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Blood, 1 September 2004, Vol. 104, No. 5, pp. 1442-1449. Prepublished online as a Blood First Edition Paper on May 20, 2004; DOI 10.1182/blood-2004-02-0588.
NEOPLASIA CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosomepositive acute lymphoblastic leukemia cellsFrom the Division of Molecular Therapy, Advanced Clinical Research Center, University of Tokyo, Tokyo, Japan; the Department of Hematology/Oncology, Research Hospital, University of Tokyo, Tokyo, Japan; the Division of Cell Processing, Institute of Medical Science, University of Tokyo, Tokyo, Japan; the Division of Clinical Research and Development, Therapeutic Product Development, Amgen Limited, Tokyo, Japan; the Department of Advanced Molecular and Cell Therapy, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; the Faculty of Pharmaceutical Science, Teikyo University, Kanagawa, Japan; the Department of Industrial Science and Technology, Science University of Tokyo, Chiba, Japan; and the Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
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.
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