title: Enhanced antibody-dependent cellular phagocytosis by chimeric monoclonal antibodies with tandemly repeated Fc domains.
abstract: We previously reported that chimeric monoclonal antibodies (mAbs) with tandemly repeated Fc domains, which were developed by introducing tandem repeats of Fc domains downstream of 2 Fab domains, augmented binding avidities for all Fcγ receptors, resulting in enhanced antibody (Ab)-dependent cellular cytotoxicity. Here we investigated regarding Ab-dependent cellular phagocytosis (ADCP) mediated by these chimeric mAbs, which is considered one of the most important mechanisms that kills tumor cells, using two-color flow cytometric methods. ADCP mediated by T3-Ab, a chimeric mAb with 3 tandemly repeated Fc domains, was 5 times more potent than that by native anti-CD20 M-Ab (M-Ab hereafter). Furthermore, T3-Ab-mediated ADCP was resistant to competitive inhibition by intravenous Ig (IVIG), although M-Ab-mediated ADCP decreased in the presence of IVIG. An Fcγ receptor-blocking study demonstrated that T3-Ab mediated ADCP via both FcγRIA and FcγRIIA, whereas M-Ab mediated ADCP exclusively via FcγRIA. These results suggest that chimeric mAbs with tandemly repeated Fc domains enhance ADCP as well as ADCC, and that Fc multimerization may significantly enhance the efficacy of therapeutic Abs.
authors.affiliation: Tokyo University of Science, Yamazaki 2641, Noda, Chiba 278-8510, Japan. nagashimahra@chugai-pharm.co.jp
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagashima
authors.forename: Michiko
authors.initials: M
authors.lastname: Ootsubo
authors.forename: Mizuki
authors.initials: M
authors.lastname: Fukazawa
authors.forename: Sotaro
authors.initials: S
authors.lastname: Motoi
authors.forename: Shu
authors.initials: S
authors.lastname: Konakahara
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Masuho
mesh_terms: D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D018951:Antigens, CD20 / Q000276:immunology; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000502:physiology*; D016756:Immunoglobulins, Intravenous / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D010587:Phagocytosis; D017434:Protein Structure, Tertiary; D017452:Receptors, IgG / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D020449:Repetitive Sequences, Amino Acid
chemical_list: D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D007141:Immunoglobulin Fc Fragments; D016756:Immunoglobulins, Intravenous; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins