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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.

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-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.

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  • Authors+Show Affiliations

    ,

    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

    , , , , , , , , , , , ,

    Source

    Cancer immunology, immunotherapy : CII 58:8 2009 Aug pg 1195-206

    MeSH

    Animals
    Antibodies, Monoclonal
    Antibodies, Neoplasm
    Antibody-Dependent Cell Cytotoxicity
    Cell Line, Tumor
    Disease Models, Animal
    Hodgkin Disease
    Humans
    Immunotherapy
    Ki-1 Antigen
    Killer Cells, Natural
    Lymphoma, T-Cell, Cutaneous
    Male
    Mice
    Mice, SCID
    Receptors, CCR4
    T-Lymphocytes, Regulatory

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    19048251

    Citation

    Ito, Asahi, et al. "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." Cancer Immunology, Immunotherapy : CII, vol. 58, no. 8, 2009, pp. 1195-206.
    Ito A, Ishida T, Yano H, et al. 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. Cancer Immunol Immunother. 2009;58(8):1195-206.
    Ito, A., Ishida, T., Yano, H., Inagaki, A., Suzuki, S., Sato, F., ... Ueda, R. (2009). 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. Cancer Immunology, Immunotherapy : CII, 58(8), pp. 1195-206. doi:10.1007/s00262-008-0632-0.
    Ito A, et al. 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. Cancer Immunol Immunother. 2009;58(8):1195-206. PubMed PMID: 19048251.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - 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. AU - Ito,Asahi, AU - Ishida,Takashi, AU - Yano,Hiroki, AU - Inagaki,Atsushi, AU - Suzuki,Susumu, AU - Sato,Fumihiko, AU - Takino,Hisashi, AU - Mori,Fumiko, AU - Ri,Masaki, AU - Kusumoto,Shigeru, AU - Komatsu,Hirokazu, AU - Iida,Shinsuke, AU - Inagaki,Hiroshi, AU - Ueda,Ryuzo, Y1 - 2008/12/02/ PY - 2008/09/20/received PY - 2008/11/12/accepted PY - 2008/12/3/pubmed PY - 2009/6/13/medline PY - 2008/12/3/entrez SP - 1195 EP - 206 JF - Cancer immunology, immunotherapy : CII JO - Cancer Immunol. Immunother. VL - 58 IS - 8 N2 - 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-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. SN - 1432-0851 UR - https://www.unboundmedicine.com/medline/citation/19048251/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_ L2 - https://dx.doi.org/10.1007/s00262-008-0632-0 DB - PRIME DP - Unbound Medicine ER -