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SHR-1916:一种新型聚乙二醇化白介素-2 类似物,具有改变的细胞选择性和改善的药代动力学特性,用于癌症免疫治疗
Authors Kong X , Lin Y, Ouyang C, Chen H, Gao X
Received 21 October 2024
Accepted for publication 6 February 2025
Published 24 February 2025 Volume 2025:19 Pages 1251—1270
DOI https://doi.org/10.2147/DDDT.S493011
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Manfred Ogris
Xianglin Kong,1,2 Yuan Lin,2 Chao Ouyang,2 Hao Chen,2 Xiangdong Gao1
1Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China; 2Jiangsu Hengrui Pharmaceuticals Co., Ltd, Lianyungang, 222047, People’s Republic of China
Correspondence: Xiangdong Gao, Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China, Email xdgao@cpu.edu.cn
Purpose: Human interleukin-2 (IL-2) stimulates the differentiation and expansion of diverse immune cells dose-dependently. As an immunotherapy agent to treat metastatic cancers, IL-2 has been used in clinical practice and has demonstrated clear antitumor effects; however, its short half-life, the risk of capillary leak syndrome, and the unintended activation of immunosuppressive Treg cells hinder its clinical application. To address these challenges, a novel PEGylated interleukin-2 analogue, SHR-1916, was designed. Its cellular selectivity, efficacy, and improved pharmacokinetic profiles were investigated.
Methods: The binding affinities were characterized by surface plasmon resonance (SPR) in vitro. Subsequently, the stimulatory properties were investigated in a murine cell line (CTLL-2), a human cell line (M07e), and human peripheral blood mononuclear cells (PBMCs). To assess the anti-tumor efficacy, a CT-26 colon carcinoma syngeneic model in BALB/c mice and a A375 human melanoma xenograft model using PBMC humanized NCG mice were used in vivo. Moreover, the pharmacokinetic behavior following a single intravenous or subcutaneous dose was evaluated in Sprague-Dawley rats.
Results: SHR-1916 abolished binding to its receptor IL-2Rα, as evidenced by SPR assays, and exerted its activity mainly through binding to IL-2Rβγ, as confirmed by CTLL-2 and M07e cell proliferation assays. In contrast to IL-2, SHR-1916 exhibited a more biased activation of CD8+ T and NK cells compared to Treg cells and stimulated an increase in IFNγ secretion in PBMCs dose-dependently without triggering the release of other potential side effect-associated cytokines. In CT26 colon carcinoma and A375 melanoma models, SHR-1916 significantly reduced the tumor burden. Pharmacokinetic results showed that SHR-1916 had a significantly prolonged half-life in rats.
Conclusion: SHR-1916 exhibited excellent cellular selectivity, anti-tumor efficacies, and improved pharmacokinetics. It has the potential to serve as a novel immunotherapeutic agent designed to enhance IL-2’s immune-stimulating activities and promote its tolerability while reducing the immunoregulatory function of Treg cells.
Keywords: interleukin-2 mutein, long-acting, receptor-binding bias, antitumor effect