title: Defucosylated chimeric anti-CC chemokine receptor 4 IgG1 with enhanced antibody-dependent cellular cytotoxicity shows potent therapeutic activity to T-cell leukemia and lymphoma.
abstract: Human IgG1 antibodies with low fucose contents in their asparagine-linked oligosaccharides have been shown recently to exhibit potent antibody-dependent cellular cytotoxicity (ADCC) in vitro. To additionally investigate the efficacy of the human IgG1 with enhanced ADCC, we generated the defucosylated chimeric anti-CC chemokine receptor 4 (CCR4) IgG1 antibody KM2760. KM2760 exhibited much higher ADCC using human peripheral blood mononuclear cells (PBMCs) as effector cells compared with the highly fucosylated, but otherwise identical IgG1, KM3060. In addition, KM2760 also exhibited potent ADCC in the presence of lower concentrations of human PBMCs than KM3060. Because CCR4 is a selective marker of T-cell leukemia/lymphoma, the effectiveness of KM2760 for T-cell malignancy was evaluated in several mouse models. First, to compare the antitumor activity of KM2760 and KM3060, we constructed a human PBMC-engrafted mouse model to determine ADCC efficacy with human effector cells. In this model, KM2760 showed significantly higher antitumor efficacy than KM3060, indicating that KM2760 retains its high potency in vivo. Second, KM2760 suppressed tumor growth in both syngeneic and xenograft mouse models in which human PBMCs were not engrafted. Although murine effector cells exhibited marginal ADCC mediated by KM2760 and KM3060, KM2760 unexpectedly showed higher efficacy than KM3060 in a syngeneic mouse model, suggesting that KM2760 functions in murine effector system in vivo via an unknown mechanism that differs from that in human. These results indicate that defucosylated antibodies with enhanced ADCC as well as potent antitumor activity in vivo are promising candidates for the novel antibody-based therapy.
authors.affiliation: Tokyo Research Laboratories, Kyowa Hakko Kogyo Co. Ltd., 3-6-6 Asahi-machi, Machida-shi, Tokyo 194-8533, Japan.
authors.forename: Rinpei
authors.initials: R
authors.lastname: Niwa
authors.forename: Emi
authors.initials: E
authors.lastname: Shoji-Hosaka
authors.forename: Mikiko
authors.initials: M
authors.lastname: Sakurada
authors.forename: Toyohide
authors.initials: T
authors.lastname: Shinkawa
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Uchida
authors.forename: Kazuyasu
authors.initials: K
authors.lastname: Nakamura
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Ueda
authors.forename: Nobuo
authors.initials: N
authors.lastname: Hanai
authors.forename: Kenya
authors.initials: K
authors.lastname: Shitara
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D002240:Carbohydrate Sequence; D002470:Cell Survival; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005643:Fucose; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D015458:Leukemia, T-Cell / Q000276:immunology / Q000628:therapy*; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000628:therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D016513:Mice, SCID; D008969:Molecular Sequence Data; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D000912:Antibodies, Neoplasm; C515354:CCR4 protein, human; C515355:Ccr4 protein, mouse; D007074:Immunoglobulin G; D054398:Receptors, CCR4; D019707:Receptors, Chemokine; D011993:Recombinant Fusion Proteins; D005643:Fucose