Leridistim, a chimeric dual G-CSF and IL-3 receptor agonist, enhances multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression: effect of schedule, dose, and route of administration.
Leridistim is from the myelopoietin family of proteins, which are dual receptor agonists of the human interleukin-3 and G-CSF receptor complexes. This study investigated the effect of dosage, administration route, and schedule of leridistim to stimulate multilineage hematopoietic recovery in total body irradiated rhesus monkeys. Animals were x-irradiated on day 0 (600 cGy, 250 kVp) and then received, on day 1, leridistim s.c. in an abbreviated, every-other-day schedule at 200 microg/kg, or daily at 50 microg/kg, or i.v. daily or every-other-day schedules at 200 microg/kg dose. Other cohorts received G-CSF (Neupogen((R)) [Filgrastim]) in an every-other-day schedule at 100 microg/kg/day, or autologous serum (0.1%) s.c. daily. 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. Leridistim, administered s.c. every other day, or i.v. daily, significantly improved neutrophil, platelet, and lymphocyte nadirs, shortened the respective durations of cytopenia, hastened trilineage hematopoietic recovery, and reduced antibiotic and transfusion requirements. A lower dose of leridistim administered daily s.c. enhanced recovery of neutrophil and platelet parameters but did not affect lymphocyte recovery relative to controls. Leridistim, a novel engineered hematopoietic growth factor administered at the appropriate dose, route and schedule, stimulates multilineage hematopoietic reconstitution in radiation-myelosuppressed nonhuman primates.
Farese
A M
AM
University of Maryland, Greenebaum Cancer Center, 655 West Baltimore Street, BRB 7-049, Baltimore, MD 21201, USA. afarese@umaryland.edu
Casey
D B
DB
Smith
W G
WG
Vigneulle
R M
RM
McKearn
J P
JP
MacVittie
T J
TJ
D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D019070:Cell Lineage; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007377:Interleukin-3 / Q000737:chemistry / Q000494:pharmacology*; D019891:Leukopoiesis / Q000187:drug effects* / Q000528:radiation effects; D016131:Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D008253:Macaca mulatta; D008297:Male; D023421:Models, Animal; D009503:Neutropenia / Q000209:etiology / Q000517:prevention & control; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000819:agonists*; D016185:Receptors, Interleukin-3 / Q000819:agonists*; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D013921:Thrombocytopenia / Q000209:etiology / Q000517:prevention & control; D013997:Time Factors; D014916:Whole-Body Irradiation / Q000009:adverse effects
D007377:Interleukin-3; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016185:Receptors, Interleukin-3; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C400711:leridistim