Anti-CD3/anti-epidermal growth factor receptor-bispecific antibody retargeting of lymphocytes against human neoplastic keratinocytes in an autologous organotypic culture model.
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.
Renard
Isabelle
I
Department of Pathology, University of Liège, Liège, Belgium. isabelle.renard@student.ulg.ac.be
Mezzanzanica
Delia
D
Canevari
Silvana
S
Ferrini
Silvano
S
Boniver
Jacques
J
Delvenne
Philippe
P
Jacobs
Nathalie
N
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
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D066246:ErbB Receptors