Dual Mechanisms of Novel CD73-Targeted Antibody and Antibody-Drug Conjugate in Inhibiting Lung Tumor Growth and Promoting Antitumor Immune-Effector Function

doi:10.1158/1535-7163.MCT-20-0076

	Dual Mechanisms of Novel CD73-Targeted Antibody and Antibody-Drug Conjugate in Inhibiting Lung Tumor Growth and Promoting Antitumor Immune-Effector Function
	Jin, Rui 1; Liu, Liang 1; Xing, Yun 1; Meng, Tao 2; Ma, Lanping 2; Pei, Jinpeng 1; Cong, Ying 1; Zhang, Xuesai 1; Ren, Zhiqiang 1; Wang, Xin 2
刊名	MOLECULAR CANCER THERAPEUTICS
	2020-11-01
卷号	19 期号:11 页码:2340-2352
ISSN号	1535-7163
DOI	10.1158/1535-7163.MCT-20-0076
通讯作者	Yu, Ker(keryu@fudan.edu.cn)
英文摘要	Although tyrosine kinase inhibitor therapy and immunotherapy have significantly improved lung cancer management, many patients do not benefit or become resistant to treatment, highlighting the need for novel treatments. We found elevated CD73 expression to be prevalent in non-small cell lung cancer (NSCLC) including those harboring the RAS- or RTK (EGFR, EML4-ALK) oncogenes. CD73 expression is enriched closely with the transcriptome signature of epithelial-mesenchymal transition and the immune-tolerant tumor microenvironment, which are increasingly relevant for disease progression and therapy resistance. We developed two novel series of CD73 antibody, Ab001/Ab002 and humanized version Hu001/Hu002, which demonstrated high CD73 binding affinity, potent enzyme inhibition, and efficiently protected effector T lymphocyte function from adenosine/cancer-imposed toxicity. Hu001/Hu002 inhibited growth of RAS-mutant NSCLC tumors in mice via enhanced antibody-dependent cell-mediated cytotoxicity and multifaceted remodeling of the tumor immune environment, reflecting diminished levels of tumor-associated macrophages, myeloid-derived suppressor cells, and tumor vasculature. A novel MMAE-conjugated CD73-ADC (Hu001-MMAE) elicited potent cytotoxicity against CD73-high expressing tumor cells (IC50<0.1 nmol/L) and suppressed in vivo growth of multiple NSCLC and glioma tumors, including the RAS-mutant models [minimum effective dose <1 mg/kg]. Treatment with CD73-ADC triggered a robust intratumoral accumulation of proinflammatory macrophages and activated dendritic cells (DC), which were not observed with naked CD73 antibody or standard chemotherapy. Studies with human PBMC-derived systems confirmed CD73-ADC as fully functional in protecting effector T cells and stimulating DCs thus providing dual benefits in killing CD73-high tumors and improving cancer immunity response. These results warrant clinical investigation of CD73-targeted antibody and ADC for treating advanced lung cancer.
资助项目	Fudan University[EZF301002] ; National Science Foundation of China[81373442] ; National Science & Technology Major Project of China[2018ZX09711002-008] ; National Basic Research 973 Program of China[2013CB932500] ; Fudan University School of Pharmacy Animal Facility, Instrument Center ; CDSER/SIMM facility
WOS关键词	DENDRITIC CELLS ; POOR-PROGNOSIS ; CD73 ; RESISTANCE ; EXPRESSION ; ECTO-5'-NUCLEOTIDASE ; HETEROGENEITY ; ANTI-PD-1 ; BLOCKADE
WOS研究方向	Oncology
语种	英语
出版者	AMER ASSOC CANCER RESEARCH
WOS记录号	WOS:000587913900011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/292497]
专题	中国科学院上海药物研究所
通讯作者	Yu, Ker
作者单位	1.Fudan Univ, Dept Pharmacol, Sch Pharm, 826 Zhangheng Rd,Res Bldg Room 915, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Jin, Rui,Liu, Liang,Xing, Yun,et al. Dual Mechanisms of Novel CD73-Targeted Antibody and Antibody-Drug Conjugate in Inhibiting Lung Tumor Growth and Promoting Antitumor Immune-Effector Function[J]. MOLECULAR CANCER THERAPEUTICS,2020,19(11):2340-2352.
APA	Jin, Rui.,Liu, Liang.,Xing, Yun.,Meng, Tao.,Ma, Lanping.,...&Yu, Ker.(2020).Dual Mechanisms of Novel CD73-Targeted Antibody and Antibody-Drug Conjugate in Inhibiting Lung Tumor Growth and Promoting Antitumor Immune-Effector Function.MOLECULAR CANCER THERAPEUTICS,19(11),2340-2352.
MLA	Jin, Rui,et al."Dual Mechanisms of Novel CD73-Targeted Antibody and Antibody-Drug Conjugate in Inhibiting Lung Tumor Growth and Promoting Antitumor Immune-Effector Function".MOLECULAR CANCER THERAPEUTICS 19.11(2020):2340-2352.