title: Anti-CCR4 monoclonal antibody mogamulizumab for the treatment of EBV-associated T- and NK-cell lymphoproliferative diseases.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Kanazawa
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hiramatsu
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Iwata
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Siddiquey
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Fumi
authors.initials: F
authors.lastname: Goshima
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Murata
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan. hkimura@med.nagoya-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D005260:Female; D015870:Gene Expression; D004854:Herpesvirus 4, Human; D006801:Humans; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000378:metabolism / Q000473:pathology*; D008232:Lymphoproliferative Disorders / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D054398:Receptors, CCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D054398:Receptors, CCR4; C549035:mogamulizumab