CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells
CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells
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DOI：
10.1182/blood-2004-02-0588
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发表时间：
2004-09-01
期刊：
影响因子：
20.3
通讯作者：
Asano, S
中科院分区：
文献类型：
--
作者：
Harata, M;Soda, Y;Asano, S
费城染色体阳性急性淋巴细胞白血病（Ph+ ALL）患者尽管进行了强化治疗干预，但预后不良。最近，伊马替尼，一种BCR-ABL酪氨酸激酶抑制剂，已被证明是一种有效的治疗Ph+ ALL，但几乎所有的患者迅速获得耐药。高剂量伊马替尼给药可能会克服这种耐药性;然而，全身毒性可能会限制这种方法。因此，迫切需要一种新的允许特异性靶向伊马替尼的递送系统。由于几乎所有Ph+ ALL细胞表面都表达CD 19，因此我们开发了一种携带抗CD 19抗体的免疫脂质体（CD 19-脂质体）。在所有Ph+ ALL细胞中，CD 19-脂质体的内化效率接近100%，但在CD 19（-）细胞中非常低。伊马替尼包封的CD 19-脂质体（伊马替尼-CD 19-脂质体）对Ph+ ALL细胞系和Ph+ ALL患者的原代白血病细胞的杀细胞作用远大于伊马替尼加或不加对照脂质体。重要的是，伊马替尼-CD 19-脂质体不影响CD 34（+）造血细胞的殖民地形成，即使在游离伊马替尼的抑制浓度下。总之，这些数据清楚地表明伊马替尼-CD 19-脂质体诱导Ph+ ALL细胞特异性和有效死亡。这种新的治疗方法可能是一种有用的治疗Ph+ ALL的副作用比游离伊马替尼少。(C)2004年，美国血液学会。
Patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) have poor prognosis despite intensive therapeutic intervention. Recently, imatinib, a BCR-ABL tyrosine kinase inhibitor, has been proven to be an effective treatment for Ph+ ALL, but nearly all patients rapidly acquire resistance. High-dose imatinib administration might overcome this resistance; however, systemic toxicities would likely limit this approach. Therefore, a new delivery system allowing for the specific targeting of imatinib is urgently needed. Because almost all Ph+ ALL cells express CD19 on their surface, we have developed an immunoliposome carrying anti-CD19 antibody (CD19-liposomes). The internalization efficiency of the CD19-liposomes approached 100% in all Ph+ ALL cells but was very low in CD19(-) cells. The cytocidal effect of imatinib-encapsulated CD19-liposomes (imatinib-CD19-liposomes) on Ph+ ALL cell lines and primary leukemia cells from patients with Ph+ ALL was much greater than that of imatinib with or without control liposomes. Importantly, the imatinib-CD19-liposomes did not affect the colony formation of CD34(+) hematopoietic cells, even at inhibitory concentration of free imatinib. Taken together, these data clearly demonstrate that the imatinib-CD19-liposomes induced specific and efficient death of Ph+ ALL cells. This new therapeutic approach might be a useful treatment for Ph+ ALL with fewer side effects than free imatinib. (C) 2004 by The American Society of Hematology.