Original Article

Leukemia (2014) 28, 2213–2221; doi:10.1038/leu.2014.128; published online 9 May 2014

Targeting of acute myeloid leukemia in vitro and in vivo with an anti-CD123 mAb engineered for optimal ADCC

S J Busfield1, M Biondo1, M Wong1, H S Ramshaw2, E M Lee3, S Ghosh1, H Braley1, C Panousis1, A W Roberts4,5,6, S Z He4,5, D Thomas2, L Fabri1, G Vairo1, R B Lock3, A F Lopez2 and A D Nash1

  1. 1CSL Limited, Bio21 Institute, Parkville, Victoria, Australia
  2. 2The Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia
  3. 3Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, New South Wales, Australia
  4. 4Royal Melbourne Hospital, Parkville, Victoria, Australia
  5. 5Faculty of Medicine, Dentistry and Health Science, University of Melbourne, Melbourne, Victoria, Australia
  6. 6The Walter and Elisa Hall Institute of Medical Research, Melbourne, Parkville, Victoria, Australia

Correspondence: Dr SJ Busfield, CSL Limited, Bio21 Institute, 30 Flemington Road, Parkville, Victoria 3010, Australia. E-mail: samantha.busfield@csl.com.au

Received 17 December 2013; Revised 19 March 2014; Accepted 21 March 2014
Accepted article preview online 7 April 2014; Advance online publication 9 May 2014



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-3Rα/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+CD38CD123+ 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.