Open AccessTislelizumab uniquely binds to the CC′ loop of PD‐1 with slow‐dissociated rate and complete PD‐L1 blockage
Author(s) -
Hong Yuan,
Feng Yingcai,
Sun Hanzi,
Zhang Bo,
Wu Hongfu,
Zhu Qing,
Li Yucheng,
Zhang Tong,
Zhang Yilu,
Cui Xinxin,
Li Zhuo,
Song Xiaomin,
Li Kang,
Liu Mike,
Liu Ye
Publication year - 2021
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1002/2211-5463.13102
Subject(s) - surface plasmon resonance , pd l1 , epitope , antibody , chemistry , cancer research , immunotherapy , immune checkpoint , receptor–ligand kinetics , cancer immunotherapy , immune system , ligand (biochemistry) , microbiology and biotechnology , receptor , biophysics , biology , immunology , biochemistry , materials science , nanotechnology , nanoparticle
Programmed cell death protein 1 (PD‐1), an immune checkpoint receptor expressed by activated T, B, and NK cells, is a well‐known target for cancer immunotherapy. Tislelizumab (BGB‐A317) is an anti‐PD‐1 antibody that has recently been approved for treatment of Hodgkin's lymphoma and urothelial carcinoma. Here, we show that tislelizumab displayed remarkable antitumor efficacy in a B16F10/GM‐CSF mouse model. Structural biology and Surface plasmon resonance (SPR) analyses revealed unique epitopes of tislelizumab, and demonstrated that the CC′ loop of PD‐1, a region considered to be essential for binding to PD‐1 ligand 1 (PD‐L1) but not reported as targeted by other therapeutic antibodies, significantly contributes to the binding of tislelizumab. The binding surface of tislelizumab on PD‐1 overlaps largely with that of the PD‐L1. SPR analysis revealed the extremely slow dissociation rate of tislelizumab from PD‐1. Both structural and functional analyses align with the observed ability of tislelizumab to completely block PD‐1/PD‐L1 interaction, broadening our understanding of the mechanism of action of anti‐PD‐1 antibodies.