Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rgamma(null) mouse model.
OBJECTIVE
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.


METHODS
NOD/Shi-scid, IL-2Rgamma(null) (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.
Ito
Asahi
A
Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-chou, Mizuho-ku, Nagoya, Aichi, Japan. itakashi@med.nagoya-cu.ac.jp
Ishida
Takashi
T
Yano
Hiroki
H
Inagaki
Atsushi
A
Suzuki
Susumu
S
Sato
Fumihiko
F
Takino
Hisashi
H
Mori
Fumiko
F
Ri
Masaki
M
Kusumoto
Shigeru
S
Komatsu
Hirokazu
H
Iida
Shinsuke
S
Inagaki
Hiroshi
H
Ueda
Ryuzo
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000494:pharmacology / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006689:Hodgkin Disease / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy; D017730:Ki-1 Antigen / Q000097:blood; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016410:Lymphoma, T-Cell, Cutaneous / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D017730:Ki-1 Antigen; D054398:Receptors, CCR4