Anti-CCR4 monoclonal antibody mogamulizumab for the treatment of EBV-associated T- And NK-cell lymphoproliferative diseases

Tetsuhiro Kanazawa, Yutaka Hiramatsu, Seiko Iwata, Mohammed Siddiquey, Yoshitaka Sato, Michio Suzuki, Yoshinori Ito, Fumi Goshima, Takayuki Murata, Hiroshi Kimura

Research output: Contribution to journalArticle

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Abstract

Purpose: Epstein-Barr virus (EBV) infects not only B cells but also T cells and natural killer (NK) cells, and T- and NK-cell lymphoproliferative diseases (T/NK-LPD) that are refractory to conventional chemotherapies may develop. To identify a molecular-targeted therapy for EBV-associated T/NK-LPDs, we investigated whether CC chemokine receptor 4 (CCR4) was expressed on EBV-infected T and/or NK cells and whether a humanized anti-CCR4 monoclonal antibody, mogamulizumab, was effective. Experimental Design: CCR4 expression was examined in various cell lines. In vitro, the effects of mogamulizumab on cell lines were evaluated in the presence of peripheral blood mononuclear cells from volunteers. In vivo, the effects of mogamulizumab were evaluated using a murine xenograft model. CCR4 expression was examined on EBV-infected cells from patients with EBV-associated T/NK-LPDs. Ex vivo, the effects of mogamulizumab were evaluated using patient lymphocytes. Results: CCR4 expression was confirmed in most EBV-positive T and NK cell lines. Mogamulizumab induced antibody-dependent cellular cytotoxicity (ADCC) activity against CCR4-positive cell lines, and inhibited the growth of EBV-positive NK-cell lymphomas in a murine xenograft model. Furthermore, CCR4 was expressed on EBV-infected cells in 8 of 17 patients with EBV-associated T/NK-LPDs. Interestingly, CCR4 was positive in 5 of 5 patients with hydroa vacciniforme, a photodermatosis caused by the clonal expansion of EBV-infected γδT cells. EBV-positive γδT cells were obtained from a patient with hydroa vacciniforme and subjected to an antibody-dependent cell-mediated cytotoxicity (ADCC) assay. The γδT cells that were positive for CCR4 were killed by mogamulizumab via ADCC. Conclusions: These results indicate that mogamulizumab may be a therapeutic option against EBV-associated T/NK-LPDs.

Original languageEnglish
Pages (from-to)5075-5084
Number of pages10
JournalClinical Cancer Research
Volume20
Issue number19
DOIs
Publication statusPublished - 01-10-2014
Externally publishedYes

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CCR4 Receptors
Natural Killer T-Cells
Human Herpesvirus 4
Monoclonal Antibodies
Hydroa Vacciniforme
Therapeutics
T-Lymphocytes
Cell Line
Heterografts
Natural Killer Cells
mogamulizumab
Molecular Targeted Therapy
Antibody-Dependent Cell Cytotoxicity
Antibodies

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Kanazawa, Tetsuhiro ; Hiramatsu, Yutaka ; Iwata, Seiko ; Siddiquey, Mohammed ; Sato, Yoshitaka ; Suzuki, Michio ; Ito, Yoshinori ; Goshima, Fumi ; Murata, Takayuki ; Kimura, Hiroshi. / Anti-CCR4 monoclonal antibody mogamulizumab for the treatment of EBV-associated T- And NK-cell lymphoproliferative diseases. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 19. pp. 5075-5084.
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title = "Anti-CCR4 monoclonal antibody mogamulizumab for the treatment of EBV-associated T- And NK-cell lymphoproliferative diseases",
abstract = "Purpose: Epstein-Barr virus (EBV) infects not only B cells but also T cells and natural killer (NK) cells, and T- and NK-cell lymphoproliferative diseases (T/NK-LPD) that are refractory to conventional chemotherapies may develop. To identify a molecular-targeted therapy for EBV-associated T/NK-LPDs, we investigated whether CC chemokine receptor 4 (CCR4) was expressed on EBV-infected T and/or NK cells and whether a humanized anti-CCR4 monoclonal antibody, mogamulizumab, was effective. Experimental Design: CCR4 expression was examined in various cell lines. In vitro, the effects of mogamulizumab on cell lines were evaluated in the presence of peripheral blood mononuclear cells from volunteers. In vivo, the effects of mogamulizumab were evaluated using a murine xenograft model. CCR4 expression was examined on EBV-infected cells from patients with EBV-associated T/NK-LPDs. Ex vivo, the effects of mogamulizumab were evaluated using patient lymphocytes. Results: CCR4 expression was confirmed in most EBV-positive T and NK cell lines. Mogamulizumab induced antibody-dependent cellular cytotoxicity (ADCC) activity against CCR4-positive cell lines, and inhibited the growth of EBV-positive NK-cell lymphomas in a murine xenograft model. Furthermore, CCR4 was expressed on EBV-infected cells in 8 of 17 patients with EBV-associated T/NK-LPDs. Interestingly, CCR4 was positive in 5 of 5 patients with hydroa vacciniforme, a photodermatosis caused by the clonal expansion of EBV-infected γδT cells. EBV-positive γδT cells were obtained from a patient with hydroa vacciniforme and subjected to an antibody-dependent cell-mediated cytotoxicity (ADCC) assay. The γδT cells that were positive for CCR4 were killed by mogamulizumab via ADCC. Conclusions: These results indicate that mogamulizumab may be a therapeutic option against EBV-associated T/NK-LPDs.",
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Kanazawa, T, Hiramatsu, Y, Iwata, S, Siddiquey, M, Sato, Y, Suzuki, M, Ito, Y, Goshima, F, Murata, T & Kimura, H 2014, 'Anti-CCR4 monoclonal antibody mogamulizumab for the treatment of EBV-associated T- And NK-cell lymphoproliferative diseases', Clinical Cancer Research, vol. 20, no. 19, pp. 5075-5084. https://doi.org/10.1158/1078-0432.CCR-14-0580

