TNFR2 is highly expressed on the surface of activated T effector cells, T regulatory cells and myeloid cells, and it plays essential roles in modulating the tumor microenvironment. In most cancer types, higher TNFR2 expression correlates with increased immune cell infiltration. Furthermore, the TNFR2 gene is differentially expressed in various cancer types, including breast, lung, renal, liver and skin cancers. In cancers such as head and neck cancer and cutaneous melanoma, high TNFR2 expression correlates with better overall survival. The therapeutic potential of antibodies targeting TNFR2 has been demonstrated by agonist antibodies for the T effector cells, and antibodies that antagonize or deplete the T regulatory cells and suppressive myeloid cells. We discovered novel TNFR2 antibodies that demonstrate unique mechanisms to overcome T cell exhaustion and the suppressive tumor microenvironment for more effective immunotherapy. In vitro studies have shown that our antibodies block TNFα ligand binding and potently inhibit TNFR2 signaling in the monocytic cells. Moreover, these antibodies enhance CD8 T cell function to overcome the suppressive effect from the T regulatory cells and can invigorate exhausted CD8 T cells in an FcγR-dependent manner. In a humanized mouse model, our antibodies demonstrate strong anti-tumor efficacy as single agents or in combination with a PD-L1 inhibitor. Therefore, these antibodies offer potential advantages when the tumor microenvironment is enriched in the exhausted T cells, the suppressive myeloid cells, or the regulatory T cells, as found in anti-PD-1/PD-L1 resistant and PD-1 refractory patients. In conclusion, the data obtained indicate that our TNFR2 antibodies are a novel and promising class of drug candidates for cancer immunotherapeutics. Our lead antibody is currently at the IND-enabling stage with the target of entering clinical studies in early 2022.

Citation Format: Chi Shing Sum, Makenzie Danton, Qii hu, Alla Pritsker, Ray Lin, Raymond Yu, Kevin Chen, Fangqiang Tang, Thomas Pohl, Samantha Wallner, Ahmed Hassan, Huarui Lu, Haichun Huang, James Pei, Zhong Liu, Han Li, Ming Lei. Novel TNFR2 antibodies to overcome T cell exhaustion and suppressive tumor microenvironment [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 1869.