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Next-generation anti-PD-L1/IL-15 immunocytokine elicits superior antitumor immunity in cold tumors with minimal toxicity

文献类型：期刊论文

作者Shi, Wenqiang7,8; Liu, Nan6; Liu, Zexin7,8; Yang, Yuqi5,6; Zeng, Qiongya7,8; Wang, Yang7,8; Song, Luyao7,8; Hu, Fang2; Fu, Jin2; Chen, Junsheng7
刊名CELL REPORTS MEDICINE
出版日期2024-05-21
卷号5期号:5页码:20
ISSN号2666-3791
DOI10.1016/j.xcrm.2024.101531
通讯作者Jiang, Long(jiang_long@shsmu.edu.cn) ; Lu, Huili(roadeer@sjtu.edu.cn)
英文摘要The clinical applications of immunocytokines are severely restricted by dose-limiting toxicities. To address this challenge, here we propose a next-generation immunocytokine concept involving the design of LH05, a tumor-conditional anti-PD-L1/interleukin-15 (IL-15) prodrug. LH05 innovatively masks IL-15 with steric hindrance, mitigating the "cytokine sink"effect of IL-15 and reducing systemic toxicities associated with wild- type anti-PD-L1/IL-15. Moreover, upon specific proteolytic cleavage within the tumor microenvironment, LH05 releases an active IL-15 superagonist, exerting potent antitumor effects. Mechanistically, the antitumor efficacy of LH05 depends on the increased infiltration of CD8+ + T and natural killer cells by stimulating the chemokines CXCL9 and CXCL10, thereby converting cold tumors into hot tumors. Additionally, the tumor- conditional anti-PD-L1/IL-15 can synergize with an oncolytic virus or checkpoint blockade in advanced and metastatic tumor models. Our findings provide a compelling proof of concept for the development of next-generation immunocytokines, contributing significantly to current knowledge and strategies of immunotherapy.
WOS关键词MOLECULE
资助项目Fundamental Research Funds for the Central Universities[YG2023QNB24] ; Shanghai Municipal Health Commission[20214Y0418] ; Natural Science Foundation of Chongqing[2022NSCQ-MSX2319] ; Science and Technology Commission of Shanghai Municipality[21S11906300] ; Science and Technology Commission of Shanghai Municipality[23ZR1431800] ; National Key Laboratory of Lead Druggability Research (Shanghai Institute of Pharmaceutical Industry Co.Ltd.)[NKLKF2023001]
WOS研究方向Cell Biology ; Research & Experimental Medicine
语种英语
WOS记录号WOS:001293718000001
出版者CELL PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/312818]  
专题中国科学院上海药物研究所
通讯作者Jiang, Long; Lu, Huili
作者单位1.Shanghai Jiao Tong Univ, Shanghai Chest Hosp, Shanghai Lung Canc Ctr, Sch Med, Shanghai 200030, Peoples R China
2.Hangzhou Converd Inc, Hangzhou 311121, Zhejiang, Peoples R China
3.Fudan Univ, Huashan Hosp, Dept Neurosurg, Shanghai 200052, Peoples R China
4.Shanghai Jiao Tong Univ, Sch Med, Shanghai Ninth Peoples Hosp, Dept Urol, Shanghai 200023, Peoples R China
5.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
7.Shanghai Jiao Tong Univ, Engn Res Ctr Cell & Therapeut Antibody, Sch Pharm, Minist Educ, Shanghai 200240, Peoples R China
8.Shanghai Jiao Tong Univ, Shanghai Frontiers Sci Ctr Drug Target Identificat, Sch Pharm, Natl Key Lab Innovat Immunotherapy, Shanghai 200240, Peoples R China
推荐引用方式
GB/T 7714		 Shi, Wenqiang,Liu, Nan,Liu, Zexin,et al. Next-generation anti-PD-L1/IL-15 immunocytokine elicits superior antitumor immunity in cold tumors with minimal toxicity[J]. CELL REPORTS MEDICINE,2024,5(5):20.
APA Shi, Wenqiang.,Liu, Nan.,Liu, Zexin.,Yang, Yuqi.,Zeng, Qiongya.,...&Lu, Huili.(2024).Next-generation anti-PD-L1/IL-15 immunocytokine elicits superior antitumor immunity in cold tumors with minimal toxicity.CELL REPORTS MEDICINE,5(5),20.
MLA Shi, Wenqiang,et al."Next-generation anti-PD-L1/IL-15 immunocytokine elicits superior antitumor immunity in cold tumors with minimal toxicity".CELL REPORTS MEDICINE 5.5(2024):20.

入库方式： OAI收割

来源：上海药物研究所

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