Mg1131, A Novel Tigit-Targeting Monoclonal Antibody, Enhances Anti-Tumor Immune Responses By Modulating Nk And T Cell Activity

As the recent rise of immune checkpoint inhibitors has resulted in durable clinical outcomes in cancer patients, the need for a newer and more widely effective target for immunotherapy has been vigorously sought in the field; T cell immunoreceptor with Ig and ITIM domain (TIGIT) is an immune checkpoint molecule expressed on CD8+ T cells, CD4+ T cells, NK cells, and regulatory T cells (Treg). TIGIT induces exhaustion of effector T cells (Teff) and NK cells in the tumor microenvironment via engagement with its ligand PVR (CD155) which is dominantly expressed on malignant tumor cells. After initial screening processes from a synthetic library, MG1131 clone was chosen based on the strongest binding affinity to human TIGIT and the superior PVR-blocking activity. MG1131 was cross-reactive with the cynomolgus monkey TIGIT, but not with the mouse TIGIT. Our in vitro efficacy data demonstrated that MG1131 activated NF-κB signaling in T cells, and enhanced NK-mediated tumor killing activities in a PVR-dependent manner. In vitro Treg suppression assays showed that MG1131 inhibited immunosuppressive functionality of Treg, leading to restoration of proliferation and IFN-γ secretion capacities of Teff even in the presence of Treg. In addition, expression levels of TIGIT on CD8+ T cells from PBMCs of cancer patient samples were higher compared with other immune inhibitory molecules such as PD-1, Tim-3, CTLA-4, or LAG-3, and the blockade of TIGIT by MG1131 resulted in increased IFN-γ secretion. Thus, our data indicate that MG1131 is a promising candidate for cancer immunotherapy by modulating NK and T cell functions. Citation Format: Jeewon Lee, Munkyung Kim, Hye-mi Nam, Joong Hyuk Sheen, Eun Jung Song, Hye In Yum, So Jung Lim, Hye-Young Park. MG1131, a novel TIGIT-targeting monoclonal antibody, enhances anti-tumor immune responses by modulating NK and T cell activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2230.