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Updated: Aug 12, 2025
11:02
Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction
Published on: September 14, 2018
7.8K
Peroxide-cleavable linkers for antibody-drug conjugates
Nicola Ashman1, Jonathan D Bargh1, Stephen J Walsh1,2
1Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK. spring@ch.cam.ac.uk.
Chemical Communications (Cambridge, England)
|February 1, 2023
Summary
New antibody-drug conjugates utilize peroxide-cleavable linkers to target cancer's reactive oxygen species (ROS). These linkers release drugs effectively in tumors while remaining stable in plasma, showing potent anti-cancer activity.
Area of Science:
- Bioconjugation Chemistry
- Cancer Therapeutics
- Drug Delivery Systems
Background:
- Cancer cells exhibit elevated levels of reactive oxygen species (ROS).
- Targeted drug delivery systems are crucial for enhancing cancer treatment efficacy.
- Antibody-drug conjugates (ADCs) offer a promising approach for targeted cancer therapy.
Purpose of the Study:
- To develop novel antibody-drug conjugates (ADCs) employing peroxide-cleavable arylboronic acid linkers.
- To leverage the high ROS environment within tumors for targeted drug release.
- To evaluate the stability and efficacy of these ADCs in preclinical cancer models.
Main Methods:
- Synthesis of antibody-drug conjugates featuring peroxide-cleavable arylboronic acid linkers.
- Assessment of linker stability in plasma conditions.
- Evaluation of payload release kinetics in the presence of hydrogen peroxide (H2O2).
- In vitro cytotoxicity assays using anti-HER2 and PD-L1 ADCs against relevant cancer cell lines.
Main Results:
- The developed arylboronic acid linkers demonstrated rapid payload release in the presence of hydrogen peroxide.
- Linkers exhibited excellent stability in plasma, minimizing off-target drug release.
- Anti-HER2 and PD-L1 peroxide-cleavable ADCs showed potent in vitro cytotoxicity against cancer cells.
Conclusions:
- Peroxide-cleavable arylboronic acid linkers represent a viable strategy for ROS-activated drug delivery in cancer.
- These novel ADCs demonstrate significant potential for targeted cancer therapy with improved safety profiles.
- Further investigation in vivo is warranted to confirm the therapeutic efficacy of these targeted drug delivery systems.
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