A novel anti-human HB-EGF monoclonal antibody with multiple antitumor mechanisms against ovarian cancer cells

Shingo Miyamoto, Ryo Iwamoto, Akiko Furuya, Kumiko Takahashi, Yuka Sasaki, Hiroshi Ando, Fusanori Yotsumoto, Tomoko Yoneda, Miki Hamaoka, Hiroshi Yagi, Takuya Murakami, Sayaka Hori, Kenya Shitara, Eisuke Mekada

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)6733-6741
Number of pages9
JournalClinical Cancer Research
Volume17
Issue number21
DOIs
Publication statusPublished - Nov 1 2011

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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