title: 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.affiliation: *Indiana University School of Medicine, Indianapolis, IN; †University of Maryland School of Medicine, Baltimore, MD; ‡Maxygen, Inc., San Mateo, CA.
authors.forename: Hui Lin
authors.initials: HL
authors.lastname: Chua
authors.forename: P Artur
authors.initials: PA
authors.lastname: Plett
authors.forename: Carol H
authors.initials: CH
authors.lastname: Sampson
authors.forename: Barry P
authors.initials: BP
authors.lastname: Katz
authors.forename: Gilbert W
authors.initials: GW
authors.lastname: Carnathan
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: MacVittie
authors.forename: Keith
authors.initials: K
authors.lastname: Lenden
authors.forename: Christie M
authors.initials: CM
authors.lastname: Orschell
mesh_terms: D000818:Animals; D005260:Female; D008297:Male; D051379:Mice; D054508:Acute Radiation Syndrome / Q000097:blood / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D001772:Blood Cell Count; D001835:Body Weight / Q000187:drug effects / Q000528:radiation effects; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects; D016026:Bone Marrow Transplantation; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006410:Hematopoiesis / Q000187:drug effects / Q000528:radiation effects; D008810:Mice, Inbred C57BL; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; C545207:Maxy G34; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D011994:Recombinant Proteins