RT Journal Article
SR Electronic
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
FD BMJ Publishing Group Ltd
SP e002428
DO 10.1136/jitc-2021-002428
VO 9
IS 7
A1 Jeong, Seongju
A1 Park, Eunyoung
A1 Kim, Hyung-Don
A1 Sung, Eunsil
A1 Kim, Hyunjoo
A1 Jeon, Jaehyoung
A1 Kim, Youngkwang
A1 Jung, Ui-jung
A1 Son, Yong-Gyu
A1 Hong, Youngeun
A1 Lee, Hanbyul
A1 Lee, Shinai
A1 Lim, Yangmi
A1 Won, Jonghwa
A1 Jeon, Minwoo
A1 Hwang, Shin
A1 Fang, Lei
A1 Jiang, Wenqing
A1 Wang, Zhengyi
A1 Shin, Eui-Cheol
A1 Park, Su-Hyung
A1 Jung, Jaeho
YR 2021
UL http://jitc.bmj.com/content/9/7/e002428.abstract
AB 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.