title: The induction of prolonged myelopoietic effects in monkeys by GW003, a recombinant human granulocyte colony-stimulating factor genetically fused to recombinant human albumin.
abstract: GW003, a genetic fusion protein of human serum albumin and granulocyte colony-stimulating factor (G-CSF), was developed based on a novel strategy for producing long-acting proteins. The purpose of this study was to evaluate the hematologic, pharmacokinetic, and toxicokinetic effects of GW003 on cynomolgus monkeys. We show that following a single subcutaneous administration of GW003, the absolute neutrophil count increased significantly compared with monkeys that received only the vehicle, and the magnitude of the neutrophilic response to GW003 was dose dependent. After an injection at equal molar dose, the clearance of GW003 in the monkeys was approximately fourfold slower, and the terminal half-life (T1/2 ) was fivefold longer than the corresponding values for recombinant methionyl human G-CSF. Interestingly, both the clearance and T1/2 decreased with increasing doses of GW003, and much faster elimination was observed after multidose exposure. In toxicokinetic studies, the serum concentration of GW003 after the eighth injection was much lower than it was after the first injection, and a neutralizing antibody against G-CSF was found to have a dose-dependent effect upon the treatment groups. Overall, the favorable pharmacokinetic and pharmacodynamic properties supported the selection and development of GW003 as a promising candidate for neutropenia therapy.
authors.affiliation: Department of Pharmacy, Second Artillery General Hospital, Beijing, China.
authors.forename: Xianxing
authors.initials: X
authors.lastname: Xu
authors.forename: Jingwen
authors.initials: J
authors.lastname: Yang
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
authors.forename: Chengqi
authors.initials: C
authors.lastname: Shan
authors.forename: Qiushi
authors.initials: Q
authors.lastname: Wang
authors.forename: Zhihang
authors.initials: Z
authors.lastname: Chen
authors.forename: Yuanguo
authors.initials: Y
authors.lastname: Cheng
mesh_terms: D000818:Animals; D019677:Artificial Gene Fusion / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005260:Female; D050939:Gene Fusion / Q000235:genetics*; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood / Q000235:genetics* / Q000494:pharmacology*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D038042:Myelopoiesis / Q000187:drug effects*; D011994:Recombinant Proteins / Q000097:blood / Q000235:genetics / Q000494:pharmacology; D012709:Serum Albumin / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D011994:Recombinant Proteins; D012709:Serum Albumin; D016179:Granulocyte Colony-Stimulating Factor
keywords: G-CSF; albumin; clearance; fusion protein; pharmacodynamics; pharmacokinetics; toxicokinetics