近日，美国麻省理工学院教授Jeremiah A. Johnson及其课题组提出了靶向癌症治疗的抗体-瓶刷前药偶联物。这一研究成果发表在2025年9月9日出版的国际学术期刊《自然—生物技术》上。

在这里，该课题组研究人员介绍了一种技术来克服这些限制，称为“抗体瓶前药偶联物”（ABCs）。ABC由IgG1单克隆抗体共价偶联到紧凑的二价瓶状前体药物的末端，该前体药物通过可切割的连接体和聚乙二醇分支结合有效载荷。这种设计能够合成具有可调平均药物-抗体比率的抗体，比传统ADCs高出两个数量级。小组通过合成超过10种不同的靶向HER2或MUC1主题药物的ABC来展示该技术的功能灵活性和制造效率，这些药物的效力跨越几个数量级，以及用于ABC可视化的显像剂和用于基于邻近度标记ABC相互作用组的光催化剂。与传统的HER2靶向ADCs相比，ABCs在肿瘤模型中表现出高靶向性、高细胞摄取和更高的疗效，这表明其有望用于临床转化。

据介绍，抗体-药物偶联物（ADCs）是一种有效的靶向治疗方法，但其结合低效有效载荷、不同的药物作用机制、不同的药物释放机制和可调的药物-抗体比率的能力有限。

附：英文原文

Title: Antibody–bottlebrush prodrug conjugates for targeted cancer therapy

Author: Liu, Bin, Nguyen, Hung V.-T., Jiang, Yivan, Wang, Aiden X., Lensch, Valerie, Sun, Zehao, Boyer, Zane H., Raftopoulos, Philip A., Dai, Yutong, MacNicol, Piper L., Wang, Yuyan, Jyotsana, Nidhi, Wang, Wencong, Bhagchandani, Sachin, Hemdev, Sanjana, Shieh, Peyton, Kristufek, Samantha L., Boucher, Magalie, Downes, Michael, Evans, Ronald M., MacMillan, David W. C., Johnson, Jeremiah A.

Issue&Volume: 2025-09-09

Abstract: Antibody–drug conjugates (ADCs) are effective targeted therapeutics but are limited in their ability to incorporate less-potent payloads, varied drug mechanisms of action, different drug release mechanisms and tunable drug-to-antibody ratios. Here we introduce a technology to overcome these limitations called ‘antibody–bottlebrush prodrug conjugates’ (ABCs). An ABC consists of an IgG1 monoclonal antibody covalently conjugated to the terminus of a compact bivalent bottlebrush prodrug that has payloads bound through cleavable linkers and polyethylene glycol branches. This design enables the synthesis of ABCs with tunable average drug-to-antibody ratios up to two orders of magnitude greater than those of traditional ADCs. We demonstrate the functional flexibility and manufacturing efficiency of this technology by synthesizing more than 10 different ABCs targeting either HER2 or MUC1 using drugs with potencies spanning several orders of magnitude as well as imaging agents for ABC visualization and photocatalysts for proximity-based labeling of the ABC interactome. ABCs display high target engagement, high cell uptake and improved efficacy in tumor models compared to conventional HER2-targeted ADCs, suggesting promise for clinical translation.

DOI: 10.1038/s41587-025-02772-z

Source: https://www.nature.com/articles/s41587-025-02772-z