Abstract
Abstract 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 naïve 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 R&D Project, Ministry for Health & Welfare Affairs (A092255 and A040016) and Advanced Medi-cluster R&D Project, Daejeon TechnoPark, Republic of Korea). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 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
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