Journal
BLOOD
Volume 133, Issue 19, Pages 2069-2078Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2018-06-858159
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Funding
- Walter V. and Idun Berry Postdoctoral Fellowship
- Howard Hughes Medical Institute Medical Research Training Fellowship
- Stanford University Medical Scholars Fellowship
- Paul and Daisy Soros Fellowship for New Americans
- Virginia and D. K. Ludwig Fund for Cancer Research
- California Institute for Regenerative Medicine [RT3-07683, DR2A-05365]
- National Institutes of Health (National Cancer Institute) [R01 CA86065]
- National Institutes of Health (National Heart, Lung, and Blood Institute) [R01HL058770]
- Gunn/Olivier Research Fund
- H. L. Snyder Medical Foundation
- Stinehart-Reed Foundation
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The myelodysplastic syndromes (MDS) represent a group of clonal disorders that result in ineffective hematopoiesis and are associated with an increased risk of transformation into acute leukemia. MDS arises from hematopoietic stem cells (HSCs); therefore, successful elimination of MDS HSCs is an important part of any curative therapy. However, current treatment options, including allogeneic hematopoietic cell transplantation (HCT), often fail to ablate disease-initiating MDS HSCs, and thus have low curative potential and high relapse rates. Here, we demonstrate that human HSCs can be targeted and eliminated by monoclonal antibodies (mAbs) that bind cell-surface CD117 (c-Kit). We show that an antihuman CD117 mAb, SR-1, inhibits normal cord blood and bone marrow HSCs in vitro. Furthermore, SR-1 and clinical-grade humanized anti-human CD117 mAb, AMG 191, deplete normal and MDS HSCs in vivo in xenograft mouse models. Anti-CD117 mAbs also facilitate the engraftment of normal donor human HSCs in MDS xenograft mouse models, restoring normal human hematopoiesis and eradicating aggressive pathologic MDS cells. This study is the first to demonstrate that anti-human CD117 mAbs have potential as novel therapeutics to eradicate MDS HSCs and augment the curative effect of allogeneic HCT for this disease. Moreover, we establish the foundation for use of these antibody agents not only in the treatment of MDS but also for the multitude of other HSC-driven blood and immune disorders for which transplant can be disease-altering.
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