Abstract 6070: A novel epitope specific TIM-3 antibody significantly enhanced anti-tumor activities with bispecific format, not with combination strategy

Abstract Introduction: T-cell immunoglobulin and mucin domain containing-3 (TIM-3) is expressed on T cells, NK cells and some myeloid cells, like macrophage and dendritic cells. Moreover, TIM-3 plays as a negative regulatory receptor and increased expression upon resistance to checkpoint inhibitor therapy. Particularly, recent studies strongly suggest that TIM-3 on myeloid cells, like dendritic cells, play a critical role for anti-tumor activity. Therefore, the dual blockade of PD-1 and TIM-3 holds hopes for enhanced clinical benefits. Results: we have designed a bispecific anti-PD-1/TIM-3 antibody to optimize the immune response and anti-tumor activities by utilizing a novel epitope-specific anti-human TIM-3 antibody which displays enhancing NK cell activity and improving antigen processing ability of antigen presenting cells (APC), like DCs. This PD-1/TIM-3 bispecific antibody has demonstrated high affinity binding to human TIM-3 and PD-1 in the low nanomolar range. Moreover, it simultaneously binds to TIM-3 and PD-1 receptors through a trans manner, suggesting its potent capacity to enhance the interaction between T-cells and dendritic cells (DCs). In both MLR (mixed lymphocyte reaction) and T cell stimulation assays, the PD-1/TIM-3 exhibits synergistic activity compared to combination of PD-1 mAb and TIM-3 monoclonal antibodies or mAb alone. In addition, we have demonstrated superior anti- tumor activities in PBMC humanized xenograft mouse model as well as syngeneic human PD-(L)1 and human TIM-3 knock-in mice. Conclusion: A bispecific humanized PD-1/TIM-3 antibody binds to both human PD-1 and TIM-3 strongly and effectively blocks the interaction with its ligand. This bispecific antibody enhances immune responses and anti-tumor activities in vitro and in vivo as measured by MLR assay, various animal models, etc., supporting the synergistic effects by targeting both acquired and innate immunity with this bispecific antibody. Citation Format: Xin Dong, Bu Tining, Bishnu Nayak, Jinyu Dong, Meiguang Xiong, Binbin Wang, Dong Wang, Haojie Wang, Yu Zhang. A novel epitope specific TIM-3 antibody significantly enhanced anti-tumor activities with bispecific format, not with combination strategy [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 6070.