Preclinical antibody-PET imaging of PD-L1

Abstract

Programmed cell death protein-1/ligand-1 (PD-1/PD-L1) blockade, including antibody therapeutics, has transformed cancer treatment. However, a major challenge in the field relates to selecting patients who are likely to respond to immune checkpoint inhibitors. Indeed, biopsy-based diagnostic tests to determine immune checkpoint protein levels do not accurately capture the inherent spatial and temporal heterogeneity of PD-L1 tumor expression. As a result, not all PD-L1-positive tumors respond to immunotherapies, and some patients with PD-L1-negative tumors have shown clinical benefits. In 2018, a first-in-human study of the clinically-approved anti-PD-L1 antibody Atezolizumab labeled with the positron emitter zirconium-89 validated the ability of positron emission tomography (PET) to visualize PD-L1 expression in vivo and predict tumor response to immunotherapy. These studies have triggered the expansion of PD-L1-targeted immunoPET to assess PD-L1 protein levels and PD-L1 expression heterogeneity in real time and across the whole tumor. First, this mini-review introduces new PD-L1 PET imaging studies of the last 4 years, focusing on the expansion of preclinical tumor models and anti-PD-L1 antibodies/antibody fragments in development. Then, the review discusses how these preclinical models and targeting agents can be utilized to study spatial and temporal heterogeneity of PD-L1 expression.

Navigating the landscape of PD-1/PD-L1 imaging tracers: from challenges to opportunities

“…However, IHC is known to be a poor reflection of PD-L1 dynamic expression levels in both tumor and healthy tissue ( 31 ). Non-invasive detection of PD-1 or PD-L1 status using imaging techniques could be complementary to IHC and both preclinical and clinical trials have demonstrated its utility ( 32 – 34 ).…”

“…Non-invasive PET imaging using suitable tracers to track and assess the dynamic expression of PD-L1 and PD-1 has the potential to bring us one step closer to finding a more desirable response predictor, and could enable us to optimize those currently in use ( 36 ). Extensive preclinical and clinical research has been dedicated toward mAb-based PD-1/PD-L1 binders, and since there are already a number approved for clinical use, they were the obvious choice for initial development of PD-1/PD-L1-targeting imaging tracers ( 32 ). Notwithstanding the promising results from a number of PET imaging studies using mAbs, some intrinsic properties make them less suited as imaging tracers to assess the dynamics of PD-1/PD-L1 expression ( 38 – 42 ).…”

“…This in turn can aid in the design of new tracers and optimization of those already in development. For a more extensive overview of preclinical and clinical imaging results of PD-1 and PD-L1 imaging tracers the reader is referred to the following reviews: ( 32 – 34 , 50 , 51 ). In this review, an overview is provided of current PET tracers of different molecular classes targeting the PD-1/PD-L1 axis.…”