"However, recombinant human G-CSF has shortened in vivo half life (t.sub.1/2 of about 1.3-4.2 h) and activity, and tends to be hydrolyzed by enzymes and cleared from the kidney, therefore needs to be injected many times, which is very inconvenient for the patient and may cause some undesired responses which will affect the efficacy.
"Recently, the development of polyethylene glycol (PEG) modification technique has provided an alternative for solving the above-mentioned technical problem.
"PEG is a nontoxic and dissolvable neutral polymer. It is biocompatible and hemocompatible, and has been approved by
"PEG is the polymer of ethylene glycol and ethylene oxide, also called carbowax, with the structure shown in the following formula: CH.sub.2(OH)--(CH.sub.2CH.sub.2O)n--CH.sub.2OH
"The appearance of conventional PEG changes as its molecular weight increases: it appears from colorless viscous liquid (190-630 Dalton), white paste (950-1050 Dalton) to white waxy or flaky solid (>1200 Dalton). Usually, PEG for modifying proteins or other drugs has a large molecular weight (Table 1), such as the U-shaped double-stranded PEG with a molecular weight of 40 KD employed in Pegasys (PEGylated interferon .alpha.2a injection, PEGASYS.RTM., Roche,
"TABLE-US-00001 TABLE 1 The parameters for basic physicochemical properties of currently marketed PEGylated protein drugs.sup. t.sub.1/2 before t.sub.1/2 after Product (Trade name) Average MW MW of PEG pegylation pegylation Manufacture Pegylated L-asparaginase (Oncaspar) 143 kDa 5 kDa 20 h 2 weeks Enzon Pegylated IFN.alpha.2b (PEGIntron) 31 kDa 12 kDa 4-12 h 40 h
"Proteinaceous drugs after polyethylene-glycolation (PEGylation) will have significantly improved properties, including prolonged pharmacokinetic half-life (Table 1), reduced immunogenicity, improved safety, increased efficacy, decreased frequency of administration, increased solubility, enhanced protease resistance, which facilitate the controlled release of the drugs. For example, as disclosed in U.S. Pat. No. 4,179,337, after the conjugation of PEG with enzymes and insulin, the immunogenicity of the proteins is reduced, while a certain percentage of the original activity of the proteins still remains. Another unique effect of pegylation is that the in vitro activity of the protein is decreased, but the in vivo activity is increased. For example, as disclosed in U.S. Pat. No. 4,179,337, after the conjugation of PEG with an enzyme or insulin, the immunogenicity of the protein is reduced, and the activity of the protein is significantly decreased, but the protein still retains a certain percentage of the original activity.
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