Modulation of interferon-specific gene expression by albumin-interferon-alpha in interferon-alpha-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 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.
Balan
Vijayan
V
Mayo Clinic, Phoenix, AZ, USA. Balan.Vijayan@mayo.edu
Nelson
David R
DR
Sulkowski
Mark S
MS
Everson
Gregory T
GT
Lambiase
Louis R
LR
Wiesner
Rusell H
RH
Dickson
Rolland C
RC
Garcia
Andy
A
Moore
Paul A
PA
Yu
Ren
R
Subramanian
G Mani
GM
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism; D000941:Antigens / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D016174:Hepacivirus; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000821:virology; D006801:Humans; D007279:Injections, Subcutaneous; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D007372:Interferons; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D011994:Recombinant Proteins; D012709:Serum Albumin / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D019562:Viral Load
D000941:Antigens; D003598:Cytoskeletal Proteins; C406887:IFI27 protein, human; C065888:IFI44 protein, human; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008565:Membrane Proteins; D011994:Recombinant Proteins; D012709:Serum Albumin; D007372:Interferons; C475085:OAS1 protein, human; D015088:2',5'-Oligoadenylate Synthetase