Modulation of interferon-specific gene expression by albumin-interferon-α in interferon -α-experienced patients with chronic hepatitis C

Albumin-interferon-alpha (alb-IFN) is a novel recombinant protein derived from IFN-alpha2b genetically fused to human albumin. The resulting single polypeptide combines in one molecule the antiviral properties of IFN-alpha with the long serum half-life of albumin. IFN-mediated biological responses s...

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Bibliographic Details
Published in:	Antiviral therapy Vol. 11; no. 7; pp. 901 - 908
Main Authors:	BALAN, Vijayan, NELSON, David R, MANI SUBRAMANIAN, G, SULKOWSKI, Mark S, EVERSON, Gregory T, LAMBIASE, Louis R, WIESNER, Rusell H, DICKSON, Rolland C, GARCIO, Andy, MOORE, Paul A, REN YU
Format:	Journal Article
Language:	English
Published:	London International Medical Press 01-01-2006
Subjects:	2',5'-Oligoadenylate Synthetase - genetics 2',5'-Oligoadenylate Synthetase - metabolism Antibiotics. Antiinfectious agents. Antiparasitic agents Antigens - genetics Antigens - metabolism Antiviral agents Biological and medical sciences Cohort Studies Cytoskeletal Proteins - genetics Cytoskeletal Proteins - metabolism Female Gene Expression Regulation Hepacivirus Hepatitis C, Chronic - drug therapy Hepatitis C, Chronic - genetics Hepatitis C, Chronic - virology Human viral diseases Humans Infectious diseases Injections, Subcutaneous Interferon Regulatory Factor-7 - genetics Interferon Regulatory Factor-7 - metabolism Interferon-alpha - administration & dosage Interferon-alpha - therapeutic use Interferons Leukocytes, Mononuclear - immunology Leukocytes, Mononuclear - metabolism Male Medical sciences Membrane Proteins - genetics Membrane Proteins - metabolism Middle Aged Pharmacology. Drug treatments Recombinant Proteins Serum Albumin - administration & dosage Serum Albumin - therapeutic use Time Factors Treatment Outcome United States Viral diseases Viral hepatitis Viral Load Infection Human Alpha interferon Viral disease Cytokine Albumin Digestive diseases Hepatic disease Gene expression Viral hepatitis C
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Summary:	Albumin-interferon-alpha (alb-IFN) is a novel recombinant protein derived from IFN-alpha2b genetically fused to human albumin. The resulting single polypeptide combines in one molecule the antiviral properties of IFN-alpha with the long serum half-life of albumin. IFN-mediated biological responses stem from the engagement of IFN-alpha with its target receptor and subsequent modulation of IFN-specific gene (ISG) expression. To evaluate the pharmacodynamics of alb-IFN during the Phase I/II study conducted in patients with chronic hepatitis C (CHC) who had previously failed IFN-alpha-containing regimens, ISG induction was evaluated in peripheral blood and compared with antiviral response. Whole blood was obtained at day 0, day 7 and day 28 from 21 patients enrolled in the higher dose (500-900 microg) alb-IFN cohort, who received two injections on day 0 and day 14. Taqman real-time PCR was used to assess candidate ISG expression. There was sustained induction on day 7 and day 28 of the ISG's OAS1, IRF-7, IFI44 and IFI27. Although all patients showed a molecular response to alb-IFN, individual variability in pretreatment gene expression levels and fold of modulation during treatment was observed. At day 28, induction of OAS1, IFI44 and IRF7 showed pairwise correlation in individual patients (P < 0.05). Moreover, the induction of expression at day 28, and pretreatment levels of OAS1 and IFI44 correlated with hepatitis C virus RNA reduction at day 28 (P < 0.05). In conclusion, alb-IFN demonstrated robust induction of ISG that was consistent with the response associated with an IFN-alpha.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	1359-6535 2040-2058
DOI:	10.1177/135965350601100710