Tags

Type your tag names separated by a space and hit enter

Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia/lymphoma.

Abstract

PURPOSE

Adult T-cell leukemia/lymphoma (ATLL) has a very poor prognosis. We have developed the humanized defucosylated anti-CC chemokine receptor 4 (CCR4) monoclonal antibody KW-0761 as a next generation immunotherapeutic agent. The first aim of the present study was to evaluate whether the antitumor activity of KW-0761 would likely be sufficient for therapeutic clinical application against ATLL. The second aim was to fully elucidate the mechanism of antibody-dependent cellular cytotoxicity (ADCC) mediated by this defucosylated monoclonal antibody.

EXPERIMENTAL DESIGN

The antitumor activity of KW-0761 against ATLL cell lines was evaluated in vitro using human cells and in mice in vivo. Primary ATLL cells from 23 patients were evaluated for susceptibility to autologous ADCC with KW-0761 by two independent methods.

RESULTS

KW-0761 showed potent antitumor activity against ATLL cell lines both in vitro and in the ATLL mouse model in vivo. In addition, KW-0761 showed potent antitumor activity mediated by highly enhanced ADCC against primary ATLL cells both in vitro and ex vivo in an autologous setting. The degree of KW-0761 ADCC against primary ATLL cells in an autologous setting was mainly determined by the amount of effector natural killer cells present, but not the amount of the target molecule CCR4 on the ATLL cell surface.

CONCLUSION

KW-0761 should be sufficiently active for therapeutic clinical application for ATLL. In addition, combination treatment strategies that augment natural killer cell activity should be promising for amplifying the effect of KW-0761. In the near future, the actual efficacy of KW-0761 will be established in pivotal clinical trials.

Links

  • FREE Publisher Full Text
  • Authors+Show Affiliations

    ,

    Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.

    , , , , , , , , , ,

    Source

    MeSH

    Adult
    Animals
    Antibodies, Monoclonal
    Antibodies, Monoclonal, Humanized
    Antibody-Dependent Cell Cytotoxicity
    Antineoplastic Agents
    Biosensing Techniques
    Cell Separation
    Flow Cytometry
    Humans
    Immunotherapy
    Leukemia-Lymphoma, Adult T-Cell
    Male
    Mice
    Mice, SCID
    Receptors, CCR4

    Pub Type(s)

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

    Language

    eng

    PubMed ID

    20160057

    Citation

    Ishii, Toshihiko, et al. "Defucosylated Humanized anti-CCR4 Monoclonal Antibody KW-0761 as a Novel Immunotherapeutic Agent for Adult T-cell Leukemia/lymphoma." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 16, no. 5, 2010, pp. 1520-31.
    Ishii T, Ishida T, Utsunomiya A, et al. Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia/lymphoma. Clin Cancer Res. 2010;16(5):1520-31.
    Ishii, T., Ishida, T., Utsunomiya, A., Inagaki, A., Yano, H., Komatsu, H., ... Ueda, R. (2010). Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia/lymphoma. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 16(5), pp. 1520-31. doi:10.1158/1078-0432.CCR-09-2697.
    Ishii T, et al. Defucosylated Humanized anti-CCR4 Monoclonal Antibody KW-0761 as a Novel Immunotherapeutic Agent for Adult T-cell Leukemia/lymphoma. Clin Cancer Res. 2010 Mar 1;16(5):1520-31. PubMed PMID: 20160057.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Defucosylated humanized anti-CCR4 monoclonal antibody KW-0761 as a novel immunotherapeutic agent for adult T-cell leukemia/lymphoma. AU - Ishii,Toshihiko, AU - Ishida,Takashi, AU - Utsunomiya,Atae, AU - Inagaki,Atsushi, AU - Yano,Hiroki, AU - Komatsu,Hirokazu, AU - Iida,Shinsuke, AU - Imada,Kazunori, AU - Uchiyama,Takashi, AU - Akinaga,Shiro, AU - Shitara,Kenya, AU - Ueda,Ryuzo, Y1 - 2010/02/16/ PY - 2010/2/18/entrez PY - 2010/2/18/pubmed PY - 2010/5/21/medline SP - 1520 EP - 31 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 16 IS - 5 N2 - PURPOSE: Adult T-cell leukemia/lymphoma (ATLL) has a very poor prognosis. We have developed the humanized defucosylated anti-CC chemokine receptor 4 (CCR4) monoclonal antibody KW-0761 as a next generation immunotherapeutic agent. The first aim of the present study was to evaluate whether the antitumor activity of KW-0761 would likely be sufficient for therapeutic clinical application against ATLL. The second aim was to fully elucidate the mechanism of antibody-dependent cellular cytotoxicity (ADCC) mediated by this defucosylated monoclonal antibody. EXPERIMENTAL DESIGN: The antitumor activity of KW-0761 against ATLL cell lines was evaluated in vitro using human cells and in mice in vivo. Primary ATLL cells from 23 patients were evaluated for susceptibility to autologous ADCC with KW-0761 by two independent methods. RESULTS: KW-0761 showed potent antitumor activity against ATLL cell lines both in vitro and in the ATLL mouse model in vivo. In addition, KW-0761 showed potent antitumor activity mediated by highly enhanced ADCC against primary ATLL cells both in vitro and ex vivo in an autologous setting. The degree of KW-0761 ADCC against primary ATLL cells in an autologous setting was mainly determined by the amount of effector natural killer cells present, but not the amount of the target molecule CCR4 on the ATLL cell surface. CONCLUSION: KW-0761 should be sufficiently active for therapeutic clinical application for ATLL. In addition, combination treatment strategies that augment natural killer cell activity should be promising for amplifying the effect of KW-0761. In the near future, the actual efficacy of KW-0761 will be established in pivotal clinical trials. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/20160057/Defucosylated_humanized_anti_CCR4_monoclonal_antibody_KW_0761_as_a_novel_immunotherapeutic_agent_for_adult_T_cell_leukemia/lymphoma_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=20160057 DB - PRIME DP - Unbound Medicine ER -