title: Dual mode of action of a human anti-epidermal growth factor receptor monoclonal antibody for cancer therapy.
abstract: Epidermal growth factor receptor (EGF-R) overexpression is common in a large number of solid tumors and represents a negative prognostic indicator. Overexpression of EGF-R is strongly tumor associated, and this tyrosine kinase type receptor is considered an attractive target for Ab therapy. In this study, we describe the evaluation of mAb 2F8, a high avidity human mAb (IgG1kappa) directed against EGF-R, developed using human Ig transgenic mice. mAb 2F8 effectively blocked binding of EGF and TGF-alpha to the EGF-R. At saturating concentrations, 2F8 completely blocked EGF-R signaling and inhibited the in vitro proliferation of EGF-R-overexpressing A431 cells. At much lower concentrations, associated with low receptor occupancy, 2F8 induced efficient Ab-dependent cell-mediated cytotoxicity (ADCC) in vitro. In vivo studies showed potent antitumor effects in models with A431 tumor xenografts in athymic mice. Ex vivo analysis of the EGF-R status in tumor xenografts in 2F8-treated mice revealed that there are two therapeutic mechanisms. First, blocking of EGF-R signaling, which is most effective at complete receptor saturation and therefore requires a relatively high Ab dose. Second, at very low 2F8 receptor occupancy, we observed potent antitumor effects in mice, which are likely based on the engagement of immune effector mechanisms, in particular ADCC. Taken together, our findings indicate that ADCC represents an important effector mechanism of this Ab, which is effective at relatively low dose.
authors.affiliation: Genmab BV, Utrecht, The Netherlands.
authors.forename: Wim K
authors.initials: WK
authors.lastname: Bleeker
authors.forename: Jeroen J
authors.initials: JJ
authors.lastname: Lammerts van Bueren
authors.forename: Heidi H
authors.initials: HH
authors.lastname: van Ojik
authors.forename: Arnout F
authors.initials: AF
authors.lastname: Gerritsen
authors.forename: Marielle
authors.initials: M
authors.lastname: Pluyter
authors.forename: Mischa
authors.initials: M
authors.lastname: Houtkamp
authors.forename: Ed
authors.initials: E
authors.lastname: Halk
authors.forename: Joel
authors.initials: J
authors.lastname: Goldstein
authors.forename: Janine
authors.initials: J
authors.lastname: Schuurman
authors.forename: Marc A
authors.initials: MA
authors.lastname: van Dijk
authors.forename: Jan G J
authors.initials: JG
authors.lastname: van de Winkel
authors.forename: Paul W H I
authors.initials: PW
authors.lastname: Parren
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001666:Binding Sites, Antibody; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000502:physiology; D005260:Female; D006131:Growth Inhibitors / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control / Q000628:therapy*; D011485:Protein Binding; D015398:Signal Transduction / Q000276:immunology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D066246:ErbB Receptors