title: Defucosylated anti-CCR4 monoclonal antibody exerts potent ADCC against primary ATLL cells mediated by autologous human immune cells in NOD/Shi-scid, IL-2R gamma(null) mice in vivo.
abstract: There is a lack of suitable small animal models to evaluate human Ab-dependent cellular cytotoxicity (ADCC) in vivo, because of the species incompatibility between humans and animals or due to nonspecific allogeneic immune reactions. To overcome these problems, we established a human tumor-bearing mouse model, using NOD/Shi-scid, IL-2Rgamma(null) (NOG) mice as recipients, in which autologous human immune cells are engrafted and mediate ADCC but in which endogenous murine cells are unable to mediate ADCC. In the present study, we used NOG mice bearing primary adult T cell leukemia/lymphoma (ATLL) cells and a therapeutic chimeric anti-CCR4 mAb, the Fc region of which is defucosylated to enhance ADCC. We report significant antitumor activity in vivo associated with robust ADCC mediated by autologous effector cells from the same patients. The present study is the first to report a mouse model in which a potent antitumor effect of the therapeutic mAb against primary tumor cells is mediated by autologous human immune cells. Human autologous ADCC in mice in vivo was confirmed by the depletion of human immune cells before ATLL PBMC inoculation. In addition, NOG mice bearing primary ATLL cells presented features identical with patients with ATLL. In conclusion, this approach makes it possible to model the human immune system active in Ab-based immunotherapy in vivo, and thus to perform more appropriate preclinical evaluations of novel therapeutic mAb. Furthermore, the potent ADCC mediated by defucosylated anti-CCR4 mAb, observed here in vivo in humanized mice, will be exploited in clinical trials in the near future.
authors.affiliation: Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan.
authors.forename: Asahi
authors.initials: A
authors.lastname: Ito
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishida
authors.forename: Atae
authors.initials: A
authors.lastname: Utsunomiya
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Sato
authors.forename: Fumiko
authors.initials: F
authors.lastname: Mori
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yano
authors.forename: Atsushi
authors.initials: A
authors.lastname: Inagaki
authors.forename: Susumu
authors.initials: S
authors.lastname: Suzuki
authors.forename: Hisashi
authors.initials: H
authors.lastname: Takino
authors.forename: Masaki
authors.initials: M
authors.lastname: Ri
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kusumoto
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Komatsu
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Iida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inagaki
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Ueda
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005643:Fucose / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000037:antagonists & inhibitors / Q000097:blood / Q000172:deficiency* / Q000235:genetics*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D018655:Lymphocyte Count; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D054398:Receptors, CCR4 / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; C515354:CCR4 protein, human; D053631:Interleukin Receptor Common gamma Subunit; D054398:Receptors, CCR4; D005643:Fucose