The Notch ligand delta-like 4 (Dll4) has been identified as a promising new target in tumor angiogenesis in preclinical studies, and Dll4 inhibitors have recently entered clinical trials for solid tumors, including ovarian cancers. We previously demonstrated that pharmacological blockade of the Dll4-Notch axis results in tumor vessel abnormalization and associated reduction of tumor growth. Using VelocImmune® mice, we identified a fully human IgG1 monoclonal antibody, REGN421 (called enoticumab), which binds human Dll4 with sub-nanomolar affinity and potently inhibits Notch signaling. Treatment of immunodeficient mice engineered to express human Dll4 with enoticumab inhibited growth of several human tumor xenografts and induced non-functional tumor blood vessels. In ovarian tumor xenograft models, Dll4 was expressed specifically by tumor endothelium, and blockade of Dll4 with either human- or mouse-specific Dll4 antibodies showed potent anti-tumor activity was entirely dependent on targeting stromal Dll4 but not tumor cell-expressed Dll4. Blockade of Dll4 reduced Notch signaling in both blood vessels and in tumor cells surrounding blood vessels, suggesting that Dll4 on endothelial cells could induce Notch signaling on ovarian tumor cells. The anti-tumor activity of Dll4 blockade in ovarian tumors was markedly augmented by simultaneous inhibition of VEGF signaling. Importantly, the combined blockade of Dll4 and VEGF reversed normal organ vascular changes that were induced by Dll4 blockade alone. These studies lend further support for therapeutic targeting of Dll4 as a promising new angiogenesis-based anticancer strategy in ovarian cancer, in particular in combination with anti-VEGF agents.

Citation Format: Frank Kuhnert, Guoying Chen, Sandra Coetzee, Jessica Kirshner, Gavin Thurston. Potent antitumor activity of Dll4 blockade in ovarian xenografts mediated by blocking stromal Dll4. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr A19.