title: Anti-CD3/anti-epidermal growth factor receptor-bispecific antibody retargeting of lymphocytes against human neoplastic keratinocytes in an autologous organotypic culture model.
abstract: Local cellular immune defects have been described in several tumors including human papillomavirus (HPV)-associated cervical cancer. This observation suggests the potential therapeutic benefit of immune manipulations that restore cellular immunity. Here, we evaluated the ability of bispecific monoclonal antibodies (bimAbs) to redirect T cells against keratinocytes transformed in vitro by HPV in an autologous three-dimensional culture model (organotypic cultures). The epidermal growth factor receptor (EGFR) was chosen as target for an anti-CD3/anti-EGFR bimAb because it is overexpressed in many malignant epithelial lesions and only weakly expressed in the basal layers of normal squamous epithelium. Interestingly, in organotypic cultures, the pattern of expression of EGFR was similar to that observed in vivo. The ability of T cells retargeted by CD3/EGFR bimAb to lyse HPV-transformed cell lines was confirmed in monolayer cultures. In autologous organotypic cultures, an increase in apoptotic HPV(+) keratinocytes and a significant decrease in the thickness of HPV(+) organotypic cultures were observed when activated lymphocytes and bimAbs were added to the cultures, whereas organotypic cultures of normal keratinocytes were not significantly affected. These data were similar to those obtained in the allogeneic model. These results suggest the potential usefulness of CD3-EGFR bimAb-retargeted lymphocytes in immunotherapeutic protocols for malignant epithelial lesions.
authors.affiliation: Department of Pathology, University of Liège, Liège, Belgium. isabelle.renard@student.ulg.ac.be
authors.forename: Isabelle
authors.initials: I
authors.lastname: Renard
authors.forename: Delia
authors.initials: D
authors.lastname: Mezzanzanica
authors.forename: Silvana
authors.initials: S
authors.lastname: Canevari
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
authors.forename: Jacques
authors.initials: J
authors.lastname: Boniver
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
authors.forename: Nathalie
authors.initials: N
authors.lastname: Jacobs
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000918:Antibody Specificity; D017252:CD3 Complex / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D066246:ErbB Receptors / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D008214:Lymphocytes / Q000187:drug effects* / Q000502:physiology*; D009924:Organ Culture Techniques; D027383:Papillomaviridae / Q000302:isolation & purification; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D066246:ErbB Receptors