F-627, a G-CSF Dimer, Stimulated a More Rapid Neutrophil Recovery In Cyclophosphamide-Treated Monkeys Compared to Monomer Rhg-CSFs.

Abstract 1485

Recombinant human granulocyte colony-stimulating factors (rhG-CSF) including filgrastim, lenograstim and pegfilgrastim are widely used to treat chemotherapy-induced neutropenia. However, it remains a challenge to manage severe neutropenia in cancer patients after high dose chemotherapy. The activation of G-CSFR by the G-CSF requires dimerization of two receptor chains bound to two G-CSF ligands. We hypothesized that a G-CSF dimer might generate a faster in vivo response, thus to benefit patients with severe neutropenia. F-627 is a recombinant human G-CSF dimer expressed in mammalian cells. In vitro, F-627 was able to activate STAT3 and to stimulate the proliferation of 32D-GCSFR and M-NSF60 cell lines. To evaluate the efficacy of F-627 in chemotherapy-induced neutropenia, 36 adult cynomolgus monkeys (3/sex) were injected with cyclophoshamide (CY, i.v., 60 mg/kg on day 0 and 65 mg/kg on day 1). Animals were randomized to receive (s.c.) either carrier, or F-627 on day 5 and day 10, at 25, 60 and 150 μg/kg, or rhG-CSF at 10 μg/kg /day (daily injection), or pegfilgrastim at 60 μg/kg on day 5 and day 10. Pharmacokinetics and pharmacodynamics (PK/PD) were evaluated. Significant absolute neutrophil count (ANC) increase was observed in animals treated with F-627 at 25 μg/kg compared to carrier-treated monkeys. At nadir, F-627 at 60 μg/kg generated optimal ANC response with 6.9- and 3.0-fold higher ANC compared to pegfilgrastim- (0.17 × 10⁹/L) and rhG-CSF- (0.39 × 10⁹/L) treated monkeys, respectively. The PK parameters of F627 at 60 ug/kg including MRT, Cmax, Tmax, AUC and CL were comparable to that of pegfilgrastim-treated monkeys, despite the relative G-CSF molar dose in F-627-treated animals was 2.5x lower than the pegfilgrastim-treated animals. The results demonstrate that the G-CSF dimer generated a faster response in CY-treated monkeys compared to the G-CSF monomer-treated animals, suggesting that F-627 could benefit cancer patients with severe neutropenia after high-dose chemotherapy.