Abstract 1029: Dissecting the mechanism of action targeting TNFR2 with a lignd blocking anti-TNFR2 antibody that elicits potent anti-tumor activity

Abstract

Abstract Tumor necrosis factor receptor-2 (TNFR2) is a TNF receptor superfamily member and has been reported to have restricted expression in the immune system, including potent suppressive Tregs, myeloid suppressor cells and endothelial cells. The therapeutic potential of targeting TNFR2 for cancers has been previously demonstrated but with conflicting data reported by different groups. In order to gain further insight into the mechanism of action (MoA) of targeting TNFR2, we used an anti-murine TNFR2 surrogate antibody (suAb) and tested its functional activities both in vitro and in vivo. suAb was able to bind murine TNFR2 with high sub-nanomolar affinity, in the meantime, it can also block the interaction between murine TNFα and TNFR2 at both protein and cellular levels. CD4+ T cells were isolated from spleens of wildtype Balb/c mice, the co-incubation of which with murine TNFα and IL-2 rendering the significant proliferation of Treg within the CD4+ T cell population. Addition of suAb can potently reduce Treg proliferation while downregulating the expression of TNFR2 on these Tregs. Further detailed analysis by using isolated mouse FoxP3+ Treg confirmed that suAb could effectively suppress murine Treg proliferation induced by TNFα and IL-2. In vivo, suAb treatment resulted in significant tumor growth inhibition across various syngeneic tumor models (CT26, EMT6 and LL/2) as single agent or when combined with anti-mPD-1 (CT26). Tumor infiltrating lymphocytes (TILs) analysis revealed dramatic increase of the effective-memory pool of both CD4+ and CD8+ T cells together with an significantly improved CD8/Treg ratio. In addition, treatment with suAb led to decreased expression of PD-1 on tumor infiltrating CD8+ T cells suggesting a potential relieved exhaustion phenotype after the treatment. Based on this careful MoA characterization, corresponding human anti-TNFR2 lead antibodies have been identified and are currently under development as potential novel treatment for cancer patients. Citation Format: Xiaofeng Zhao, Xiaoqing Liu, Zhenna Gao, Mengyu Wang, Wenjing Li, Ran Pang, Wenqing Yang, Zhuoxiao Cao, Renhong Tang. Dissecting the mechanism of action targeting TNFR2 with a lignd blocking anti-TNFR2 antibody that elicits potent anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1029.