title: Hematopoietic properties of granulocyte colony-stimulating factor/immunoglobulin (G-CSF/IgG-Fc) fusion proteins in normal and neutropenic rodents.
abstract: Previously we showed that granulocyte colony-stimulating factor (G-CSF) in vitro bioactivity is preserved when the protein is joined via a flexible 7 amino acid linker to an immunoglobulin-1 (IgG1)-Fc domain and that the G-CSF/IgG1-Fc fusion protein possessed a longer circulating half-life and improved hematopoietic properties compared to G-CSF in normal rats. We have extended this analysis by comparing the relative hematopoietic potencies of G-CSF/IgG1-Fc to G-CSF in normal mice and to G-CSF and polyethylene glycol (PEG) -modified G-CSF in neutropenic rats. Mice were treated for 5 days using different doses and dosing regimens of G-CSF/IgG1-Fc or G-CSF and circulating neutrophil levels in the animals measured on Day 6. G-CSF/IgG1-Fc stimulated greater increases in blood neutrophils than comparable doses of G-CSF when administered using daily, every other day or every third day dosing regimens. In rats made neutropenic with cyclophosphamide, G-CSF/IgG1-Fc accelerated recovery of blood neutrophils to normal levels (from Day 9 to Day 5) when administered as 5 daily injections or as a single injection on Day 1. By contrast, G-CSF accelerated neutrophil recovery when administered as 5 daily injections, but not when administered as a single injection. G-CSF/IgG1-Fc was as effective as PEG-G-CSF at accelerating neutrophil recovery following a single injection in neutropenic rats. G-CSF/IgG1-Fc and G-CSF/IgG4-Fc fusion proteins in which the 7 amino acid linker was deleted also were effective at accelerating neutrophil recovery following a single injection in neutropenic rats. These studies confirm the enhanced in vivo hematopoietic properties of G-CSF/IgG-Fc fusion proteins.
authors.affiliation: Bolder BioTechnology, Inc., Boulder, Colorado, United States of America.
authors.forename: George N
authors.initials: GN
authors.lastname: Cox
authors.affiliation: BolderPATH, Inc., University of Colorado, Boulder, Colorado, United States of America.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Chlipala
authors.affiliation: Bolder BioTechnology, Inc., Boulder, Colorado, United States of America.
authors.forename: Darin J
authors.initials: DJ
authors.lastname: Smith
authors.affiliation: Bolder BioTechnology, Inc., Boulder, Colorado, United States of America.
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Carlson
authors.affiliation: Bolder BioTechnology, Inc., Boulder, Colorado, United States of America.
authors.forename: Stacie J
authors.initials: SJ
authors.lastname: Bell
authors.affiliation: Bolder BioTechnology, Inc., Boulder, Colorado, United States of America.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Doherty
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects*; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D007958:Leukocyte Count; D051379:Mice; D009503:Neutropenia / Q000188:drug therapy* / Q000209:etiology; D009504:Neutrophils / Q000187:drug effects; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D016179:Granulocyte Colony-Stimulating Factor