Sung-Woo Kim

Anticancer activity of TTAC-0001, a fully human anti-vascular endothelial growth factor receptor 2 (VEGFR-2/KDR) monoclonal antibody, is associated with inhibition of tumor angiogenesis

Vascular endothelial growth factor (VEGF) and its receptors are considered the primary cause of tumor-induced angiogenesis. Specifically, VEGFR-2/kinase insert domain receptor (KDR) is part of the major signaling pathway that plays a significant role in tumor angiogenesis, which is associated with the development of various types of tumor and metastasis. In particular, KDR is involved in tumor angiogenesis as well as cancer cell growth and survival. In this study, we evaluated the therapeutic potential of TTAC-0001, a fully human antibody against VEGFR-2/KDR. To assess the efficacy of the antibody and pharmacokinetic (PK) relationship in vivo, we tested the potency of TTAC-0001 in glioblastoma and colorectal cancer xenograft models. Antitumor activity of TTAC-0001 in preclinical models correlated with tumor growth arrest, induction of tumor cell apoptosis, and inhibition of angiogenesis. We also evaluated the combination effect of TTAC-0001 with a chemotherapeutic agent in xenograft models. We were able to determine the relationship between PK and the efficacy of TTAC-0001 through in vivo single-dose PK study. Taken together, our data suggest that targeting VEGFR-2 with TTAC-0001 could be a promising approach for cancer treatment.

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.

Abstract 4244: TTAC-0001, fully human anti-VEGFR2/KDR neutralizing antibody blocks tumor angiogenesis and tumor growth

Angiogenesis, the recruitment of new blood vessels is a crucial mechanism required for both tumor growth and metastasis. Vascular endothelial growth factor (VEGF) and its receptors, particularly VEGF receptor 2 (VEGFR2, or kinase insert domain-containing receptor, KDR), play a critical role in tumor-associated angiogenesis. Monoclonal antibodies (mAb), due to their high specificity towards a given target, represent a unique class of novel therapeutics as angiogenesis inhibitors. We developed TTAC-0001, anti-KDR antibody from a fully human naive single chain variable fragment (ScFv) phage library. Interestingly, TTAC-0001 displayed cross reactivity against murine homologue, Flk-1, which allows us to evaluate the anti-tumor efficacy in various in vivo models. TTAC-0001 inhibits VEGF-mediated proliferation and migration. In HUVEC, TTAC-0001 inhibited the phosphorylation of VEGFR2/KDR and ERK mediated by VEGF. TTAC-0001 inhibited VEGF-mediated sprouting endothelial cells from rat aortic rings and showed a potent anti-angiogenic activity in VEGF-mediated matrigel model in nude mice. Further in vivo anti-tumor efficacy of TTAC-0001 was seen in the xenografts of A549 (lung) and HCT116 (colorectal) human cancer. These changes were accompanied by the inhibition of microvessel density and induction of apoptosis in the tumors. In summary, our data indicates that TTAC-0001 blocks the binding of VEGF to VEGFR2/KDR and inhibits VEGFR-induced angiogenesis. Therefore, this data strongly supports for the further development of TTAC-0001 as an anti-cancer agent (This study was supported by grants of the Korea Healthcare technology RD 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4244. doi:10.1158/1538-7445.AM2011-4244