Ortho-functionalized pyridinyl-tetrazines break the inverse correlation between click reactivity and cleavage yields in click-to-release chemistry.

ABSTRACT: The bioorthogonal tetrazine-triggered cleavage of trans-cyclooctene(TCO)-linked payloads has strong potential for widespread use in drug delivery and in particular in click-cleavable antibody-drug conjugates (ADCs). However, clinical translation is hampered by an inverse correlation between click reactivity and payload release yield, requiring high doses of less reactive tetrazines to drive in vivo TCO reactions and payload release to completion. Herein we report that the cause for the low release when using the highly reactive bis-(2-pyridinyl)-tetrazine is the stability of the initially formed 4,5-dihydropyridazine product, precluding tautomerization to the releasing 1,4-dihydropyridazine tautomer. We demonstrate that efficient tautomerization and payload elimination can be achieved by o

SUBMITTER: Versteegen RM 

PROVIDER: S-EPMC11659415 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature