Tyrosine-Based Click Chemistry to Access Potent Anti-Cancer Antibody Conjugates

The work described in this thesis focuses on the development of targeted anti-cancer therapeutics based on monoclonal antibodies. Given the ongoing pursuit of safer and more effective cancer treatments, antibody-based therapeutics have garnered significant attention within the biopharmaceutical industry. In this thesis, we explored the generation of different classes of antibody conjugates for cancer therapy, utilizing strain-promoted oxidation-controlled ortho-quinone (SPOCQ) cycloaddition as a key bioconjugation strategy. Our modular chemoenzymatic approach provided access to DAR2 ADCs, dual-payload ADCs, and two formats of bispecific T cell-engagers. In the context of this thesis, we were primarily interested in generating antibody conjugates using off-the-shelf antibodies. This platform facilitated the installation of a chemical handle on the antibody, which was subsequently functionalized with appropriately labelled cytotoxic agents or proteins with complementary biological functions to yield site-specific antibody conjugates.