Targeted cancer therapies using immunotoxins has achieved remarkable efficacies in hematological malignancies. However, the clinical development of immunotoxins is also faced with many challenges like anti-drug antibodies and dose-limiting toxicity issues. Such a poor efficacy/safety ratio is also the major hurdle in the research and development of antibody-drug conjugates. From an antibody engineering perspective, various strategies were summarized/proposed to tackle the notorious on target off tumor toxicity issues, including passive strategy (XTENylation of immunotoxins) and active strategies (modulating the affinity and valency of the targeting moiety of immunotoxins, conditionally activating immunotoxins in the tumor microenvironments and reconstituting split toxin to reduce systemic toxicity etc.). By modulating the functional characteristics of the targeting moiety and the toxic moiety of immunotoxins, selective tumor targeting can be augmented while sparing the healthy cells in normal tissues expressing the same target of interest. If successful, the improved therapeutic index will likely help to address the dose-limiting toxicities commonly observed in the clinical trials of various immunotoxins.
Regulatory T cells (Tregs) are a subset of immunosuppressive CD4+ T lymphocytes which can inhibit effector T cell activity in the tumor microenvironment (TME) and promote tumor growth. Depletion of Tregs is a promising immunotherapy strategy for treatment of cancers. Tumor necrosis factor receptor-2 (TNFR2) is highly expressed on both Tregs and many kinds of tumor cells, making it a potential candidate for tumor-targeted antibody therapy. A fully human, non-blocking agonist antibody to TNFR2, 1C3, was generated from RenMab™ mice, which contain the full human immunoglobulin variable domain. 1C3 was selected from a large panel of antibody candidates after unbiased, high-throughput efficacy screening conducted in syngeneic tumor mouse models established in humanized TNFR2 mice. In vitro, 1C3 effectively promoted proliferation of cytotoxic T cells. Subsequently, the in vivo anti-tumor efficacy and safety of 1C3 was evaluated in syngeneic tumor mouse models expressing human TNFR2. The results demonstrated that 1C3 monotherapy significantly inhibited tumor growth in a dose-dependent manner. In combination with anti-human PD-1 or PD-L1 antibodies, 1C3 also greatly potentiated anti-tumor responses compared to monotherapy of each agent. Analysis of tumor-infiltrating lymphocytes (TIL) demonstrated that 1C3 treatment significantly increased the ratio of effector T cells to Tregs in the TME. Moreover, 1C3 was well tolerated in mice, and no adverse effects were observed even at high doses (e.g. 100 mg/kg). In conclusion, these data demonstrate that 1C3 is a novel anti-human TNFR2 non-blocking agonist antibody with effective anti-tumor efficacy and favorable safety. 1C3 may exert these effects by regulating Treg and effector T cell activities. Citation Format: Yongfei Yang, Shuzhen Cao, Wenjiao Zhang, Jing Zhang, Zhe Shao, Xueyuan Jiang, Qingya Duan, Maopeng Tian, Sen Mei, Zhaoxue Yu. 1C3, a novel non-blocking anti-human TNFR2 antibody, promotes effector T cell responses and demonstrates potent anti-tumor activity [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 6436.
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 IgG mice (RenMice), which is an effective platform for human antibody generation. 1C3 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-1 or PD-L1 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. Citation Format: Yongfei Yang, Shuzhen Cao, Jing Zhang, Zhe Shao, Xueyuan Jiang, Qingya Duan, Maopeng Tian, Sen Mei, Luke (Zhaoxue) Yu. 1C3, a Novel non-blocking anti-human TNFR2 antibody generated from RenMice, exhibits promising anti-tumor activity and safety in syngeneic tumor models in humanized TNFR2 mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2907.
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