Programmed cell death protein 1 (PD-1) dominant negative receptor (PD-1 DNR)

The Programmed cell death protein 1 (PD-1) dominant negative receptor (PD-1 DNR) is an engineered protein used in advanced cell therapies to overcome immune suppression in the tumor microenvironment (Cherkassky et al., 2016, J Clin Invest). Naturally, the PD-1 receptor (CD279) acts as an immune checkpoint that, when bound by its ligands PD-L1 or PD-L2, inhibits T-cell activation and promotes exhaustion (UniProt Q15116). The PD-1 DNR is designed to include the extracellular binding domain of PD-1 but lacks the intracellular immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM). When expressed on the surface of Chimeric Antigen Receptor (CAR) T-cells, this truncated receptor functions as a decoy, competitively binding to PD-L1 and preventing it from engaging with the functional, endogenous PD-1 receptors. This mechanism effectively shields the therapeutic T-cells from inhibitory signals, enhancing their persistence and anti-tumor activity, particularly in solid tumors where PD-L1 expression is high (Choi et al., 2022, Mol Ther). Clinical applications of this technology are currently being explored in various cancers, including gastric and pancreatic malignancies, often in combination with CARs targeting specific tumor antigens like Claudin 18.2 (e.g., CT041, NCT04404595).

Other names

dnPD-1Truncated PD-1PD-1ΔcytoPD-1 dominant negative receptor

Competitive inhibition of the PD-1/PD-L1 signaling axis by acting as a decoy receptor that lacks intracellular inhibitory signaling domains.