title: Cross-linking tumor cells with effector cells via CD55 with a bispecific mAb induces beta-glucan-dependent CR3-dependent cellular cytotoxicity.
abstract: Complement (C) regulatory proteins decrease the effectiveness of immunotherapeutic anti-cancer antibodies. Bispecific mAb (bi-mAb) that target a tumor antigen and simultaneously inhibit a C regulator increase the effectiveness of such a therapy. Here we investigated the mechanism by which bi-mAb increase tumor cell lysis. Apart from C-dependent cytotoxicity, C activation can lead to complement receptor 3 (CR3)-dependent cellular cytotoxicity (CR3-DCC) by CR3-positive effector cells in the presence of beta-glucan. Here we show that an anti-Ep-CAM*anti-CD55 bi-mAb induced more than threefold higher CR3-DCC (71%) of human colorectal cancer cells compared with anti-Ep-CAM alone (20%). This CR3-DCC was dependent on the binding of the anti-CD55 arm of tumor-bound anti-Ep-CAM*anti-CD55 bi-mAb to effector cell CD55, CR3 priming by beta-glucan and the presence of iC3b on the target cell. Comparable lysis could be obtained in the absence of iC3b, when CR3 and CD55 were cross-linked on the effector cells, suggesting cooperation between CD55 and CR3 in signal transduction. Tumor cells with low antigen expression were effectively lysed via this mechanism in contrast to direct C-dependent cytotoxicity. These data imply that the effectiveness of mAb immunotherapy can be improved using anti-tumor antigen*anti-CD55 bi-mAb and beta-glucan, thereby initiating CR3-DCC as an additional effector mechanism that is efficient for eradication of tumor cells with lower antigen expression.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Kyra A
authors.initials: KA
authors.lastname: Gelderman
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lam
authors.forename: Cornelis F
authors.initials: CF
authors.lastname: Sier
authors.forename: Arko
authors.initials: A
authors.lastname: Gorter
mesh_terms: D018033:Antibodies, Bispecific / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D018958:CD55 Antigens / Q000276:immunology* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000276:immunology; D003432:Cross-Linking Reagents; D003602:Cytotoxicity, Immunologic; D000071858:Epithelial Cell Adhesion Molecule; D005434:Flow Cytometry; D006801:Humans; D016177:Macrophage-1 Antigen / Q000276:immunology* / Q000378:metabolism; D047071:beta-Glucans / Q000276:immunology* / Q000378:metabolism
chemical_list: D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D018958:CD55 Antigens; D015815:Cell Adhesion Molecules; D003432:Cross-Linking Reagents; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D016177:Macrophage-1 Antigen; D047071:beta-Glucans