A novel cyclic peptide targeting LAG-3 for cancer immunotherapy by activating antigenspecific CD8^+ T cell responses

作     者：Wenjie Zhai Xiuman Zhou Hongfei Wang Wanqiong Li Guanyu Chen Xinghua Sui Guodong Li Yuanming Qi Yanfeng Gao Wenjie Zhai;Xiuman Zhou;Hongfei Wang;Wanqiong Li;Guanyu Chen;Xinghua Sui;Guodong Li;Yuanming Qi;Yanfeng Gao

作者机构：School of Life SciencesZhengzhou UniversityZhengzhou 450001China School of Pharmaceutical Sciences(Shenzhen)Sun Yat-sen UniversityGuangzhou 510006China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2020年第10卷第6期

页      面：1047-1060页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China(No.81822043,U1604286) Key Scientific Research Projects of Henan Higher Education Institutions(No.18A180033) 

主　　题：LAG-3 Phage display Cyclic peptide Immune checkpoint blockade CD8^+T cell Cancer immunotherapy 

摘      要：PD-1 and CTLA-4 antibodies offer great hope for cancer ***,many patients are incapable of responding to PD-1 and CTLA-4 blockade and show low response rates due to insufficient immune *** combination of checkpoint blockers has been proposed to increase the response ***,antibody drugs have disadvantages such as inclined to cause immune-related adverse events and infiltration *** this study,we developed a cyclic peptide C25 by using Ph.D.-C7C phage display technology targeting *** a result,C25 showed a relative high affinity with human LAG-3 protein and could effectively interfere the binding between LAG-3 and HLA-DR(MHC-II).Additionally,C25 could significantly stimulate CD8^+T cell activation in human *** results also demonstrated that C25 could inhibit tumor growth of CT26,B16 and B 16-OVA bearing mice,and the infiltration of CD8^+T cells was significantly increased while FOXP3^+Tregs significantly decreased in the tumor ***,the secretion of IFN-γby CD8^+T cells in spleen,draining lymph nodes and especially in the tumors was ***,we exploited T cells depletion models to study the anti-tumor mechanisms for C25 peptide,and the results combined with MTT assay confirmed that C25 exerted anti-tumor effects via CD8+T cells but not direct *** conclusion,cyclic peptide C25 provides a rationale for targeting the immune checkpoint,by blockade of LAG-3/HLA-DR interaction in order to enhance anti-tumor immunity,and C25 may provide an alternative for cancer immunotherapy besides antibody drugs.