IL-2K35C-moFA, a Long-Acting Engineered Cytokine with Decreased Interleukin 2 Receptor α Binding, Improved the Cellular Selectivity Profile and Antitumor Efficacy in a Mouse Tumor Model

• Published in: Cancers 2022-09, Vol.14 (19), p.4742
• Main Authors: Wang, Xiaoze, Chen, Gang, Nie, Lei, Wu, Zhenhua, Wang, Xinzeng, Pan, Chenxiao, Chen, Xuchen, Zhao, Xiaobei, Zhu, Jie, He, Qiaojun, Wang, Haibin
• Format: Article
• Language: English
• Subjects: Affinity; Antitumor activity; Cancer; Cancer immunotherapy; Care and treatment; CD8 antigen; Cell growth; Cell receptors; Cytokines; Effector cells; Health aspects; Immunological memory; Immunotherapy; Interleukin 2; Interleukin 2 receptors; Laboratory animals; Lymphocytes T; Lysine; Memory cells; Proteins; Toxicity; Tumors
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14194742

Human interleukin 2 (IL-2) has shown impressive results as a therapeutic agent for cancer. However, IL-2-based cancer therapy is limited by strong Treg amplification owing to its high binding affinity to IL-2 receptor α (IL-2Rα) and its short half-life owing to its small molecular size. In this study, we solved these problems using a covalent modification strategy of the IL-2 variant, i.e., substituting cysteine (C) for lysine (K) at position 35, using octadecanedicarboxylic acid through maleimide chemistry, creating IL-2K35C-moFA. IL-2K35C-moFA was equipotent to human IL-2 wild type (IL-2WT) in activating tumor-killing CD8+ memory effector T cells (CD8+ T) and NK cells bearing the intermediate affinity IL-2 receptors, and less potent than IL-2WT on CTLL-2 cells bearing the high-affinity IL-2 receptors. Moreover, it was shown to support the preferential activation of IL-2 receptor β (IL-2Rβ) over IL-2Rα because of the mutation and fatty acid conjugation. In a B16F10 murine tumor model, IL-2K35C-moFA showed efficacy as a single dose and provided durable immunity for 1 week. Our results support the further evaluation of IL-2K35C-moFA as a novel cancer immunotherapy.