Trans-cyclooctene-modified antigen (TCO-antigen)

Trans-cyclooctene-modified antigens are a class of synthetic therapeutic targets created by functionalizing proteins or polysaccharides with bioorthogonal chemical handles. This approach is the foundation of the Click Activated Protodrugs Against Cancer (CAPAC) platform, which utilizes the rapid and selective inverse electron-demand Diels-Alder (IEDDA) reaction to localize drug activation (Wu & Devaraj, 2018). In this system, a targeting agent—such as an antibody or a biopolymer—is first administered to populate the disease site with TCO handles. A tetrazine-modified prodrug is then introduced, which remains non-toxic until it reacts with the TCO-modified antigen to release its active payload (Shasqi, 2023). This decoupling of targeting and drug release allows for significantly higher local concentrations of chemotherapy while reducing systemic side effects (Rossin et al., 2010). The platform is highly adaptable, as the TCO handle can be attached to various antigens depending on the specific disease being treated (Mejia Oneto et al., 2016). Safety considerations include the potential immunogenicity of the synthetic handles and the need for efficient clearance of the targeting agent to prevent off-target click reactions in the blood.

Other names

TCO-bearing antigenClick-compatible antigenBioorthogonal targetTrans-cyclooctene-labeled biomoleculeTCO-modified proteinTCO-modified polysaccharideCAPAC target

The target functions via an inverse electron-demand Diels-Alder (IEDDA) reaction between a trans-cyclooctene (TCO) handle and a tetrazine-functionalized prodrug, resulting in the localized release of a cytotoxic or therapeutic payload.