Targeting of acute myeloid leukemia in vitro and in vivo with an anti-CD123 mAb engineered for optimal ADCC
- Author(s)
- Busfield, SJ; Biondo, M; Wong, M; Ramshaw, HS; Lee, EM; Ghosh, S; Braley, H; Panousis, C; Roberts, AW; He, SZ; Thomas, D; Fabri, L; Vairo, G; Lock, RB; Lopez, AF; Nash, AD;
- Details
- Publication Year 2014-11,Volume 28,Issue #11,Page 2213-21
- Journal Title
- Leukemia
- Publication Type
- Journal Article
- Abstract
- Acute myeloid leukemia (AML) is a biologically heterogeneous group of related diseases in urgent need of better therapeutic options. Despite this heterogeneity, overexpression of the interleukin (IL)-3 receptor alpha-chain (IL-3 Ralpha/CD123) on both the blast and leukemic stem cell (LSC) populations is a common occurrence, a finding that has generated wide interest in devising new therapeutic approaches that target CD123 in AML patients. We report here the development of CSL362, a monoclonal antibody to CD123 that has been humanized, affinity-matured and Fc-engineered for increased affinity for human CD16 (FcgammaRIIIa). In vitro studies demonstrated that CSL362 potently induces antibody-dependent cell-mediated cytotoxicity of both AML blasts and CD34(+)CD38(-)CD123(+) LSC by NK cells. Importantly, CSL362 was highly effective in vivo reducing leukemic cell growth in AML xenograft mouse models and potently depleting plasmacytoid dendritic cells and basophils in cynomolgus monkeys. Significantly, we demonstrated CSL362-dependent autologous depletion of AML blasts ex vivo, indicating that CSL362 enables the efficient killing of AML cells by the patient's own NK cells. These studies offer a new therapeutic option for AML patients with adequate NK-cell function and warrant the clinical development of CSL362 for the treatment of AML.
- Publisher
- NPG
- Research Division(s)
- Cancer And Haematology
- PubMed ID
- 24705479
- Publisher's Version
- https://doi.org/10.1038/leu.2014.128
- NHMRC Grants
- NHMRC/637309, NHMRC/1016647,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2015-05-19 02:05:27
Last Modified: 2015-05-19 03:24:45