N-Terminally PEGylated Human Interferon-β-1a with Improved Pharmacokinetic Properties and in Vivo Efficacy in a Melanoma Angiogenesis Model

• DOI: 10.1021/bc050237q
• Publication Date: 2006-01-18T05:21:07Z
• Authors: 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 Whitty; Alan Gill; Daniel J. Lindner; R. Blake Pepinsky
• Keywords: Aldehydes; 0303 health sciences; Neovascularization, Pathologic; Metabolic Clearance Rate; Melanoma, Experimental; Mice, Nude; Interferon-beta; Antiviral Agents; Cell Line; Polyethylene Glycols; Rats; 3. Good health; Mice; 03 medical and health sciences; Cell Line, Tumor; Animals; Humans; Female; Encephalomyocarditis virus; Interferon beta-1a; Neoplasm Transplantation; Cell Proliferation; Half-Life

PEGylation of IFN-α has been used successfully to improve the pharmacokinetic properties and efficacy drug. To prepare a PEGylated form human interferon-β-1a (IFN-β-1a) suitable for testing in vivo, we have synthesized 20 kDa mPEG-O-2-methylpropionaldehyde it modify N-terminal α-amino group cytokine. The protein retained ∼50% activity unmodified had significantly improved following intravenous administration rats. clearance volume distribution at steady state were reduced ∼30-fold ∼4-fold, respectively, resulting significant increase systemic exposure as determined by area under curve. elimination half-life was ∼13-fold greater than protein. proteins tested their ability inhibit formation radially oriented blood vessels entering periphery SK-MEL-1 melanoma tumors athymic nude homozygous (nu/nu) mice. In single dose comparison study, 1 × 106 units IFN-β-1a resulted 29% reduction vessel number, while 58% reduction. Both treatments statistically reductions mean number compared vehicle (control)-treated mice, with IFN-β-1a-treated mice showing multiple versus daily 9 days 51% 66% vehicle-treated Therefore, modified translated into efficacy. Since IFN-β is treatment sclerosis hepatitis C virus infection, such mPEG-O-2-methylpropionaldehyde-modified may serve useful adjunct these diseases. addition, antiangiogenic effects be harnessed certain cancers, either sole agent or combination other antitumor drugs.