrics; Heparin-binding EGF-like Growth Factor; Humans; Immunodeficiency; Immunoglobulin G - immunology; Intercellular Signaling Peptides and Proteins - immunology; Medical sciences; Mice; Mice, SCID; Monoclonal antibodies; Ovarian cancer; Ovarian Neoplasms - immunology; Ovarian Neoplasms - therapy; Pharmacology. Drug treatments; Substrate Specificity; Tumors; Vero Cells; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-11-1029

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. 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. 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. 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.