PEGS-EU 2022:1C3—A Differentiated Non-Blocking Agonist TNFR2 Antibody for Cancer Immunotherapy
Regulatory T Cells (Treg) inhibit effector T cell (Teff) activity in the tumor microenvironment (TME). Therefore, depletion of regulatory T cells (Treg cells) is a promising therapeutic strategy for tumor immunotherapy. Tumor necrosis factor receptor-2 (TNFR2) is highly expressed on Treg cells and is a potential target for anti-tumor therapy. A TNFR2 non-blocking antibody (1C3) was generated from humanized lgG mice (RenMice), which is an effective platform for human antibody generation. IC3 was selected from a large panel of antibody candidates through an unbiased, high-throughput in vivo efficacy screen in syngeneic tumor mouse models in humanized TNFR2 mice. Compared with other TNFR2 antagonistic antibodies, 1C3 effectively promoted the proliferation of CD8+ cytotoxic T cells in vitro, a population that is inhibited by Treg cells. To evaluate 1C3 efficacy and safety in vivo, syngeneic mouse tumor models were established. 1C3 monotherapy significantly inhibited tumor growth in a dose-dependent manner in syngeneic tumor mouse models In TNFR2 humanized mice. In combination with anti-human PD-I or PD-LI antibody, 1C3 also greatly increased antitumor activity compared to the monotherapy of each therapeutic agent. Mechanistically, 1C3 treatment significantly increased the ratio of Teff/Treg in the TME. In addition, 1C3 was well tolerated in TNFR2 humanized mice, and no side effects were observed even when the dose was increased to 100 mg/kg. Taken together, our data demonstrates that 1C3 is a novel anti-TNFR2 antibody for anti-tumor therapy and provides a great potential for the next generation of immunotherapy.