Augmentation of antitumour activity of defucosylated chimeric anti-CCR4 monoclonal antibody in SCID mouse model of adult T-cell leukaemia/lymphoma using G-CSF
Abstract
Adult T-cell leukaemia/lymphoma (ATLL) has a very poor prognosis (Uchiyama et al, 1977; Taylor & Matsuoka, 2005). Because tumour cells from most ATLL patients express CCR4 (Ishida et al, 2003), we postulated that this molecule might represent a novel molecular target for immunotherapy and developed a chimeric anti-CCR4 monoclonal antibody (mAb), KM2760 (Niwa et al, 2004). Antibody-dependent cellular cytotoxicity (ADCC) is one of the most important mechanisms of action of therapeutic mAb (Ishida & Ueda, 2006). Although ADCC depends on the cytotoxic activity of effector cells, such as natural killer (NK) cells, monocytes/macrophages and neutrophils, these cells are commonly qualitatively suppressed and quantitatively reduced in cancer patients. To overcome this problem, the Fc region of KM2760 is defucosylated, which results in enhanced ADCC (Niwa et al, 2004). We have previously reported that a robust KM2760-induced ADCC mediated by autologous effector cells were triggered in some ATLL patients (Ishida et al, 2004), whereas little autologous KM2760-induced ADCC was observed in other ATLL patients, especially those with few effector cells in their peripheral blood mononuclear cells (data not shown). These findings prompted us to seek ways in which to augment KM2760-induced ADCC using the immunomodulatory agent granulocyte colony-stimulating factor (G-CSF; Nartograstim, Kyowa Hakko Kogyo Incorporation, Tokyo, Japan), which is commonly used clinically.
Human G-CSF increased…
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