841 LBL-019, a novel TNFR2 agonist antibody, shows potent anti-tumor efficacy through preferentially activating CD8+ T cells and alleviating the suppressive effect of Treg cells

• Published in: Journal for immunotherapy of cancer Vol. 11; no. Suppl 1; p. A939
• Main Authors: Wang, Baohui, Wang, Hailin, Li, Tingting, Sun, Jianming, Huang, Xiao, Lin, Huan, Dan, Yujia, Qin, Yurong, Zhang, Peng, Guan, Jing, Wu, Guojin, Hou, Xiaofan, Lai, Shoupeng, Kang, Xiaoqiang, Ling, Hong
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.11.2023; BMJ Publishing Group LTD; BMJ Publishing Group
• Subjects: Antibodies; Cytotoxicity; Immunotherapy; Lymphocytes; Regular and Young Investigator Award Abstracts; Tumor necrosis factor-TNF; Tumors
• ISSN: 2051-1426
• DOI: 10.1136/jitc-2023-SITC2023.0841

BackgroundTumor necrosis factor receptor-2 (TNFR2), representing co-stimulatory and survival signaling, is selectively expressed on immune cells, especially Treg and memory T cells, promoting both Tregs and cytotoxic T cells proliferation. Due to the paradoxical functions, two types of TNFR2 antibodies are under development: depletion or agonistic antibody. The depletion antibodies eliminate TNFR2+ Tregs and MDSC through ADCC or CDC, while the agonistic antibodies activate and expand cytotoxic T cells to inhibit tumors. Here, we report a novel TNFR2 agonistic antibody, LBL-019, which preferentially activates CD8+ T cells compared to CD4+ T cells, and in addition, can alleviate the suppressive effect of Treg cells.MethodsA diverse panel of antibodies against TNFR2 was screened and developed using mouse hybridoma technology. Robust in vitro assessments of candidates, including TNFR2 binding, TNF-α blockade, NF-κB report gene and cell functional assays validated and identified LBL-019 as the lead therapeutic candidate. In vivo, efficacy of LBL-019 and its combination with PD-1 antibody was evaluated in MC38 tumor models.ResultsLBL-019 is a human/cyno cross-reactive TNFR2 antibody that binds TNFR2 with high affinity and specificity and recognizes a unique epitope in the CRD1 domain of TNFR2; LBL-019 is a potent agonist and blocks the TNFR2-TNF-α interaction in cell-based ligand binding assays and activating downstream NF-κB signal independent of TNF-α. LBL-019 plays anti-tumor efficacy through two distinct mechanisms. Firstly, it preferentially stimulated a 200% expansion of CD8 T cells compared to a 30% increase in CD4+ T cells, triggered the release of IFN-γ and up-regulated the expression of activation maker such as CD25, PD-1, and 41BB, depending on Fc crosslinking. Secondly, LBL-019 could alleviate the inhibitory effects of Treg cells on CD4/CD8 T cells, thereby promoting T cell proliferation and activation. Moreover, the combinational efficacy of LBL-019 with anti-PD1 has been demonstrated in vitro and in vivo, inhibiting tumor growth in the MC38 tumor model (TGI=80%).ConclusionsLBL-019 is a potent TNFR2 agonistic antibody. It effectively activated TNFR2 downstream signaling independent of TNF-α. By preferentially co-stimulating CD8+ T cells, LBL-019 promoted cytotoxic T cells proliferation and activation, and counteracted the immunosuppressive function of Tregs cells. The in-vitro and in-vivo anti-tumor activity of LBL-019 was evaluated both as a monotherapy and in combination with an anti-PD-1 antibody. The results demonstrate potent anti-tumor efficacy, supporting the advancement of LBL-019 in clinical development for the treatment of various human tumors.