RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
IL-2K35C-moFA，一种长效工程化细胞因子，具有降低的白细胞介素 2 受体α结合能力，在小鼠肿瘤模型中改善了细胞选择性特征和抗肿瘤疗效
英文原题：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.
查看英文原题
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.
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中文摘要
人白细胞介素2（IL-2）作为癌症治疗药物已显示出令人瞩目的效果。然而，基于IL-2的癌症治疗受到限制，原因在于其对IL-2受体α（IL-2Rα）的高结合亲和力导致强烈的Treg扩增，以及其小分子尺寸导致的短半衰期。
在本研究中，我们通过IL-2变体的共价修饰策略解决了这些问题，即利用马来酰亚胺化学将第35位赖氨酸（K）替换为半胱氨酸（C），并通过十八烷二羧酸进行修饰，从而创建了IL-2K35C-moFA。IL-2K35C-moFA在激活具有中等亲和力IL-2受体的肿瘤杀伤性CD8+记忆效应T细胞（CD8+T）和NK细胞方面与人IL-2野生型（IL-2WT）等效，而在具有高亲和力IL-2受体的CTLL-2细胞上其效力低于IL-2WT。
此外，由于突变和脂肪酸偶联，它显示出优先激活IL-2受体β（IL-2Rβ）而非IL-2Rα。在B16F10小鼠肿瘤模型中，IL-2K35C-moFA作为单次剂量显示出疗效，并提供了持续1周的持久免疫。
我们的结果支持进一步评估IL-2K35C-moFA作为一种新型癌症免疫疗法。
展开英文摘要原文
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.
论文信息
- 作者
- Wang X、Chen G、Nie L、Wu Z、Wang X、Pan C、Chen X、Zhao X
- 第一作者单位
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.China
- 通讯作者单位
- Zhejiang Bioray Biopharmaceutical Co., Ltd., Taizhou 318000, China.China
- 期刊
- Cancers2022 Sep 28
- 原文标识
- PubMed 36230665 · DOI 10.3390/cancers14194742
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