Site-specific bioconjugation technologies are frequently employed to generate homogeneous antibody–drug conjugates (ADCs) and are generally considered superior to stochastic approaches like lysine coupling. However, most of the technologies developed so far require undesired manipulation of the antibody sequence or its glycan structures. Herein, we report the successful engineering of microbial transglutaminase enabling efficient, site-specific conjugation of drug-linker constructs to position HC-Q295 of native, fully glycosylated IgG-type antibodies. ADCs generated via this approach demonstrate excellent stability in vitro as well as strong efficacy in vitro and in vivo. As it employs different drug-linker structures and several native antibodies, our study additionally proves the broad applicability of this approach.

中文翻译：

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使用工程微生物转谷氨酰胺酶的天然抗体的位点特异性缀合。

特定于位点的生物缀合技术通常用于生成均质的抗体-药物缀合物（ADC），通常被认为优于诸如赖氨酸偶联之类的随机方法。但是，迄今为止开发的大多数技术都需要对抗体序列或其聚糖结构进行不良操作。在本文中，我们报告了微生物转谷氨酰胺酶的成功工程改造，该过程可实现药物连接器构建体的高效，位点特异性缀合，以定位天然的，完全糖基化的IgG型抗体的HC-Q295。通过这种方法生成的ADC具有出色的体外稳定性以及强大的体外和体内功效。由于它采用不同的药物接头结构和几种天然抗体，因此我们的研究进一步证明了该方法的广泛适用性。