Dual Mechanisms of Novel CD73-Targeted Antibody and Antibody-Drug Conjugate in Inhibiting Lung Tumor Growth and Promoting Antitumor Immune-Effector Function
文献类型：期刊论文
| 作者 | Jin, Rui2; Liu, Liang2; Xing, Yun2; Meng, Tao1 ; Ma, Lanping1; Pei, Jinpeng2; Cong, Ying2; Zhang, Xuesai2; Ren, Zhiqiang2; Wang, Xin1
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| 刊名 | MOLECULAR CANCER THERAPEUTICS
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| 出版日期 | 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. |
| WOS关键词 | DENDRITIC CELLS ; POOR-PROGNOSIS ; CD73 ; RESISTANCE ; EXPRESSION ; ECTO-5'-NUCLEOTIDASE ; HETEROGENEITY ; ANTI-PD-1 ; BLOCKADE |
| 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研究方向 | Oncology |
| 语种 | 英语 |
| WOS记录号 | WOS:000587913900011 |
| 出版者 | AMER ASSOC CANCER RESEARCH |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/292497]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Yu, Ker |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai, Peoples R China 2.Fudan Univ, Dept Pharmacol, Sch Pharm, 826 Zhangheng Rd,Res Bldg Room 915, Shanghai 201203, 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. |
入库方式： OAI收割
来源：上海药物研究所
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