The target specific and controlled delivery of toxic payloads represents a central paradigm for antibody-drug conjugates (ADCs). The efficacy of the drug to impart cytotoxic activity has been shown to depend on its controlled release inside the cell to access cytoplasmic or nuclear targets. This has been efficiently achieved by incorporation of peptidic, cleavable linker sequences that are specifically recognized and cleaved by cathepsins in the endosome. However, the kinetics of release remain difficult to predict and control. Here, we show that the introduction of a coordination complex within the cleavage sequence allows us to directly tune the kinetics of enzymatic cleavage depending on the identity of the complexed metal ion. We demonstrate the metal-mediated control of enzyme activity in a peptide-based model system, wherein trivalent metals are incorporated via cyclen-based chelators (Figure 1). In addition, we can observe the in vitro cleavage kinetics of an antibody-conjugate system using a radiochemical approach. Solution-phase IR, Raman and NMR spectroscopies are employed to show that cleavage efficacy of the substrate closely correlates to coordinative structure. The metal-dependent, direct control of the local coordinative environment on substrate avidity opens possibilities to tune the half-life of drug cargo release.

Trivalent metal complex geometry of the substrate governs enzymatic cleavage rate

Macromolecular Chemistry: The Second Century

[Author Benefits](https://scimeetings.acs.org/?utm_source=pubs_content_marketing&utm_medium=website&utm_campaign=0320_MCF_NPI_Launch_Spring_Homepage&ref=pubs_content_marketing)

[How to use SciMeetings](https://storage.googleapis.com/dl.morressier.com/acs/SciMeetings-ACSSpring2020-HowToGuide_M3020-Final.pdf)

[Frequently Asked Questions](https://storage.googleapis.com/dl.morressier.com/acs/SciMtng_ACSNMSp2020_FAQ_M3120_Final.pdf)

ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.