Abstract
Abstract T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed mainly on T cell and NK cells. And because of its central role in limiting antitumor immune response and few immune-related adverse events with defect TIGIT, it has been an attractive target in cancer immunotherapy recently. Here we describe a humanized antibody against TIGIT by blocking its function and mediating ADCC to deplete TIGIT positive Treg cells. The antibody was derived from hybridoma of mice immunized with TIGIT-mFc. Comparing to TIGIT antibody in clinical (Tiragolumab), this antibody had higher affinity to 293T cells overexpressing human TIGIT (EC50=0.45nM vs 1.3nM) or cyno TIGIT (EC50=2.6nM vs 13nM), and also had higher binding affinity to activated CD8 T cell from PBMC (EC50=0.65nM vs 1.47nM), with lower Kd (0.9nM vs 1.8nM). This antibody also more efficiently blocked TIGIT binding to its ligand CD155 overexpressed on 293T cells with FACS assay than Tiragolumab (IC50=1nM vs. 1.4nM). In the cell-based reporter assay, the antibody had a lower IC50 than Tiragolumab (5nM vs. 21nM). When the primary CD8 T cell was co-cultured with 293T cells overexpressing CD155 and anti-CD3 scFv (OKT3) on the surface, the antibody increased the secretion of INF-γ along with an increase of antibody concentration. At last, this antibody-mediated depletion of TIGIT positive Treg from PBMC cultured in vitro with higher efficiency than Tiragolumab. In sum, the antibody described here was a better candidate drug targeting TIGIT for cancer immunotherapy Citation Format: Hui Zhao, Meng Zhang, Zhengcheng Guo, Cong Zhang, Shuliang Li, Guojin Wu. Therapeutical antibody against TIGIT disrupts inhibitory signaling and restores antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5300.
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