A Platform for the Generation of Site-Specific Antibody-Drug Conjugates That Allows for Selective Reduction of Engineered Cysteines.,Bioconjugate Chemistry

当前位置： X-MOL 学术 › Bioconjugate Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

A Platform for the Generation of Site-Specific Antibody-Drug Conjugates That Allows for Selective Reduction of Engineered Cysteines.
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-07-22 , DOI: 10.1021/acs.bioconjchem.0c00337
Ruud G E Coumans ₁ , Gerry J A Ariaans ₁ , Henri J Spijker ₁ , Pascal Renart Verkerk ₁ , Patrick H Beusker ₁ , Bas P A Kokke ₁ , Jan Schouten ₁ , Marion Blomenröhr ₁ , Miranda M C van der Lee ₁ , Patrick G Groothuis ₁ , Ruud Ubink ₁ , Wim H A Dokter ₁ , C Marco Timmers ₁

Affiliation

Engineering cysteines at specific sites in antibodies to create well-defined ADCs for the treatment of cancer is a promising approach to increase the therapeutic index and helps to streamline the manufacturing process. Here, we report the development of an in silico screening procedure to select for optimal sites in an antibody to which a hydrophobic linker–drug can be conjugated. Sites were identified inside the cavity that is naturally present in the Fab part of the antibody. Conjugating a linker–drug to these sites demonstrated the ability of the antibody to shield the hydrophobic character of the linker–drug while resulting ADCs maintained their cytotoxic potency in vitro. Comparison of site-specific ADCs versus randomly conjugated ADCs in an in vivo xenograft model revealed improved efficacy and exposure. We also report a selective reducing agent that is able to reduce the engineered cysteines while leaving the interchain disulfides in the oxidized state. This enables us to manufacture site-specific ADCs without introducing impurities associated with the conventional reduction/oxidation procedure for site-specific conjugation.

中文翻译：

用于产生特定位点的抗体-药物缀合物的平台，该平台允许选择性还原工程半胱氨酸。

在抗体的特定位点改造半胱氨酸以创建定义明确的ADC以治疗癌症是增加治疗指数并有助于简化制造过程的一种有前途的方法。在这里，我们报告了一种计算机筛选程序的发展，以选择可以与疏水性接头药物偶联的抗体中的最佳位点。在抗体的Fab部分中天然存在的腔内鉴定出位点。将接头药物与这些位点缀合证明了抗体具有屏蔽接头药物疏水特性的能力，而由此产生的ADC则在体外保持了其细胞毒性。体内特定部位ADC与随机偶联ADC的比较异种移植模型显示出改善的功效和暴露。我们还报告了一种选择性还原剂，该还原剂能够还原工程化的半胱氨酸，同时使链间二硫键保持氧化状态。这使我们能够制造出特定位置的ADC，而不会引入与传统还原/氧化过程相关的杂质来进行特定位置的共轭。

更新日期：2020-09-16

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11