title: 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.
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.
authors.affiliation: *Indiana University School of Medicine, Indianapolis, IN; †Bolder Biotechnology, Inc., Boulder, CO.
authors.forename: Paul Artur
authors.initials: PA
authors.lastname: Plett
authors.forename: Hui Lin
authors.initials: HL
authors.lastname: Chua
authors.forename: Carol H
authors.initials: CH
authors.lastname: Sampson
authors.forename: Barry P
authors.initials: BP
authors.lastname: Katz
authors.forename: Christine M
authors.initials: CM
authors.lastname: Fam
authors.forename: Lana J
authors.initials: LJ
authors.lastname: Anderson
authors.forename: George N
authors.initials: GN
authors.lastname: Cox
authors.forename: Christie M
authors.initials: CM
authors.lastname: Orschell
mesh_terms: D054508:Acute Radiation Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006410:Hematopoiesis / Q000187:drug effects* / Q000528:radiation effects; D006801:Humans; D017370:Interleukin-11 / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D017370:Interleukin-11; C486981:pegylated granulocyte colony-stimulating factor, human; D016179:Granulocyte Colony-Stimulating Factor; D011092:Polyethylene Glycols; D016178:Granulocyte-Macrophage Colony-Stimulating Factor