CD26は, 正常ヒト破骨細胞に機能的に発現し, ヒトがんの溶骨性骨転移において, 活性化破骨細胞に高発現する。CD26はヒト破骨細胞発生において, 単球, マクロファージ, 破骨前駆細胞, 破骨細胞と, 分化するにつれ発現が増強した。ヒト化抗CD26モノクローナル抗体は, 破骨前駆細胞分化段階で作用し, RANK下流シグナルにおいて, 細胞質内のMKK3/6, p38MAPKリン酸化, 続く核内のmi/Mitfリン酸化を阻害し, TRAP発現を抑制し, 破骨細胞への分化を阻害する一方, 直接成熟破骨細胞に作用しなかった。ヒト化抗CD26抗体は, ヒト溶骨性骨腫瘍において, 骨破壊抑制に有用な治療戦略となりうる。
CD26 is expressed on normal human osteoclasts (OCs) and is intensely expressed on activated OCs in osteolytic bone tumors. M-CSF and sRANKL induced human OC differentiation in association with CD26 expression on monocyte-macrophage lineage cells. CD26 expression was accompanied by increased phosphorylation of p38 MAPK, which was crucial for early human OC differentiation. Humanized anti-CD26 monoclonal antibody, huCD26mAb, dose-dependently impaired the formation and function of TRAP/CD26 positive multi-nucleated OCs. It was revealed that huCD26mAb inhibited early OC differentiation via the inactivation of MKK3/6, p38 MAPK in the cytoplasm and subsequent dephosphorylation of mi/Mitf in the nucleus of human OC precursor cells, immediately after RANKL bound to RANK. However, it did not directly inhibit mature OCs. Our results suggest that targeting human OC precursor cells with huCD26mAb may have therapeutic potential for the treatment of osteolytic tumors to reduce bone destruction.
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