Preclinical and clinical development of pegylated interferon-lambda 1 in chronic hepatitis C
ABSTRACT 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.
- SourceAvailable from: Rune Hartmann
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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. "
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.The EMBO Journal 10/2013; DOI:10.1038/emboj.2013.232 · 10.75 Impact Factor
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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  . 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 . 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 . "
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)λ3, 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 IFNλ in the treatment and natural history of this disease is also discussed.Clinical and Developmental Immunology 08/2012; 2012:849373. DOI:10.1155/2012/849373 · 2.93 Impact Factor
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- "They also discuss the differential expression of IFN-lR1 and IL-10R2 by various cell types, and provide data that shows that primary human hepatocytes express significant levels of the IFN-lR1 and IL-10R2 genes. These findings compliment the review by Eleanor Ramos (2010) in which she discusses the preclinical rationale for the use of pegylated-recombinant hIFN-l1 as a novel therapeutic agent for the treatment of chronic HCV infection. She also discusses the results of the initial Phase-1 clinical studies of IFN-l1 in patients with chronic HCV infection. "
ABSTRACT: The discovery and initial description of the interferon-lambda (IFN-lambda) family in early 2003 opened an exciting new chapter in the field of IFN research. There are 3 IFN-lambda genes that encode 3 distinct but highly related proteins denoted IFN-lambda1, -lambda2, and -lambda3. These proteins are also known as interleukin-29 (IL-29), IL-28A, and IL-28B, respectively. Collectively, these 3 cytokines comprise the type III subset of IFNs. They are distinct from both type I and type II IFNs for a number of reasons, including the fact that they signal through a heterodimeric receptor complex that is different from the receptors used by type I or type II IFNs. Although type I IFNs (IFN-alpha/beta) and type III IFNs (IFN-lambda) signal via distinct receptor complexes, they activate the same intracellular signaling pathway and many of the same biological activities, including antiviral activity, in a wide variety of target cells. Consistent with their antiviral activity, expression of the IFN-lambda genes and their corresponding proteins is inducible by infection with many types of viruses. Therefore, expression of the type III IFNs (IFN-lambdas) and their primary biological activity are very similar to the type I IFNs. However, unlike IFN-alpha receptors which are broadly expressed on most cell types, including leukocytes, IFN-lambda receptors are largely restricted to cells of epithelial origin. The potential clinical importance of IFN-lambda as a novel antiviral therapeutic agent is already apparent. In addition, preclinical studies by several groups indicate that IFN-lambda may also be useful as a potential therapeutic agent for other clinical indications, including certain types of cancer.Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 08/2010; 30(8):555-64. DOI:10.1089/jir.2010.0078 · 3.90 Impact Factor