Use of peginterferon alfa-2a (40 KD) (Pegasys®) for the treatment of hepatitis C

Reddy, K. Rajender; Modi, Marlene; Pedder, Simon

doi:10.1016/s0169-409x(02)00028-5

Cited by 223 publications

(58 citation statements)

References 34 publications

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“…This differs from results of earlier studies, which showed diminished cell counts in subjects with Kaposi's sarcoma (and presumably co-infected with HHV-8) during IFN-α therapy [49]–[51]. One of the major differences between this study and the earlier studies was the use of peglyated interferon alpha-2a Pegylated interferon-α has an increased half-life, providing a longer antiviral effect than the nonpegylated forms [52], [53]. Pegylated interferon alpha- 2a also has a more favorable safety profile than the previously available interferon-alpha formulations [54].…”

Section: Discussioncontrasting

confidence: 87%

Interferon-Alpha Administration Enhances CD8+ T Cell Activation in HIV Infection

et al. 2012

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BackgroundType I interferons play important roles in innate immune defense. In HIV infection, type I interferons may delay disease progression by inhibiting viral replication while at the same time accelerating disease progression by contributing to chronic immune activation.MethodsTo investigate the effects of type I interferons in HIV-infection, we obtained cryopreserved peripheral blood mononuclear cell samples from 10 subjects who participated in AIDS Clinical Trials Group Study 5192, a trial investigating the activity of systemic administration of IFNα for twelve weeks to patients with untreated HIV infection. Using flow cytometry, we examined changes in cell cycle status and expression of activation antigens by circulating T cells and their maturation subsets before, during and after IFNα treatment.ResultsThe proportion of CD38+HLA-DR+CD8+ T cells increased from a mean of 11.7% at baseline to 24.1% after twelve weeks of interferon treatment (p = 0.006). These frequencies dropped to an average of 20.1% six weeks after the end of treatment. In contrast to CD8+ T cells, the frequencies of activated CD4+ T cells did not change with administration of type I interferon (mean percentage of CD38+DR+ cells = 2.62% at baseline and 2.17% after 12 weeks of interferon therapy). As plasma HIV levels fell with interferon therapy, this was correlated with a “paradoxical” increase in CD8+ T cell activation (p<0.001).ConclusionAdministration of type I interferon increased expression of the activation markers CD38 and HLA DR on CD8+ T cells but not on CD4+ T cells of HIV+ persons. These observations suggest that type I interferons may contribute to the high levels of CD8+ T cell activation that occur during HIV infection.

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Section: Discussioncontrasting

confidence: 87%

Interferon-Alpha Administration Enhances CD8+ T Cell Activation in HIV Infection

et al. 2012

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“…The half-lives of IFN-α/Fc-WT and IFN-α/Fc-MD were 38.2 and 68.3 h, respectively. These proteins showed a superior potency compared to PEG-IFN-α, with a half-life of 20.2 h in our study, consistent with other studies [21, 22]. Thus, both IFN-α/Fc-WT and IFN-α/Fc-MD possess advantages over commercial PEG-IFN-α regarding half-life elongation.…”

Section: Discussionsupporting

confidence: 91%

Elimination of N-glycosylation by site mutation further prolongs the half-life of IFN-α/Fc fusion proteins expressed in Pichia pastoris

