Defucosylated anti-CCR4 monoclonal antibody exercises potent ADCC-mediated antitumor effect in the novel tumor-bearing humanized NOD/Shi-scid, IL-2Rγnull mouse model

• DOI: 10.1007/s00262-008-0632-0
• Publication Date: 2008-12-01T18:58:23Z
• 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
• Keywords: Male; 0301 basic medicine; Cancer Research; Receptors, CCR4; Antibodies, Neoplasm; Immunology; Ki-1 Antigen; Mice, SCID; T-Lymphocytes, Regulatory; Mice; 03 medical and health sciences; 0302 clinical medicine; Cell Line, Tumor; Immunology and Allergy; Animals; Humans; Antibody-Dependent Cell Cytotoxicity; Antibodies, Monoclonal; Hodgkin Disease; Lymphoma, T-Cell, Cutaneous; 3. Good health; Killer Cells, Natural; Disease Models, Animal; Oncology; Original Article; Immunotherapy

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.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.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.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.