Abstract 3118: IBI3026, a first-in-class anti-PD-1/IL-12 fusion protein, demonstrates the potential to be a new immuno-oncology therapy by releasing the break in immune response and strongly activating T and NK cells in the tumor microenvironment

Abstract Interleukin 12 (IL-12) is a cytokine that is able to activate both innate (NK cells) and adaptive (T cells) immunities, making it an ideal candidate for immuno-oncology therapy. Administration of IL-12 drugs locally has shown promising clinical results in treating tumors. However, when applying IL-12 systemically, severe dose-limiting toxicities are induced, greatly impeding the drug development process and its potential in cancer treatment. Herein, we designed IBI3026, an immune agonist that targets both IL-12 receptor and PD-1. By weakening the potency of IL-12, the safety profile of IBI3026 is extensively improved, guaranteeing the feasibility of systemic drug administration. By incorporating a high affinity, bivalent anti-PD-1 antibody, in addition to blocking PD-1/PD-L1 signaling pathway, IBI3026 could be efficiently enriched to PD-1+ T cells for maximal IL-12 activation in the tumor microenvironment. This “cis-activation” mode largely widened the therapeutic window of IL-12. In vitro, IBI3026 potently activates CD3/CD28-pretreated human PBMCs (hPBMCs) by showing strong STAT4 phosphorylation and high IFN-gamma secretion, while leaving untreated hPBMCs intact. In EMT6 (triple-negative breast cancer) and CT26 (colorectal cancer) cell line-derived xenograft (CDX) models, IBI3026 mouse surrogate strongly inhibited tumor growth with complete response in nearly all mice. In humanized A375 (melanoma) and BxPC-3 (pancreatic cancer) CDX models, IBI3026 showed much stronger tumor inhibitory effects than IBI308 (anti-PD-1 monoclonal antibody) and showed good safety profiles. In pilot toxicity studies, cynomolgus monkeys were administered 3 weekly doses of 10, 30, 80, and 150 mg/kg IBI3026 intravenously. No mortality or serious toxicities were observed in any group. The highest non-severely toxic dose (HNSTD) of IBI3026 is 150 mg/kg and the calculated therapeutic index is 63. These results demonstrate the good safety profile of IBI3026. In conclusion, IBI3026 is a first-in-class anti-PD-1/IL-12 immune agonist with high tumor inhibition potential and excellent safety profiles. Citation Format: Xinran Liu, Fenggen Fu, Shuaixiang Zhou, Weiwei Wu, Haoyu Wen, Yang Liu, Min Wu, Meng Ni, Yan Liu, Enhong Zhong, Yayao Yan, Ying Zhang, Zhihai Wu, Yuting Wei, Kaijie He. IBI3026, a first-in-class anti-PD-1/IL-12 fusion protein, demonstrates the potential to be a new immuno-oncology therapy by releasing the break in immune response and strongly activating T and NK cells in the tumor microenvironment [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 3118.