title: The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells.
abstract: Bispecific antibodies (bsAb) are considered as promising tools for the elimination of disseminated tumour cells in a minimal residual disease situation. The bsAb-mediated recruitment of an immune effector cell in close vicinity of a tumour cell is thought to induce an antitumoural immune response. However, classical bispecific molecules activate only a single class of immune effector cell that may not yield optimal immune responses. We therefore constructed an intact bispecific antibody, BiUII (anti-CD3 x anti-EpCAM), that not only recognizes tumour cells and T lymphocytes with its two binding arms, but also binds and activates Fcgamma-receptor positive accessory cells through its Fc-region. We have demonstrated recently that activated accessory cells contribute to the bsAb-induced antitumoural activity. We now analyse this stimulation in more detail and demonstrate here the BiUII-induced upregulation of activation markers like CD83 and CD95 on accessory cells and the induction of neopterin and biopterin synthesis. Experiments with pure cell subpopulations revealed binding of BiUII to CD64+ accessory cells and CD16+ NK cells, but not to CD32+ B lymphocytes. We provide further evidence for the importance of the Fc-region in that this bispecific molecule stimulates Fcgamma-R-positive accessory cells to eliminate tumour cells in vitro by direct phagocytosis.
authors.affiliation: Department of Otorhinolaryngology, Ludwig-Maximillans-University, Munich, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Zeidler
authors.forename: J
authors.initials: J
authors.lastname: Mysliwietz
authors.forename: M
authors.initials: M
authors.lastname: Csánady
authors.forename: A
authors.initials: A
authors.lastname: Walz
authors.forename: I
authors.initials: I
authors.lastname: Ziegler
authors.forename: B
authors.initials: B
authors.lastname: Schmitt
authors.forename: B
authors.initials: B
authors.lastname: Wollenberg
authors.forename: H
authors.initials: H
authors.lastname: Lindhofer
mesh_terms: D018033:Antibodies, Bispecific / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000276:immunology*; D015295:Antigens, Tumor-Associated, Carbohydrate / Q000276:immunology; D001708:Biopterins / Q000096:biosynthesis; D017252:CD3 Complex / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D066298:In Vitro Techniques; D007694:Killer Cells, Natural / Q000276:immunology*; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D009000:Monocytes / Q000276:immunology; D019798:Neopterin / Q000096:biosynthesis; D010587:Phagocytosis / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D018033:Antibodies, Bispecific; D015295:Antigens, Tumor-Associated, Carbohydrate; D017252:CD3 Complex; D007141:Immunoglobulin Fc Fragments; D018950:Lipopolysaccharide Receptors; D011993:Recombinant Fusion Proteins; D001708:Biopterins; D019798:Neopterin