期刊
LEUKEMIA
卷 27, 期 5, 页码 1107-1115出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2012.341
关键词
bispecific antibodies; tumor immunology; cytotoxic T-cells; T-cell mediated immunity; CD33; acute myeloid leukemia
资金
- Amgen Research (Munich) GmbH
- Deutsche Forschungs Gemeinschaft (DFG)
- [GRK643 (SFB643)]
Patients with acute myelogenous leukemia (AML) are in high need of novel targeted therapies. Here we explored the ex vivo activity of AMG330, a novel T-cell-engaging BiTE (bi-specific T-cell engagers) antibody (Ab) construct, that is bispecific for the myeloid differentiation antigen, CD33 and CD3, in primary samples from AML patients (N = 23) and AML cell lines. KG-1 and U937 cells were lysed in co-culture with healthy donor T-cells at AMG330 concentrations as low as 0.1 ng/ml (1.8 pM). T-cells derived from AML patient samples were found to be as active in redirected lysis by AMG330 as T-cells from healthy donors. In an autologous setting, AMG330 could activate and expand T-cells in primary AML patient samples, and effectively mediated the redirected lysis of AML blasts and normal myeloid cells. A deficiency in target-cell lysis was only observed in samples with very low initial effector-to-target (E: T) ratio. However, this could be overcome if previously stimulated autologous T-cells were tested in patient samples at a higher E: T ratio. In vivo experiments in immunodeficient mice demonstrated significant inhibition of tumor growth by AMG330 and an inducible infiltration of human T-cells into subcutaneous HL60 tumors. The activities of the CD33/CD3-bispecific BiTE Ab construct AMG330 warrant further development for the treatment of AML.
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