Development of LAG-3/FGL1 blocking peptide and combination with radiotherapy for cancer immunotherapy

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外文摘要：Aside from antibodies,peptides show great potential as immune checkpoint inhibitors(ICIs)due to several advantages,such as better tumor penetration and lower cost.Lymphocyte-activation gene 3(LAG-3)is an immune checkpoint which can induce T cell dysfunction through interaction with its soluble ligand fibrinogen like protein-l(FGL1).Here,we found that LAG-3 expression was higher than programmed cell death protein 1(PD-1)in multiple human cancers by TCGA databases,and successfully identified a LAG-3 binding peptide LFP-6 by phage display bio-panning,which specifically blocks the interaction of LAG-3/FGL1 but not LAG-3/MHC-Ⅱ.Subsequently,D-amino acids were introduced to substitute the N-and C-terminus of LFP-6 to obtain the proteolysis-resistant peptide LFP-D1,which restores T cell function in vitro and inhibits tumor growth in vivo.Further,a bispecific peptide LFOP targeting both PD-1/PD-L1 and LAG-3/FGL1 was designed by conjugating LFP-D1 with PD-1/PD-L1 blocking peptide OPBP-1(8-12),which activates T cell with enhanced proliferation and IFN-γproduction.More importantly,LFOP combined with radiotherapy significantly improve the T cell infiltration in tumor and elevate systemic antitumor immune response.In conclusion,we developed a novel peptide blocking LAG-3/FGL1 which can restore T cell function,and the bispecific peptide syner-gizes with radiotherapy to further enhance the antitumor immune response.

外文关键词：

LAG-3FGL1PD-1PD-L1PeptideImmune checkpointRadiotherapyCancer immunotherapy

作者：

Yuzhen Qian、Yixuan Sun、Peishang Shi、Xiuman Zhou、Qiongqiong Zhang、Qingyu Dong、Shengzhe Jin、Lu Qiu、Xiaoshuang Niu、Xiaowen Zhou、Wenshan Zhao、Yahong Wu、Wenjie Zhai、Yanfeng Gao

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作者单位：

School of Life Sciences,Zhengzhou University,Zhengzhou 450001,China

School of Pharmaceutical Sciences(Shenzhen),Shenzhen Campus of Sun Yat-sen University,Shenzhen 518107,China

International Joint Laboratory for Protein and Peptide Drugs of Henan Province,Zhengzhou University,Zhengzhou 450001,China

基金：

国家自然科学基金"Pearl River Talent Plan"Innovation and Entrepreneurship Team Project of Guangdong ProvinceGuangdong Basic and Applied Basic Research Foundation深圳市科技计划Henan Provincial Key Research and Development and Promotion Special(Scientific Problem Tackling)

项目编号：

U20A203692019ZT08Y4642022B1515120085KQTD20190929173853397222102310344

出版年：

2024

DOI：

10.1016/j.apsb.2023.12.011

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(3)

参考文献量59