Valine-Alanine-Based Peptidomimetic Linker for Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) hold immense potential
for novel
linker modifications. However, the instability of current ADC peptide
linkers in long-term in vivo circulation can lead to premature toxin
release and safety concerns. This study explored novel peptidomimetic
ADCs, which linker were created by introducing a triazole group next
to its valine-alanine (–VA–) chain via click chemistry.
The highly active camptothecin molecule 11b developed
in our laboratory was selected as the payload for evaluation, subsequently
yielding the preferred ADC compounds Tras-TL1 and Tras-TS2 to verify the effectiveness of the linker. Notably,
Although the release rate of cathepsin B is lower than that of the
positive control, both compounds are effectively internalized into
lysosomes, releasing toxins and inducing cell cycle arrest, while
also exhibiting a significant bystander effect. Furthermore, Tras-TL1 and Tras-TS2 show tumor-suppressive
activity comparable to T-DXd in vivo. In conclusion, triazole peptidomimetic-based
ADCs offer various possibilities for future development.