et al. 2016

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BackgroundInterferon (IFN)-α has been commonly used as an antiviral drug worldwide; however, its short half-life in circulation due to its low molecular weight and sensitivity to proteases impacts its efficacy and patient compliance.ResultsIn this study, we present an IgG1 Fc fusion strategy to improve the circulation half-life of IFN-α. Three different forms of IgG1 Fc fragments, including the wild type, aglycosylated homodimer and aglycosylated single chain, were each fused with IFN-α and designated as IFN-α/Fc-WT, IFN-α/Fc-MD, and IFN-α/Fc-SC, respectively. The recombinant proteins were expressed in Pichia pastoris and tested using antiviral and pharmacokinetic assays in comparison with the commercial pegylated-IFN-α (PEG-IFN-α). The in vitro study demonstrated that IFN-α/Fc-SC has the highest antiviral activity, while IFN-α/Fc-WT and IFN-α/Fc-MD exhibited antiviral activities comparable to that of PEG-IFN-α. The in vivo pharmacokinetic assay showed that both IFN-α/Fc-WT and IFN-α/Fc-MD have a longer half-life than PEG-IFN-α in SD rats, but IFN-α/Fc-SC has the shortest half-life among them. Importantly, the circulating half-life of 68.3 h for IFN-α/Fc-MD was significantly longer than those of 38.2 h for IFN-α/Fc-WT and 22.2 h for PEG-IFN-α.ConclusionsThe results demonstrate that the elimination of N-glycosylation by mutation of putative N-glycosylation site further prolongs the half-life of the IFN-α/Fc fusion protein and could present an alternative strategy for extending the half-life of low-molecular-weight proteins expressed by P. pastoris for in vivo studies as well as for future clinical applications.Electronic supplementary materialThe online version of this article (doi:10.1186/s12934-016-0601-9) contains supplementary material, which is available to authorized users.

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“…In addition, the direct antiviral effects of type I IFN will continue (4). These latter aspects may explain some of the benefits of IFN-␣ treatment of patients with viral hepatitis (54).…”

Section: Discussionmentioning

confidence: 98%

Timing of IFN-β Exposure during Human Dendritic Cell Maturation and Naive Th Cell Stimulation Has Contrasting Effects on Th1 Subset Generation: A Role for IFN-β-Mediated Regulation of IL-12 Family Cytokines and IL-18 in Naive Th Cell Differentiation

Nagai

Devergne

Mueller

et al. 2003

The Journal of Immunology

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Type I IFNs, IFN-α and IFN-β, are early effectors of innate immune responses against microbes that can also regulate subsequent adaptive immunity by promoting antimicrobial Th1-type responses. In contrast, the ability of IFN-β to inhibit autoimmune Th1 responses is thought to account for some of the beneficial effects of IFN-β therapy in the treatment of relapsing remitting multiple sclerosis. To understand the basis of the paradoxical effects of IFN-β on the expression of Th1-type immune responses, we developed an in vitro model of monocyte-derived dendritic cell (DC)-dependent, human naive Th cell differentiation, in which one can observe both positive and negative effects of IFN-β on the generation of Th1 cells. In this model we found that the timing of IFN-β exposure determines whether IFN-β will have a positive or a negative effect on naive Th cell differentiation into Th1 cells. Specifically, the presence of IFN-β during TNF-α-induced DC maturation strongly augments the capacity of DC to promote the generation of IFN-γ-secreting Th1 cells. In contrast, exposure to IFN-β during mature DC-mediated primary stimulation of naive Th cells has the opposite effect, in that it inhibits Th1 cell polarization and promotes the generation of an IL-10-secreting T cell subset. Studies with blocking mAbs and recombinant cytokines indicate that the mechanism by which IFN-β mediates these contrasting effects on Th1 cell generation is at least in part by differentially regulating DC expression of IL-12 family cytokines (IL-12 and/or IL-23, and IL-27) and IL-18.

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Use of peginterferon alfa-2a (40 KD) (Pegasys®) for the treatment of hepatitis C

Cited by 223 publications

References 34 publications

Interferon-Alpha Administration Enhances CD8+ T Cell Activation in HIV Infection

Interferon-Alpha Administration Enhances CD8+ T Cell Activation in HIV Infection

Elimination of N-glycosylation by site mutation further prolongs the half-life of IFN-α/Fc fusion proteins expressed in Pichia pastoris

Timing of IFN-β Exposure during Human Dendritic Cell Maturation and Naive Th Cell Stimulation Has Contrasting Effects on Th1 Subset Generation: A Role for IFN-β-Mediated Regulation of IL-12 Family Cytokines and IL-18 in Naive Th Cell Differentiation

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