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用高 afinity Siglec 配体对 NK 细胞进行一步的糖基工程,用于癌症免疫疗法

Shuai Hu¹, Ben Huang¹, Lingyan Wang¹

¹Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.

Advanced science (Weinheim, Baden-Wurttemberg, Germany)

|March 2, 2026

概括

研究人员设计了一种酶,以创建用于免疫治疗的新型酸衍生物. 这种方法增强了自然杀手 (NK) 细胞对癌细胞的向,提高了下一代免疫疗法的瘤杀伤能力.

科学领域:

生物化学生物化学
免疫学免疫学免疫学
合成生物学合成生物学

背景情况:

西格莱克是免疫细胞受体,结合酸 (Sia),是免疫治疗的关键标.
目前合成Sia衍生物的方法受到酶基质耐受性的限制,阻碍了治疗应用.

研究的目的:

为了设计一个CMP-酸合成酶 (CSS) 以提高与重的类同类的活性.
开发一个可扩展的合成平台,用于多种类型的sialoside类似物.
应用工程细胞用于向癌症免疫疗法.

主要方法:

在结构指导下,Neisseria meningitidis CMP-Sia合成酶 (NmCSS) 用于增强对硬质要求高的基质的活性.
一两酶 (OPTE) 合成使用工程NmCSS和一个sialyltransferase的sialoside类似物.
用量身定制的Siglec配体对自然杀手 (NK) -92MI细胞进行糖基工程.
在体外评估工程NK细胞细胞毒性对B细胞淋巴瘤和急性髓性白血病模型.

主要成果:

一种优化的NmCSS变体与重的Sia基质表现出增强的活性.
该OPTE系统使得可扩展合成具有选择性Siglec结合特征的多种sialoside类似物.
工程NK-92MI细胞对Siglec-2+和Siglec-3+癌症模型表现出强大的细胞毒性.
增强的NK细胞功能包括增加的花粉酶释放和细胞因子生产,并保持活力.

结论:

建立了一个模块化平台,用于修改的化的酶合成,并将其显示在治疗细胞上.
这种方法克服了合成和利用Sia类似物用于免疫治疗的局限性.
工程NK细胞显示了下一代免疫疗法的前景,以提高特异性和有效性准Sia-Siglec轴.

关键词:

CMP-酸合成酶的演化过程化学酶的糖基工程学计算建模计算建模高亲属性西格莱克配体的配体.免疫治疗用甘氨酸改造免疫治疗用甘氨酸改造

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