Tetrazine functional group on tumor-localized carrier (Tz-carrier)

The tetrazine functional group on a tumor-localized carrier is a synthetic target used in bioorthogonal pre-targeting therapies, most notably the Click Activated Protodrugs Against Cancer (CAPAC) platform (Shasqi, Inc.). This strategy involves a two-step process: first, a carrier molecule (such as a biopolymer or antibody) modified with tetrazine is administered to localize within the tumor microenvironment. Subsequently, a prodrug modified with a trans-cyclooctene (TCO) moiety is administered systemically. The tetrazine and TCO undergo a rapid and highly specific inverse electron-demand Diels-Alder (IEDDA) reaction, which triggers the release of the active drug directly at the site of the carrier (Wu et al., 2021, Chemical Science). This approach decouples the targeting and therapeutic phases, allowing for significantly higher drug doses at the tumor site while minimizing systemic toxicity (Mejia Oneto et al., 2016, ACS Central Science). It is currently being investigated in clinical trials (e.g., SQ3370) for the treatment of advanced solid tumors where traditional chemotherapy is limited by systemic side effects.

Other names

Tetrazine-modified biopolymerTetrazine-functionalized targeting agentBioorthogonal click chemistry targetTz-functionalized tumor-targeting agentSQL70

The tetrazine functional group acts as a bioorthogonal reactive site that captures trans-cyclooctene (TCO)-modified prodrugs via an inverse electron-demand Diels-Alder (IEDDA) reaction, which triggers the localized release of an active therapeutic agent at the tumor site (Wu et al., 2021, Chemical Science; Rossin et al., 2010, Angewandte Chemie).