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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.

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  • Authors+Show Affiliations

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    Tokyo Research Laboratories, Kyowa Hakko Kogyo Co. Ltd., 3-6-6 Asahi-machi, Machida-shi, Tokyo 194-8533, Japan.

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    Source

    Cancer research 64:6 2004 Mar 15 pg 2127-33

    MeSH

    Animals
    Antibodies, Neoplasm
    Antibody-Dependent Cell Cytotoxicity
    Carbohydrate Sequence
    Cell Survival
    Disease Models, Animal
    Flow Cytometry
    Fucose
    Humans
    Immunoglobulin G
    Leukemia, T-Cell
    Lymphoma, T-Cell
    Male
    Mice
    Mice, Inbred BALB C
    Mice, Inbred C57BL
    Mice, Inbred ICR
    Mice, Nude
    Mice, SCID
    Molecular Sequence Data
    Receptors, CCR4
    Receptors, Chemokine
    Recombinant Fusion Proteins
    Tumor Cells, Cultured

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    15026353

    Citation

    Niwa, Rinpei, et al. "Defucosylated Chimeric anti-CC Chemokine Receptor 4 IgG1 With Enhanced Antibody-dependent Cellular Cytotoxicity Shows Potent Therapeutic Activity to T-cell Leukemia and Lymphoma." Cancer Research, vol. 64, no. 6, 2004, pp. 2127-33.
    Niwa R, Shoji-Hosaka E, Sakurada M, et al. Defucosylated chimeric anti-CC chemokine receptor 4 IgG1 with enhanced antibody-dependent cellular cytotoxicity shows potent therapeutic activity to T-cell leukemia and lymphoma. Cancer Res. 2004;64(6):2127-33.
    Niwa, R., Shoji-Hosaka, E., Sakurada, M., Shinkawa, T., Uchida, K., Nakamura, K., ... Shitara, K. (2004). Defucosylated chimeric anti-CC chemokine receptor 4 IgG1 with enhanced antibody-dependent cellular cytotoxicity shows potent therapeutic activity to T-cell leukemia and lymphoma. Cancer Research, 64(6), pp. 2127-33.
    Niwa R, et al. Defucosylated Chimeric anti-CC Chemokine Receptor 4 IgG1 With Enhanced Antibody-dependent Cellular Cytotoxicity Shows Potent Therapeutic Activity to T-cell Leukemia and Lymphoma. Cancer Res. 2004 Mar 15;64(6):2127-33. PubMed PMID: 15026353.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Defucosylated chimeric anti-CC chemokine receptor 4 IgG1 with enhanced antibody-dependent cellular cytotoxicity shows potent therapeutic activity to T-cell leukemia and lymphoma. AU - Niwa,Rinpei, AU - Shoji-Hosaka,Emi, AU - Sakurada,Mikiko, AU - Shinkawa,Toyohide, AU - Uchida,Kazuhisa, AU - Nakamura,Kazuyasu, AU - Matsushima,Kouji, AU - Ueda,Ryuzo, AU - Hanai,Nobuo, AU - Shitara,Kenya, PY - 2004/3/18/pubmed PY - 2004/4/9/medline PY - 2004/3/18/entrez SP - 2127 EP - 33 JF - Cancer research JO - Cancer Res. VL - 64 IS - 6 N2 - 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. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/15026353/Defucosylated_chimeric_anti_CC_chemokine_receptor_4_IgG1_with_enhanced_antibody_dependent_cellular_cytotoxicity_shows_potent_therapeutic_activity_to_T_cell_leukemia_and_lymphoma_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=15026353 DB - PRIME DP - Unbound Medicine ER -