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

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.