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Targeting of acute myeloid leukemia in vitro and in vivo with an anti-CD123 mAb engineered for optimal ADCC.
- Source :
-
Leukemia [Leukemia] 2014 Nov; Vol. 28 (11), pp. 2213-21. Date of Electronic Publication: 2014 Apr 07. - Publication Year :
- 2014
-
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 α-chain (IL-3 Rα/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 (FcγRIIIa). 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.
- Subjects :
- Animals
Antibodies, Monoclonal, Humanized immunology
Antibody-Dependent Cell Cytotoxicity immunology
Disease Models, Animal
Female
GPI-Linked Proteins immunology
Humans
Killer Cells, Natural immunology
Leukemia, Erythroblastic, Acute immunology
Leukemia, Myeloid, Acute immunology
Macaca fascicularis
Mice, Inbred NOD
Mice, SCID
Neoplasm Transplantation
Protein Engineering
Receptors, IgG immunology
Xenograft Model Antitumor Assays
Antibodies, Monoclonal, Humanized pharmacology
Interleukin-3 Receptor alpha Subunit immunology
Leukemia, Erythroblastic, Acute drug therapy
Leukemia, Myeloid, Acute drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 28
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 24705479
- Full Text :
- https://doi.org/10.1038/leu.2014.128