Myelopoietin, an engineered chimeric IL-3 and G-CSF receptor agonist, stimulates multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression

Myelopoietins (MPOs) constitute a family of engineered, chimeric molecules that bind and activate the IL-3 and G-CSF receptors on hematopoietic cells, This study investigated the in vivo hematopoietic response of rhesus monke ys administered MPO after radiation-induced myelosuppression, Animals were total body irradiated (TBI) in 2 series, with biologically equivalent doses consisting of either a 700 cGy dose of Cobalt-60 (Co-60) gamma-radiation o r 600 cGy, 250 kVp x-irradiation. First series: On day 1 after 700 cGy irra diation, cohorts of animals were subcutaneously (SC) administered MPO at 20 0 mu g/kg/d (n = 4), or 50 mu g/kg/d (n = 2), twice daily, or human serum a lbumin (HSA) (n = 10), Second series: The 600 cGy x-irradiated cohorts of a nimals were administered either MPO at 200 mu g/kg/d, in a daily schedule(n = 4) or 0.1% autologous serum (AS), daily, SC (n = 11) for 23 days. MPO re gardless of administration schedule (twice a day or every day) significantl y reduced the mean durations of neutropenia (absolute neutrophil count [ANC ] < 500/mu L) and thrombocytopenia (platelet < 20 000/mu L) Versus respecti ve control-treated cohorts. Mean neutrophil and platelet nadirs were signif icantly improved and time to recovery for neutrophills (ANC to < 500/mu L) and platelets (PLT < 20 000/mu L) were significantly enhanced in the MPO-tr eated cohorts Versus controls. Red cell recovery was further improved relat ive to control-treated cohorts that received whole blood transfusions. Sign ificant increases in bone marrow-derived clonogenic activity was observed b y day 14 after TBI in MPO-treated cohorts versus respective time-matched co ntrols. Thus, MPO, administered daily was as effective as a twice daily sch edule for multilineage recovery in nonhuman primates after high-dose, radia tion-induced myelosuppression. (C) 2000 by The American Society of Hematology.