Progenipoietins

Progenipoietins (ProGPs) are another class of engineered proteins containing both fetal liver tyrosine kinase-3 (flt-3) and G-CSF receptor agonist activities (27). Initial in vitro and in vivo studies suggested that the ProGP family of dual receptor agonists were potent HGFs, combining the synergistic potential of flt-3 ligand and G-CSF in a single molecule. In vitro, the ProGP molecules bound to flt-3 ligand and G-CSF receptors with approximately the same equilibrium dissociation constants as the native ligands and can bind both flt-3 and G-CSF receptors simultaneously, promote the proliferation of flt-3-and G-CSF-responsive cell lines, and stimulate growth of clonogenic colony-forming cells with potency greater than the combination of flt-3 and G-CSF (27). A series of in vivo studies in normal mice confirmed the hematopoietic potential of these molecules to include the mobilization of significant numbers of dendritic cells into peripheral blood and spleen (27). These early results suggested the continued evaluation of selected prog-enipoietins in an effort to decipher their therapeutic utility in enhancing myeloid and immune reconstitution after radiation-induced myelosuppression.

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Structurally distinct members of the progenipoietins, ProGP-1, -2, and -4 were evaluated for their ability to stimulate hematopoietic recovery in a well-codified model of radiation-induced myelosuppression in the rhesus macaque (23,25). The ProGPs were assessed in a conventional daily administration and in an abbreviated, every-other-day schedule, beginning on d 1 after irradiation and continuing until the ANC was >3 x 109/L (range: 12-14 d). ProGP-1, -2, and -4, at all doses and administration schedules, significantly improved neutrophil nadirs, duration of neutropenia, and time to recovery of ANC to >0.5 x 109/L. Additionally, the number of days in which antibiotic support was required were significantly reduced relative to the control cohort. Control, neutropenic nadirs were improved from a range of 8-16/^L to 350-413/^L, and neutropenic durations (days of ANC < 0.5 x 109/L) were improved from approx d 16 in controls to <d 2 after ProGP administration. The ProGP molecules can effectively stimulate recovery of neutrophils in high-dose, irradiated rhesus macaques and therefore may have had an important role in the clinical setting for management of the myelosuppressed host.

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