Biased action of the CXCR4-targeting drug plerixafor is essential for its superior hematopoietic stem cell mobilization

Following the FDA-approval of the hematopoietic stem cell (HSC) mobilizer plerixafor, orally available and potent CXCR4 antagonists were pursued. One such proposition was AMD11070, which was orally active and had superior antagonism in vitro; however, it did not appear as effective for HSC mobilization in vivo. Here we show that while AMD11070 acts as a full antagonist, plerixafor acts biased by stimulating beta -arrestin recruitment while fully antagonizing G protein. Consequently, while AMD11070 prevents the constitutive receptor internalization, plerixafor allows it and thereby decreases receptor expression. These findings are confirmed by the successful transfer of both ligands' binding sites and action to the related CXCR3 receptor. In vivo, plerixafor exhibits superior HSC mobilization associated with a dramatic reversal of the CXCL12 gradient across the bone marrow endothelium, which is not seen for AMD11070. We propose that the biased action of plerixafor is central for its superior therapeutic effect in HSC mobilization. JOrgensen et al. investigate the effects of the CXCR4 targeting agents, AMD3100 (Plerixafor) and AMD11070, and show that AMD3100, unlike AMD11070, is biased with intrinsic beta -arrestin recruitment agonism and full G protein antagonism. They finally propose that this biased action of AMD3100 is central for its superior therapeutic effect on mobilizing stem cells.