IL-2-mediated hepatotoxicity: knowledge gap identification based on the irAOP concept

Area of Science:

• Toxicology
• Immunology
• Pharmacology

Background:

• Drug-induced hepatotoxicity is a significant challenge in pharmaceutical development, often poorly predicted by preclinical models.
• Integrating immune system responses into safety assessments is crucial for identifying potential drug-induced liver injury.
• Current preclinical models often fail to accurately predict human hepatic damage from drugs.

Approach:

• The Immune Safety Avatar (imSAVAR) consortium utilizes the immune-related Adverse Outcome Pathway (irAOP) approach to understand and predict immune-mediated adverse events.
• A model irAOP for drug-induced hepatotoxicity was developed using recombinant human IL-2 (aldesleukin) due to extensive available data.
• This model aims to validate the predictive capacity of irAOPs by comparing predictions with clinical data for IL-2 therapy.

Key Points:

• Recombinant human IL-2 (aldesleukin), a cancer immunotherapeutic, can cause liver damage despite its therapeutic benefits.
• The study establishes a hepatotoxicity-based irAOP model for IL-2, leveraging comprehensive existing data.
• This model serves to validate the irAOP methodology for predicting immune-mediated liver injury.

Conclusions:

• The irAOP approach, exemplified by the IL-2 hepatotoxicity model, provides a novel framework for assessing drug-induced liver injury.
• This methodology is essential for improving the preclinical safety assessment of pharmaceuticals, particularly immunotherapies.
• The developed irAOP guideline will advance research into immune-mediated hepatotoxicity and enhance drug safety evaluations.