VEGFR2-targeted antibody fused with IFNαmut 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
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（2）
• 所属期刊栏目: Original articles
• 页码范围: 420-433
• 页数: 14页
• 语种: 英文

摘要

Although interferon α(IFNα)and anti-angiogenesis antibodies have shown appropriate clin-ical 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)-IFNα fusion 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 IFNαcomponent 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-IFNαmut,which was used to target VEGFR2 with enhanced anti-tumor and anti-metastasis efficacy.Anti-VEGFR2-IFNαmut specifically inhibited proliferation of tumor cells and promoted apoptosis.In addition,anti-VEGFR2-IFNαmut inhibited migration of colorectal cancer cells and invasion by regulating the PI3K-AKT-GSK3β-snail signal pathway.Anti-VEGFR2-IFNαmut showed superior anti-tumor efficacy with improved tumor microenvironment(TME)by enhancing dendritic cell maturation,dendritic cell ac-tivity,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 immu-notherapy.