Interferon lambda (IFN-λ) belongs to type III interferons. It is one of the more recently discovered members of the interferon family – signaling proteins of the immune system that help the body fight viruses.
When a virus enters a cell, interferons trigger the innate immune response. They activate the JAK-STAT signaling pathway and induce the expression of a specific group of genes, known as interferon-stimulated genes (ISGs). These genes initiate defense mechanisms that prevent the virus from multiplying inside the cell.
Type I and type III interferons activate similar antiviral genes, but they act differently. Type I interferons trigger a faster and stronger antiviral response, but excessive IFN-I signaling can lead to excessive inflammation and immunopathology.
Unlike the ubiquitously expressed receptors for type I interferons, IFN-λ receptors are mainly found on epithelial cells, allowing type III interferons to be produced early in response to viral infection and to act locally on epithelial surfaces.
This limited expression of IFN-λ receptors reduces systemic side effects. While type I interferons have long been used for viral hepatitis, their use is often accompanied by flu-like symptoms and fatigue. Therefore, IFN-λ may be considered an alternative with fewer side effects.
Antiviral properties of IFN-λ: clinical trials
Hepatitis B
Hepatitis B virus (HBV) can persist in hepatocyte nuclei as covalently closed circular DNA (cccDNA), a form that current therapies do not fully eliminate. Long-term use of reverse transcriptase inhibitors is associated with the development of drug resistance and side effects affecting the bones and kidneys. All of this increases interest in new immunomodulatory treatment methods.
In the phase II LIRA-B study, pegylated PEG-IFN-λ was compared with PEG-IFN-α2a in patients with chronic HBV. During the first 24 weeks, IFN-λ reduced HBV DNA and HBsAg levels more rapidly, but overall treatment efficacy was higher in the PEG-IFN-α2a group.
In this study, a separate group of patients received entecavir, a reverse transcriptase inhibitor, for 12 weeks before PEG-IFN-λ therapy. This treatment enhanced the immune response: it increased natural killer cell activity and supported HBV-specific CD4+ and CD8+ T cells. These results suggest a potential role for IFN-λ in immune control of chronic HBV infection and in suppressing cccDNA activity.
Hepatitis C
In 1992, IFN-α was approved in the United States for the treatment of hepatitis C (HCV). Later, in 1998, ribavirin began to be used in combination with IFN-α – this combination more than doubled treatment efficacy compared with IFN-α alone.
In 2001, pegylated IFN-α was approved for the treatment of chronic HBV and HCV. PEG-IFN-α remained in the serum longer at higher concentrations, and the addition of ribavirin improved treatment efficacy.
Clinical studies have shown that PEG-IFN-λ can effectively suppress HCV with minimal side effects (fatigue, hematological changes). In early studies, PEG-IFN-λ was well tolerated at doses up to 5.0 mcg/kg and caused a dose-dependent reduction in HCV RNA levels, especially in combination with ribavirin.
A phase 2a study evaluated fixed doses of PEG-IFN-λ (80, 120, 180, or 240 mcg) plus ribavirin in patients with HCV and compared the results with PEG-IFN-α2a (180 mcg) plus ribavirin. At weeks 4 and 12, the proportion of patients with undetectable HCV RNA levels was comparable between the PEG-IFN-λ and PEG-IFN-α2a groups. In addition, this study identified an effective PEG-IFN-λ dose range of 120–240 mcg.
In phase 2 and 3 studies, PEG-IFN-λ in combination with ribavirin and a direct-acting antiviral drug produced a sustained virological response comparable to or higher than that seen with PEG-IFN-α treatment. At the same time, fewer side effects were reported.
Another study showed that PEG-IFN-λ in combination with ribavirin and telaprevir (a direct-acting antiviral drug) was less effective than PEG-IFN-α in achieving key treatment outcomes, including sustained virological response and biochemical remission. High efficacy of PEG-IFN-λ was also demonstrated in difficult patient groups, including people with HIV infection and hemophilia. Depending on the HCV genotype, the sustained virological response rate reached 72–95% in patients with HIV. In patients with hemophilia, PEG-IFN-λ achieved higher sustained virological response rates than PEG-IFN-α/ribavirin therapy.
Despite these encouraging results, further development of HCV treatment methods using PEG-IFN-λ was discontinued after the appearance of modern oral direct-acting antivirals with efficacy of up to 99%.
Hepatitis D
Hepatitis D (HDV) is the most aggressive form of viral hepatitis. HDV requires a prior HBV infection, which accelerates liver damage and increases the risk of cirrhosis and hepatocellular carcinoma. Standard IFN-α therapy has limited efficacy and is often followed by relapse after treatment.
