The Stone Guest: How Does pH Affect Binding Properties of PD‐1/PD‐L1 Inhibitors?. (10th November 2020)

• Record Type: Journal Article
• Authors: Riccio, Alessandra; Coletti, Alice; Dolciami, Daniela; Mammoli, Andrea; Cerra, Bruno; Moretti, Sonia; Gioiello, Antimo; Ferlin, Simone; Puxeddu, Efisio; Macchiarulo, Antonio
• Is Part Of: ChemMedChem. Volume 16:Number 3(2021)
• Page Start: 568
• Page End: 577
• Publication Date: 2020-11-10
• Subjects: Immunotherapy -- Checkpoint inhibitors -- Thermophoresis -- Molecular dynamics -- Cancer; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000760
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: The interaction between programmed cell death‐1 (PD‐1) and its ligand PD−L1 activates a coinhibitory signal that blocks T‐cell activation, promoting the immune escape process in the tumor microenvironment. Development of monoclonal antibodies targeting and inhibiting PD‐1/PD−L1 interaction as anticancer immunotherapies has proved successful in multiple clinical settings and for various types of cancer. Notwithstanding, limitations exist with the use of these biologics, including drug resistance and narrow therapeutic response rate in a majority of patients, that demand for the design of more efficacious small molecule‐based immunotherapies. Alteration of pH in the tumor microenvironment is a key factor that is involved in promoting drug resistance, tumor survival and progression. In this study, we have investigated the effect of pH shifts on binding properties of distinct classes of PD−L1 inhibitors, including macrocyclic peptide and small molecules. Results expand structure‐activity relationships of PD−L1 inhibitors, providing insights into structural features and physicochemical properties that are useful for the design of ligands that may escape a drug resistance mechanism associated to variable pH conditions of tumor microenvironment. Abstract : Enforcing target engagement : While inhibitors of the PD‐1/PD−L1 interaction are being developed as anticancer immunotherapies, alteration of pH in the tumor microenvironment is thought to promote drug resistance. In this study, we show that pH variation affects dissociation constants of PD−L1 inhibitors, influencing polar interactions. These results suggest that a decrease in pH may enforce target engagement of PD−L1 inhibitors bearing amine groups, thereby allowing them to escape acidosis as a tumor resistance mechanism.