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
Presenter: Yuan Liu, PhD Session: Redefining Targeted Therapy: Bispecific T-Cell Engagers and Antibody-Drug Conjugates 1 Time: 4/20/2026 9:00:00 AM → 4/20/2026 12:00:00 PM
Authors
Rui Zhang , Cheng Liu , Yuan Liu Affinity Biopharmaceutical Co., Ltd., Shanghai, China
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.
Disclosure
R. Zhang, Affinity Biopharmaceutical Co., Ltd. Employment, Stock. C. Liu, Affinity Biopharmaceutical Co., Ltd. Employment, Stock. Y. Liu, Affinity Biopharmaceutical Co., Ltd. Employment, Stock.
Cited in
Control: 254 · Presentation Id: 9639 · Meeting 21436