TTAC-0001, a human monoclonal antibody targeting VEGFR-2/KDR, blocks tumor angiogenesis.
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 naïve 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.
a PharmAbcine, Inc. , #402; DaejeonBioventure Town; Jeonmin-dong; Yusung-gu; Daejeon , Korea.
Weon Sup
WS
Lee
Bo-Jeong
BJ
Pyun
Sung-Woo
SW
Kim
Sang Ryeol
SR
Shim
Ju Ryoung
JR
Nam
Ji Young
JY
Yoo
Younggeon
Y
Jin
Juyoun
J
Jin
Young-Guen
YG
Kwon
Chae-Ok
CO
Yun
Do-Hyun
DH
Nam
Keunhee
K
Oh
Dong-Sup
DS
Lee
Sang Hoon
SH
Lee
Jin-San
JS
Yoo
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009389:Neovascularization, Pathologic; D051381:Rats; D020349:Surface Plasmon Resonance; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D040301:Vascular Endothelial Growth Factor Receptor-2; C570591:olinvacimab
TTAC-0001; VEGF; VEGFR-2(KDR); angiogenesis; anti-VEGFR2 monoclonal antibody; cross species reactivity