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 <b>11b</b> developed in our laboratory was selected as the payload for evaluation, subsequently yielding the preferred ADC compounds <b>Tras-TL1</b> and <b>Tras-TS2</b> 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, <b>Tras-TL1</b> and <b>Tras-TS2</b> show tumor-suppressive activity comparable to T-DXd in vivo. In conclusion, triazole peptidomimetic-based ADCs offer various possibilities for future development.