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

4-1BB (CD137) is a potent costimulatory member of the tumor necrosis factor receptor superfamily (TNFRSF) expressed on activated T cells and natural killer cells. While 4-1BB agonism significantly enhances anti-tumor T cell activity, early clinical trials of monospecific agonists like urelumab were hindered by severe, dose-limiting hepatotoxicity caused by systemic Fc-gamma receptor-mediated clustering (Claus et al., 2019, Science Translational Medicine). To mitigate this, bispecific therapeutic strategies have been developed to provide conditional engagement, where 4-1BB activation is strictly dependent on the simultaneous binding of the molecule to Programmed cell death 1 ligand 1 (PD-L1). This mechanism ensures that 4-1BB clustering and subsequent T cell costimulation occur primarily within the tumor microenvironment where PD-L1 is highly expressed, thereby localizing the immune response and reducing systemic toxicity (Hinner et al., 2019, Clinical Cancer Research). Additionally, these bispecific agents simultaneously block the PD-1/PD-L1 inhibitory pathway, providing a dual-action approach to overcome tumor-induced immunosuppression. By combining checkpoint blockade with localized costimulation, these molecules aim to reinvigorate exhausted T cells more effectively than monotherapies. Several candidates, including acinatamab (GEN1046) and cinrebafusp alfa (PRS-343), are currently being evaluated in clinical trials for the treatment of various advanced solid tumors, demonstrating a manageable safety profile and evidence of clinical activity (Muik et al., 2022, Nature Communications; Genmab, 2023).

Other names

CD137/PD-L1TNFRSF9/CD2744-1BB-PD-L1 bispecificPD-L1-conditional 4-1BB agonist

Conditional agonism of 4-1BB (CD137) triggered by PD-L1-mediated clustering, combined with the blockade of the PD-1/PD-L1 inhibitory signaling axis.