title: A novel anti-human HB-EGF monoclonal antibody with multiple antitumor mechanisms against ovarian cancer cells.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Obstetrics and Gynecology, Fukuoka University, Fukuoka, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Ryo
authors.initials: R
authors.lastname: Iwamoto
authors.forename: Akiko
authors.initials: A
authors.lastname: Furuya
authors.forename: Kumiko
authors.initials: K
authors.lastname: Takahashi
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ando
authors.forename: Fusanori
authors.initials: F
authors.lastname: Yotsumoto
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yoneda
authors.forename: Miki
authors.initials: M
authors.lastname: Hamaoka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yagi
authors.forename: Takuya
authors.initials: T
authors.lastname: Murakami
authors.forename: Sayaka
authors.initials: S
authors.lastname: Hori
authors.forename: Kenya
authors.initials: K
authors.lastname: Shitara
authors.forename: Eisuke
authors.initials: E
authors.lastname: Mekada
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000302:isolation & purification / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D000918:Antibody Specificity; D016466:CHO Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy*; D013379:Substrate Specificity; D014709:Vero Cells; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D007074:Immunoglobulin G; D036341:Intercellular Signaling Peptides and Proteins