AUTHOR=Krache Anis , Fontan Charlotte , Pestourie Carine , Bardiès Manuel , Bouvet Yann , Payoux Pierre , Chatelut Etienne , White-Koning Melanie , Salabert Anne-Sophie 

TITLE=Preclinical Pharmacokinetics and Dosimetry of an 89Zr Labelled Anti-PDL1 in an Orthotopic Lung Cancer Murine Model

JOURNAL=Frontiers in Medicine

VOLUME=Volume 8 - 2021

YEAR=2022

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2021.741855

DOI=10.3389/fmed.2021.741855

ISSN=2296-858X

ABSTRACT=Anti-PDL1 is a monoclonal antibody targeting the programmed death-cell ligand (PD-L1) by blocking the programmed death-cell (PD-1)/PD-L1 axis. It restores the immune system response in several tumours such as Non-Small Cell Lung Cancer (NSCLC). Anti-PDL1 or anti-PD1 treatments rely on PD-L1 tumoral expression assessed by immunohistochemistry on biopsy tissue. However, depending on biopsy extraction site, PD-L1 expression can vary greatly. Non-invasive imaging enables whole-body mapping of PD-L1 sites and could improve the assessment of tumoral PD-L1 expression. Methods: Pharmacokinetics (PK), biodistribution and dosimetry of a murine anti-PDL1 radiolabelled with zirconium-89, were evaluated in both healthy mice and immunocompetent mice with lung cancer. Preclinical Positron Emission Tomography (µPET) imaging was used to analyse [89Zr]DFO-Anti-PDL1 distribution in both groups of mice. Non-compartmental and compartmental PK analyses were performed in order to describe PK parameters and assess area under the concentration-time curve (AUC) for dosimetry evaluation in human. Results: Organ distribution was correctly estimated using PK modelling in both healthy mice and mice with lung cancer. Tumoral uptake occurred within 24h post-injection of [89Zr]DFO-Anti-PDL1 and best imaging time was at 48h according to the signal-to-noise ratio and image quality. An in vivo blocking study confirmed that [89Zr]DFO-anti-PDL1 specifically targeted PD-L1 in CMT167 lung tumours in mice. AUC in organs was estimated using a 1-compartment PK model and extrapolated to human (using allometric scaling) in order to estimate the radiation exposure in human. Human estimated effective dose was 131 µSv/MBq. Conclusion: The predicted dosimetry was similar or lower than other antibodies radiolabelled with zirconium-89 for immunoPET imaging.