Safety, Tolerability, and Immunogenicity of Interferons

Area of Science:

• Immunology
• Cytokine Signaling
• Therapeutic Proteins

Background:

• Interferons (IFNs) are vital class II cytokines in innate immunity against viral infections.
• Type I, II, and III IFNs exist in humans, with recombinant type I IFNs (IFNα2, IFNβ1) used for viral hepatitis and multiple sclerosis.
• Type II IFN (IFN gamma) treats chronic granulomatous disease, and type III IFNs (IFN lambda) are evaluated for viral hepatitis.

Approach:

• This review examines the signaling pathways and therapeutic applications of different IFN types.
• It details the molecular mechanisms of IFN receptor binding, kinase activation (Jak1, Tyk2, Jak2), and STAT protein phosphorylation.
• The study analyzes the distribution of IFN receptors and their correlation with observed toxicities.

Key Points:

• Type I and II IFNs activate ubiquitous receptors, leading to broad cellular responses and potential toxicities like flu-like symptoms, cytopenias, and neuropsychiatric effects.
• IFNγ shares signaling pathways with type I IFNs, resulting in similar adverse events.
• Type III IFNs, with restricted receptor distribution, may offer a safer therapeutic profile with fewer side effects.
• Neutralizing antibodies (NABs) against recombinant IFNs can emerge, impacting treatment efficacy.

Conclusions:

• The widespread receptor distribution of type I and II IFNs contributes to their diverse toxicities.
• Type III IFNs present a potentially safer alternative due to targeted receptor expression.
• Understanding IFN signaling and receptor interactions is key to developing more effective and safer IFN-based therapies.