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PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent way

文献类型：期刊论文

作者Yu, Xiaolu6,7; Long, Yiru6,7; Chen, Binfan5; Tong, Yongliang6,7; Shan, Mengwen4,7; Jia, Xiaomin6,7; Hu, Chao3,7; Liu, Meng6,7; Zhou, Ji2; Tang, Feng6,7
刊名JOURNAL FOR IMMUNOTHERAPY OF CANCER
出版日期2022-10-01
卷号10期号:10页码:15
关键词PD-L1 TLR7 nanobody-drug-conjugate cancer immunotherapy
DOI10.1136/jitc-2022-004590
通讯作者Li, Jia(jli@simm.ac.cn) ; Jin, Guangyi(gyjin@szu.edu.cn) ; Gong, Likun(lkgong@simm.ac.cn)
英文摘要Background Various tumors are insensitive to immune checkpoint blockade (ICB) therapy. Toll-like receptors (TLRs) establish the link between innate and adaptive immunity, which can assist T-cell activation and serve as promising targets for combination to enhance ICB therapy. Here, we aimed to improve efficacy for anti-programmed death ligand 1 (PD-L1) therapy by developing a PD-L1/TLR7 dual-targeting nanobody-drug conjugate (NDC), based on the PD-L1 nanobodies and TLR7 agonist we developed. Methods PD-L1 nanobodies were obtained by phage display screening and identified through T-cell activation bioassay, in vivo imaging and quantitative biodistribution study. Immune activation and PD-L1-inducing of TLR7 agonists were evaluated in diverse innate cell models. We constructed PD-L1/TLR7 dual-targeting NDCs by chemically coupling PD-L1 nanobodies and TLR7 agonists. The antitumor effect was evaluated via several murine or humanized solid tumor models. Immunophenotyping, immune cell depletion, tumor rechallenge, RNA sequencing and PD-L1-deficient models were combined to determine the mechanism for NDCs function. The dynamics of the in vivo behaviors of NDCs were assessed based on multiorgan changes in PD-L1 levels. Results The screened PD-L1 nanobodies were characterized as tumor-targeting and alleviated T-cell immunosuppression. The TLR7 agonists induced broad innate immune responses and intratumoral PD-L1 expression on antigen-presenting cells (APCs), and its antitumor effect was dependent on intratumoral delivery. The combination of TLR7 agonists and PD-L1 nanobodies activated both innate and adaptive immunity and upregulated PD-L1-related signaling pathways. After coupling to form dual-targeting NDCs, TLR7 agonists and PD-L1 nanobodies exerted synergistic antitumor effects and safety in either 'hot' or 'cold' tumor and early or advanced tumor models, reshaped the tumor immune microenvironment and induced antitumor immune memory. CD8(+) T cells and natural killer cells were the main effector cells for NDCs to function. NDCs can promote PD-L1 expression on intratumoral APCs and tumor cells, and subsequently achieve targeted enrichment in tumors. Moreover, the efficacy of NDCs is biased toward dependence on host expression of PD-L1. Conclusions The novel PD-L1/TLR7 dual-targeting NDC exhibited potent efficacy against heterogeneous tumors through orchestrating innate and adaptive immunity, which could act as a promising strategy to improve ICB therapy and shows prospects for clinical development.
WOS关键词TOLL-LIKE RECEPTORS ; CELL-CARCINOMA ; CANCER ; INNATE ; NIVOLUMAB ; MPDL3280A ; EFFICACY ; AGONIST ; B7-H1 ; LEADS
资助项目National New Drug Creation Program of China[2019ZX09732002--013] ; National New Drug Creation Program of China[2018ZX09201017--004] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA 12050305]
WOS研究方向Oncology ; Immunology
语种英语
出版者BMJ PUBLISHING GROUP
WOS记录号WOS:000870720000001
源URL[http://119.78.100.183/handle/2S10ELR8/303217]  
专题新药研究国家重点实验室
通讯作者Li, Jia; Jin, Guangyi; Gong, Likun
作者单位1.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Zhongshan, Peoples R China
2.Shenzhen Univ, Int Canc Ctr, Sch Pharmaceut Sci, Nat Reg Engn Lab Synthet Biol Med,Hlth Sci Ctr, Shenzhen, Peoples R China
3.Shenyang Pharmaceut Univ, Wuya Coll Innovat, Dept Pharmaceut, Shenyang, Peoples R China
4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China
5.Fudan Univ, Sch Basic Med Sci, Key Lab Med Mol Virol, Minist Educ & Hlth, Shanghai, Peoples R China
6.Univ Chinese Acad Sci, Beijing, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Yu, Xiaolu,Long, Yiru,Chen, Binfan,et al. PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent way[J]. JOURNAL FOR IMMUNOTHERAPY OF CANCER,2022,10(10):15.
APA Yu, Xiaolu.,Long, Yiru.,Chen, Binfan.,Tong, Yongliang.,Shan, Mengwen.,...&Gong, Likun.(2022).PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent way.JOURNAL FOR IMMUNOTHERAPY OF CANCER,10(10),15.
MLA Yu, Xiaolu,et al."PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent way".JOURNAL FOR IMMUNOTHERAPY OF CANCER 10.10(2022):15.

入库方式： OAI收割

来源：上海药物研究所

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