Abstract 3427: HY07121, a new generation of immune oncology therapeutics overcoming tumor immune resistance

Abstract Objective: The majority of cancer patients develop resistance to immune checkpoint inhibitors (primary and acquired drug resistance), which may be related to immune cell exhaustion mediated by additional immune checkpoints and the immunosuppressive tumor microenvironment. Developing next-generation immunotherapy drugs to address tumor immune resistance is a pressing clinical need. Methods: We engineered and optimized a bispecific fusion protein, HY07121, by integrating PD-1 and TIGIT-targeted antibodies with IL-15/IL15Ra fusion cytokine. The molecule utilizes steric hindrance and tumor-specific targeting of PD-1 and TIGIT to minimize IL-15 exposure to peripheral tissues and balance toxicity with efficacy. Additionally, HY07121 synergistically enhances the intratumoral targeting of stem-like CD8+ T cells through PD-1 and IL-15 co-stimulation, inducing their expansion and differentiation. This replenishes tumor-killing effector T cells, thus overcoming immune exhaustion-induced resistance. The pharmacodynamic (PD), mechanistic, pharmacokinetic (PK), and toxicological profiles of HY07121 were evaluated through in vitro, in vivo, and cynomolgus monkey studies. Results: In vitro pharmacodynamic studies demonstrated that HY07121 significantly stimulated IFN-γ secretion from human PBMCs at levels superior to the combination treatment group, demonstrating a strong synergistic potential that went beyond additive effects. In vivo, HY07121 exhibited dose-dependent tumor inhibition in both the human bladder cancer cell derived xenograft model and the immune-resistant human melanoma cell (A375) derived xenograft model, significantly outperforming the combination of Pembrolizumab and Tiragolumab. Mechanistically, HY07121 markedly upregulated the transcription of stem-like CD8+ T cell and NKT-related gene sets. Cynomolgus monkey pharmacokinetic analysis revealed dose-dependent systemic exposure (Cmax and AUClast) in the 0.2 mg/kg, 0.6 mg/kg, and 1.8 mg/kg groups, indicating nonlinear pharmacokinetics. The half-life (T1/2) across different doses ranged from 6.25 to 13.7 hours, with an accumulation ratio of less than 1.17 after four consecutive doses. During the entire GLP toxicity study, all monkeys were in good condition, with no abnormal clinical findings, and all animals survived until the planned necropsy. The maximum tolerated dose (MTD) was determined to be 2.4 mg/kg, and the highest non-severe toxic dose (HNSTD) was 1.8 mg/kg, indicating a therapeutic safety window of approximately 10-fold. Conclusion: The in vitro and in vivo findings suggest that HY07121 is a novel, mechanism-driven therapeutic with the potential to enhance the efficacy of immunotherapy and address both primary and acquired resistance. The pharmacological and toxicological profiles strongly support the continued clinical development of HY07121. Citation Format: Xuan Zheng, Yan Chen, Guibin Dong, Yujing Zhang, Mengyun Zhang, Bo An, Chunxia Li, Jinxi Zhan, Xiaoqiang Chai, Jiangshan Dai, Ping Yang, Dan Sun, Ao Fu, Tao Wei. HY07121, a new generation of immune oncology therapeutics overcoming tumor immune resistance [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 3427.