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.
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.
Ito
Asahi
A
Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601, Japan.
Ishida
Takashi
T
Utsunomiya
Atae
A
Sato
Fumihiko
F
Mori
Fumiko
F
Yano
Hiroki
H
Inagaki
Atsushi
A
Suzuki
Susumu
S
Takino
Hisashi
H
Ri
Masaki
M
Kusumoto
Shigeru
S
Komatsu
Hirokazu
H
Iida
Shinsuke
S
Inagaki
Hiroshi
H
Ueda
Ryuzo
R
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
D000911:Antibodies, Monoclonal; C515354:CCR4 protein, human; D053631:Interleukin Receptor Common gamma Subunit; D054398:Receptors, CCR4; D005643:Fucose