Efficacy of an Fc-modified anti-CD123 antibody (CSL362) combined with chemotherapy in xenograft models of acute myelogenous leukemia in immunodeficient mice

  • Haematologica. 2015 Jul;100(7):914-26. doi: 10.3324/haematol.2014.113092.
Erwin M Lee  1 ,  Dean Yee  1 ,  Samantha J Busfield  2 ,  Julie F McManus  3 ,  Nik Cummings  4 ,  Gino Vairo  2 ,  Andrew Wei  4 ,  Hayley S Ramshaw  5 ,  Jason A Powell  6 ,  Angel F Lopez  5 ,  Ian D Lewis  7 ,  Martin N McCall  1 ,  Richard B Lock  8
Affiliations
  • 1. Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
  • 2. CSL Limited, Parkville, Australia.
  • 3. Department of Microbiology, The Alfred Hospital and Monash University, Melbourne, Australia.
  • 4. Department of Haematology, The Alfred Hospital and Monash University, Melbourne, Australia.
  • 5. The Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
  • 6. The Centre for Cancer Biology, SA Pathology, Adelaide, Australia School of Medicine, University of Adelaide, Adelaide, Australia.
  • 7. Division of Haematology and Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
  • 8. Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Sydney, Australia [email protected].
PMID: 26130514 DOI: 10.3324/haematol.2014.113092
Abstract

The prognosis of older patients with acute myelogenous leukemia is generally poor. The interleukin-3 receptor α-chain (CD123) is highly expressed on the surface of acute leukemia cells compared with normal hematopoietic stem cells. CSL362 is a fully humanized, CD123-neutralizing monoclonal antibody containing a modified Fc structure, which enhances human natural killer cell antibody-dependent cell-mediated cytotoxicity. Six continuous acute myelogenous leukemia xenografts established from patient explants and characterized by cell and molecular criteria, produced progressively lethal disease 42-202 days after transplantation. CSL362 alone reduced engraftment of one of four and three of four acute myelogenous leukemia xenografts in the bone marrow and peripheral organs, respectively. A cytarabine and daunorubicin regimen was optimized using this model to identify potentially synergistic interactions with CSL362. Cytarabine/daunorubicin improved the survival of mice engrafted with four of four acute myelogenous leukemia xenografts by 31-41 days. Moreover, CSL362 extended the survival of cytarabine/daunorubicin-treated mice for two of two acute myelogenous leukemia xenografts, while augmentation of natural killer cell-deficient NSG mice with adoptively transferred human natural killer cells improved survival against a single xenograft. Interestingly, this enhanced CSL362 efficacy was lost in the absence of chemotherapy. This study shows that acute myelogenous leukemia xenografts provide a platform for the evaluation of new therapeutics, simulating complex in vivo interactions, and that the in vivo efficacy of CSL362 supports continued clinical development of this drug.

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