title: Trifunctional bispecific antibodies induce tumor-specific T cells and elicit a vaccination effect.
abstract: A major goal of tumor immunotherapy is the induction of long-lasting systemic T-cell immunity. Bispecific antibodies (bsAbs) that lack the immunoglobulin Fc region confer T-cell-mediated killing of tumor cells but do not induce long-term memory. In contrast, trifunctional bsAbs comprise an appropriate Fc region and, therefore, not only recruit T cells but also accessory cells that bear activating Fcγ receptors (FcγR), providing additional T-cell-activating signals and securing presentation of tumor-derived antigens to T cells. In this study, we show that trifunctional bsAbs induce a polyvalent T-cell response and, therefore, a vaccination effect. Mice were treated with melanoma cells and with a trifunctional bsAb directed against the melanoma target antigen ganglioside GD2 in addition to murine CD3. The trifunctional bsAb activated dendritic cells and induced a systemic immune response that was not replicated by treatment with the F(ab')2-counterpart lacking the Fc region. Restimulation of spleen and lymph node cells in vitro yielded T-cell lines that specifically produced interferon-γ in response to tumor. In addition, trifunctional bsAb-induced T cells recognized various specific peptides derived from melanoma-associated antigens. Moreover, these polyvalent responses proved to be tumor-suppressive and could not be induced by the corresponding bsF(ab')2-fragment. Taken together, our findings provide preclinical proof of concept that trifunctional bsAbs can induce tumor-specific T cells with defined antigen specificity.
authors: Helmholtz-Zentrum München, Institut für Molekulare Immunologie; Trion Research GmbH, München, Germany.
authors: Nina
authors: N
authors: Eissler
authors: Peter
authors: P
authors: Ruf
authors: Josef
authors: J
authors: Mysliwietz
authors: Horst
authors: H
authors: Lindhofer
authors: Ralph
authors: R
authors: Mocikat
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology*; D017252:CD3 Complex / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D005732:Gangliosides / Q000276:immunology; D008213:Lymphocyte Activation; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018033:Antibodies, Bispecific; D017252:CD3 Complex; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D005732:Gangliosides; C019403:ganglioside, GD2