N-Terminally PEGylated Human Interferon--1a with Improved Pharmacokinetic Properties and in Vivo Efficacy in a Melano
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- 作者：Darren P. Baker ; Edward Y. Lin ; KoChung Lin ; Maria Pellegrini ; Russell C. Petter ; Ling Ling Chen ; Robert M. Arduini ; Margot Brickelmaier ; Dingyi Wen ; Donna M. Hess ; Liqing Chen ; Donna Grant ; Adrian W
- 刊名：Bioconjugate Chemistry
- 出版年：2006
- 出版时间：January 2006
- 年：2006
- 卷：17
- 期：1
- 页码：179 - 188
- 全文大小：174K
- 年卷期：v.17,no.1(January 2006)
- ISSN：1520-4812
文摘
PEGylation of IFN-
has been used successfully to improve the pharmacokinetic properties and efficacy of thedrug. To prepare a PEGylated form of human interferon-
-1a (IFN--1a) suitable for testing in vivo, we havesynthesized 20 kDa mPEG-O-2-methylpropionaldehyde and used it to modify the N-terminal -amino group ofthe cytokine. The PEGylated protein retained ~50% of the activity of the unmodified protein and had significantlyimproved pharmacokinetic properties following intravenous administration in rats. The clearance and volume ofdistribution at steady state were reduced ~30-fold and ~4-fold, respectively, resulting in a significant increase insystemic exposure as determined by the area under the curve. The elimination half-life of the PEGylated proteinwas ~13-fold greater than for the unmodified protein. The unmodified and PEGylated proteins were tested fortheir ability to inhibit the formation of radially oriented blood vessels entering the periphery of human SK-MEL-1 melanoma tumors in athymic nude homozygous (nu/nu) mice. In a single dose comparison study,administration of 1 × 106 units of unmodified IFN--1a resulted in a 29% reduction in vessel number, while 1× 106 units of PEGylated IFN--1a resulted in a 58% reduction. Both treatments resulted in statistically significantreductions in mean vessel number as compared to the vehicle (control)-treated mice, with the PEGylated IFN--1a-treated mice showing a statistically significantly greater reduction in mean vessel number as compared tothe unmodified IFN--1a-treated mice. In a multiple versus single dose comparison study, daily administration of1 × 106 units of unmodified IFN--1a for 9 days resulted in a 51% reduction in vessel number, while a singledose of 1 × 106 units of the PEGylated protein resulted in a 66% reduction. Both treatments resulted in statisticallysignificant reductions in mean vessel number as compared to the vehicle-treated mice, with the PEGylated IFN--1a-treated mice showing a statistically significantly greater reduction in mean vessel number as compared tothe unmodified IFN--1a-treated mice. Therefore, the improved pharmacokinetic properties of the modified proteintranslated into improved efficacy. Since unmodified IFN- is used for the treatment of multiple sclerosis andhepatitis C virus infection, a PEGylated form of the protein such as 20 kDa mPEG-O-2-methylpropionaldehyde-modified IFN--1a may serve as a useful adjunct for the treatment of these diseases. In addition, the antiangiogeniceffects of PEGylated IFN--1a may be harnessed for the treatment of certain cancers, either as a sole agent or incombination with other antitumor drugs.
has been used successfully to improve the pharmacokinetic properties and efficacy of thedrug. To prepare a PEGylated form of human interferon--1a (IFN--1a) suitable for testing in vivo, we havesynthesized 20 kDa mPEG-O-2-methylpropionaldehyde and used it to modify the N-terminal -amino group ofthe cytokine. The PEGylated protein retained ~50% of the activity of the unmodified protein and had significantlyimproved pharmacokinetic properties following intravenous administration in rats. The clearance and volume ofdistribution at steady state were reduced ~30-fold and ~4-fold, respectively, resulting in a significant increase insystemic exposure as determined by the area under the curve. The elimination half-life of the PEGylated proteinwas ~13-fold greater than for the unmodified protein. The unmodified and PEGylated proteins were tested fortheir ability to inhibit the formation of radially oriented blood vessels entering the periphery of human SK-MEL-1 melanoma tumors in athymic nude homozygous (nu/nu) mice. In a single dose comparison study,administration of 1 × 106 units of unmodified IFN--1a resulted in a 29% reduction in vessel number, while 1× 106 units of PEGylated IFN--1a resulted in a 58% reduction. Both treatments resulted in statistically significantreductions in mean vessel number as compared to the vehicle (control)-treated mice, with the PEGylated IFN--1a-treated mice showing a statistically significantly greater reduction in mean vessel number as compared tothe unmodified IFN--1a-treated mice. In a multiple versus single dose comparison study, daily administration of1 × 106 units of unmodified IFN--1a for 9 days resulted in a 51% reduction in vessel number, while a singledose of 1 × 106 units of the PEGylated protein resulted in a 66% reduction. Both treatments resulted in statisticallysignificant reductions in mean vessel number as compared to the vehicle-treated mice, with the PEGylated IFN--1a-treated mice showing a statistically significantly greater reduction in mean vessel number as compared tothe unmodified IFN--1a-treated mice. Therefore, the improved pharmacokinetic properties of the modified proteintranslated into improved efficacy. Since unmodified IFN- is used for the treatment of multiple sclerosis andhepatitis C virus infection, a PEGylated form of the protein such as 20 kDa mPEG-O-2-methylpropionaldehyde-modified IFN--1a may serve as a useful adjunct for the treatment of these diseases. In addition, the antiangiogeniceffects of PEGylated IFN--1a may be harnessed for the treatment of certain cancers, either as a sole agent or incombination with other antitumor drugs.