Abstract 5737: Preclinical study of a novel long-acting receptor-biased rhIL-2 drug with sustained activation of cytotoxic T cells

Abstract Purpose: Human Interlukin-2 (hIL-2) targets at malignant tumors, such as renal cell carcinoma and melanoma, and has been on the market for many years. Due to its adverse effects, hIL-2 is limited in clinical use. However, with in-depth studies on the mechanism of action of IL-2 related drugs, IL-2 has been found to have a high potential for use in immunotherapy of oncology, setting off the upsurge of developing improved innovative IL-2 related drugs at home and abroad. The joint application of these drugs and PD-1 in clinical trials for malignant tumors displays a better efficacy and huge market potential. A lot of drug companies have developed IL-2 related drugs and now they are conducting phase I and II clinical trials for metastatic solid tumors and other indications. All of these IL-2 related drugs are designed and developed by half-life extension methods such as molecular mutagenesis and PEGylation, while problems are also existed, for example, a weak-effect and severe side effects. Consequently, according to QbD drug design concept, we have combined molecular mutagenesis with PEGylation to design new molecules and screen out feasible drugs through in vitro and in vivo evaluation experiments, and devoted to developing a novel long-acting IL-2 drug of sustained activation of T cells, offering an alternative choice for current tumor immunotherapy. Method: Facing the defects of these products under development, we carried out molecule design and completed molecular screening of drug candidates through in vitro and in vivo evaluation experiments and pharmacological studies. After that, non-clinical studies were carried out and the comparison with analogous drugs in development was implemented in aspects of efficacy, safety and pharmacy. Result: ZHB114 was screened out as a drug candidate with a better efficacy and fewer side effects. According to the pharmacological studies, ZHB114 was capable of releasing drug activity in a controlled and sustained manner within a safe therapeutic window, thereby enhancing its safety profile. In a number of animal models bearing tumors, ZHB114 has been demonstrated to possess a significantly higher potency than analogous drugs under development. In some models, ZHB114 can elicit complete tumor growth inhibition. The repeated dosing toxicity studies conducted on rats and cynomolgus monkeys have shown that ZHB114 has a wide security window and minimal adverse effects at efficacious doses. It is noteworthy that ZHB114 has been approved by CDE in China, and now it is in the process of preparing for the approval of FDA. Conclusion: Compared with other analogous drugs in development, ZHB114 is more potent and is expected to become a novel long-acting IL-2 agent for tumor immunotherapy, with fewer side effects. Citation Format: Peipei Cao, Biaxue Zhao, Jun Wang, Chenyang Jiang, Yu Zhuang, Bruce Y. Ma. Preclinical study of a novel long-acting receptor-biased rhIL-2 drug with sustained activation of cytotoxic T cells [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 5737.