Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rγnull mouse model |
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Authors: | Asahi Ito Takashi Ishida Hiroki Yano Atsushi Inagaki Susumu Suzuki Fumihiko Sato Hisashi Takino Fumiko Mori Masaki Ri Shigeru Kusumoto Hirokazu Komatsu Shinsuke Iida Hiroshi Inagaki Ryuzo Ueda |
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Institution: | (1) 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;(2) Department of Clinical Pathology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-chou, Mizuho-ku, Nagoya Aichi, 467-8601, Japan |
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Abstract: | Purpose There are no suitable small animal models to evaluate human antibody-dependent cellular cytotoxicity (ADCC) in vivo, due to
species incompatibilities. Thus, the first aim of this study was to establish a human tumor-bearing mouse model in which human
immune cells can engraft and mediate ADCC, but where the endogenous mouse immune cells cannot mediate ADCC. The second aim
was to evaluate ADCC mediated in these humanized mice by the defucosylated anti-CC chemokine receptor 4 (CCR4) monoclonal
antibody (mAb) which we have developed and which is now in phase I clinical trials.
Experimental design NOD/Shi-scid, IL-2Rγnull (NOG) mice were the recipients of human immune cells, and CCR4-expressing Hodgkin lymphoma (HL) and cutaneous T-cell lymphoma
(CTCL) cell lines were used as target tumors.
Results Humanized mice have been established using NOG mice. The chimeric defucosylated anti-CCR4 mAb KM2760 showed potent antitumor
activity mediated by robust ADCC in these humanized mice bearing the HL or CTCL cell lines. KM2760 significantly increased
the number of tumor-infiltrating CD56-positive NK cells which mediate ADCC, and reduced the number of tumor-infiltrating FOXP3-positive
regulatory T (Treg) cells in HL-bearing humanized mice.
Conclusions Anti-CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill CCR4-expressing tumor
cells, but also to overcome the suppressive effect of Treg cells on the host immune response to tumor cells. In addition,
using our humanized mice, we can perform the appropriate preclinical evaluation of many types of antibody based immunotherapy. |
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Keywords: | NOD/Shi-scid IL-2Rγ null mice ADCC CCR4 NK cell Regulatory T cell |
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