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.