Abstract Inhibition of tumor angiogenesis via blockade of vascular endothelial growth factor (VEGF) has proven to be beneficial in several solid tumors. However, anti-VEGF therapies are not curative; thus, there is a significant opportunity to improve efficacy through combination therapy with agents that target other essential angiogenic pathways. Angiopoietin-2 (Ang2), a ligand for the endothelial cell-specific receptor Tie2, is selectively expressed in remodeling blood vessels such as those found in tumors. Furthermore, genetic and pharmacologic data indicate that Ang2 is essential for angiogenesis in several settings. These properties make Ang2 an attractive target for specific inhibition of tumor angiogenesis. We generated a fully-human, Ang2-specific IgG1 monoclonal antibody (REGN910) using VelocImmune technology. REGN910 binds human Ang2 with very high affinity (KD ∼ 18 pM), and potently blocks its interaction with Tie2 (IC50 ∼ 50 pM), thereby inhibiting downstream signaling. In contrast, REGN910 exhibits no binding to Ang1, a Tie2 ligand that is broadly-expressed in normal tissues, and has no effect on Ang1/Tie2 signaling. In tumor xenograft models, REGN910 significantly inhibited the growth of several tumor types in a dose-dependent manner, including PC3 (prostate), Colo205 (colorectal) and A431 (epidermoid carcinoma). Furthermore, the combination of REGN910 plus the potent VEGF blocker aflibercept (VEGF Trap) inhibited tumor growth significantly better than the single agents in both the Colo205 and MMT models, promoting significant regression of Colo205 tumors. Consistent with the potent effect of this combination on tumor growth, REGN910 plus aflibercept reduced Colo205 tumor vascularity and tumor perfusion much more dramatically than the single agents, as monitored by histological and micro-ultrasound analyses. Thus, REGN910 significantly potentiates the effect of VEGF blockade on the function of tumor blood vessels, even in a tumor model (Colo205) that is very sensitive to anti-VEGF therapy. These results indicate that REGN910 is a promising candidate to selectively inhibit tumor angiogenesis, both as a single agent and in combination with anti-VEGF therapies. 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 3290. doi:10.1158/1538-7445.AM2011-3290