Mild Method for Succinimide Hydrolysis on ADCs: Impact on ADC Potency, Stability, Exposure, and Efficacy

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• 作者：L. Nathan Tumey ; Manoj Charati ; Tao He ; Eric Sousa ; Dangshe Ma ; Xiaogang Han ; Tracey Clark ; Jeff Casavant ; Frank Loganzo ; Frank Barletta ; Judy Lucas ; Edmund I. Graziani
• 刊名：Bioconjugate Chemistry
• 出版年：2014
• 出版时间：October 15, 2014
• 年：2014
• 卷：25
• 期：10
• 页码：1871-1880
• 全文大小：515K
• ISSN：1520-4812

文摘

The stability of the connection between the antibody and the toxin can have a profound impact on ADC safety and efficacy. There has been increasing evidence in recent years that maleimide-based ADCs are prone to payload loss via a retro-Michael type reaction. Herein, we report a mild method for the hydrolysis of the succinimide-thioether ring which results in a 鈥渞ing-opened鈥?linker. ADCs containing this hydrolyzed succinimide linker show equivalent cytotoxicity, improved in vitro stability, improved PK exposure, and improved efficacy as compared to their nonhydrolyzed counterparts. This method offers a simple way to improve the stability, exposure, and efficacy of maleimide-based ADCs.