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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 m -amide p -aminobenzyl carbamate (MA-PABC) group that resulted in linkers with dramatic improvement of mouse serum stability without affecting the desired proteolytic cleavage.

Chemical Modification of Linkers Provides Stable Linker–Payloads for the Generation of Antibody–Drug Conjugates