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Tislelizumab uniquely binds to the CC′ loop of PD‐1 with slow‐dissociated rate and complete PD‐L1 blockage

Authors :
Yuan Hong
Yingcai Feng
Hanzi Sun
Bo Zhang
Hongfu Wu
Qing Zhu
Yucheng Li
Tong Zhang
Yilu Zhang
Xinxin Cui
Zhuo Li
Xiaomin Song
Kang Li
Mike Liu
Ye Liu
Source :
FEBS Open Bio, Vol 11, Iss 3, Pp 782-792 (2021)
Publication Year :
2021
Publisher :
Wiley, 2021.

Abstract

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.

Details

Language :
English
ISSN :
22115463
Volume :
11
Issue :
3
Database :
Directory of Open Access Journals
Journal :
FEBS Open Bio
Publication Type :
Academic Journal
Accession number :
edsdoj.7566c20ed34c4efea2984437bc6264ed
Document Type :
article
Full Text :
https://doi.org/10.1002/2211-5463.13102