%0 Journal Article %A Seongju Jeong %A Eunyoung Park %A Hyung-Don Kim %A Eunsil Sung %A Hyunjoo Kim %A Jaehyoung Jeon %A Youngkwang Kim %A Ui-jung Jung %A Yong-Gyu Son %A Youngeun Hong %A Hanbyul Lee %A Shinai Lee %A Yangmi Lim %A Jonghwa Won %A Minwoo Jeon %A Shin Hwang %A Lei Fang %A Wenqing Jiang %A Zhengyi Wang %A Eui-Cheol Shin %A Su-Hyung Park %A Jaeho Jung %T Novel anti-4-1BB×PD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade %D 2021 %R 10.1136/jitc-2021-002428 %J Journal for ImmunoTherapy of Cancer %P e002428 %V 9 %N 7 %X Background Stimulation of 4-1BB with agonistic antibodies is a promising strategy for improving the therapeutic efficacy of immune checkpoint inhibitors (ICIs) or for overcoming resistance to ICIs. However, dose-dependent hepatotoxicity was observed in clinical trials with monoclonal anti-4-1BB agonistic antibodies due to the activation of 4-1BB signaling in liver resident Kupffer cells.Methods To avoid this on-target liver toxicity, we developed a novel bispecific antibody (4-1BB×PD-L1 bispecific antibody, termed “ABL503”) uniquely designed to activate 4-1BB signaling only in the context of PD-L1, while also blocking PD-1/PD-L1 signaling.Results Functional evaluation using effector cells expressing both 4-1BB and PD-1 revealed superior biological activity of ABL503 compared with the combination of each monoclonal antibody. ABL503 also augmented T-cell activation in in vitro assays and further enhanced the anti-PD-L1-mediated reinvigoration of tumor-infiltrating CD8+ T cells from patients with cancer. Furthermore, in humanized PD-L1/4-1BB transgenic mice challenged with huPD-L1-expressing tumor cells, ABL503 induced superior anti-tumor activity and maintained an anti-tumor response against tumor rechallenge. ABL503 was well tolerated, with normal liver function in monkeys.Conclusion The novel anti-4-1BB×PD-L1 bispecific antibody may exert a strong anti-tumor therapeutic efficacy with a low risk of liver toxicity through the restriction of 4-1BB stimulation in tumors.Data are available on reasonable request. The data that support the findings of this study are available from the corresponding authors S-HP or JJ on reasonable request. %U https://jitc.bmj.com/content/jitc/9/7/e002428.full.pdf