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

Acta Pharmaceutica Sinica B 2024年第3期14卷 1150-1165页

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 School of Life Sciences Zhengzhou UniversityZhengzhou 450001China School of Pharmaceutical Sciences(Shenzhen) Shenzhen Campus of Sun Yat-sen UniversityShenzhen 518107China International Joint Laboratory for Protein and Peptide Drugs of Henan Province Zhengzhou UniversityZhengzhou 450001China

Aside from antibodies,peptides show great potential as immune checkpoint inhibitors(ICIs)due to several advantages,such as better tumor penetration and lower ***-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/***,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 ***,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 *** importantly,LFOP combined with radiotherapy significantly improve the T cell infiltration in tumor and elevate systemic antitumor immune *** 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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