Evaluating the dynamic expression of the immune checkpoint protein PD-L1 on both tumour and immune cells is crucial to understanding the efficacy of anti-PD-L1 checkpoint inhibitor immunotherapies. These therapies have shown dramatic improvements in disease control and survival when combined with standard chemo-radiotherapy treatment, yet the benefit is only observed in a subset of patients. Biopsy-based immunohistochemistry evaluation is not able to capture temporal changes or the heterogeneous nature of PD-L1 expression. Here we have used our novel chelator and linker chemistry to label the anti-human-PD-L1 antibody durvalumab with zirconium-89 enabling positron emission tomography (PET) imaging. The combination of therapeutic-grade antibody preparations and desferrioxamine B squaramide (DFOSq) linker chemistry resulted in highly pure antibody conjugates that demonstrated efficient radiolabelling with 89Zr.
In a pre-clinical model of human non-small cell lung cancer in immunocompromised mice, the 89Zr-DFOSq-durvalumab shows robust and specific uptake in PD-L1-positive HCC-827 xenografts compared with PD-L1-low/negative A549 xenografts. SUVmax was already >7.5 after 24 h, and increased further in the week after injection. In the absence of non-tumour sources of human PD-L1, there was minimal non-specific tissue accumulation with the initial signal in the blood pool and kidneys at 24 h declining over subsequent days with minor accumulation in spleen and bone by 144 h. This novel PD-L1 PET tracer is soon to enter clinical trials, where safety, radiation dosimetry and imaging characteristics will be further evaluated. The ability to visualise and quantify PD-L1 expression and distribution in patients with cancer before, during and after treatment will help to identify which patients may benefit most from anti-PD-L1 therapy and potential mechanisms of resistance.