Abstract 593: Bispecific antibody against TIGIT and PVRIG enhances antitumor immunity

Abstract

Abstract T cell immunoreceptor with Ig and ITIM domains (TIGIT) and poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG) are two immune checkpoint receptors. They compete with CD226 for binding to CD155 or CD112 and suppress the activity of NK cells and T cells. Here we developed a bispecific antibody KA-1874 targeting TIGIT with an anti-PVRIG scFv fused to the C-terminus. KA-1874 is a fully human IgG4 with high binding affinity to TIGIT (KD=0.08nM) and PVRIG (KD=0.17nM). KA-1874 blocks both bindings of PVRIG-mFc to PVRL2 and TIGIT-mFc to CD155. In cell-based luciferase reporter assays, KA-1874 blocks PVRIG and TIGIT-mediated inhibitory signaling and enhances CD3 signaling with EC50 of 1.1nM and 1.4nM respectively, while COM701 against PVRIG and EOS488 against TIGIT both with EC50 above 2nM. In a CMV recall assay, PBMC increases INF-γ secretion when cultured with KA-1874, suggesting KA-1874 enhances primary T cell function. Immunodeficient mice humanized with PBMC are transplanted with A374 tumor cells. Co-injection of KA-1874 and pembrolizumab, which against PD-1, suppress established tumor growth. In comparison, KA-1874 or pembrolizumab alone fails to inhibit tumor growth. The above results indicate KA-1874 is an excellent candidate therapeutical antibody for cancer immunotherapy. Citation Format: Jiabei Liang, Xiao Gao, Cong Zhang, Hui Zhao, Hao Peng, Feng Hao, Jinying Ning, Guojin Wu. Bispecific antibody against TIGIT and PVRIG enhances antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 593.