At present, PEG-IFN-λ is being evaluated in clinical trials both as monotherapy and in combination with other drugs.
In the LIMT-1 study, PEG-IFN-λ therapy caused a dose-dependent reduction in HDV RNA levels: approximately 250-fold at a dose of 180 mcg and approximately 25-fold at 120 mcg. Side effects – flu-like symptoms and hyperbilirubinemia – were less pronounced than with PEG-IFN-α treatment. However, the LIMT-2 clinical study was suspended because of four cases of adverse effects leading to liver decompensation.
In the LIFT-1 study, the combination of PEG-IFN-λ with lonafarnib reduced HDV RNA levels below the detection threshold in 50% of patients, although 23% of participants later experienced relapse.
Hepatitis E
Chronic hepatitis E (HEV) infection poses a danger to transplant recipients receiving immunosuppressive therapy. Existing treatments, including ribavirin and PEG-IFN-α, are accompanied by severe side effects.
In a preclinical study in mice, PEG-IFN-λ demonstrated antiviral activity against chronic genotype 3 HEV infection for the first time. With PEG-IFN-λ treatment lasting more than 8 weeks at doses up to 0.3 mg/kg, no side effects were observed. However, further studies are needed to determine whether these results can be applied to patients.
COVID-19
Because of new SARS-CoV-2 variants and the limited availability of antiviral drugs, interferons are being considered as an alternative treatment for COVID-19. In vitro studies showed that type I and type III interferons effectively suppress coronavirus replication.
The results of PEG-IFN-λ clinical trials were mixed. In the COVID-LAMBDA study, a single dose of the drug did not reduce viral shedding or improve symptoms, whereas the ILIAD study showed accelerated viral clearance after a single 180 mcg injection of PEG-IFN-λ. Subsequent analysis showed that the strongest effect was observed with early use of PEG-IFN-λ and a high initial viral load.
A phase III clinical study showed a reduced risk of hospitalization for COVID-19 in mostly vaccinated patients after a single dose of PEG-IFN-λ, likely because of faster viral clearance and effects on the innate immune response at the epithelial surface. In addition, a double dose of the drug in hospitalized patients with mild COVID-19 contributed to a more pronounced reduction in viral load.
Use of IFN-λ in cancer, autoimmune diseases, and bacterial infections
Cancer
Interferons have long been studied as anti-cancer agents, but the need for high doses and pronounced side effects limits the use of IFN-α.
Studies have shown that IFN-λ has anti-cancer activity in various tumor types, including melanoma, lung cancer, breast cancer, prostate cancer, esophageal cancer, and liver cancer.
In an experimental hepatoma model, a combination of IFN-α and IFN-λ was more effective than IFN-α monotherapy and led to complete tumor regression.
Although IFN-λ may be considered an alternative treatment for tumors resistant to IFN-α, it may be more useful in combination with low-dose IFN-α rather than as monotherapy.
Autoimmune diseases
Patients with systemic lupus erythematosus and rheumatoid arthritis have elevated levels of IFN-α and IFN-λ, indicating a link between chronic excessive interferon signaling and the development of inflammation and autoimmune pathology.
At the same time, laboratory studies have shown that recombinant IFN-λ can reduce inflammation in mouse models of arthritis, colitis, and thromboinflammation by modulating neutrophil activity.
The effects of IFN-λ depend on the disease context and may be either pro-inflammatory or anti-inflammatory. Further studies are needed to assess the safety and therapeutic potential of PEG-IFN-λ in autoimmune diseases.
Bacterial infections
Studies in mice have shown that the role of IFN-λ in bacterial infections is mixed. In infections with P. aeruginosa, S. aureus, and K. pneumoniae, the absence of IFN-λ signaling was associated with reduced lung damage and more effective bacterial clearance. In S. aureus infection, IFNLR1 deficiency reduced neutrophil IL-1β release and lowered bacterial burden. In K. pneumoniae, IFN-λ disrupted epithelial barrier integrity and promoted bacterial spread from the airways. In addition, during B. pertussis infection, IFN-λ worsened lung damage without affecting bacterial burden.
Conclusion
IFN-λ activates the same antiviral mechanisms as type I interferons, but causes fewer side effects because of its limited receptor expression. The most promising results for PEG-IFN-λ have been demonstrated in COVID-19 and hepatitis D.
IFN-λ may also play an important role in protection against other viruses, including norovirus, West Nile virus, Zika virus, and influenza. In addition, evidence is emerging for a role of IFN-λ in bacterial and fungal infections, as well as its potential use in oncology and the treatment of autoimmune diseases.
Reference
Interferon Lambda: The Next Frontier in Antiviral Therapy?
