Abstract 4345: A multi-modal IL-2, SLC-3010, reprograms the tumor immune environment toward antitumor responses

Abstract Purpose CD122-biased IL-2 signaling has gained recognition as a refined immunomodulatory strategy for strengthening antitumor T cell responses. However, the modest clinical efficacy of CD122-focused IL-2 approaches, including CD122-biased variants, suggests that targeting CD122 alone does not fully leverage the complexity of endogenous IL-2. We developed SLC-3010, a noncovalent conjugate of human IL-2 and the anti-IL-2 antibody TCB2, designed to reinforce CD122-biased signaling and enable a dynamic interplay among TCB2, IL-2, and IL-2 receptors. This novel structure enables a triple action - CD122-biased IL-2 delivery, prevention of Treg-mediated negative feedback, and restimulation of T cells in conjunction with endogenous IL-2 - while maintaining activation of CD25+CD8 T cells. While the design and primary activity of SLC-3010 have been characterized before, the biological significance of free TCB2 generated through in vivo dissociation remains incompletely understood. In this study, we aimed to characterize the multifaceted features of SLC-3010 through a series of studies assessing its pharmacokinetic profile and other drug properties under various experimental settings. Methods Dynamic interplay between SLC-3010 and free TCB2 was evaluated by ELISA in mouse serum. STAT5 phosphorylation in fresh and activated PBMCs was assessed by flow cytometry. The immunologic role of free TCB2 and transcriptomic alterations in MP CD8 T cells were analyzed in hIL-2 TG and wt mice. Antitumor efficacy was then evaluated in MC38- and EO771-bearing mice of both strains. Results Free TCB2 persisted longer in vivo than SLC-3010 and bound endogenous IL-2, generating additional CD122-biased yet CD25-permissive signaling consistent with enhanced STAT5 phosphorylation in CD25+CD8 T cells. The dynamic interplay between free TCB2 and re-formed SLC-3010 further enhanced CD122-biased IL-2 signaling, leading to suppressed Treg expansion and a 3.65-fold increase in the tumor-infiltrating CD8/Treg ratio in hIL-2 TG mice. Free TCB2-driven signaling promoted a proliferative transcriptional program in MP CD8 T cells. SLC-3010 showed greater antitumor efficacy in hIL-2 TG mice than in wt mice in both MC38 and EO771 tumor models. Conclusions SLC-3010 functions through a unified triple-action mechanism that combines CD122-biased yet CD25-accessible IL-2 signaling to activate antitumor effector cells, while concurrently disrupting Treg homeostasis and re-amplifying immune stimulation through in vivo complexing between free TCB2 and endogenous IL-2. Citation Format: Junhyeok Heo, Daeun Kim, Geona Kim, Junyoung Lee, Sun Young Rha. A multi-modal IL-2, SLC-3010, reprograms the tumor immune environment toward antitumor responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4345.