Subsequent to cloning of the mpl ligands, a family of novel, engineered, chimeric cytokine receptor agonists for the IL-3 and mpl receptor called promegapoietin (PMP) was developed (62).
PMP showed significant therapeutic efficacy for restoration of platelets in preclinical models of irradiation-induced myelosuppression in a manner comparable to that noted for PEG-rHuMGDF and rHuTPO. It was shown that, similar to PEG-rHuMGDF or rHuTPO, a single dose of PMP administered within 1-2 h after exposure was comparable in therapeutic efficacy to the conventional daily administration of PMP in enhancing thrombopoietic recovery from severe radiation-induced myelosuppression (Fig. 6) (22). PMP was evaluated in four administration schedules: daily for 18 d; 9 doses every other day for 3 wk; a single high dose at 20 h; or a single high dose 2 h after 600-cGy total body irradiation in the rhesus macaque. PMP, irrespective of administration schedule, significantly improved all platelet-related parameters, thrombocytopenia was eliminated, severity of platelet nadirs was significantly improved, and duration of thrombocytopenia was significantly reduced relative to the control-treated cohort. Consequently, all PMP-treated cohorts were transfusion-independent (22). These results provided a clear rationale for the clinical evaluation of promegapoietin and its potential for increased efficacy owing to the IL-3 component of the chimeric molecule.
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