Doing chemistry in tumours

Angew. Chem. Int. Ed. 49, 3375–3378 (2010)

Pre-targeting tumours with an antibody and subsequently binding a radiolabel probe to the tumour-bound antibody provides superior image contrast, but current pre-targeting systems that use biotin–streptavidin suffer from immune reactions. Now Marc Robillard and co-workers at the Philips Research High Tech Campus in the Netherlands have exploited the fast reaction kinetics and selectivity of a Diels–Alder reaction as a chemical pre-targeting approach to imaging tumour antigens in mice.

Robillard and colleagues attached trans-cyclooctene (an eight-membered-ring molecule) to an antibody that binds to the CC49 antigen found on many solid tumours. A second molecule (an electron-deficient ¹¹¹In-labelled tetrazine), when administered into the mice, reacts with the cyclooctene through the inverse-electron-demand Diels–Alder reaction to form a radiolabelled conjugate on the tumour-bound antibody. Computed tomography imaging showed pronounced localization of radioactivity in the tumour, with low uptake in blood and non-targeted tissues such as the liver. Besides the tumour, radioactivity was seen in the bladder and kidney, suggesting that the probe was eliminated through the urinary tract. Antibodies that did not have the cyclooctene accumulated in the tumour but showed low ¹¹¹In radioactivity, indicating that the cyclooctene-modified antigen is specific and tetrazine accumulated only in tissues containing the cycooctene-modified antibody.

This reaction can potentially be effective for imaging low concentrations of tumour antigens and for tracking other antibodies inside the body.