Targeting of acute myeloid leukemia in vitro and in vivo with an anti-CD123 mAb engineered for optimal ADCC.
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.
CSL Limited, Bio21 Institute, Parkville, Victoria, Australia.
S J
SJ
Busfield
CSL Limited, Bio21 Institute, Parkville, Victoria, Australia.
M
M
Biondo
CSL Limited, Bio21 Institute, Parkville, Victoria, Australia.
M
M
Wong
The Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.
H S
HS
Ramshaw
Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, New South Wales, Australia.
E M
EM
Lee
CSL Limited, Bio21 Institute, Parkville, Victoria, Australia.
S
S
Ghosh
CSL Limited, Bio21 Institute, Parkville, Victoria, Australia.
H
H
Braley
CSL Limited, Bio21 Institute, Parkville, Victoria, Australia.
C
C
Panousis
1] Royal Melbourne Hospital, Parkville, Victoria, Australia [2] Faculty of Medicine, Dentistry and Health Science, University of Melbourne, Melbourne, Victoria, Australia [3] The Walter and Elisa Hall Institute of Medical Research, Melbourne, Parkville, Victoria, Australia.
A W
AW
Roberts
1] Royal Melbourne Hospital, Parkville, Victoria, Australia [2] Faculty of Medicine, Dentistry and Health Science, University of Melbourne, Melbourne, Victoria, Australia.
S Z
SZ
He
The Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.
D
D
Thomas
CSL Limited, Bio21 Institute, Parkville, Victoria, Australia.
L
L
Fabri
CSL Limited, Bio21 Institute, Parkville, Victoria, Australia.
G
G
Vairo
Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, New South Wales, Australia.
R B
RB
Lock
The Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia.
A F
AF
Lopez
CSL Limited, Bio21 Institute, Parkville, Victoria, Australia.
A D
AD
Nash
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology; D006801:Humans; D053650:Interleukin-3 Receptor alpha Subunit / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy* / Q000276:immunology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology; D008252:Macaca fascicularis; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D015202:Protein Engineering; D017452:Receptors, IgG / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D061067:Antibodies, Monoclonal, Humanized; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; C115022:IL3RA protein, human; D053650:Interleukin-3 Receptor alpha Subunit; D017452:Receptors, IgG