Companion diagnostics are crucial for drug development and disease management with regard to patient selection, therapy planning and monitoring. Nanomedicines such as antibodies have been proven to be optimal disease-targeting agents because they generally exhibit superior target uptake and retention. However, to date, nuclear imaging of nanomedicines has been limited to the use of long-lived isotopes to be compatible with the slow pharmacokinetics of these large molecules. Major drawbacks are high radiation doses, precluding routine and repeated companion imaging procedures.
The Click-It consortium aimed to circumvent this issue by using pretargeting approach, which centers on the administration and target binding of a tagged nanomedicine followed by administration and binding of a small, fast-clearing, short-lived radiolabelled probe to the tag of the nanomedicine. This results in lower absorbed radiation doses and in a boost in target-blood ratios, which in turn leads to a superior imaging contrast. PET scan snapshots at multiple time-points provide long-term imaging information by applying short-lived nuclides. Before the project, only the fastest click reaction, the tetrazine ligation, had demonstrated potential in clinically relevant conditions.
This project aimed at expanding the scope of click-pretargeted imaging to intracellular targets, because a majority of nanomedicines internalize and is thus not accessible with the current approach. Furthermore, we wanted to expand our approach to short-lived, non-metal based, small molecule 18F-PET tracers, since PET offers a higher spatial and temporal resolution than SPECT enabling quantitative decision making in disease diagnosis and management. Finally, the project aimed to translate the developed click-pretargeting technology into a clinically applicable nanomedicine-based imaging approach.
The project has concluded with three promising leads that are now planned for translation into more advanced animal models. This was originally planned to take place during the project but was delayed due to COVID-19. It is still the consortium’s intention to deliver on this. Pretargeted probes have in animal studies been shown to outperform conventional monoclonal antibody based probes with respect to image contrast at early timepoints. Promising clearing agents have been discovered and further tests await to decide the optimal clearing agent for clinical translation.
The consortium has over the years built up knowledge and expertise. The project has resulted in expansion of the partners’ IP portfolios and resulted in new innovative project ideas, both for the partners to pursue individually and in collaboration.
