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Extended Activity in Cynomolgus Monkeys of a Granulocyte Colony-Stimulating Factor Mutein Conjugated With High Molecular Weight Polyethylene Glycol

^a Dept. of Internal Medicine, Wayne State School of Medicine, Detroit, Michigan, USA;
^b Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA;
^c Drug Metabolism and Pharmacokinetics;
^d Drug Discovery, Roche Research Center, F. Hoffmann-La Roche, Inc., Nutley, New Jersey, USA;
^e Dept. of Toxicology, Nippon Roche Research Center, Kamakura Japan;
^f Tokyo Research Laboratories;
^g Pharmaceutical Research & Development Division, Kyowa Hakko Kogyo Co. Ltd. Tokyo Japan

Key Words. G-CSF • Neutrophils • In vivo • Mutein • Monkeys • Pharmacokinetics

James F. Eliason, Ph.D., Karmanos Cancer Institute, HWCRC 724, 110 E. Warren Avenue, Detroit, Michigan 48201 USA. Telephone: 313-966-7858; Fax: 313-966-7558; e-mail: eliasonj{at}karmanos.org

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 were given 10 µg/kg, 30 µg/kg, or 100 µg/kg. For comparison, one group of monkeys was given 5 µg/kg of recombinant human G-CSF (rHuG-CSF) daily for six days. In monkeys given 100 µg/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 µg/kg, 6,140 ng•h/ml at 30 µg/kg to 27,900 ng•h/ml at 100 µg/kg. In a separate study, the effects of single doses of 100 µg/kg of PEG-NTG, rHuG-CSF, and unmodified NTG were compared. In this experiment, peak numbers of neutrophils were 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- 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 weight PEG results in a preparation that can induce prolonged elevation of neutrophils in normal nonhuman primates following a single injection.