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

Abstract

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.

Figure 1. Mobilization by α4- and CXCR4-blockade

One pigtail monkey (A) or groups of mice (B,C) were treated as indicated, and CD34+ cells and/or CFU-C were enumerated as indicated at the time points indicated (A), 1 hour after AMD3100 bolus injection (n=5 per group, B), or after 5-day AMD3100 infusion (n=4 per group, C). Circulating CFU-C were significantly higher in AMD3100 treated α4-/- mice than in identically treated WT mice (p<0.01).