CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells.
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.
Harata
Masamitsu
M
Department of Advanced Molecular and Cell Therapy, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Soda
Yasushi
Y
Tani
Kenzaburo
K
Ooi
Jun
J
Takizawa
Tomoko
T
Chen
Minghan
M
Bai
Yuansong
Y
Izawa
Kiyoko
K
Kobayashi
Seiichiro
S
Tomonari
Akira
A
Nagamura
Fumitaka
F
Takahashi
Satoshi
S
Uchimaru
Kaoru
K
Iseki
Tohru
T
Tsuji
Takashi
T
Takahashi
Tsuneo A
TA
Sugita
Kanji
K
Nakazawa
Shinpei
S
Tojo
Arinobu
A
Maruyama
Kazuo
K
Asano
Shigetaka
S
D018941:Antigens, CD19 / Q000378:metabolism*; D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D002051:Burkitt Lymphoma; D016923:Cell Death / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D066298:In Vitro Techniques; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D015473:Leukemia, Promyelocytic, Acute; D008081:Liposomes / Q000378:metabolism; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018941:Antigens, CD19; D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001549:Benzamides; D008081:Liposomes; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate