@article{6d1bc81082324807befef9a8bb99e910,
title = "Monoclonal Antibody-Mediated Targeting of CD123, IL-3 Receptor α Chain, Eliminates Human Acute Myeloid Leukemic Stem Cells",
abstract = "Leukemia stem cells (LSCs) initiate and sustain the acute myeloid leukemia (AML) clonal hierarchy and possess biological properties rendering them resistant to conventional chemotherapy. The poor survival of AML patients raises expectations that LSC-targeted therapies might achieve durable remissions. We report that an anti-interleukin-3 (IL-3) receptor α chain (CD123)-neutralizing antibody (7G3) targeted AML-LSCs, impairing homing to bone marrow (BM) and activating innate immunity of nonobese diabetic/severe-combined immunodeficient (NOD/SCID) mice. 7G3 treatment profoundly reduced AML-LSC engraftment and improved mouse survival. Mice with pre-established disease showed reduced AML burden in the BM and periphery and impaired secondary transplantation upon treatment, establishing that AML-LSCs were directly targeted. 7G3 inhibited IL-3-mediated intracellular signaling of isolated AML CD34+CD38- cells in vitro and reduced their survival. These results provide clear validation for therapeutic monoclonal antibody (mAb) targeting of AML-LSCs and for translation of in vivo preclinical research findings toward a clinical application.",
keywords = "STEMCELL",
author = "Liqing Jin and Lee, {Erwin M.} and Ramshaw, {Hayley S.} and Busfield, {Samantha J.} and Peoppl, {Armando G.} and Lucy Wilkinson and Guthridge, {Mark A.} and Daniel Thomas and Barry, {Emma F.} and Andrew Boyd and Gearing, {David P.} and Gino Vairo and Lopez, {Angel F.} and Dick, {John E.} and Lock, {Richard B.}",
note = "Funding Information: This work was supported by Children's Cancer Institute Australia for Medical Research and by research grants from CSL Limited (A.B., A.F.L., J.E.D., and R.B.L.). Children's Cancer Institute Australia for Medical Research is affiliated with the University of New South Wales and Sydney Children's Hospital. H.S.R. is the Peter Nelson Leukaemia Research Fund Senior Research Fellow. The authors wish to thank Dr. Mark Minden (University Health Network, Toronto, Canada) and Naomi Sprigg, Rosemary Hoyt, and Dr. Andrew Roberts (Royal Melbourne Hospital, Melbourne, Australia) for providing patient biopsy specimens; Thu Tran, Soo Min Heng, and Dean Inwood (Department of Radiation Oncology, Prince of Wales Hospital, Sydney, Australia) for mouse irradiation; CSL Protein Group for antibody reagents; and Dr. Andrew Roberts for helpful discussions. The authors wish to declare the following potential conflicts of interest: employees of CSL Limited (S.J.B., D.P.G., and G.V.) and consultants of CSL Limited (A.F.L. and R.B.L.). ",
year = "2009",
month = jul,
day = "2",
doi = "10.1016/j.stem.2009.04.018",
language = "English",
volume = "5",
pages = "31--42",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "1",
}