Cancer Therapy: Preclinical Anti-CCR4 Monoclonal Antibody Mogamulizumab for the Treatment of EBV-Associated T- and NK-Cell Lymphoproliferative Diseases

Purpose:Epstein–Barr virus (EBV) infects not only B cells but also T cells andnatural killer (NK) cells, and TandNK-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 amurine 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 gdT cells. EBV-positive gdT cells were obtained from a patient with hydroa vacciniforme and subjected to an antibody-dependent cell-mediated cytotoxicity (ADCC) assay. The gdT cells that were positive for CCR4 were killed by mogamulizumab via ADCC. Conclusions: These results indicate that mogamulizumab may be a therapeutic option against EBVassociated T/NK-LPDs. Clin Cancer Res; 20(19); 1–10. 2014 AACR.