A new form of Filgrastim with sustained duration in vivo and enhanced ability to mobilize PBPC in both mice and humans.
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.
Molineux
G
G
Department of Pharmacology, Amgen Inc., Thousand Oaks, CA 91320, USA. grahamm@amgen.com
Kinstler
O
O
Briddell
B
B
Hartley
C
C
McElroy
P
P
Kerzic
P
P
Sutherland
W
W
Stoney
G
G
Kern
B
B
Fletcher
F A
FA
Cohen
A
A
Korach
E
E
Ulich
T
T
McNiece
I
I
Lockbaum
P
P
Miller-Messana
M A
MA
Gardner
S
S
Hunt
T
T
Schwab
G
G
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
D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000069585:Filgrastim