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

查看全文 作　　者：Yuzhen [1]Qian;Yixuan [2]Sun;Peishang [1]Shi;Xiuman [2]Zhou;Qiongqiong [1]Zhang;Qingyu [2]Dong;Shengzhe [1]Jin;Lu [1,2]Qiu;Xiaoshuang [2]Niu;Xiaowen [1]Zhou;Wenshan [1]Zhao;Yahong [1,3]Wu;Wenjie [1,3]Zhai;Yanfeng [1,2]Gao

机构地区：[1]School of Life Sciences,Zhengzhou University,Zhengzhou 450001,China;[2]School of Pharmaceutical Sciences(Shenzhen),Shenzhen Campus of Sun Yat-sen University,Shenzhen 518107,China;[3]International Joint Laboratory for Protein and Peptide Drugs of Henan Province,Zhengzhou University,Zhengzhou 450001,China

出　　处：《Acta Pharmaceutica Sinica B》索引2024年第14卷第3期,共16页

基　　金：supported by the grants from National Science Foundation of China(U20A20369);“Pearl River Talent Plan”Innovation and Entrepreneurship Team Project of Guangdong Province(2019ZT08Y464,China);Guangdong Basic and Applied Basic Research Foundation(2022B1515120085,China);Shenzhen Science and Technology Program(KQTD20190929173853397,China);Henan Provincial Key R&D and Promotion Special(Scientific Problem Tackling)(222102310344,China)。 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-1(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-L1blocking peptide OPBP-1(8-12),which activates T cell with enhanced proliferation and IFN-γ production.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 synergizes with radiotherapy to further enhance the antitumor immune response. 关键词：LAG-3 FGL1 PD-1 PD-L1 PEPTIDE Immune checkpoint RADIOTHERAPY Cancer immunotherapy

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

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