TY - JOUR T1 - Novel anti-4-1BB×PD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1136/jitc-2021-002428 VL - 9 IS - 7 SP - e002428 AU - Seongju Jeong AU - Eunyoung Park AU - Hyung-Don Kim AU - Eunsil Sung AU - Hyunjoo Kim AU - Jaehyoung Jeon AU - Youngkwang Kim AU - Ui-jung Jung AU - Yong-Gyu Son AU - Youngeun Hong AU - Hanbyul Lee AU - Shinai Lee AU - Yangmi Lim AU - Jonghwa Won AU - Minwoo Jeon AU - Shin Hwang AU - Lei Fang AU - Wenqing Jiang AU - Zhengyi Wang AU - Eui-Cheol Shin AU - Su-Hyung Park AU - Jaeho Jung Y1 - 2021/07/01 UR - http://jitc.bmj.com/content/9/7/e002428.abstract N2 - 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. ER -