Novel anti-4-1BB×PD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade
2021; BMJ; Volume: 9; Issue: 7 Linguagem: Inglês
10.1136/jitc-2021-002428
ISSN2051-1426
AutoresSeongju Jeong, Eun Young Park, Hyung‐Don Kim, Eun-Sil Sung, Hyun Joo Kim, Jaehyoung Jeon, Youngkwang Kim, Ui-jung Jung, Yong-Gyu Son, Youngeun Hong, Hanbyul Lee, Shinai Lee, Yangmi Lim, Jonghwa Won, Minwoo Jeon, Shin Hwang, Lei Fang, Wenqing Jiang, Zhengyi Wang, Eui‐Cheol Shin, Su‐Hyung Park, Jaeho Jung,
Tópico(s)Immunotherapy and Immune Responses
ResumoStimulation 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.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.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.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.
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