Abstract 3426: Preclinical development of CD-001, a novel fusion protein combining PD-1 blockade with IL-21 for solid tumors

Background: Immune checkpoint blockade (ICB) has revolutionized cancer immunotherapy, offering significant clinical benefits. However, these successes are unfortunately limited to a minority of patients. Meanwhile, cytokine-based therapies have shown promise in cancer treatment, but are accompanied by potential severe systemic toxicity. CD-001 is a novel fusion protein integrating anti-PD-1 antibody with mutated IL-21. This dual-targeting approach enables simultaneous blockade of the PD-1/PD-L1 axis and targeted delivery of IL-21 to PD-1+ T cells, aiming to enhance tumor-specific immune responses while minimizing systemic adverse effects. Methods: Comprehensive nonclinical studies, including pharmacology, pharmacokinetics (PK), and toxicology assessments, were conducted to evaluate the safety and efficacy of CD-001. Pharmacology studies were performed to assess CD-001’s binding affinity to PD-1 and IL-21R as well as its functional targeting of PD-1+ T cells. In vivo efficacy was explored in various mouse tumor models including melanoma, lung cancer, and lymphoma. Toxicology and PK were also evaluated in cynomolgus monkeys. Results: CD-001 exhibited high affinity to both PD-1 and IL-21R, and effectively targeted PD-1+ T cells to exert its biological function. In vivo, CD-001 demonstrated superior antitumor activity compared to anti-PD-1 monotherapy or its combination with IL-21. Enhanced tumor-reactive CD8+ T cell responses were observed. PK studies showed dose-proportional systemic exposure of CD-001 with no significant accumulation after repeated dosing in cynomolgus monkeys, and receptor occupancy results illustrated more than 30% of target engagement within 7 days. GLP toxicity studies in cynomolgus monkeys demonstrated a favorable toxicity profile, with no significant cardiovascular or neurological dysfunctions observed. Immunotoxicity observed in the GLP study tended to resolve or was fully resolved by the end of the recovery period. Conclusion: CD-001 exhibits a well-characterized safety profile and potent antitumor activity in preclinical models, supporting its future development as a therapeutic candidate for advanced solid tumors. The dual mechanism of CD-001, combining PD-1 inhibition with targeted IL-21 delivery, represents a novel therapeutic strategy to enhance T cell-mediated immunity in cancer patients. Citation Format: Ying Li, Xiao Luan, Shaonan Zhou, Xiangrui Cheng, Jitao Zhao, Guoju Sang, Hao Shen, Naibo Yang, Junjie Yang, Jian Xu, Shengdian Wang. Preclinical development of CD-001, a novel fusion protein combining PD-1 blockade with IL-21 for solid tumors [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 3426.