Promegapoietin-1a, an engineered chimeric IL-3 and Mpl-L receptor agonist,stimulates hematopoietic recovery in conventional and abbreviated schedules following radiation-induced myelosuppression in nonhuman primates

Promegapoietin-1a (PMP-la), a multifunctional agonist for the human interle ukin 3 and MpI receptors, was evaluated for its ability to stimulate hemato poietic reconstitution in nonhuman primates following severe radiation-indu ced myelosuppression. Animals were total body x-irradiated (250 kVp) to 600 cGy total midline tissue dose. PMP-1a was administered s.c. in several pro tocols: A) daily (50 mug/kg) for 18 days; B) nine doses (5 mug/kg) every ot her day for 3 weeks; C) a single high dose (100 mug/kg) at 20 hours, or D) a single high dose (100 mug/kg) at 1 hour following TBI. The irradiation co ntrols received 0.1% autologous serum for 18 consecutive days. Hematopoieti c recovery was assessed by bone marrow clonogenic activity, peripheral bloo d cell nadirs, duration of cytopenias, time to recovery to cellular thresho lds, and requirements for clinical support. PMP-la, irrespective of adminis tration schedule, significantly improved all platelet-related parameters: t hrombocytopenia was eliminated, the severity of platelet nadirs was signifi cantly improved, and recovery of platelet counts to greater than or equal t o 20,000/mul was significantly reduced in all PMP-la-treated cohorts. As a consequence, all PMP-1a-treated cohorts were transfusion-independent. Neutr ophil regeneration was augmented in all treatment schedules. Additionally, all PMP-1a-treated cohorts showed an improvement in red blood cell nadir an d recovery. PMP-la in conventional or abbreviated schedules induced signifi cant thrombopoietic regeneration relative to the control cohort, whereas si gnificant improvement in neutrophil recovery was schedule-dependent in radi ation-myelosuppressed nonhuman primates.