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null Mice In Vivo1
* Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan;
Department of Hematology, Imamura Bun-in Hospital, Kagoshima, Japan; and
Department of Clinical Pathology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
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-2R
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants-in-Aid for General Scientific Research (No. 19390266 to R.U. and No. 80405183 to T.I.) and for Scientific Research on Priority Areas (Nos. 17016065 and 16062101 to R.U.) from the Ministry of Education, Culture, Science, Sports, and Technology, Japan; Grants-in-Aid for Cancer Research from the Ministry of Health, Labor, and Welfare, Japan (Nos. 17S-1 and 17-16 to S.I. and No. 19-8 to T. Ishida); Grant-in-Aid from the Nagono Medical Foundation (T. Ishida) and Kato Memorial Bioscience Foundation (R.U.).
2 Address correspondence and reprint requests to Dr. Takashi Ishida, Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-chou, Mizuho-ku, Nagoya, Aichi, 467-8601, Japan. E-mail address: itakashi{at}med.nagoya-cu.ac.jp
3 Abbreviations used in this paper: ADDC, Ab-dependent cellular cytotoxicity; ATLL, adult T cell leukemia/lymphoma; FSC-H, forward scatter height; LDH, lactate dehydrogenase; NOG, NOD/Shi-scid, IL-2Rnull; sIL2R, soluble IL2R; SSC-H, side scatter height.
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