期刊
BRITISH JOURNAL OF HAEMATOLOGY
卷 150, 期 5, 页码 574-586出版社
WILEY
DOI: 10.1111/j.1365-2141.2010.08300.x
关键词
CD33; CD123; dual targeting; leukaemia stem cell; single-chain Fv triplebody
类别
资金
- DFG (Deutsche Forschungsgemeinschaft
- German Research Community) [GK592]
- Bayerische Eliteforderung (Bavarian Scholarship Foundation)
- German Jose-Carreras Leukemia-Foundation
- Wilhelm Sander Foundation, Neustadt, Germany [2007.049.1]
- Stiftung Deutsche Krebshilfe
- Beitlich Foundation, Tubingen
- Association 'Kaminkehrer helfen krebskranken Kindern'
P>Two trivalent constructs consisting of single-chain Fv antibody fragments (scFvs) specific for the interleukin-3 receptor alpha chain (CD123), CD33 and the Fc gamma-receptor III (CD16) were designed and characterized for the elimination of acute myeloid leukaemia (AML) cells. The dual targeting single-chain Fv triplebody (sctb) [123 x ds16 x 33] and the mono targeting sctb [123 x ds16 x 123] both specifically bound their respective target antigens and were stable in human serum at 37 degrees C for at least 5 d. Both constructs induced potent antibody-dependent cellular cytotoxicity (ADCC) of two different AML-derived CD33- and CD123 double-positive cell lines in the low picomolar range using isolated mononuclear cells (MNCs) as effector cells. In these experiments the dual targeting molecule produced significantly stronger lysis than the mono targeting agent. In addition, the sctbs showed a high potency in mediating ADCC of primary leukaemia cells isolated from peripheral blood or bone marrow of seven AML patients. Hence, these novel molecules displayed potent anti-leukaemic effects against AML cells in vitro and represent attractive candidates for further preclinical development.
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