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AXL antibody and AXL-ADC mediate antitumor efficacy via targeting AXL in tumor-intrinsic epithelial-mesenchymal transition and tumor-associated M2-like macrophage

文献类型：期刊论文

作者Pei, Jin-peng1; Wang, Yue1; Ma, Lan-ping2; Wang, Xin2; Liu, Liang1; Zhang, Yu1; Jin, Rui1; Ren, Zhi-qiang1; Deng, Yan1; Shen, Jing-kang2
刊名ACTA PHARMACOLOGICA SINICA
出版日期2023-01-17
页码14
ISSN号1671-4083
关键词AXL NSCLC TNBC M2-macrophage antibody-drug conjugate
DOI10.1038/s41401-022-01047-6
通讯作者Shen, Jing-kang(jkshen@simm.ac.cn) ; Meng, Tao(tmeng@simm.ac.cn) ; Yu, Ker(keryu@fudan.edu.cn)
英文摘要The receptor tyrosine kinase AXL is an emerging driver of cancer recurrence, while its molecular mechanism remains unclear. In this study we investigated how AXL regulated the disease progression and poor prognosis in non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We performed AXL transcriptome analysis from TCGA datasets, and found that AXL expression was significantly elevated in NSCLC and TNBC correlating with poor prognosis, epithelial-mesenchymal transition (EMT) and immune-tolerant tumor microenvironment (TME). Knockdown of AXL or treatment with two independent AXL antibodies (named anti-AXL and AXL02) all diminished cell migration and EMT in AXL-high expressing NSCLC and TNBC cell lines. In a mouse model of 4T1 TNBC, administration of anti-AXL antibody substantially inhibited lung metastases formation and growth, accompanied by reduced downstream signaling activation, EMT and proliferation index, as well as an increased apoptosis and activated anti-tumor immunity. We found that AXL was abundantly activated in tumor nodule-infiltrated M2-macrophages. A specific anti-AXL antibody blocked bone marrow-derived macrophage (BMDM) M2-polarization in vitro. Targeting of AXL in M2-macrophage in addition to tumor cell substantially suppressed CSF-1 production and eliminated M2-macrophage in TME, leading to a coordinated enhancement in both the innate and adaptive immunity reflecting M1-like macrophages, mature dendritic cells, cytotoxic T cells and B cells. We generated a novel and humanized AXL-ADC (AXL02-MMAE) employing a site-specific conjugation platform. AXL02-MMAE exerted potent cytotoxicity against a panel of AXL-high expressing tumor cell lines (IC50 < 0.1 nmol/L) and suppressed in vivo growth of multiple NSCLC and glioma tumors (a minimum efficacy dose<1 mg/kg). Compared to chemotherapy, AXL02-MMAE achieved a superior efficacy in regressing large sized tumors, eliminated AXL-H tumor cell-dependent M2-macrophage infiltration with a robust accumulation of inflammatory macrophages and mature dendritic cells. Our results support AXL-targeted therapy for treatment of advanced NSCLC and TNBC.
WOS关键词RECEPTOR TYROSINE KINASE ; CANCER ; CELL ; EXPRESSION ; RESISTANCE ; BLOCKADE ; THERAPY
资助项目Fudan University[EZF301002] ; National Natural Science Foundation of China[81373442] ; NST Major Project of China[2018ZX09711002-008] ; NBR 973 Program of China[2013CB932500]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
出版者NATURE PUBL GROUP
WOS记录号WOS:000914702900002
源URL[http://119.78.100.183/handle/2S10ELR8/303666]  
专题新药研究国家重点实验室
通讯作者Shen, Jing-kang; Meng, Tao; Yu, Ker
作者单位1.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Pei, Jin-peng,Wang, Yue,Ma, Lan-ping,et al. AXL antibody and AXL-ADC mediate antitumor efficacy via targeting AXL in tumor-intrinsic epithelial-mesenchymal transition and tumor-associated M2-like macrophage[J]. ACTA PHARMACOLOGICA SINICA,2023:14.
APA Pei, Jin-peng.,Wang, Yue.,Ma, Lan-ping.,Wang, Xin.,Liu, Liang.,...&Yu, Ker.(2023).AXL antibody and AXL-ADC mediate antitumor efficacy via targeting AXL in tumor-intrinsic epithelial-mesenchymal transition and tumor-associated M2-like macrophage.ACTA PHARMACOLOGICA SINICA,14.
MLA Pei, Jin-peng,et al."AXL antibody and AXL-ADC mediate antitumor efficacy via targeting AXL in tumor-intrinsic epithelial-mesenchymal transition and tumor-associated M2-like macrophage".ACTA PHARMACOLOGICA SINICA (2023):14.

入库方式： OAI收割

来源：上海药物研究所

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