Pegylated interferons Lambda-1a and alfa-2a display different gene induction and cytokine and chemokine release profiles in whole blood, human hepatocytes and peripheral blood mononuclear cells.
Pegylated interferon-lambda-1a (Lambda), a type III interferon (IFN) in clinical development for the treatment of chronic HCV infection, has shown comparable efficacy and an improved safety profile to a regimen based on pegylated IFN alfa-2a (alfa). To establish a mechanistic context for this improved profile, we investigated the ex vivo effects of Lambda and alfa on cytokine and chemokine release, and on expression of IFN-stimulated genes (ISGs) in primary human hepatocytes and peripheral blood mononuclear cells (PBMCs) from healthy subjects. Our findings were further compared with changes observed in blood analysed from HCV-infected patients treated with Lambda or alfa in clinical studies. mRNA transcript and protein expression of the IFN-λ-limiting receptor subunit was lower compared with IFN-α receptor subunits in all cell types. Upon stimulation, alfa and Lambda induced ISG expression in hepatocytes and PBMCs, although in PBMCs Lambda-induced ISG expression was modest. Furthermore, alfa and Lambda induced release of cytokines and chemokines from hepatocytes and PBMCs, although differences in their kinetics of induction were observed. In HCV-infected patients, alfa treatment induced ISG expression in whole blood after single and repeat dosing. Lambda treatment induced modest ISG expression after single dosing and showed no induction after repeat dosing. Alfa and Lambda treatment increased IP-10, iTAC, IL-6, MCP-1 and MIP-1β levels in serum, with alfa inducing higher levels of all mediators compared with Lambda. Overall, ex vivo and in vivo induction profiles reported in this analysis strongly correlate with clinical observations of fewer related adverse events for Lambda vs those typically associated with alfa.
Zymogenetics, Bristol Myers-Squibb, Seattle, WA, USA.
J
J
Freeman
S
S
Baglino
J
J
Friborg
Z
Z
Kraft
T
T
Gray
M
M
Hill
F
F
McPhee
J
J
Hillson
J C
JC
Lopez-Talavera
M
M
Wind-Rotolo
D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000187:drug effects* / Q000276:immunology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007378:Interleukins / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D000095022:Interferon Lambda
D000998:Antiviral Agents; D016207:Cytokines; D016898:Interferon-alpha; D007378:Interleukins; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; C000600496:peginterferon lambda-1a; D000095022:Interferon Lambda; C100416:peginterferon alfa-2a
EMERGE; HCV; interferon receptors; interferon-lambda; interferon-stimulated genes; side effects