guthridge-monoclonalantibodymediated-2009.pdf (1.12 MB)
Monoclonal antibody-mediated targeting of CD123, IL-3 receptor ∝ chain, eliminates human acute myeloid lukemic stem cells
journal contribution
posted on 2009-07-02, 00:00 authored by Liqing Jin, Erwin M Lee, Hayley S Ramshaw, Samantha J Busfield, Armando G Peoppl, Lucy Wilkinson, Mark GuthridgeMark Guthridge, Daniel Thomas, Emma F Barry, Andrew Boyd, David P Gearing, Gino Vairo, Angel F Lopez, John E Dick, Richard B LockLeukemia 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.
History
Journal
Cell Stem CellVolume
5Issue
1Pagination
31 - 42Publisher
Cell PressLocation
Cambridge, Mass.Publisher DOI
Link to full text
ISSN
1934-5909eISSN
1875-9777Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2009, ElsevierUsage metrics
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