PEGylated G-CSF (BBT-015), GM-CSF (BBT-007), AND IL-11 (BBT-059) analogs enhance survival and hematopoietic cell recovery in a mouse model of the hematopoietic syndrome of the acute radiation syndrome

Paul Artur Plett, Hui Lin Chua, Carol H. Sampson, Barry Katz, Christine M. Fam, Lana J. Anderson, George N. Cox, Christie Orschell

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

ABSTRACT: Hematopoietic growth factors (HGF) are recommended therapy for high dose radiation exposure, but unfavorable administration schedules requiring early and repeat dosing limit the logistical ease with which they can be used. In this report, using a previously described murine model of H-ARS, survival efficacy and effect on hematopoietic recovery of unique PEGylated HGF were investigated. The PEGylated-HGFs possess longer half-lives and more potent hematopoietic properties than corresponding non-PEGylated-HGFs. C57BL/6 mice underwent single dose lethal irradiation (7.76-8.72 Gy, Cs, 0.62-1.02 Gy min) and were treated with various dosing regimens of 0.1, 0.3, and 1.0 mg kg of analogs of human PEG-G-CSF, murine PEG-GM-CSF, or human PEG-IL-11. Mice were administered one of the HGF analogs at 24-28 h post irradiation, and in some studies, additional doses given every other day (beginning with the 24-28 h dose) for a total of three or nine doses. Thirty-day (30 d) survival was significantly increased with only one dose of 0.3 mg kg of PEG-G-CSF and PEG-IL-11 or three doses of 0.3 mg kg of PEG-GM-CSF (p ≤ 0.006). Enhanced survival correlated with consistently and significantly enhanced WBC, NE, RBC, and PLT recovery for PEG-G- and PEG-GM-CSF, and enhanced RBC and PLT recovery for PEG-IL-11 (p ≤ 0.05). Longer administration schedules or higher doses did not provide a significant additional survival benefit over the shorter, lower dose, schedules. These data demonstrate the efficacy of BBT's PEG-HGF to provide significantly increased survival with fewer injections and lower drug doses, which may have significant economic and logistical value in the aftermath of a radiation event.

Original languageEnglish
Pages (from-to)7-20
Number of pages14
JournalHealth Physics
Volume106
Issue number1
DOIs
StatePublished - Jan 2014

Fingerprint

Acute Radiation Syndrome
Interleukin-11
Granulocyte Colony-Stimulating Factor
Granulocyte-Macrophage Colony-Stimulating Factor
Cell Survival
Intercellular Signaling Peptides and Proteins
Survival
Appointments and Schedules
Inbred C57BL Mouse
Economics
Radiation
Injections
Pharmaceutical Preparations

Keywords

  • biological factors
  • blood
  • bonemarrow
  • mice
  • modeling

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Health, Toxicology and Mutagenesis
  • Epidemiology

Cite this

PEGylated G-CSF (BBT-015), GM-CSF (BBT-007), AND IL-11 (BBT-059) analogs enhance survival and hematopoietic cell recovery in a mouse model of the hematopoietic syndrome of the acute radiation syndrome. / Plett, Paul Artur; Chua, Hui Lin; Sampson, Carol H.; Katz, Barry; Fam, Christine M.; Anderson, Lana J.; Cox, George N.; Orschell, Christie.

In: Health Physics, Vol. 106, No. 1, 01.2014, p. 7-20.

Research output: Contribution to journalArticle

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AU - Orschell, Christie

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AB - ABSTRACT: Hematopoietic growth factors (HGF) are recommended therapy for high dose radiation exposure, but unfavorable administration schedules requiring early and repeat dosing limit the logistical ease with which they can be used. In this report, using a previously described murine model of H-ARS, survival efficacy and effect on hematopoietic recovery of unique PEGylated HGF were investigated. The PEGylated-HGFs possess longer half-lives and more potent hematopoietic properties than corresponding non-PEGylated-HGFs. C57BL/6 mice underwent single dose lethal irradiation (7.76-8.72 Gy, Cs, 0.62-1.02 Gy min) and were treated with various dosing regimens of 0.1, 0.3, and 1.0 mg kg of analogs of human PEG-G-CSF, murine PEG-GM-CSF, or human PEG-IL-11. Mice were administered one of the HGF analogs at 24-28 h post irradiation, and in some studies, additional doses given every other day (beginning with the 24-28 h dose) for a total of three or nine doses. Thirty-day (30 d) survival was significantly increased with only one dose of 0.3 mg kg of PEG-G-CSF and PEG-IL-11 or three doses of 0.3 mg kg of PEG-GM-CSF (p ≤ 0.006). Enhanced survival correlated with consistently and significantly enhanced WBC, NE, RBC, and PLT recovery for PEG-G- and PEG-GM-CSF, and enhanced RBC and PLT recovery for PEG-IL-11 (p ≤ 0.05). Longer administration schedules or higher doses did not provide a significant additional survival benefit over the shorter, lower dose, schedules. These data demonstrate the efficacy of BBT's PEG-HGF to provide significantly increased survival with fewer injections and lower drug doses, which may have significant economic and logistical value in the aftermath of a radiation event.

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