Extended activity in cynomolgus monkeys of a granulocyte colony-stimulating factor mutein conjugated with high molecular weight polyethylene glycol

被引:12
作者
Eliason, JF
Greway, A
Tare, N
Inoue, T
Bowen, S
Dar, M
Yamasaki, M
Okabe, M
Horii, I
机构
[1] Karmanos Canc Inst, Detroit, MI 48201 USA
[2] Wayne State Univ, Sch Med, Dept Internal Med, Detroit, MI 48201 USA
[3] Hoffmann La Roche Inc, Drug Metab & Pharmacokinet, Nutley, NJ 07110 USA
[4] Hoffmann La Roche Inc, Drug Discovery, Roche Res Ctr, Nutley, NJ 07110 USA
[5] Nippon Roche Res Ctr, Dept Toxicol, Kamakura, Kanagawa 247, Japan
[6] Kyowa Hakko Kogyo Co Ltd, Tokyo Res Labs, Tokyo 194, Japan
[7] Kyowa Hakko Kogyo Co Ltd, Div Pharmaceut Res & Dev, Tokyo 194, Japan
关键词
G-CSF; neutrophils; in vivo; mutein; monkeys; pharmacokinetics;
D O I
10.1634/stemcells.18-1-40
中图分类号
Q813 [细胞工程];
学科分类号
摘要
The activity of a granulocyte colony-stimulating factor (G-CSF) mutein (nartograstim; [NTG]) conjugated with an average of two polyethylene glycol (PEG) chains per protein molecule was examined in cynomolgus monkeys following a single s.c. injection, Groups of monkeys mere given 10 mu g/kg, 30 mu g/kg, or 100 mu g/kg. For comparison, one group of monkeys was given 5 mu g/kg of recombinant human G-CSF (rHuG-CSF) daily for six days. In monkeys given 100 mu g/kg of PEG-NTG, neutrophil levels reached a peak one day after injection approximately 20-fold higher than baseline levels. Neutrophil numbers in these animals were still significantly elevated six days after injection, In contrast, peak neutrophil levels in monkeys given six injections of rHuG-CSF reached a peak only on day 6 and were approximately the same as that in monkeys given a single dose of PEG-NTG six days before, Pharmacokinetics of PEG-NTG in these monkeys indicated that the area under the plasma concentration time curve (AUC) increased with increasing the dose from 497 ng.h/ml at 10 mu g/kg, 6,140 ng.h/ml at 30 mu g/kg to 27,900 ng.h/ml at 100 mu g/kg. In a separate study, the effects of single doses of 100 mu g/kg of PEG-NTG, rHuG-CSF, and unmodified NTG were compared, In this experiment, peak numbers of neutrophils mere reached two days after injection in animals receiving PEG-NTG and one day after in animals given unmodified proteins, The pharmacokinetic parameters demonstrated increased exposure for PEG-NTG relative to the unmodified proteins with an AUC(0). (infinity) of 21,012 ng.h/ml compared with 5,492 ng.h/ml for rHuG-CSF and 5,153 ng.h/ml for NTG, These results demonstrate that conjugation of a G-CSF mutein with high molecular n eight PEG results in a preparation that can induce prolonged elevation of neutrophils in normal nonhuman primates following a single injection.
引用
收藏
页码:40 / 45
页数:6
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