The Nobel-prize winning discovery that we can ‘release the brakes’ of our own immune system and use it to fight tumour cells heralded a breakthrough in cancer treatment. In a fully functioning immune system, the body’s own healthy cells are discerned from those that have become cancerous by a mechanism known as immune checkpoint. The presence of specific cell surface proteins, such as PD-L1, on healthy cells act as an ‘off switch’ for the body’s immune system. Some cancer cells hijack this system and overexpress PD-L1 in order to evade the body’s own cancer defence systems.

Durvalumab, a therapeutic antibody that blocks the PD-L1 immune checkpoint signalling pathway, has been revolutionary in treating cancer. To learn more about the role of PD-L1 and its dynamic changes in expression, we developed an imaging agent using our previously reported desferrioxamine squaramide (DFOSq) chelator^1,2,3 conjugated to durvalumab (Figure 1) and radiolabelled this with zirconium-89.

This seminar will present a chemist’s perspective of the development of this agent, from initial chemical synthesis through the long and winding path to clinical trial.

Figure 1 caption: (Left) Proposed structure of [⁸⁹Zr]ZrDFOSq-Durvalumab and (right) PET image of a patient imaged 5 days after administration with [⁸⁹Zr]ZrDFOSq-Durvalumab

References

¹Rudd, S. E., Roselt, P., Cullinane, C., et al., Chem. Commun., 2016, 52, 11889-11892
²Rudd, S. E, Van Zuylekom, J. K., Raicevic, A., et al., Chem Sci, 2021, 12, 9004-9016
³Rudd, S. E., Noor, A., Morgan, K. A. and Donnelly P. S., Acc. Chem. Res., 2024, 57, 1421-1433.

Dr Stacey Rudd is a Research Fellow at the University of Melbourne. She is a synthetic inorganic chemist with a particular interest in bioinorganic chemistry, radiochemistry and cell biology. Her research focus has been on the design and synthesis of metal-based pharmaceuticals, particularly radiopharmaceuticals for imaging and therapeutic applications.