Abstract
Targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) interaction has become an established strategy for cancer immunotherapy. Although hundreds of small-molecule, peptide, and peptidomimetic inhibitors have been proposed in recent years, only a limited number of drug candidates show good PD-1/PD-L1 blocking activity in cell-based assays. In this article, we compare representative molecules from different classes in terms of their PD-1/PD-L1 dissociation capacity measured by HTRF and in vitro bioactivity determined by the immune checkpoint blockade (ICB) co-culture assay. We point to recent discoveries that underscore important differences in the mechanisms of action of these molecules and also indicate one principal feature that needs to be considered, which is the eventual human PD-L1 specificity.
Highlights
Multiple studies have shown a central role of immune checkpoint molecules (ICMs) in the immune evasion of cancer cells
We performed a comparison of the in vitro targeting of the PD-1/PD-L1 immune checkpoint with molecules selected from various classes, including small molecules, macrocyclic peptides, and monoclonal antibodies
Two standardized and popular techniques used in the available literature were applied: the protein-based Homogeneous Time-Resolved Fluorescence (HTRF) method and the cell-based Immune Checkpoint Blockade (ICB) assay
Summary
Multiple studies have shown a central role of immune checkpoint molecules (ICMs) in the immune evasion of cancer cells. The therapeutic potential of immune checkpoint blockade was first presented for the CTLA-4/CD80/86 immune checkpoint with ipilimumab (Yervoy), a firstin-class ICM-blocking antibody that was approved in 2011 for the treatment of late-stage melanoma [1]. Seven therapeutic antibodies targeting either PD-1 or PD-L1 have been approved by the FDA for the treatment of human cancers [2]. The list of approvals is constantly expanding towards more and more cancer types and therapeutic antibodies, which reflects the interest in PD-1/PD-L1 blockade and its prospects for clinical use (Cancer Research Institute, FDA Approval Timeline of Active Immunotherapies, www.cancerresearch.org, 3 October 2021). Considerable effort has been made in a search for small-molecule drug candidates, which often possess characteristics that can be considered alternative, if not superior, to antibodies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
