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

Area of Science:

• Medicinal Chemistry
• Oncology
• Bioconjugation Chemistry

Background:

• Current antibody-drug conjugates (ADCs) face challenges with peptide linker instability, leading to premature payload release and safety issues.
• Novel linker strategies are crucial for enhancing ADC efficacy and therapeutic windows.

Purpose of the Study:

• To develop and evaluate novel peptidomimetic antibody-drug conjugates (ADCs) with enhanced linker stability.
• To assess the in vitro and in vivo efficacy of newly synthesized ADCs utilizing a triazole-modified valine-alanine linker.

Main Methods:

• Synthesized novel peptidomimetic linkers incorporating a triazole group via click chemistry.
• Conjugated camptothecin derivative 11b to trastuzumab to create ADC candidates Tras-TL1 and Tras-TS2.
• Evaluated ADC internalization, toxin release, cell cycle arrest, bystander effect, and in vivo tumor suppression.

Main Results:

• Tras-TL1 and Tras-TS2 showed effective lysosomal internalization and payload release, despite a lower cathepsin B release rate compared to controls.
• Both ADCs induced cell cycle arrest and exhibited a significant bystander effect.
• In vivo studies demonstrated tumor-suppressive activity comparable to T-DXd.

Conclusions:

• Triazole peptidomimetic linkers represent a promising strategy for developing more stable and effective antibody-drug conjugates.
• These novel ADCs offer potential for improved cancer therapy with enhanced safety profiles.