Abstract 3475: KGX103, a conditionally active prodrug of PD-1-targeting IL-15 induces antitumor activity by preferentially activating PD-1+ intratumoral T cells in cis

Abstract Interleukin-2 (IL-2) and IL-15 have both similar and contrasting functional roles in the proliferation and regulation of lymphocytes. They share the β/γ heterodimeric receptors while having distinct α-receptors. IL-15 is thought to be superior to IL-2 for the treatment of cancer in the aspects of lower vascular endothelium associated toxicity, much weaker Treg-stimulating activity and stronger expanding NK and CD8+ T cells abilities. However, the application of IL-15 in tumor immunotherapy remains challenging due to short half-life and severe adverse events caused by excessive and systemic immune activation. To address these challenges, we have developed KGX103, a PD-1-targeting non-α attenuated IL-15 prodrug fused with anti-HSA antibody. The IL-15 mutein is concealed by an inactivation domain linked with tumor-specific protease cleavable peptide, to prevent systemic immune activation. Once mask is cleaved in tumor microenvironment (TME), KGX103 could effectively stimulate intratumoral antigen-experienced CD8+ T cells with elevated PD-1 expression. With PD-1 targeting and tumor-specific activation, KGX103 could greatly potentiate tumor-specific T cell proliferation and function while ameliorating systemic immune activation. The pSTAT5 activation of either fresh or pre-activated peripheral blood mononuclear cells (PBMCs) were tested with KGX103 and unmasked KGX103. KGX103 showed almost no pSTAT5 activation signal in fresh PBMCs with low PD-1 expression and weak activation in pre-activated PBMCs with elevated PD-1 expression. Meanwhile, KGX103 showed significantly reduced potency of >3000-fold than the unmasked KGX103, which could be recovered after tumor-specific protease cleavage. Then we evaluated KGX103's in vivo antitumor efficacy in xenograft models using B-NDG β2m KO mice plus. Mice were subcutaneously implanted with a mixture of A375 tumor cells and hPBMCs. After grouping, mice were treated with vehicle or KGX103. Compared to the vehicle group, KGX103 demonstrated its antitumor efficacy and safety as evidenced by significant tumor growth inhibition while no obvious body weight change during the dosing period. The pilot toxic study to evaluate the safety and toxicokinetics of KGX103 is ongoing in Cynomolgus monkeys. Citation Format: Jiangfeng Fan, Zhiqiang Bai, Jing Wang, Shumin Yang, Yucheng Luo, Jie Huang, Hui Chen, Haixiang Wu, Yi Wu, Weidong Jiang. KGX103, a conditionally active prodrug of PD-1-targeting IL-15 induces antitumor activity by preferentially activating PD-1+ intratumoral T cells in cis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3475.