title: Design Rationale and Development Approach for Pegfilgrastim as a Long-Acting Granulocyte Colony-Stimulating Factor.
abstract: Filgrastim, a recombinant methionyl human granulocyte colony-stimulating factor (G-CSF) (r-metHuG-CSF), is efficacious in stimulating neutrophil production and maturation to prevent febrile neutropenia (FN) in response to chemotherapy. Because of its relatively short circulating half-life, daily filgrastim injections are required to stimulate neutrophil recovery. In an effort to develop a long-acting form of filgrastim that was as safe and efficacious as filgrastim but had a longer in vivo residence time, a number of strategies were considered. Ultimately, fusion of filgrastim to polyethylene glycol (PEG) was selected. Following extensive analysis of conjugation chemistries as well as in vitro and in vivo characterization of a panel of PEGylated proteins, a construct containing a 20 kDa PEG moiety covalently conjugated to the N-terminus of filgrastim was chosen for advancement as pegfilgrastim. Pegfilgrastim is primarily cleared by neutrophils and neutrophil precursors (rather than the kidneys), meaning that clearance from the circulation is self-regulating and pegfilgrastim is eliminated only after neutrophils start to recover. Importantly, addition of PEG did not alter the mechanism of action and safety profile compared to filgrastim. Clinical evaluation revealed that a single 6 mg dose effectively reduces the duration of neutropenia and risk of FN in patients receiving chemotherapy. This work demonstrates the benefit of using PEGylation to generate pegfilgrastim, which allows for once-per-chemotherapy cycle administration while maintaining similar safety and efficacy profiles as those for multiple daily administration of filgrastim. Approaches that may provide advances for therapeutic agonists of G-CSF receptor are also discussed.
authors.affiliation: Amgen Inc., 14-1-B, One Amgen Center Drive, Thousand Oaks, CA, 91320-1799, USA, tara.arvedson@amgen.com.
authors.forename: Tara
authors.initials: T
authors.lastname: Arvedson
authors.forename: James
authors.initials: J
authors.lastname: O'Kelly
authors.forename: Bing-Bing
authors.initials: BB
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D003692:Delayed-Action Preparations / Q000138:chemical synthesis / Q000494:pharmacology; D064147:Febrile Neutropenia / Q000139:chemically induced / Q000517:prevention & control; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000138:chemical synthesis / Q000494:pharmacology; D006207:Half-Life; D006401:Hematologic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D011092:Polyethylene Glycols; D011994:Recombinant Proteins / Q000138:chemical synthesis / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D006401:Hematologic Agents; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim