The CCR4 as a novel-specific molecular target for immunotherapy in Hodgkin lymphoma.
Here, we report that tumor cells from some patients (23.8%) with Hodgkin lymphoma (HL) are positive for CC chemokine receptor 4 (CCR4). We therefore tested the chimeric anti-CCR4 monoclonal antibody (mAb), KM2760, the Fc region of which is defucosylated to enhance antibody-dependent cellular cytotoxicity (ADCC), as a novel immunotherapy for refractory HL. KM2760 demonstrated a promising antitumor activity in the CCR4-positive HL-bearing mouse model in the therapeutic setting. Although KM2760 did not induce any ADCC mediated by mouse natural killer (NK) cells, it significantly enhanced phagocytosis mediated by mouse monocytes/macrophages against the CCR4-positive HL cell line in vitro. Together with the findings that KM2760 did not exhibit any complement-dependent cytotoxicity or direct antiproliferation activity in vitro, these data indicated that KM2760 exerted its robust in vivo antitumor activity via monocytes/macrophages in mice. In the human system, KM2760 enhanced phagocytic activity mediated by monocytes/macrophages. Furthermore, it induced robust ADCC mediated by NK cells against the CCR4-positive HL cell line in vitro. Thus, it is conceivable that KM2760 would have much more potent antitumor activity in humans than in mice. Collectively, this study strongly indicates that anti-CCR4 mAb could be a novel treatment modality for patients with CCR4-positive HL.
Ishida
T
T
Department of Internal Medicine & Molecular Science, Nagoya City University Graduate School of Medical Sciences, Mizuho-chou, Mizuho-ku, Nagoya-shi, Aichi, Japan. itakashi@med.nagoya-cu.ac.jp
Ishii
T
T
Inagaki
A
A
Yano
H
H
Kusumoto
S
S
Ri
M
M
Komatsu
H
H
Iida
S
S
Inagaki
H
H
Ueda
R
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity; D006689:Hodgkin Disease / Q000276:immunology / Q000628:therapy*; D006801:Humans; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010587:Phagocytosis; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000032:analysis / Q000037:antagonists & inhibitors*; D016539:Reed-Sternberg Cells / Q000737:chemistry
D000911:Antibodies, Monoclonal; C515354:CCR4 protein, human; C515355:Ccr4 protein, mouse; D054398:Receptors, CCR4; D019707:Receptors, Chemokine