Anti-CCR4 monoclonal antibody mogamulizumab for the treatment of EBV-associated T- And NK-cell lymphoproliferative diseases. / Kanazawa, Tetsuhiro; Hiramatsu, Yutaka; Iwata, Seiko; Siddiquey, Mohammed; Sato, Yoshitaka; Suzuki, Michio; Ito, Yoshinori; Goshima, Fumi; Murata, Takayuki; Kimura, Hiroshi.

In: Clinical Cancer Research, Vol. 20, No. 19, 01.10.2014, p. 5075-5084.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Anti-CCR4 monoclonal antibody mogamulizumab for the treatment of EBV-associated T- And NK-cell lymphoproliferative diseases

AU - Kanazawa, Tetsuhiro

AU - Hiramatsu, Yutaka

AU - Iwata, Seiko

AU - Siddiquey, Mohammed

AU - Sato, Yoshitaka

AU - Suzuki, Michio

AU - Ito, Yoshinori

AU - Goshima, Fumi

AU - Murata, Takayuki

AU - Kimura, Hiroshi

PY - 2014/10/1

Y1 - 2014/10/1

N2 - Purpose: Epstein-Barr virus (EBV) infects not only B cells but also T cells and natural killer (NK) cells, and T- and NK-cell lymphoproliferative diseases (T/NK-LPD) that are refractory to conventional chemotherapies may develop. To identify a molecular-targeted therapy for EBV-associated T/NK-LPDs, we investigated whether CC chemokine receptor 4 (CCR4) was expressed on EBV-infected T and/or NK cells and whether a humanized anti-CCR4 monoclonal antibody, mogamulizumab, was effective. Experimental Design: CCR4 expression was examined in various cell lines. In vitro, the effects of mogamulizumab on cell lines were evaluated in the presence of peripheral blood mononuclear cells from volunteers. In vivo, the effects of mogamulizumab were evaluated using a murine xenograft model. CCR4 expression was examined on EBV-infected cells from patients with EBV-associated T/NK-LPDs. Ex vivo, the effects of mogamulizumab were evaluated using patient lymphocytes. Results: CCR4 expression was confirmed in most EBV-positive T and NK cell lines. Mogamulizumab induced antibody-dependent cellular cytotoxicity (ADCC) activity against CCR4-positive cell lines, and inhibited the growth of EBV-positive NK-cell lymphomas in a murine xenograft model. Furthermore, CCR4 was expressed on EBV-infected cells in 8 of 17 patients with EBV-associated T/NK-LPDs. Interestingly, CCR4 was positive in 5 of 5 patients with hydroa vacciniforme, a photodermatosis caused by the clonal expansion of EBV-infected γδT cells. EBV-positive γδT cells were obtained from a patient with hydroa vacciniforme and subjected to an antibody-dependent cell-mediated cytotoxicity (ADCC) assay. The γδT cells that were positive for CCR4 were killed by mogamulizumab via ADCC. Conclusions: These results indicate that mogamulizumab may be a therapeutic option against EBV-associated T/NK-LPDs.

AB - Purpose: Epstein-Barr virus (EBV) infects not only B cells but also T cells and natural killer (NK) cells, and T- and NK-cell lymphoproliferative diseases (T/NK-LPD) that are refractory to conventional chemotherapies may develop. To identify a molecular-targeted therapy for EBV-associated T/NK-LPDs, we investigated whether CC chemokine receptor 4 (CCR4) was expressed on EBV-infected T and/or NK cells and whether a humanized anti-CCR4 monoclonal antibody, mogamulizumab, was effective. Experimental Design: CCR4 expression was examined in various cell lines. In vitro, the effects of mogamulizumab on cell lines were evaluated in the presence of peripheral blood mononuclear cells from volunteers. In vivo, the effects of mogamulizumab were evaluated using a murine xenograft model. CCR4 expression was examined on EBV-infected cells from patients with EBV-associated T/NK-LPDs. Ex vivo, the effects of mogamulizumab were evaluated using patient lymphocytes. Results: CCR4 expression was confirmed in most EBV-positive T and NK cell lines. Mogamulizumab induced antibody-dependent cellular cytotoxicity (ADCC) activity against CCR4-positive cell lines, and inhibited the growth of EBV-positive NK-cell lymphomas in a murine xenograft model. Furthermore, CCR4 was expressed on EBV-infected cells in 8 of 17 patients with EBV-associated T/NK-LPDs. Interestingly, CCR4 was positive in 5 of 5 patients with hydroa vacciniforme, a photodermatosis caused by the clonal expansion of EBV-infected γδT cells. EBV-positive γδT cells were obtained from a patient with hydroa vacciniforme and subjected to an antibody-dependent cell-mediated cytotoxicity (ADCC) assay. The γδT cells that were positive for CCR4 were killed by mogamulizumab via ADCC. Conclusions: These results indicate that mogamulizumab may be a therapeutic option against EBV-associated T/NK-LPDs.

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U2 - 10.1158/1078-0432.CCR-14-0580

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