Abstract 7301: FP011, A tri-specific immune checkpoint inhibitor targeting PD-1 × TIGIT × PVRIG for cancer immunotherapy

Abstract Immune checkpoint inhibitors, such as anti-PD-1/PD-L1 antibodies, have rapidly changed the treatment paradigm for multiple tumor types. Unfortunately, many patients still remain unresponsive or acquire resistance after initial response to treatment. The complex network of immunosuppressive molecules and their upregulation after initial treatment may contribute to such resistance, and lead to terminal exhaustion and fixed loss of effector functions of T cells. Here, we developed FP011, a tri-specific antibody which can simultaneously block the inhibitory signals of PD-1, PVRIG and TIGIT on effector T cells, so as to better activate T cells to kill tumor cells. In vitro, by interacting with T cells in cis, FP011 can act on T cells with higher avidity, exerting synergistic blockade of these three immunosuppressive signals. In a tri-target reporter assay, both FP011 and the combination group induced much stronger luminescence signal than those induced by bi-specific antibodies and monoclonal antibodies. In an antigen-specific (CMV) T cell activation assay, in which T cells were induced to exhaustion after long-term stimulation with CMV antigens, FP011 also induced a more significant degree of T cell activation than what bi-specific antibodies, pembrolizumab and the combination of anti-PD-1, anti-PVRIG and anti-TIGIT monoclonal antibodies could do. In a PBMC-engrafted NOD-dKO-A375 mice model, FP011 inhibited tumor growth (93%, P < 0.0001) in a way significantly better than anti-PD-1 antibody (39.45%, P = 0.0627), the combination of anti-PD1, anti-PVRIG and anti-TIGIT antibodies (90% P < 0.0001), and another tri-specific positive control (66.18%, P = 0.0007). The inhibition of tumor growth was associated with an increase of tumor-infiltrating T cells following the FP011 treatment. In conclusion, these data provide insight into the efficacy of FP011, both in vitro and in vivo, which indicates that targeting three immune checkpoints simultaneously can synergistically enhance T cell activation to achieve a better tumor-killing effect. Citation Format: Yuanyuan Wang, Liang Xiao, Fan Wu, Baiguang Ren, Chang Zhou, Peipei Hu, Ke Chen, Xiaodong Wu, Di Lu, Yongting Huo. FP011, A tri-specific immune checkpoint inhibitor targeting PD-1 × TIGIT × PVRIG for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7301.