title: The novel bispecific diabody alphaCD40/alphaCD28 strengthens leukaemic dendritic cell-induced T-cell reactivity.
abstract: Dendritic cell (DC)-based immunotherapy faces new challenges because the efficacy of DC vaccines in clinical trials has been inconsistent. Strategies to improve immune responses induced by DC are currently being explored. We have recently shown the feasibility of generating fully functional DC from acute myeloid leukaemic (AML) blasts, but with varying expression levels of the important costimulatory molecule CD86. To overcome this variability, we developed a novel bispecific diabody that simultaneously and agonistically targeted CD40 on AML-DC and CD28 on naïve T cells. Beside optimization of CD28-mediated signalling, the resulting cellular cross-linking was also hypothesized to increase the strength and duration of T cell/AML-DC interactions, thus increasing T-cell responsiveness to AML antigens. The alphaCD40/alphaCD28-bispecific diabody was found to bind to its target antigens and provoked increased T-cell-DC cluster formation. The alphaCD40/alphaCD28 diabody is capable of increasing T-cell proliferation induced by AML-DC as well as the induction of DC maturation. Importantly, priming efficacy of tumour-specific cytotoxic T cells can also be improved by cross-linking AML-DC and T cells with the alphaCD40/alphaCD28 diabody. We propose that the alphaCD40/alphaCD28-bispecific diabody can serve as a potent therapeutic tool to effectively augment anti-tumour T-cell responses elicited by AML-DC.
authors.affiliation: Department of Haematology, VU University Medical Centre, Amsterdam, the Netherlands.
authors.forename: Ilse
authors.initials: I
authors.lastname: Houtenbos
authors.forename: Saskia
authors.initials: S
authors.lastname: Santegoets
authors.forename: Theresia M
authors.initials: TM
authors.lastname: Westers
authors.forename: Quinten
authors.initials: Q
authors.lastname: Waisfisz
authors.forename: Sergey
authors.initials: S
authors.lastname: Kipriyanov
authors.forename: Fedor
authors.initials: F
authors.lastname: Denkers
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: Arjan A
authors.initials: AA
authors.lastname: van de Loosdrecht
mesh_terms: D018033:Antibodies, Bispecific / Q000096:biosynthesis / Q000276:immunology / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D019013:CD40 Antigens; D019496:Cancer Vaccines