设计和合成靶向 TROP2 的新型位点特异性抗体-药物共轭物。

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Bioorganic & Medicinal Chemistry Pub Date : 2024-07-02 DOI:10.1016/j.bmc.2024.117828

Caili Luo , Anni Ren , Zixuan Jin , Jianxin Zhang , Wei Shi , Yue Zeng , Zhaojun Liu , Mengru Lu , Yajing Hou , Feng Tang , Wei Huang

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引用次数: 0

摘要

Trodelvy®的批准验证了TROP2是一种可用于治疗转移性三阴性乳腺癌（mTNBC）的抗体-药物共轭物（ADC）的靶点，但这一靶点具有挑战性。在此，我们以TROP2靶向抗体sacituzumab为基础，通过IgG糖工程或亲和导向的无踪共轭，设计并开发了几种采用MMAE（单甲基金丝桃素E）作为毒素的位点特异性ADC候选药物。研究人员对这些位点特异性 ADC 的均匀性、亲水性、稳定性和抗肿瘤效率进行了系统评估。结果表明，通过一步糖工程制成的位点特异性 ADC gsADC 3b 具有良好的聚集稳定性和体内疗效，为靶向 TROP2 的 ADC 提供了一种新的形式。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Design and synthesis of novel site-specific antibody-drug conjugates that target TROP2

The approval of Trodelvy® validates TROP2 as a druggable but challenging target for antibody-drug conjugates (ADCs) to treat metastatic triple-negative breast cancer (mTNBC). Here, based on the TROP2-targeted antibody sacituzumab, we designed and developed several site-specific ADC candidates, which employ MMAE (monomethyl auristatin E) as the toxin, via IgG glycoengineering or affinity-directed traceless conjugation. Systematic evaluation of these site-specific ADCs in homogeneity, hydrophilicity, stability, and antitumor efficiency was conducted. The results indicate that the site-specific ADCs gsADC 3b made from one-step glycoengineering exhibit good aggregation stability and in vivo efficacy, providing a new format of ADCs that target TROP2.

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.