Abstract 5523: LBL-019, a novel anti-TNFR2 antibody, shows a potent anti-tumor efficacy in a mouse MC38 model

Abstract

Abstract Objective: Although immunotherapies, e.g., anti-PD-(L)1 has achieved great success in treating cancers, a large portion of patients still cannot benefit from it, due largely to primary refractory or acquired resistance leading to unsatisfied ORR or relapse. TNFR2 is a receptor for TNF-α, expressed highly selective in immune cells, and some tumor cells, transducing survival and immunostimulatory signal to cells expressing this receptor. Targeting TNFR2 may modulate this signaling, therefore a humanized anti-TNFR2 antibody, LBL-019, was developed for monotherapy or in combination with other anti-tumor therapies. Methods: LBL-019 is a monoclonal antibody of IgG1 subtype. The binding affinity to TNFR2 was determined by Fortebio. The epitope of TNFR2 was identified by differential binding to a serial human/mouse chimeric TNFR2 proteins. The binding of TNF-α to either TNFR2 protein or TNFR2 expressed in cells was examined by using ELISA and flow cytometry. The in vitro activity of LBL-019 was measured using several in vitro assays, e.g., cell proliferation and cytokine release in T cells, ADCC and CDC assays. The anti-tumor activity of LBL-019 was investigated in a model of human TNFR2 transgenic mice (Shanghai Model Organisms) implanted with MC38-OVA cells. Results: The binding affinity of LBL-019 was measured as 5.32 nM to human and 3.62 nM to cynomolgus TNFR2. It was found that TNFR2 was expressed in immune cells including T cells and monocytes examined in human PBMC, which was upregulated when T cells were activated. TNFR2 was also found highly expressed in some tumor cell lines and tumor TILs (from in vivo studies described below). The epitope of TNFR2 that LBL-019 binds was identified and mapped out CRD1 domain. The binding of TNF-α with either TNFR2 protein or TNFR2 expressed in immune cells was blocked by LBL-019. The growth of CD8+ T cells and CD4+ T cells was significantly enhanced, when incubated with LBL-019, along with elevated IFN-γ release. In a model of human TNFR2 transgenic mice implanted with MC38-OVA cells, LBL-019 was shown significant tumor growth inhibition (TGI) in a dose dependent manner as compared with vehicle treated mice (p<0.01). It appeared that the antibody with wild type Fc showed a better anti-tumor activity than that with silenced Fc, suggesting that Fc mediated NK killing of tumor cells or Treg may have contributed in part to the observed anti-tumor efficacy in this model. In addition, LBL-019 was also exhibited a synergy of anti-tumor activity, when dosed with anti-PD-1 (TGI reaching 79.51%). Conclusions: LBL-019, a humanized anti-TNFR2 antibody, shows great anti-tumor efficacy in a mouse tumor model, likely due to the mechanisms involving enhanced proliferation of Teff, elevated IFN-γ release, and possibly killing of tumor cells and Treg. The data support further development of LBL-019 as a novel therapeutic antibody for cancer, and clinical trial is expected to launch early 2022. Citation Format: Huan Lin, Xiao Huang, Yurong Qin, Yujia Dang, Peng Zhang, Jianming Sun, Jing Guan, Shoupeng Lai, Xiaoqiang Kang, Hong Ling. LBL-019, a novel anti-TNFR2 antibody, shows a potent anti-tumor efficacy in a mouse MC38 model [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 5523.