Survival efficacy of the PEGylated G-CSFs Maxy-G34 and neulasta in a mouse model of lethal H-ARS, and residual bone marrow damage in treated survivors.

Abstract

In an effort to expand the worldwide pool of available medical countermeasures (MCM) against radiation, the PEGylated G-CSF (PEG-G-CSF) molecules Neulasta and Maxy-G34, a novel PEG-G-CSF designed for increased half-life and enhanced activity compared to Neulasta, were examined in a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS), along with the lead MCM for licensure and stockpiling, G-CSF. Both PEG-G-CSFs were shown to retain significant survival efficacy when administered as a single dose 24 h post-exposure, compared to the 16 daily doses of G-CSF required for survival efficacy. Furthermore, 0.1 mg kg of either PEG-G-CSF affected survival of lethally-irradiated mice that was similar to a 10-fold higher dose. The one dose/low dose administration schedules are attractive attributes of radiation MCM given the logistical challenges of medical care in a mass casualty event. Maxy-G34-treated mice that survived H-ARS were examined for residual bone marrow damage (RBMD) up to 9 mo post-exposure. Despite differences in Sca-1 expression and cell cycle position in some hematopoietic progenitor phenotypes, Maxy-G34-treated mice exhibited the same degree of hematopoietic stem cell (HSC) insufficiency as vehicle-treated H-ARS survivors in competitive transplantation assays of 150 purified Sca-1+cKit+lin-CD150+cells. These data suggest that Maxy-G34, at the dose, schedule, and time frame examined, did not mitigate RBMD but significantly increased survival from H-ARS at one-tenth the dose previously tested, providing strong support for advanced development of Maxy-G34, as well as Neulasta, as MCM against radiation.

• Authors: Hui Lin Chua, P Artur Plett, Carol H Sampson, Barry P Katz, Gilbert W Carnathan, Thomas J MacVittie, Keith Lenden, Christie M Orschell
• Journal: Health physics (Health Phys) Vol. 106 Issue 1 Pg. 21-38 (Jan 2014) ISSN: 1538-5159 [Electronic] United States
• PMID: 24276547 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Maxy G34
• Recombinant Proteins
• Granulocyte Colony-Stimulating Factor
• pegfilgrastim
• Polyethylene Glycols
• Filgrastim

Topics

• Acute Radiation Syndrome (blood, drug therapy, pathology, physiopathology)
• Animals
• Blood Cell Count
• Body Weight (drug effects, radiation effects)
• Bone Marrow (drug effects, pathology, physiopathology, radiation effects)
• Bone Marrow Transplantation
• Cell Cycle (drug effects, radiation effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Female
• Filgrastim
• Granulocyte Colony-Stimulating Factor (administration & dosage, pharmacology, therapeutic use)
• Hematopoiesis (drug effects, radiation effects)
• Male
• Mice
• Mice, Inbred C57BL
• Polyethylene Glycols (administration & dosage, pharmacology, therapeutic use)
• Recombinant Proteins (administration & dosage, pharmacology, therapeutic use)
• Survival Analysis
• Survivors
• Time Factors