Abstract 3423: A novel triple action of SLC-3010 strengthens anti-tumor immunity by <i>in vivo</i> free TCB2/endogenous IL-2 complexing

Abstract Background: CD122-biased signaling has arisen as a promising approach to enhance anti-tumor T cell responses. However, the limited efficacy of CD122-biased IL-2 in clinical trials suggests that a more delicate approach beyond CD8 activation is needed. The secretion of IL-2 by activated T cells following CD122-biased IL-2 eventually leads to the expansion of Tregs, which can dampen the strength of the anti-tumor immune responses. Based on prior studies that anti-mouse IL-2 antibody (S4B6) can suppress Treg survival by blocking mouse IL-2 in vivo but boost CD8 T cells when it is complex with mIL-2, we devised a strategy leveraging this mechanism. To this end, we developed SLC-3010, which is hIL-2 and an anti-hIL-2 antibody (TCB2) conjugate via antigen-antibody interaction. Since TCB2 binds with IL-2 through CD25-binding epitope on hIL-2, the SLC-3010 provides CD122-biased IL-2 signaling. Although the primary MoA, anti-tumor efficacy and crystal structure of SLC-3010 have been previously reported, the fate and therapeutic implications of the non-covalent conjugated drug are not fully understood. Methods: PK properties of SLC-3010 and TCB2 were assessed by ELISA after SLC-3010 administration. The role of free TCB2 in augmenting anti-tumor immune responses was investigated using flow cytometry. The therapeutic impact of free TCB2 was assessed by comparing the anti-tumor efficacy of SLC-3010 in tumor-bearing hIL-2 tg and wt mice. The anti-tumor efficacy of SLC-3010 and IL-2-CD25 fusion protein, which is unable to regulate endogenous IL-2 beyond primary CD122-biased signaling, was evaluated in hIL-2 tg mice. Results: Free TCB2 dissociated from SLC-3010 remains detectable in the bloodstream for an extended duration than SLC-3010. Circulating free TCB2 can bind with lately encountered hIL-2 and provide a CD122-biased signaling again. Tregs expansion and/or survival were significantly reduced in hIL-2 tg mice, leading to a 3.65-fold higher tumor infiltrating MP CD8/Treg ratio than in wt mice. The anti-tumor efficacy of SLC-3010 was more pronounced in hIL-2 tg mice compared to wt mice. SLC-3010 exhibited superior anti-tumor efficacy compared to IL-2-CD25 fusion protein in hIL-2 tg mice. Conclusions: SLC-3010 exhibits a "triple action" mechanism: SLC-3010 selectively stimulates anti-tumor immunity, disrupts Treg homeostasis, and re-boosts the immune system through in vivo complexing with endogenous IL-2. Currently, SLC-3010 is undergoing evaluation in an open-label, multi-center phase I/II clinical trial with dose escalation and expansion. SLC-3010 has been well-tolerated and has showed promising clinical activity, including confirmed partial response and sustained stable diseases with tumor shrinkage in patients with advanced solid tumors. (NCT05525247) Citation Format: Junhyeok Heo, 1 Daeun Kim, 1 Geona Kim, 1 Kyungmi Han, 1 Junyoung Lee, 1 Sun Young Rha2. A novel triple action of SLC-3010 strengthens anti-tumor immunity by in vivo free TCB2/endogenous IL-2 complexing [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 3423.