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

Benjamin Cao, Zhen Zhang, Jochen Grassinger, Brenda Williams, Chad K. Heazlewood, Quentin I. Churches, Simon A. James, Songhui Li, Thalia Papayannopoulou and Susan K. Nilsson ()
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Benjamin Cao: Biomedical Manufacturing, CSIRO Manufacturing
Zhen Zhang: Biomedical Manufacturing, CSIRO Manufacturing
Jochen Grassinger: University Hospital Regensberg
Brenda Williams: Biomedical Manufacturing, CSIRO Manufacturing
Chad K. Heazlewood: Biomedical Manufacturing, CSIRO Manufacturing
Quentin I. Churches: Biomedical Manufacturing, CSIRO Manufacturing
Simon A. James: Biomedical Manufacturing, CSIRO Manufacturing
Songhui Li: Biomedical Manufacturing, CSIRO Manufacturing
Thalia Papayannopoulou: University of Washington Seattle
Susan K. Nilsson: Biomedical Manufacturing, CSIRO Manufacturing

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11007

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