A bispecific decoy receptor VEGFR-EGFR/Fc binding EGF-like ligands and VEGF shows potent antitumor efficacy
A bispecific decoy receptor VEGFR-EGFR/Fc binding EGF-like ligands and VEGF shows potent antitumor efficacy
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DOI：
10.1080/1061186x.2021.1961791
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发表时间：
2021-08-06
影响因子：
4.5
通讯作者：
Zhu, Xiao-Fei
中科院分区：
文献类型：
--
作者：
Guo, Xiao-Fang;Zhang, Yue-Yue;Zhu, Xiao-Fei
表皮生长因子受体(EGFR)和血管内皮生长因子受体(VEGFR)是多种人类癌症的两个临床验证靶点，EGFR和VEGF(R)的双重抑制显示出比单一EGFR抑制剂更好的活性。本研究构建了一种新型的双特异性诱骗受体VEGFR-EGFR/Fc，以人IgG1的Fc段为分子支架，将VEGFR1的免疫球蛋白样区1-3和EGFR的胞外区分别融合到Fc的N端和C端，目的是捕捉EGF样配体和血管内皮生长因子。ELISA法显示VEGFR-EGFR/Fc与EGF、TGF-α和VEGF具有较高的亲和力。四甲基偶氮唑盐比色法显示其对人非小细胞肺癌A549细胞和人脐静脉内皮细胞有明显的增殖抑制作用。创伤愈合实验和Transwell实验显示VEGFR-EGFR/FC显著抑制细胞的侵袭和迁移。在体内，VEGFR-EGFR/FC对A549移植瘤有明显的生长抑制作用。移植瘤组织中也观察到细胞凋亡和血管生成的抑制。在机制上，VEGFR-EGFR/Fc预处理阻断了EGFR和VEGFR2的磷酸化，并导致下游信号分子AKT、p44/42MAPK和p38MAPK的减少。这些数据表明VEGFR-EGFR/FC有望成为癌症靶向治疗的候选药物。
Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) represent two clinically validated targets for a variety of human cancers, and dual inhibition of EGFR and VEGF(R) has demonstrated superior activity to single EGFR inhibitors. This study was to construct a novel bispecific decoy receptor VEGFR-EGFR/Fc that contains Fc portion of human IgG1 acted as molecular scaffold, and the immunoglobulin-like domain 1-3 of VEGFR1 and extracellular domain of EGFR fused to the N-terminal and C-terminal of Fc, respectively, aiming at capturing the EGF-like ligands and VEGF. ELISA showed that VEGFR-EGFR/Fc bound to EGF, TGF-alpha and VEGF with high affinity. It displayed potent proliferation inhibitory effects on human non-small-cell lung cancer A549 cells and human umbilical vein endothelial cells revealed by MTT assays. VEGFR-EGFR/Fc significantly inhibited cell invasion and migration demonstrated by wound healing assay and transwell assay. In vivo, VEGFR-EGFR/Fc showed remarkable growth inhibition on A549 xenografts. Cell apoptosis and inhibition of angiogenesis were also observed in xenograft tumour tissues. Mechanistically, VEGFR-EGFR/Fc pre-treatment blocked the phosphorylation of EGFR and VEGFR2 and resulted in a decrease in the downstream signalling molecules, AKT, p44/42MAPK and p38MAPK. These data suggest VEGFR-EGFR/Fc would be a promising candidate for cancer targeted therapy.