title: Lysis of murine B lymphoma cells by transgenic phagocytes via a human Fc gamma RI x murine MHC class II bispecific antibody.
abstract: The class I IgG receptor (Fc gamma RI) on cytotoxic effector cells has been reported to initiate destruction of tumour cells by effector cells in vitro. We are aiming at developing an immunocompetent model to evaluate the cytotoxic capacity of human Fc gamma RI for the rejection of tumour cells in vivo. Therefore, we recently generated a transgenic mouse strain expressing human Fc gamma RI on monocytes, macrophages, and neutrophils. In these mice, the human receptor is up-regulated by granulocyte-colony-stimulating factor (G-CSF) and is able to trigger cellular responses. Subsequently, in the present study the B cell lymphoma IIA1.6 cell line is selected as a tumour target, and a human Fc gamma RI-directed antitumour bispecific antibody (bsAb) is constructed and characterized. Fab' fragments of mAb 22, which bind hFc gamma RI at an epitope that is distinct from the ligand binding site, were chemically linked to Fab' fragments of rat anti-(mMHC class II antigens) mAb M5/114, yielding bsAb 22 x M5/114. This bsAb was able to bind simultaneously to hFc gamma RI and mMHC class II antigens in a dose-dependent fashion. Binding of 22 x M5/114 to Fc gamma RI was not inhibited in the presence of human IgG. It is important to note that, MHC-class-II-expressing IIA1.6 lymphoma cells were lysed by whole blood from G-CSF-treated transgenic mice in the presence of bsAb 22 x M5/114. No lysis by whole blood from non-transgenic mice or from transgenic animals that had not received G-CSF was observed. These results indicate that human Fc gamma RI is able to mediate lysis of murine IIA1.6 lymphoma cells by transgenic effector cells via bsAb 22 x M5/114. A trial with transgenic mice, evaluating the efficacy of these hFc gamma RI-directed bsAb in combination with G-CSF for treatment of IIA1.6 B cell lymphoma, is currently in progress.
authors.affiliation: Department of Immunology and Medarex Europe, University Hospital Utrecht, The Netherlands.
authors.forename: I A
authors.initials: IA
authors.lastname: Heijnen
authors.forename: M J
authors.initials: MJ
authors.lastname: Glennie
authors.forename: J G
authors.initials: JG
authors.lastname: van de Winkel
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000627:therapeutic use*; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology*; D007167:Immunotherapy; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010586:Phagocytes / Q000276:immunology*; D010587:Phagocytosis; D011961:Receptors, Fc / Q000276:immunology*
chemical_list: D018033:Antibodies, Bispecific; D000949:Histocompatibility Antigens Class II; D007140:Immunoglobulin Fab Fragments; D011961:Receptors, Fc