De-coupling immune parameters and toxicity associated with IL-12 agonism

Area of Science:

• Immunology
• Pharmacology
• Toxicology

Background:

• Interleukin-12 (IL-12) is crucial for immune responses, stimulating natural killer (NK) and T cells to produce interferon gamma (IFN-γ).
• Clinical applications of IL-12 are limited by adverse events associated with NK cell activation.
• Developing IL-12 agonists with modified pharmacokinetics is essential for therapeutic advancement.

Purpose of the Study:

• To investigate the impact of half-life-extended IL-12 agonists, specifically full (IL-12Fc) and partial (IL-12 3x AlaFc) agonists, on the immune system.
• To compare the immunomodulatory and pathological effects of these distinct IL-12 agonists.
• To explore the potential of fine-tuned IL-12 agonism for enhancing host defense without inducing toxicity.

Main Methods:

• Treatment of naive mice with serially administered IL-12Fc and IL-12 3x AlaFc.
• Assessment of systemic IFN-γ production, multi-organ pathology, and alterations in myelopoiesis.
• Evaluation of immune cell activation (NK, CD4+, CD8+ T, NKT cells) and IFN-γ's role in toxicity and myelopoiesis.

Main Results:

• IL-12Fc induced systemic IFN-γ, multi-organ pathology, and myelopoiesis, activating NK, CD4+, CD8+ T, and NKT cells.
• IFN-γ was not required for IL-12Fc-induced systemic toxicity, though it facilitated myelopoiesis.
• IL-12 3x AlaFc activated CD4+ and CD8+ T cells, induced myelopoiesis, and importantly, avoided overt disease.
• Differential activities of IL-12 agonists were harnessed to enhance resistance to infection.

Conclusions:

• A threshold of IL-12 signaling is tolerated under steady-state conditions.
• Fine-tuning IL-12 agonism can enhance resistance to infection without triggering pathology.
• Partial IL-12 agonists offer a promising strategy for immune modulation with reduced adverse effects.