Concurrent blockade of alpha4-integrin and CXCR4 in hematopoietic stem/progenitor cell mobilization.

Publication Type:

Journal Article


Stem cells (Dayton, Ohio), Volume 27, Issue 4, p.836-7 (2009)


2009, Animals, Anti-HIV Agents, Antibodies, Blocking, Clinical Research Division, Hematopoietic Stem Cell Mobilization, Hematopoietic Stem Cells, Heterocyclic Compounds, Humans, Integrin alpha4, Macaca, MICE, Receptors, CXCR4


The important contributions of the alpha4 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. alpha4-blockade alone (in humans, macaques and mice), or genetic ablation of alpha4-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 (alpha4-integrin vs. CXCR4) might allow for additive mobilization effects, we therefore tested the efficacy of the combination of alpha4-integrin blockade with anti-functional antibodies and CXCR4 blockade with the small-molecule inhibitor AMD3100 in macaques, or the combination of conditional alpha4-integrin ablation and AMD3100 in mice. Mobilization was at least additive. While the prolonged effects of alpha4-blocking antibodies may not be suitable for clinical mobilization, future availability of small-molecule alpha4-antagonists in combination with AMD3100 could provide an alternative to granulocyte colony-stimulating factor.