title: Defucosylated anti CC chemokine receptor 4 monoclonal antibody combined with immunomodulatory cytokines: a novel immunotherapy for aggressive/refractory Mycosis fungoides and Sezary syndrome.
abstract: OBJECTIVE
  Sézary syndrome (SS) and Mycosis fungoides (MF) in the advanced stage have dismal prognoses. Because CC chemokine receptor 4 (CCR4) has an important role in the skin-homing capacity of MF/SS cells, we postulated that anti-CCR4 monoclonal antibody (mAb) could represent a novel therapeutic agent against aggressive/refractory MF/SS.
  
  
  METHODS
  The defucosylated next-generation therapeutic mAb KM2760 induces enhanced antibody-dependent cellular cytotoxicity (ADCC). Here, we assessed the therapeutic potential of this antibody against aggressive MF/SS tumor cells in vitro and in animal models in vivo.
  
  
  RESULTS
  KM2760 induced robust ADCC by peripheral blood mononuclear cell (PBMC) from healthy controls against a MF/SS cell line as well as against primary tumor cells from patients with aggressive MF/SS. KM2760 also showed significant antitumor activity in disseminated and nondisseminated MF/SS mouse models. In addition, approximately 30% of autologous MF/SS tumor cells were killed in in vitro assays of KM2760-induced ADCC mediated by patients' PBMC after only 4 h, despite the low numbers of natural killer cells present in these PBMCs. It is also shown that ADCC induced by defucosylated therapeutic mAb can be greatly augmented by the immunomodulatory cytokines interleukin-12, IFN-alpha-2b, and IFN-gamma.
  
  
  CONCLUSIONS
  The present study has encouraged us in the conducting of a phase I clinical trial of a completely defucosylated anti-CCR4 mAb in patients with CCR4-positive T-cell lymphomas, including aggressive MF/SS (ClinicalTrials.gov identifier: NCT00355472). In the near future, the efficacy not only of defucosylated anti-CCR4 mAb single-agent treatment but also of combination therapy with immunomodulatory cytokines will be clinically established to target aggressive/refractory MF/SS.
authors.affiliation: Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yano
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishida
authors.forename: Atsushi
authors.initials: A
authors.lastname: Inagaki
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ishii
authors.forename: Jianmin
authors.initials: J
authors.lastname: Ding
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kusumoto
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Komatsu
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Iida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inagaki
authors.forename: Ryuzo
authors.initials: R
authors.lastname: Ueda
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D049109:Cell Proliferation; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009182:Mycosis Fungoides / Q000378:metabolism* / Q000628:therapy*; D054398:Receptors, CCR4 / Q000737:chemistry*; D012751:Sezary Syndrome / Q000378:metabolism* / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D054398:Receptors, CCR4; D018664:Interleukin-12