Abstract 2635: Novel tumor microenvironment (TME) activated interleukin-2 (IL-2) fused to anti-PD-1 or anti-PD-1/VEGF-A antibodies for enhanced anti-tumor immunity.

Abstract IL-2 is a potent immune-activating cytokine that amplifies T-cell responses critical for anti-tumor immunity, yet its clinical use is limited by toxicity. Previous research has focused on receptor-biased IL-2 variants to selectively engage specific IL-2R subunits such as binding only to the dimeric intermediate-affinity IL-2Rβγ rather than the high-affinity trimeric IL-2Rαβγ. IMD-101 is a novel TME-activated WT IL-2 molecule engineered through chemical conjugation with a legumain-cleavable mask entity, which enables full inhibition of IL-2 activity in circulation while restoring WT IL-2 function in the TME. In cynomolgus monkeys, IMD-101 exhibited no-observed-adverse-effect-level (NOAEL) of 2.4 mg/kg with single dose and NOAEL of 0.8 mg/kg with repeated dosing. In phase I dose escalation study, IMD-101 reached markedly reduced systemic toxicity. Based on this platform, two fusion antibodies, PD1-IL2 TMEAbody (IMD2032) and PD1-VEGF-IL2 TMEAbody (IMD2035), were further developed to match the clinical dose of PD-1 and PD1-VEGF. IMD2032 was conjugated with legumain-cleavable mask entity shielding both the PD-1 antibody and engineered IL-2 (IL-2 receptor abg agonist). IMD2035 was conjugated with legumain-cleavable mask entity blocking the engineered IL-2 (IL-2 receptor a biased agonist). In syngeneic tumor models using PD-1 humanized mice, IMD2032 showed greater tumor growth inhibition compared with the parental anti-PD-1 antibody. And under the same high-dose, once-daily regimen in PD-1 humanized mice, PD1-IL2 antibody induced strong blood lymphocyte elevation and caused 100% mortality by day 4 (after 4 doses), whereas IMD2032 showed no toxicity after 10 days with 10 doses. Similarly, for preclinical tumor models in PD-1/PD-L1/VEGF-A humanized mice, IMD2035 demonstrated superior anti-tumor efficacy relative to parental anti-PD-1/VEGF-A bispecific antibody. Preclinical toxicology studies in cynomolgus monkeys indicated that IMD2035 was well tolerated following repeated doses of 12 mg/kg, exceeding the clinical exposure levels of anti-PD1-VEGF antibodies. Collectively, these findings support the favorable safety profile and therapeutic efficacy of IMD-101, IMD-2032, and IMD-2035, highlighting their potential as next-generation immunotherapeutic candidates for clinical development. Citation Format: Rui Zhang, Cheng Liu, Yuan Liu, . Novel tumor microenvironment (TME) activated interleukin-2 (IL-2) fused to anti-PD-1 or anti-PD-1/VEGF-A antibodies for enhanced anti-tumor immunity [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 2635.