Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist

  • Nat Commun. 2016 Mar 15;7:11007. doi: 10.1038/ncomms11007.
Benjamin Cao  1  2 ,  Zhen Zhang  1 ,  Jochen Grassinger  3 ,  Brenda Williams  1  2 ,  Chad K Heazlewood  1  2 ,  Quentin I Churches  1 ,  Simon A James  1  4 ,  Songhui Li  1  2 ,  Thalia Papayannopoulou  5 ,  Susan K Nilsson  1  2
Affiliations
  • 1. Biomedical Manufacturing, CSIRO Manufacturing, Bag 10, Clayton South, Victoria 3169, Australia.
  • 2. Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia.
  • 3. University Hospital Regensberg, Department of Hematology and Oncology, Franz-Josef-Strauß-Allee 11, Regensburg 93053, Germany.
  • 4. Australian Synchrotron, Clayton, Victoria 3168, Australia.
  • 5. Department of Medicine/Hematology, University of Washington Seattle, 1705 NE Pacific, Box 357710, Seattle, Washington 98195-7710, USA.
PMID: 26975966 DOI: 10.1038/ncomms11007
Abstract

The inherent disadvantages of using granulocyte colony-stimulating factor (G-CSF) for hematopoietic stem cell (HSC) mobilization have driven efforts to identify alternate strategies based on single doses of small molecules. Here, we show targeting α9β1/α4β1 integrins with a single dose of a small molecule antagonist (BOP (N-(benzenesulfonyl)-L-prolyl-L-O-(1-pyrrolidinylcarbonyl)tyrosine)) rapidly mobilizes long-term multi-lineage reconstituting HSC. Synergistic engraftment augmentation is observed when BOP is co-administered with AMD3100. Impressively, HSC in equal volumes of peripheral blood (PB) mobilized with this combination effectively out-competes PB mobilized with G-CSF. The enhanced mobilization observed using BOP and AMD3100 is recapitulated in a humanized NODSCIDIL2Rγ(-/-) model, demonstrated by a significant increase in PB CD34(+) cells. Using a related fluorescent analogue of BOP (R-BC154), we show that this class of antagonists preferentially bind human and mouse HSC and progenitors via endogenously primed/activated α9β1/α4β1 within the endosteal niche. These results support using dual α9β1/α4β1 inhibitors as effective, rapid and transient mobilization agents with promising clinical applications.

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