trans-cyclooctene (TCO) (TCO)

The trans-cyclooctene (TCO) group is a synthetic, eight-membered carbocyclic ring with a strained double bond in the trans configuration, serving as a bioorthogonal chemical handle in pretargeted therapy and imaging (Rossin et al., 2010, Angew. Chem. Int. Ed.). In this approach, TCO is covalently attached to a monoclonal antibody that targets a specific tumor antigen, such as TAG-72 or CEA. Once the TCO-modified antibody has localized at the tumor and cleared from the blood, a small-molecule effector—typically a tetrazine-functionalized radiopharmaceutical or toxin—is administered. The tetrazine rapidly reacts with the TCO via an inverse electron-demand Diels-Alder (IEDDA) reaction, which is exceptionally fast and selective under physiological conditions (van Onzen et al., 2020, Molecules). This strategy allows for high-contrast imaging and potent therapeutic delivery while significantly reducing systemic exposure and off-target toxicity compared to traditional antibody conjugates. TCO-based pretargeting is currently being evaluated in clinical trials for the treatment of solid tumors, representing a significant advancement in the field of click chemistry-mediated medicine (Tagworks Pharmaceuticals, 2023).

Other names

TCOtrans-cyclooctene moietyBioorthogonal handleIEDDA dienophileStrained alkene handle

The mechanism of action involves a two-step pretargeting process utilizing the inverse electron-demand Diels-Alder (IEDDA) reaction. First, a monoclonal antibody modified with trans-cyclooctene (TCO) groups is administered and allowed to bind to its target antigen on tumor cells. After a period of clearance from the systemic circulation, a tetrazine-functionalized effector molecule (carrying a radiolabel or drug) is introduced. This effector undergoes a rapid, bioorthogonal [4+2] cycloaddition with the TCO moiety to form a stable dihydropyridazine linkage (Blackman et al., 2008, J. Am. Chem. Soc.). This reaction occurs with high specificity and kinetic rates that exceed most other bioorthogonal reactions, enabling efficient capture of the effector at the tumor site while minimizing off-target interactions.