PET imaging of PD-L1 in a mouse model of lung cancer: zirconium-89 radiolabeling, pharmacokinetic modeling and dosimetry
Immunotherapy with anti PD-L1 monoclonal antibodies is an innovative cancer treatment, used in particular in non-small cell lung cancer (NSCLC). This antibody inhibits inhibitory checkpoints to restore the anti-tumour immune response by preventing the binding between PD-1/PD-L1. The administration of this treatment is conditional on the assessment of PD-L1 expression on tumour biopsies. However, the use of biopsies poses a problem in the completeness of the result obtained for this expression which will be linked to the site of extraction from a potentially heterogeneous tumour with respect to PD-L1. Moreover, as PD-L1 expression varies with time and exposure to treatment, the multiplication of invasive procedures such as biopsies for treatment follow-up is not ideal. It therefore seems necessary to look for biomarkers to better identify patients likely to respond to treatment, to follow the evolution of this therapy and thus to help prevent resistance. Radiolabelled antibodies are a rapidly developing tool that combines the targeting of an antibody with the sensitivity of positional emission tomography (PET) imaging. In this work, we radiolabelled an anti-PDL1 antibody with zirconium-89, a radioisotope whose physical half-life is compatible with the pharmacokinetics of monoclonal antibodies. We studied the biological properties of this radiolabelled antibody in vitro and in vivo in a syngeneic murine NSCLC model expressing PD-L1. In this mouse model, with and without treatment, we also studied the survival of the animals and the evolution of the tumour and its microenvironment using histological sections (TIM-3). With a radiochemical purity (CRP) of more than 95%, [89Zr]DFO-anti-PDL1 was correctly radiolabelled. The immunoreactivity (96%) showed that the antibody was not damaged by the radiolabelling procedure. This [89Zr]DFO-anti-PDL1 was injected into healthy mice and the NSCLC model. PET imaging was performed 24 h, 48 h, 72 h and 168 h after injection. A pharmacokinetic (PK) model was developed to describe the distribution of the tracer. It was used to estimate the different inter-compartmental transfer constants and a better imaging time at 125h. A blocking study verified the in vivo specificity of the radiotracer. Using modelling, the PK parameters of the organs were estimated and extrapolated in humans using allometric equations. This allowed us to calculate a dosimetry of 132 µSv/MBq. Treatment of NSCLC in the mouse model revealed an increase in TIM-3 over time highlighting its potential role in immunotherapy escape. The results obtained seem encouraging for the establishment of a method for the evaluation of PD-L1 expression by imaging in NSCLC using immunoPET. However, the dosimetry of 132 µSv/MBq remains a significant barrier to its use although the value found remains low compared to other zirconium-89 labelled antibodies.
Thesis defended on 21 february 2022