Interleukin-18 (IL-18) engineered for half-life extension and resistance to IL-18 binding protein (IL-18BP) to enhance anti-cancer therapeutic potential

Abstract

Recombinant interleukin-18 (IL-18) holds promise as a therapeutic for oncology, as a robust activator of adaptive and innate immune cells and a potent producer of IFN-γ. However, clinical success has been limited due to rapid upregulation of the natural IL-18 inhibitor, IL-18 binding protein (IL-18BP), and fast systemic clearance of active IL-18, unbound to IL-18BP. To overcome these limitations, human IL-18 and mouse orthologs were engineered with resistance to IL-18BP and extended half-life by fusion to an Fc scaffold, with the goal of creating an improved IL-18-based therapeutic. IL-18 variants with a range of potencies showed no detectable binding to IL-18BP and retained full biological activity in the presence of super-physiological levels of IL-18BP. Pharmacokinetic studies comparing the mouse orthologs with a “naked” IL-18BP resistant tool IL-18 variant confirmed the importance of half-life extension. Importantly, the mouse Fc orthologs exhibited stronger and more durable T_H1 cytokine production and expansion of cytotoxic NK cells and effector CD8⁺ T cells when compared to the naked IL-18 variant. Remarkably, mouse engineered IL-18 variants administered once a week demonstrated strong tumor growth inhibition and improved survival compared to vehicle treated mice in multiple syngeneic tumor models. Human IL-18 variants dosed in humanized mice mirrored in vivo findings from mouse orthologs, displaying extended pharmacokinetics and durable upregulation of serum T_H1 cytokines. These promising preclinical results highlight engineered IL-18 solutions that resist IL-18BP binding and extend half-life, unlocking its full potential for sustained anti-cancer immune responses.