Poudel Yam B, Chowdari Naidu S, Cheng Heng, Iwuagwu Christiana I, King H Dalton, Kotapati Srikanth, Passmore David, Rampulla Richard, Mathur Arvind, Vite Gregory, Gangwar Sanjeev
Bristol-Myers Squibb Research & Development, 700 Bay Road, Redwood City, California 94063, United States.
Bristol-Myers Squibb Research & Development, Princeton, New Jersey 08543, United States.
ACS Med Chem Lett. 2020 Sep 22;11(11):2190-2194. doi: 10.1021/acsmedchemlett.0c00325. eCollection 2020 Nov 12.
Stability of antibody-drug conjugates (ADCs) in mouse serum is one of the critical requirements for the evaluation of ADCs in mouse tumor models. Described herein is a strategy to address the mouse serum instability of uncialamycin linker-payloads through various chemical approaches that involve modification of different parts of the linker and payload. This effort ultimately led to the identification of a -amide -aminobenzyl carbamate (MA-PABC) group that resulted in linkers with dramatic improvement of mouse serum stability without affecting the desired proteolytic cleavage.
抗体药物偶联物（ADC）在小鼠血清中的稳定性是在小鼠肿瘤模型中评估ADC的关键要求之一。本文描述了一种通过各种化学方法解决uncialamycin连接子-载荷在小鼠血清中不稳定性的策略，这些方法涉及对连接子和载荷的不同部分进行修饰。这项工作最终导致鉴定出一种α-酰胺-α-氨基苄基氨基甲酸酯（MA-PABC）基团，该基团产生的连接子在不影响所需蛋白水解切割的情况下，小鼠血清稳定性有显著提高。
