TTAC-0001, a human monoclonal antibody targeting VEGFR-2/KDR, blocks tumor angiogenesis

被引：19

作者：

Lee, Weon Sup ^{[1
]}

Pyun, Bo-Jeong ^{[2
]}

Kim, Sung-Woo ^{[1
]}

Shim, Sang Ryeol ^{[1
]}

Nam, Ju Ryoung ^{[1
]}

Yoo, Ji Young ^{[3
]}

Jin, Younggeon ^{[4
]}

Jin, Juyoun ^{[4
]}

Kwon, Young-Guen ^{[2
]}

Yun, Chae-Ok ^{[5
]}

Nam, Do-Hyun ^{[4
]}

Oh, Keunhee ^{[6
]}

Lee, Dong-Sup ^{[6
]}

Lee, Sang Hoon ^{[1
]}

Yoo, Jin-San ^{[1
]}

机构：

[1] PharmAbcine Inc, Daejeon, South Korea

[2] Yonsei Univ, Dept Biochem, Coll Life Sci & Biotechnol, Seoul 120749, South Korea

[3] Yonsei Univ, Coll Med, Brain Korea Project Med Sci 21, Seoul, South Korea

[4] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Neurosurg, Seoul, South Korea

[5] Hanyang Univ, Coll Engn, Dept Bioengn, Seoul 133791, South Korea

[6] Seoul Natl Univ, Coll Med, Transplantat Res Inst, Dept Biomed Sci, Seoul, South Korea

来源：

MABS | 2015年 / 7卷 / 05期

关键词：

TTAC-0001; anti-VEGFR2 monoclonal antibody; angiogenesis; cross species reactivity; VEGFR-2(KDR); VEGF; ENDOTHELIAL GROWTH-FACTOR; RECEPTOR TYROSINE KINASE; IN-VIVO; ANTITUMOR-ACTIVITY; CANCER-CELLS; VEGF-C; INHIBITION; THERAPY; BEVACIZUMAB; RESISTANCE;

D O I：

10.1080/19420862.2015.1045168

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Angiogenesis is one of the most important processes for cancer cell survival, tumor growth and metastasis. Vascular endothelial growth factor (VEGF) and its receptor, particularly VEGF receptor-2 (VEGFR-2, or kinase insert domain-containing receptor, KDR), play critical roles in tumor-associated angiogenesis. We developed TTAC-0001, a human monoclonal antibody against VEGFR-2/KDR from a fully human naive single-chain variable fragment phage library. TTAC-0001 was selected as a lead candidate based on its affinity, ligand binding inhibition and inhibition of VEGFR-2 signal in human umbilical vein endothelial cells (HUVEC). TTAC-0001 inhibited binding of VEGF-C and VEGF-D to VEGFR-2 in addition to VEGF-A. It binds on the N-terminal regions of domain 2 and domain 3 of VEGFR-2. It could inhibit the phosphorylation of VEGFR-2/KDR and ERK induced by VEGF in HUVEC. TTAC-0001 also inhibited VEGF-mediated endothelial cell proliferation, migration and tube formation in vitro, as well as ex vivo vessel sprouting from rat aortic rings and neovascularization in mouse matrigel model in vivo. Our data indicates that TTAC-0001 blocks the binding of VEGFs to VEGFR-2/KDR and inhibits VEGFR-induced signaling pathways and angiogenesis. Therefore, these data strongly support the further development of TTAC-0001 as an anti-cancer agent in the clinic.

引用

页码：957 / 968

页数：12

共 45 条

[1] An Autocrine VEGF/VEGFR2 and p38 Signaling Loop Confers Resistance to 4-Hydroxytamoxifen in MCF-7 Breast Cancer Cells [J].