Interleukin 15 Pharmacokinetics and Consumption by a Dynamic Cytokine Sink

Area of Science:

• Immunology
• Pharmacology
• Oncology

Background:

• Interleukin-15 (IL-15) is vital for natural killer (NK) and CD8+ T memory cell proliferation and survival, making it a key target in immuno-oncology.
• Sustained IL-15 exposure above a threshold concentration is necessary for effective immune cell expansion.
• The short half-life (t_1/2) of native IL-15 prevents achieving therapeutic levels via single injection without significant toxicities (high C_max).

Purpose of the Study:

• To address the challenge of delivering IL-15 effectively for immuno-oncology applications.
• To develop IL-15 agonists that enable sustained therapeutic concentrations after single injections, mimicking continuous infusion.
• To overcome the limitations of existing IL-15 agonists with short systemic elimination half-lives.

Main Methods:

• Investigated half-life extension technologies for protein-based therapeutics.
• Analyzed systemic elimination half-lives of modified IL-15 agonists.
• Studied the dynamic increase in clearance of IL-15 agonists associated with target immune cell proliferation.

Main Results:

• Existing half-life extension technologies typically extend protein half-lives to weeks.
• However, reported IL-15 agonists exhibit short systemic elimination half-lives, often only hours to a day.
• This short half-life is attributed to increased clearance linked to target immune cell proliferation.

Conclusions:

• Continuous intravenous infusion is the most effective but impractical method for IL-15 delivery.
• There is a critical need for IL-15 agonists that offer the efficacy of continuous infusion with the convenience of infrequent single injections (weekly or longer).
• Current IL-15 agonists fail to maintain therapeutic levels due to accelerated clearance, highlighting the need for novel approaches.