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.
"G- CSF has emerged as the most routinely used growth factor for treatment of neutropenia in clinic  . A chimera of G-CSF and IL-3 has been used successfully to treat radiation-indu ced neutropenia in nonhuma n primates  . "
[Show abstract][Hide abstract] ABSTRACT: This study aimed to determine the role of granulocyte colony-stimulating factor (G-CSF), induced by a promising radiation countermeasure, gamma tocotrienol (GT3), in protecting mice from lethal doses of ionizing radiation. CD2F1 mice were injected with an optimal dose of GT3 and a G-CSF antibody, and their 30-d survival was monitored. An appropriate antibody isotype was used as a control. Multiplex Luminex was used to analyze GT3-induced cytokines. G-CSF neutralization by exogenous administration of a G-CSF antibody was confirmed by analyzing serum cytokine levels. Our results demonstrate that GT3 significantly protected mice against ionizing radiation, and induced high levels of G-CSF in peripheral blood 24h after administration. Injection of a G-CSF neutralizing antibody to the GT3-treated mice resulted in complete neutralization of G-CSF and abrogation of its protective efficacy. Administration of a G-CSF antibody did not affect levels of other cytokines induced by GT3. Histopathology of bone marrow from GT3-treated and -irradiated mice demonstrated protection of the hematopoietic tissue, and also that such protection was abrogated by administering a G-CSF antibody. Our results suggest that induction of high levels of G-CSF by GT3 administration is responsible for its protective efficacy against radiation injury.
"d G - CSF ligands are linked and serve to stimulate those hematopoietic progenitors bearing IL - 3 and G - CSF surface receptors . Biological properties of both molecules are enhanced in myelopoietin ( leridistim ) . Leridistim stimulated hematopoietic reconstitution in radiation myelosuppressed non - human primates better than IL - 3 or G - CSF ( Farese et al . , 2001b ) . The administration of a single high dose of pegylated leridistim significantly improved neutrophil regeneration , in a manner equal to that of conventional daily or every other day administration of leridistim in non - human primate models ( Farese et al . , 2001c ) . Progenipoietin combines Flt - 3 ( an early acting hemato - poieti"
[Show abstract][Hide abstract] ABSTRACT: Cytokines and growth factors are growing groups of proteins that are responsible for the communication between cells of the immune system, hematopoietic cells, and other cell types. The cloning and large-scale production in a recombinant form of these agents in pharmacological quantities permitted investigations aimed at assessing the benefit they may provide in preserving and restoring functions of tissues compromised by irradiation. We have extensively examined past investigations which suggest that some cytokines and growth factors protect animals from radiation lethality when given prior to or after irradiation, and even in untreated animals, these cytokines serve in innate defenses against external stimuli. In contrast, some cytokines given before irradiation sensitize the animals to radiation lethality. Unfortunately, due to their adverse side effects, these cytokines were not found suitable as radioprotectors. Recent studies suggest that new approaches may bring cytokines and growth factors in clinic for radiation injury. The information and insight gained about therapeutic potential of cytokine manipulation will allow for more rational design of treatment protocols.
[Show abstract][Hide abstract] ABSTRACT: Leridistim, a member of the myelopoietin family of dual receptor agonists that binds interleukin-3 and G-CSF receptors, has been shown to enhance hematopoietic activity in rhesus monkeys above that observed with either cytokine alone or in combination. This study demonstrated the ability of a pegylated form of leridistim (peg-leridistim), administered s.c., as a single- or two-dose regimen separated by 4 or 7 days, to significantly improve neutrophil recovery following radiation-induced myelosuppression. Rhesus macaques were total body x-irradiated (250 kVp, TBI) to 600 cGy. Following TBI, two groups received peg-leridistim (n = 5) or leridistim (n = 4) at a dose of 600 microg/kg on day 1, while two other groups (both n = 4) received peg-leridistim at 200 microg/kg on day 1 and day 4, or day 1 and day 7. The irradiation controls (n = 7) received 0.1% autologous serum for 18 days. All peg-leridistim treatment schedules significantly improved all neutrophil-related parameters following TBI as compared with nontreated controls and were equivalent in effect when compared among themselves. Administration of a single high dose or two separate lower doses of peg-leridistim significantly improved neutrophil regeneration, in a manner equal to that of conventional daily or abbreviated every-other-day administration of leridistim in this nonhuman primate model of severe myelosuppression.
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