IL28B, together with IL28A and IL29, represents a subset (type-III) of the interferon family. Their expression can be induced by viral infections in a variety of human cell types (Nat Immunol. 2003; 4(1):69-77. Nat Immunol. 2003; 4(1):63-68) and they can in turn bind and signal through a heterodimeric receptor complex composed of IL28R and IL10R2. The repertoire of genes induced by IL28B, IL28A and IL29 are essentially the same as that induced by interferon alpha. Amongst them are OAS1 and MX1, which bind and signal through a heterodimeric receptor complex composed of IFNAR1 and IFNAR2 (Gastroenterology. 2006; 131(6):1887-1898).
The antiviral activity induced by type-III interferon including IL28B, IL28A and IL29 has been demonstrated against encephalomyocarditis virus (EMCV), vesicular stomatitis virus (VSV), influenza (Eur J Immunol. 2004; 34(3):796-805. J Virol. 2006; 80(9):4501-4509.), hepatitis B virus (HBV) and hepatitis C virus (HCV) (J Virol. 2005; 79(6):3851-3854). However, the magnitude of antiviral response to type-III interferon is often smaller than that to interferon alpha in many cell types. A significant difference between type-III interferon and interferon alpha systems is the pattern of receptor distribution. While the receptors for interferon alpha are ubiquitously expressed, the IL28R component of the type-III interferon receptor is only present in a limited subset of cells, including hepatocytes (Cytokine 2005, 31, 109-118). Functional IL28R is notably absent from most hematopoietic cells (Hepatology. 2006; 44(4):896-906). Preclinical toxicology studies have shown that a PEGylated IL29 peptide, unlike PEGylated interferon alpha, does not induce inhibition of bone marrow stem cell colony formation or induce antiviral and anti-proliferative activities in peripheral blood leukocytes (Ann NY Acad Sci. 2009; 1182:80-87).
About 150 million people worldwide are chronically infected with hepatitis C virus (HCV), which is the leading cause of cirrhosis, hepatocellular carcinoma, and liver transplantation (WHO. Hepatitis C fact sheet No. 164). HCV is considered a curable disease in the majority of patients. Current topline treatment regimens consist of PEGylated interferon alpha in combination with small molecule antivirals such as ribavirin (Health Technology Assessment 2004; Vol. 8: No. 39.), telaprevir and boceprevir (Ther Adv Gastroenterol 2012; 5(2) 139-151). Unfortunately, treatment with PEGylated interferon alpha is not always well tolerated, resulting in poor patient compliance. Major toxicities related to PEGylated interferon alpha include but are not limited to flu-like symptoms such as headache, fatigue and asthenia; neuropsychiatric abnormalities such as depression, anxiety and irritability; and more importantly, hematological disorders such as neutropenia and anemia. About 350 million people worldwide are chronically infected with hepatitis B virus (HBV). Current treatments include PEGylated interferon alpha and small molecule antivirals such as lamivudine, adefovir, tenofovir, telbivudine, and entecavir. Treatment of HBV with PEGylated interferon alpha results in similar toxicity as those of HCV.