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 tumoural expression assessed by immunohistochemistry on biopsy tissue. However, depending on the 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 tumoural PD-L1 expression.MethodsPharmacokinetics (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 PET (μPET) imaging was used to analyse [89Zr]DFO-Anti-PDL1 distribution in both groups of mice. Non-compartmental (NCA) and compartmental (CA) PK analyses were performed in order to describe PK parameters and assess area under the concentration-time curve (AUC) for dosimetry evaluation in humans.ResultsOrgan distribution was correctly estimated using PK modelling in both healthy mice and mice with lung cancer. Tumoural uptake occurred within 24 h post-injection of [89Zr]DFO-Anti-PDL1, and the best imaging time was at 48 h according to the signal-to-noise ratio (SNR) 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.ConclusionThe predicted dosimetry was similar or lower than other antibodies radiolabelled with zirconium-89 for immunoPET imaging.
Highlights
Non-compartmental (NCA) and compartmental (CA) PK analyses were performed in order to describe PK parameters and assess area under the concentration-time curve (AUC) for dosimetry evaluation in humans
Tumoural uptake occurred within 24 h post-injection of [89Zr]DFO-Anti-PDL1, and the best imaging time was at 48 h according to the signal-to-noise ratio (SNR) and image quality
New classes of immunotherapy based on immune checkpoint inhibitors targeting programmed cell-death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) have been shown to be efficient in non-small cell lung cancer (NSCLC)
Summary
Lung cancer is the most common cause of death from cancer in the world with an estimated incidence of 2.09 million new cases and 1.76 million deaths in 2018 [1, 2]. In lung cancers, tumour cells can overexpress PD-L1, which binds to PD-1 on cytotoxic T cells (CTL). This interaction blocks the CTL effector signal, limiting immune response, and enabling tumoural growth and invasion. Immune checkpoint inhibitors of the PD-1/PD-L1 axis (nivolumab, pembrolizumab, or atezolizumab) represent a major advance in lung cancer treatment and have improved the overall survival of patients with NSCLC. Immunohistochemistry tests on tumoural biopsy tissue, such as SP142 for atezolizumab (antiPDL1) or 28-8 for nivolumab (anti-PD1), have been approved by health regulation authorities to determine PD-L1 expression prior to treatment to predict benefit for patients [14, 15]. Biopsy samples may present false negatives related to intra-tumoural heterogeneity of PD-L1 expression and heterogeneity between the primary and metastatic tumour sites [14, 18]
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