VEGFR2-targeted antibody fused with IFNamut regulates the tumor microenvironment of colorectal cancer and exhibits potent anti-tumor and anti-metastasis activity  

作　　者：Pengzhao Shang Rui Gao Yijia Zhu Xiaorui Zhang Yang Wang Minji Guo Hui Peng Min Wang Juan Zhang 

机构地区：[1]Antibody Engineering Laboratory,School of Life Science&Technology,China Pharmaceutical University,Nanjing 210009,China [2]Department of Operational Medicine,Tianjin Institute of Environmental&Operational Medicine,Tianjin 300050,China

出　　处：《Acta Pharmaceutica Sinica B》2021年第2期420-433,共14页药学学报（英文版）

基　　金：supported by grants from“Double First-Class”University Project(CPU2018PZQ12 and CPU2018GY14,China);National Natural Science Foundation of China(Grant 81993223);National Natural Science Foundation of China(Grant 81773755);Natural Science Foundation of Jiangsu Province(BK20161459,China);Postgraduate Research&Practice Innovation Program of Jiangsu Province(SJCX19_0162,China);the National Students’Platform for Innovation and Entrepreneurship Training Program(201810316010Y,China)

摘　　要：Although interferonα(IFNα)and anti-angiogenesis antibodies have shown appropriate clinical benefit in the treatment of malignant cancer,they are deficient in clinical applications.Previously,we described an anti-vascular endothelial growth factor receptor 2(VEGFR2)-IFNαfusion protein named JZA01,which showed increased in vivo half-life and reduced side effects compared with IFNα,and it was more effective than the anti-VEGFR2 antibody against tumors.However,the affinity of the IFNv component of the fusion protein for its receptor-IFNAR1 was decreased.To address this problem,an IFNα-mutant fused with anti-VEGFR2 was designed to produce anti-VEGFR2-IFNamut,which was used to target VEGFR2 with enhanced anti-tumor and anti-metastasis efficacy.Anti-VEGFR2-IFNamut specifically inhibited proliferation of tumor cells and promoted apoptosis.In addition,antiVEGFR2-IFNαmut inhibited migration of colorectal cancer cells and invasion by regulating the PI3 K-AKT-GSK3β-snail signal pathway.Anti-VEGFR-2-IFNamut showed superior anti-tumor efficacy with improved tumor microenvironment(TME)by enhancing dendritic cell maturation,dendritic cell activity,and increasing tumor-infiltrating CD8+T cells.Thus,this study provides a novel approach for the treatment of metastatic colorectal cancer,and this design may become a new approach to cancer immunotherapy.

关 键 词：Anti-VEGFR2 IFNamut Tumor microenvironment Colorectal cancer Liver metastasis Cancer immunotherapy 

分 类 号：R735.34[医药卫生—肿瘤]