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

Leukemia volume 28, pages 2213–2221 (2014)Cite this article

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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.

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Acknowledgements

We would like to the following for their contributions: Bill Panagopoulos and Melanie Pudney (IMVS), Laura McMillan, Kirstee Martin, Daria Kurtov, Matt Hardy and members of the CSL Research Department for excellent technical assistance. Naomi Sprigg for patient sample collection. Hayley Ramshaw is supported by the Peter Nelson Leukaemia Research Fund. Children’s Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and the Sydney Children’s Hospitals Network. Andrew Roberts is supported by funding from NHMRC (637309, 1016647) and the Leukemia and Lymphoma Society.

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Authors and Affiliations

  1. CSL Limited, Bio21 Institute, Parkville, Victoria, Australia

    S J Busfield, M Biondo, M Wong, S Ghosh, H Braley, C Panousis, L Fabri, G Vairo & A D Nash

  2. The Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia

    H S Ramshaw, D Thomas & A F Lopez

  3. Children’s Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, New South Wales, Australia

    E M Lee & R B Lock

  4. Royal Melbourne Hospital, Parkville, Victoria, Australia

    A W Roberts & S Z He

  5. Faculty of Medicine, Dentistry and Health Science, University of Melbourne, Melbourne, Victoria, Australia

    A W Roberts & S Z He

  6. The Walter and Elisa Hall Institute of Medical Research, Melbourne, Parkville, Victoria, Australia

    A W Roberts

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  1. S J Busfield
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  2. M Biondo
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Corresponding author

Correspondence to S J Busfield.

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Competing interests

CSL Limited is developing the CSL362 monoclonal antibody. AFL, HSR, EML and RBL received research funding from CSL Limited. RBL was and AFL is a consultant for CSL Limited. SJB, MB, MW, SG, HB, CP, LF, GV and ADN are employed by CSL Limited. AWR, SZH and DT declare no conflict of interest.

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Author contributions

MB, MW, HSR, HB, EML and SG designed and performed the experiments and analyzed the data. SJB designed the research, reviewed the data and wrote the manuscript. CP and LF contributed vital new reagents. GV, RBL, AFL, AWR and ADN were significantly involved in experimental design, data interpretation and manuscript preparation. SZH and DT contributed clinical samples and critically reviewed the manuscript.

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Busfield, S., Biondo, M., Wong, M. et al. Targeting of acute myeloid leukemia in vitro and in vivo with an anti-CD123 mAb engineered for optimal ADCC. Leukemia 28, 2213–2221 (2014). https://doi.org/10.1038/leu.2014.128

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