双功能VEGF受体融合蛋白突变体的生物学活性研究  

Characterization of a novel vascular endothelial growth factor receptor-immunoglobulin fusion protein variant

作　　者：王韬[1,2] 张大鹏[2,3] 杨扬[2] 许静[2] 石金平[2] 钱卫珠[2,3] 李博华[2,3] 魏于全[1] 王皓[2,3] 

机构地区：[1]四川大学国家生物治疗重点实验室,成都610065 [2]第二军医大学肿瘤研究所,上海200433 [3]抗体药物国家工程研究中心,上海201203

出　　处：《现代免疫学》2010年第5期361-364,共4页Current Immunology

基　　金：国家自然科学基金重点资助项目(30801085)

摘　　要：为了研制出能同时阻断肿瘤血管与淋巴管生成的抗肿瘤制剂,我们设计构建了同时包含VEGFR1和VEGFR3功能域的基因工程双功能融合受体(VEGFRIg)。为了改善VEGFRIg的血浆半衰期以增强其抗肿瘤疗效,我们选择VEGFRIg的3个碱性氨基酸进行突变诱导获得了双功能受体的突变体VEGFRIgm。研究结果表明,VEGFRIgm具有与VEGFRIg相似的与VEGF-A和VEGF-C结合的能力,能有效地抑制VEGF-A诱导的人脐静脉内皮细胞增殖及VEGF-C诱导的人皮肤淋巴内皮细胞增殖。进一步研究表明,VEGFRIgm在小鼠体内的半衰期比VEGFRIg显著延长,提示其可能发展成为一个新型的高效抗肿瘤药物。In an attempt to develop antitumor agent which can block both tumor angiogenesis and lymphangiogenesis,we generated a fusion protein molecule [vascular endothelial growth factor（VEGF） receptor-immunoglobulin（VEGFRIg）] which could simultaneously bind the angiogenic growth factor VEGF-A and the lymphangiogenic growth factor VEGF-C.To improve the pharmacokinetic profile of VEGFRIg,VEGFRIgM by introducing the 3 point-mutations to VEGFRIg was developed.Our data showed that VEGFRIgM had a similar ability as VEGFRIg to bind both VEGF-A and VEGF-C,effectively inhibiting the growth of VEGF-A stimulated human umbilical vein endothelial cells and VEGF-C stimulated human dermal lymphatic endothelial cells.The pharmacokinetics of VEGFRIgM were further measured in mice and compared with VEGFRIg.Results indicated that the maximal concentration of VEGFRIgM was significantly higher than that of VEGFRIg.Taken together,it is evident that the VEGFRIgM fusion protein specifically binding to both VEGF-A and VEGF-C simultaneously may provide a novel agent for treatment of metastatic diseases.

关 键 词：血管内皮生长因子受体 血管内皮细胞 淋巴管内皮细胞 半衰期 抗肿瘤活性 

分 类 号：R392.11[医药卫生—免疫学]