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自组装的抗体-寡核酸结合物用于有针对性的提供补充的反意义寡核酸

Liujuan Zhou¹, Jie Bi², Shenghai Chang^3,4

¹Assembly Medicine, LLC, Shanghai, 201203, China.

Angewandte Chemie (International ed. in English)

|September 26, 2024

概括

我们开发了一种模块化抗体-寡核酸合物 (MAOC),用于增强反感性寡核酸 (ASO) 的传递. 这种自组装的MAOC系统显著改善了ASO度和肌肉中的外离子跳转功效,没有观察到毒性.

科学领域:

生物结合化学的化学
橄核酸的治疗药物
分子输送系统是分子输送系统.

背景情况:

反感性寡核酸 (ASO) 具有治疗潜力,但在向的输送和细胞吸收方面面临挑战.
抗体-寡核酸合物 (AOCs) 改善了ASO的传递,但精确控制静脉测量和组装仍然很困难.

研究的目的:

开发一种模块化抗体-寡核酸合物 (MAOC) 方法,使抗体和ASO模块能够精确自组装.
评估MAOCs的疗效和安全性,以提供向转激素受体 (TfR1) 的外跳转ASO.

主要方法:

开发了一个模块化AOC (MAOC) 系统,使用L-DNA支架来精确地自组装抗体和ASO.
产生的同质多重体AOC具有受控的ASO-抗体比率.
使用抗TfR1单域抗体 (sdAb) 进行TfR1介导的内化,并增强ASOs的核输送.
在转基因人类TfR1小鼠模型中进行了体内功能分析.

主要成果:

与传统的ASO相比,MAOCs在心脏和骨肌肉中显示出显著更高的ASO度和外因子跳转疗效.
通过Cryo-EM识别了TfR1上的一种新型表位,与内源性连接体结合部位不同.
在体内,MAOC治疗耐受性良好,没有显示与毒性相关的发病率或死亡率.

结论:

自组装MAOC方法为准确和高效的ASO治疗提供了可行的策略.
MAOCs通过多种特定的向和改进的交付来增强ASO的治疗应用,扩大其治疗潜力.

关键词:

抗体-寡核酸结合物抗体-寡核酸结合物这是一个LDNA链接器.多重寡核酸的交付方式自动组装自动组装转移素受体转移素受体

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