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

Abstract

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. 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. 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. These results indicate that mogamulizumab may be a therapeutic option against EBV-associated T/NK-LPDs.