Abstract 5091: Potent anti-tumor activity of blocking stromal Dll4 in ovarian xenograft models.

Potent anti-tumor activity of blocking stromal Dll4 in ovarian xenograft models Delta-like ligand 4 (Dll4) is an emerging anticancer target given its predominant tumor vasculature expression and its role in regulating angiogenic sprouting. We have previously demonstrated that pharmacological blockade of the Dll4-Notch axis results in an excessive production of aberrant non-functional tumor vessels, and these changes were associated with reduced tumor growth. Using VelocImmune® mice, we identified a fully human IgG1 monoclonal antibody, termed REGN421/SAR153192, which binds human Dll4 and potently neutralizes Notch signaling. REGN421 treatment caused potent and dose-dependent inhibition of a number of human tumor xenografts grown in immunodeficient mice engineered to express human Dll4. In the current study, we found that REGN421 treatment of ovarian xenograft models produces potent anti-tumor effects that are dependent on targeting Dll4 in the tumor stroma as opposed to tumor cell-expressed Dll4. In particular, REGN421 treatment (2.5 mg/kg, once weekly) of humanized Dll4 mice bearing established subcutaneous TOV-112D or intraperitoneal A2780 human tumor xenografts resulted in growth inhibition of 86% and 83%, respectively. The inhibition of ovarian tumor growth by REGN421 was associated with a marked increase in tumor vascular structures but reduced vascular perfusion, consistent with the function of Dll4 as a regulator of angiogenic sprouting. