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-1a), a multifunctional agonist for the human interleukin 3 and Mpl receptors, was evaluated for its ability to stimulate hematopoietic reconstitution in nonhuman primates following severe radiation-induced myelosuppression. Animals were total body x-irradiated (250 kVp) to 600 cGy total midline tissue dose. PMP-1a was administered s.c. in several protocols: A) daily (50 microg/kg) for 18 days; B) nine doses (5 microg/kg) every other day for 3 weeks; C) a single high dose (100 microg/kg) at 20 hours, or D) a single high dose (100 microg/kg) at 1 hour following TBI. The irradiation controls received 0.1% autologous serum for 18 consecutive days. Hematopoietic recovery was assessed by bone marrow clonogenic activity, peripheral blood cell nadirs, duration of cytopenias, time to recovery to cellular thresholds, and requirements for clinical support. PMP-1a, irrespective of administration schedule, significantly improved all platelet-related parameters: thrombocytopenia was eliminated, the severity of platelet nadirs was significantly improved, and recovery of platelet counts to > or =20,000/miccrol was significantly reduced in all PMP-1a-treated cohorts. As a consequence, all PMP-1a-treated cohorts were transfusion-independent. Neutrophil regeneration was augmented in all treatment schedules. Additionally, all PMP-1a-treated cohorts showed an improvement in red blood cell nadir and recovery. PMP-1a in conventional or abbreviated schedules induced significant thrombopoietic regeneration relative to the control cohort, whereas significant improvement in neutrophil recovery was schedule-dependent in radiation-myelosuppressed nonhuman primates.
Farese
A M
AM
Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland 21201, USA.
Smith
W G
WG
Giri
J G
JG
Siegel
N
N
McKearn
J P
JP
MacVittie
T J
TJ
D000818:Animals; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004912:Erythrocytes / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D006410:Hematopoiesis / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007377:Interleukin-3 / Q000031:analogs & derivatives; D008253:Macaca mulatta; D008297:Male; D009503:Neutropenia / Q000188:drug therapy / Q000503:physiopathology; D010446:Peptide Fragments; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology; D015202:Protein Engineering; D016185:Receptors, Interleukin-3 / Q000008:administration & dosage / Q000819:agonists* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013921:Thrombocytopenia / Q000188:drug therapy / Q000503:physiopathology; D013926:Thrombopoietin / Q000008:administration & dosage / Q000819:agonists* / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*
D004338:Drug Combinations; D007377:Interleukin-3; D010446:Peptide Fragments; D010455:Peptides; D016185:Receptors, Interleukin-3; D011993:Recombinant Fusion Proteins; C438891:promegapoietin-1a; C093340:daniplestim; D013926:Thrombopoietin