title: The role of B cell-mediated T cell costimulation in the efficacy of the T cell retargeting bispecific antibody BIS20x3.
abstract: In this study, we investigated the role of the naturally occurring B cell-mediated T cell costimulation in the antitumor efficacy of the bispecific Ab BIS20x3. BIS20x3 has a dual specificity for both CD20 and CD3 and has previously been shown to effectively direct the lytic potential of cytolytic T cells toward malignant, CD20(+) B cells. BIS20x3 instigated T cell-B cell interaction caused a dose-dependent activation of T cells that was 30 times stronger when compared with T cell activation induced by monovalent anti-CD3 Abs. The activation of T cells by BIS20x3 and B cells appeared functional and resulted in the rapid induction of high lytic potential in freshly isolated peripheral T cells. BIS20x3-mediated T cell-B cell interaction resulted in a significant up-regulation of ICAM-1 on B cells and the activation of T cells was found to be dependent on the interaction of ICAM-1 with LFA-1 and trans-activation by the NF-kappaB pathway. Also, the lytic potential of freshly isolated T cells activated via BIS20x3 appeared to be dependent on NF-kappaB signaling in the target B cells. Interestingly, the costimulatory signaling effects described in this study appeared specifically related to the targeting against CD20 because targeting against CD19, by a CD3xCD19-directed bispecific Ab, was significantly less effective in inducing T cell activation and T cell-mediated B cell lysis. Together these results demonstrate that the malignant B cells actively contribute to their own demise upon CD20-directed bispecific Ab-mediated T cell targeting.
authors.affiliation: Department of Pathology and Laboratory Medicine, Section Medical Biology-Laboratory Tumor Immunology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. A.J.Stel@med.rug.nl
authors.forename: Alja J
authors.initials: AJ
authors.lastname: Stel
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Kroesen
authors.forename: Susan
authors.initials: S
authors.lastname: Jacobs
authors.forename: Herman
authors.initials: H
authors.lastname: Groen
authors.forename: Lou F M H
authors.initials: LF
authors.lastname: de Leij
authors.forename: Hanneke C
authors.initials: HC
authors.lastname: Kluin-Nelemans
authors.forename: Sebo
authors.initials: S
authors.lastname: Withoff
mesh_terms: D018033:Antibodies, Bispecific / Q000378:metabolism / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000627:therapeutic use*; D018951:Antigens, CD20 / Q000276:immunology / Q000502:physiology; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D016923:Cell Death / Q000276:immunology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000378:metabolism / Q000627:therapeutic use; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism / Q000502:physiology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D008211:Lymphocyte Cooperation / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D000970:Antineoplastic Agents; D017252:CD3 Complex; D003432:Cross-Linking Reagents; D016169:Lymphocyte Function-Associated Antigen-1; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1