Preclinical and Clinical Development of Pegylated Interferon-Lambda 1 in Chronic Hepatitis C

ZymoGenetics, Inc., Seattle, Washington 98101, USA.
Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research (Impact Factor: 2). 08/2010; 30(8):591-5. DOI: 10.1089/jir.2010.0066
Source: PubMed


Current treatment of chronic hepatitis C consists of pegylated interferon-alpha (PEG-IFN-alpha) in combination with ribavirin. This regimen is associated with adverse effects that can limit its use. PEG-IFN-lambda 1 (pegIFNlambda) is a novel IFN that shares many of the biological effects of IFN-alpha but may have fewer side effects due to its more selective receptor distribution. Preclinical data show that pegIFNlambda has antiviral activity against hepatitis C virus (HCV) but does not inhibit myeloid colony formation. A phase 1 study in healthy volunteers demonstrated that pegIFNlambda is well tolerated. Elevated liver enzymes resulted in a dose-limiting toxicity after a single dose of 7.5 microg/kg, the highest dose tested. A phase 1b study in genotype 1 HCV patients who either relapsed after IFN-alpha therapy or naive to therapy was initiated. Interim data from the treatment relapse subset showed viral load reductions of 2.3 to 4.0 logs when pegIFNlambda was administered weekly as a single agent with or without ribavirin for up to 4 weeks. Drug-related side effects included elevation of liver enzymes. Decreases in hemoglobin were observed only in patients receiving ribavirin. Constitutional symptoms appeared lower than historical data for PEG-IFN-alpha. These results form the basis of further development of pegIFNlambda as a novel treatment for chronic hepatitis C.

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    • "Whereas the IFNL1, -L2 and -L3 genes were described in 2003 (Kotenko et al, 2003; Sheppard et al, 2003), the IFNL4 gene was described recently and the IFNL4 gene has been inactivated in large part of the human population by a frameshift mutation (Prokunina-Olsson et al, 2013). Phase 2 of clinical trials using pegylated IFNl1 against hepatitis C virus (HCV) infection has recently been completed (Ramos, 2010), and it has now entered the phase 3 trials. IFNls are interesting pharmaceuticals, as the rather specific expression pattern of the IFNlR1 receptor should reduce the adverse effects compared to the type I IFN treatment. "
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    ABSTRACT: The IFNL4 gene is a recently discovered type III interferon, which in a significant fraction of the human population harbours a frameshift mutation abolishing the IFNλ4 ORF. The expression of IFNλ4 is correlated with both poor spontaneous clearance of hepatitis C virus (HCV) and poor response to treatment with type I interferon. Here, we show that the IFNL4 gene encodes an active type III interferon, named IFNλ4, which signals through the IFNλR1 and IL-10R2 receptor chains. Recombinant IFNλ4 is antiviral against both HCV and coronaviruses at levels comparable to IFNλ3. However, the secretion of IFNλ4 is impaired compared to that of IFNλ3, and this impairment is not due to a weak signal peptide, which was previously believed. We found that IFNλ4 gets N-linked glycosylated and that this glycosylation is required for secretion. Nevertheless, this glycosylation is not required for activity. Together, these findings result in the paradox that IFNλ4 is strongly antiviral but a disadvantage during HCV infection.
    Full-text · Article · Oct 2013 · The EMBO Journal
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    • "The potential of IFN-λ as a therapeutic alternative to IFN-α is being explored with PEG-IFN-λ1, which shows an improved safety profile over PEG-IFN-α-2a in clinical studies [4], [33]. However, rates of some serious adverse events, including dose-limiting hepatotoxicity, are similar for patients treated with PEG-IFN-λ1 and PEG-IFN-α-2a, and even more frequent in patients treated with the highest dose of PEG-IFN-λ1 [34]. "
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    ABSTRACT: The type III interferons (IFNs), comprising IFN-λ1, IFN-λ2, and IFN-λ3, behave similarly to IFN-α in eliciting antiviral, antitumor, and immune-modulating activities. Due to their more restricted cellular targets, IFN-λs are attractive as potential alternatives to existing therapeutic regimens based on IFN-αs. We have applied the DOCK-AND-LOCK™ method to improve the anti-proliferative potency of IFN-λ1 up to 1,000-fold in targeted cancer cell lines by tethering stabilized Fab dimers, derived from hRS7 (humanized anti-Trop-2), hMN-15 (humanized anti-CEACAM6), hL243 (humanized anti-HLA-DR), and c225 (chimeric anti-EGFR), to IFN-λ1 site-specifically, resulting in novel immunocytokines designated (E1)-λ1, (15)-λ1, (C2)-λ1, and (c225)-λ1, respectively. Targeted delivery of IFN-λ1 via (15)-λ1 or (c225)-λ1 to respective antigen-expressing cells also significantly increased antiviral activity when compared with non-targeting (C2)-λ1, as demonstrated in human lung adenocarcinoma cell line A549 by (15)-λ1 against encephalomyocarditis virus (EC50 = 22.2 pM versus 223 pM), and in human hepatocarcinoma cell line Huh-7 by (c225)-λ1 against hepatitis C virus (EC50 = 0.56 pM versus 91.2 pM). These promising results, which are attributed to better localization and stronger binding of IFN-λ1 to antibody-targeted cells, together with the favorable pharmacokinetic profile of (E1)-λ1 in mice (T1/2 = 8.6 h), support further investigation of selective prototypes as potential antiviral and antitumor therapeutic agents.
    Preview · Article · May 2013 · PLoS ONE
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    • "The first use of IFNλ in clinical setting has started for hepatitis C: pegylated rHu IFNλ (PEG-IFNλ) has now been evaluated in two phase 1 clinical trials [28] [29]. The initial phase 1A study was designed to evaluate the safety, tolerability, pharmacokinetic, and pharmacodynamic activity of a single dose of PEG-IFNλ in healthy volunteers; a few participants developed reversible, dose-related increases in liver transaminases, but PEG-IFNλ did not induce fever, fatigue, or any overt haematological changes [28]. The phase 1B study has been conducted in patients with chronic genotype 1 HCV infection, mostly non responders to PEG-IFN/RBV therapy; PEG-IFNλ induced significant decreases in the levels of HCV, was well tolerated, and did not induce any significant haematological toxicities such as neutropenia, thrombocytopenia, or anemia [29]. "
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    ABSTRACT: Host genetic factors may predict the outcome and treatment response in hepatitis C virus (HCV) infection. Very recently, three landmark genome-wide association studies identified single nucleotide polymorphisms near the interleukin 28B (IL28B) region which were more frequent in responders to treatment. IL28B encodes interferon (IFN) λ 3, a type III IFN involved in host antiviral immunity. Favourable variants of the two most widely studied IL28B polymorphisms, rs12979860 and rs8099917, are strong pretreatment predictors of early viral clearance and sustained viral response in patients with genotype 1 HCV infection. Further investigations have implicated IL28B in the development of chronic HCV infection versus spontaneous resolution of acute infection and suggest that IL28B may be a key factor involved in host immunity against HCV. This paper presents an overview about the biological activity and clinical applications of IL28B, summarizing the available data on its impact on HCV infection. Moreover, the potential usefulness of IFN λ in the treatment and natural history of this disease is also discussed.
    Full-text · Article · Aug 2012 · Clinical and Developmental Immunology
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