Novel hKDR mouse model depicts the antiangiogenesis and apoptosis-promoting effects of neutralizing antibodies targeting vascular endothelial growth factor receptor 2

被引:1
作者
Cao, Yuan [1 ]
Sun, Chunyun [2 ]
Huo, Guitao [3 ]
Wang, Huiyu [2 ]
Wu, Yong [1 ]
Wang, Fei [2 ]
Liu, Susu [1 ]
Zhai, Shijie [1 ]
Zhang, Xiao [2 ]
Zhao, Haoyang [1 ]
Hu, Meiling [2 ]
Gu, Wenda [1 ]
Yang, Yanwei [3 ]
Wang, Sanlong [3 ]
Liang, Chunnan [1 ]
Lyu, Jianjun [1 ]
Lu, Tiangong [4 ]
Wang, Youchun [5 ]
Xie, Liangzhi [2 ,6 ,7 ]
Fan, Changfa [1 ]
机构
[1] Natl Inst Food & Drug Control NIFDC, Natl Rodent Lab Anim Resources Ctr, Inst Lab Anim Resources, Div Anim Model Res, Beijing, Peoples R China
[2] Sinocelltech Ltd, Beijing Engn Res Ctr Prot & Antibody, 31 Kechuang 7th St, Beijing, Peoples R China
[3] Natl Inst Food & Drug Control NIFDC, Inst Food & Drug Safety Evaluat, Natl Ctr Safety Evaluat Drugs, Beijing, Peoples R China
[4] Beijing Univ Chinese Med, Sch Life Sci, Beijing, Peoples R China
[5] Natl Inst Food & Drug Control NIFDC, Inst Biol Prod Control, Div HIV AIDS & Sexually Transmitted Virus Vaccine, 31 Huatuo Rd, Beijing 102629, Peoples R China
[6] Sino Biol Inc, Beijing Key Lab Monoclonal Antibody Res & Dev, Beijing, Peoples R China
[7] Chinese Acad Med Sci & Peking Union Med Coll, Cell Culture Engn Ctr, Beijing, Peoples R China
关键词
antiangiogenesis; hKDR humanized mouse; monoclonal antibody; tumor; VEGFR2-HK19; RAMUCIRUMAB IMC-1121B; TUMOR ANGIOGENESIS; VEGF; EXPRESSION; CANCER; CELLS; MECHANISMS; INHIBITOR; AFFINITY; PATHWAY;
D O I
10.1111/cas.15594
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Vascular endothelial growth factor receptor 2 (VEGFR2)/KDR plays a critical role in tumor growth, diffusion, and invasion. The amino acid sequence homology of KDR between mouse and human in the VEGF ligand-binding domain was low, thus the WT mice could not be used to evaluate Abs against human KDR, and the lack of a suitable mouse model hindered both basic research and drug developments. Using the CRISPR/Cas9 technique, we successfully inserted different fragments of the human KDR coding sequence into the chromosomal mouse Kdr exon 4 locus to obtain an hKDR humanized mouse that can be used to evaluate the marketed Ab ramucirumab. In addition, the humanized mAb VEGFR-HK19 was developed, and a series of comparative assays with ramucirumab as the benchmark revealed that VEGFR-HK19 has higher affinity and superior antiproliferation activity. Moreover, VEGFR-HK19 selectively inhibited tumor growth in the hKDR mouse model but not in WT mice. The most important binding epitopes of VEGFR2-HK19 are D257, L313, and T315, located in the VEGF binding region. Therefore, the VEGFR2-HK19 Ab inhibits tumor growth by blocking VEGF-induced angiogenesis, inflammation, and promoting apoptosis. To our best knowledge, this novel humanized KDR mouse fills the gaps both in an animal model and the suitable in vivo evaluation method for developing antiangiogenesis therapies in the future, and the newly established humanized Ab is expected to be a drug candidate possibly benefitting tumor patients.
引用
收藏
页码:115 / 128
页数:14
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