Concurrent blockade of alpha4-integrin and CXCR4 in hematopoietic stem/progenitor cell mobilization.
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.
German Red Cross Blood Center, Institute for Transfusion Medicine and Immunohematology, Johann-Wolfgang-Goethe University, Frankfurt, Germany. hbonig@u.washington.edu
Halvard
H
Bonig
Korashon L
KL
Watts
Kai-Hsin
KH
Chang
Hans-Peter
HP
Kiem
Thalia
T
Papayannopoulou
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D019138:Antibodies, Blocking / Q000494:pharmacology; D001596:Benzylamines; D000080027:Cyclams; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000502:physiology; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D039441:Integrin alpha4 / Q000276:immunology / Q000378:metabolism*; D008251:Macaca; D051379:Mice; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D019380:Anti-HIV Agents; D019138:Antibodies, Blocking; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D039441:Integrin alpha4; C088327:plerixafor