title: A new form of Filgrastim with sustained duration in vivo and enhanced ability to mobilize PBPC in both mice and humans.
abstract: Granulocyte colony-stimulating factor (G-CSF) has proven effective in the prophylaxis of chemotherapy-induced neutropenia and as a mobilizer of peripheral blood progenitor cells. The longevity of G-CSF action is limited by its removal from the body by two mechanisms. The first is thought to be mediated via receptors (receptor mediated clearance [RMC]) predominantly on neutrophils, the second process is likely the result of renal clearance. With the intention of developing a novel form of Filgrastim (r-met HuG-CSF) with a sustained duration of action in vivo, a new derivative named SD/01 has been made by association of Filgrastim with poly(ethylene glycol). The desired properties of this new agent would include a prolonged duration of action sufficient to cover a complete single course of chemotherapy. SD/01 is shown here to sustain significantly elevated neutrophil counts in hematopoietically normal mice for 5 days. In neutropenic mice effects were noted for at least 9 days, accompanying a significant reduction in the duration of chemotherapy induced neutropenia. Normal human volunteers showed higher than baseline ANC for around 9 to 10 days after a single injection of SD/01. Data from these normal volunteers also indicate that mobilization of CD34+ cells and progenitors may occur in a more timely manner and to around the same absolute numbers as with repeated daily injections of unmodified Filgrastim. These data indicate that SD/01 represents an efficacious novel form of Filgrastim with actions sustained for between one and two weeks from a single injection.
authors.affiliation: Department of Pharmacology, Amgen Inc., Thousand Oaks, CA 91320, USA. grahamm@amgen.com
authors.forename: G
authors.initials: G
authors.lastname: Molineux
authors.forename: O
authors.initials: O
authors.lastname: Kinstler
authors.forename: B
authors.initials: B
authors.lastname: Briddell
authors.forename: C
authors.initials: C
authors.lastname: Hartley
authors.forename: P
authors.initials: P
authors.lastname: McElroy
authors.forename: P
authors.initials: P
authors.lastname: Kerzic
authors.forename: W
authors.initials: W
authors.lastname: Sutherland
authors.forename: G
authors.initials: G
authors.lastname: Stoney
authors.forename: B
authors.initials: B
authors.lastname: Kern
authors.forename: F A
authors.initials: FA
authors.lastname: Fletcher
authors.forename: A
authors.initials: A
authors.lastname: Cohen
authors.forename: E
authors.initials: E
authors.lastname: Korach
authors.forename: T
authors.initials: T
authors.lastname: Ulich
authors.forename: I
authors.initials: I
authors.lastname: McNiece
authors.forename: P
authors.initials: P
authors.lastname: Lockbaum
authors.forename: M A
authors.initials: MA
authors.lastname: Miller-Messana
authors.forename: S
authors.initials: S
authors.lastname: Gardner
authors.forename: T
authors.initials: T
authors.lastname: Hunt
authors.forename: G
authors.initials: G
authors.lastname: Schwab
mesh_terms: D000818:Animals; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D051379:Mice; D011994:Recombinant Proteins
chemical_list: D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000069585:Filgrastim