Concurrent Blockade of α4-Integrin and CXCR4 in Hematopoietic Stem/Progenitor Cell Mobilization

The important contributions of the alpha 4 integrin VLA-4 and the CXCR4/SDF-1 axis in mobilization have been demonstrated and thereby, these pathways can be suggested as rational targets for clinical stem cell mobilization in the absence of cytokine use. alpha 4-blockade alone (in humans, macaques and mice), or genetic ablation of alpha 4-integrin in mice, provides reproducible, but modest mobilization. Similarly, CXCR4 blockade with small-molecule antagonists mobilizes hematopoietic stem cells in all three species, but at least with the established single-injection schedule, the mobilization efficiency is marginally sufficient for clinical purposes. Hypothesizing that the different molecular targets (alpha 4-integrin vs. CXCR4) might allow for additive mobilization effects, we therefore tested the efficacy of the combination of alpha 4-integrin blockade with anti-functional antibodies and CXCR4 blockade with the small-molecule inhibitor AMD3100 in macaques, or the combination of conditional alpha 4-integrin ablation and AMD3100 in mice. Mobilization was at least additive. While the prolonged effects of alpha 4-blocking antibodies may not be suitable for clinical mobilization, future availability of small-molecule alpha 4-antagonists in combination with AMD3100 could provide an alternative to granulocyte colony-stimulating factor. STEM CELLS 2009;27:836-837