SHR-1916: A Novel PEGylated Interleukin-2 Analogue with Altered Cellular Selectivity and Improved Pharmacokinetic Profiles for Cancer Immunotherapy

作者：Xianglin Kong, Yuan Lin, Chao Ouyang, Hao Chen, Xiangdong Gao · 发表于：Drug Design Development and Therapy · 年份：2025 · DOI：10.2147/dddt.s493011 · 被引用次数：6 · 研究领域：Chemokine receptors and signaling、Immune cells in cancer、Virus-based gene therapy research

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 T reg 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 ...