Linker Cleavage: Selective protease cleavage of the linker is essential for the accurate release of the cytotoxic payload, ensuring ADC stability during circulation and activation only at the target site.
Off-Target Cleavage: Off-target cleavage can result in premature ADC inactivation, reducing therapeutic efficacy and potentially causing side effects due to uncontrolled payload release.
Challenges: Empirically designed linker systems may not consistently ensure precise cleavage, and validating cleavage sites experimentally remains challenging due to the complexity of ADC or linker-payload synthesis and the limitations of in vitro assays.
Approach
Linker-protease binding pose prediction through conformation sampling and Uni-Mol Docking.
Enzyme cleavage site prediction based on first-principles calculation of site reactivity.
Result
Accruate prediction of linker cleavage site based on molecular orbital energy calculations, which differs from the empirically assumed site.
