Programmed cell death 1 ligand 1 and Tumor necrosis factor receptor superfamily member 9 (PD-L1 and 4-1BB)

Programmed cell death 1 ligand 1 (PD-L1) and Tumor necrosis factor receptor superfamily member 9 (4-1BB) represent a synergistic dual-target approach in cancer immunotherapy. PD-L1 is a transmembrane protein often expressed by tumor cells to suppress T-cell activity by binding to the PD-1 receptor, while 4-1BB is a potent costimulatory receptor expressed on activated T cells and natural killer cells (UniProt: Q9NZQ7, Q07011). Bispecific antibodies targeting both molecules are designed to bridge tumor cells and immune cells, effectively blocking the inhibitory PD-1/PD-L1 axis while providing a localized stimulatory signal through 4-1BB (PMID: 35134135). This dual mechanism aims to overcome the immunosuppressive tumor microenvironment and enhance the expansion of tumor-reactive T cells. A key therapeutic advantage of this bispecific design is "conditional agonism," where 4-1BB activation occurs only upon binding to PD-L1 on the tumor surface, thereby reducing the systemic hepatotoxicity associated with traditional 4-1BB agonists (PMID: 31110075). Several candidates, such as Acinatamab and MCLA-145, are currently in clinical development for various solid tumors.

Other names

CD274 and CD137B7-H1 and TNFRSF9PD-L1 and CD137CD274 and TNFRSF9

Simultaneous blockade of the PD-1/PD-L1 inhibitory pathway and conditional agonism of the 4-1BB costimulatory pathway, triggered by PD-L1-mediated cross-linking.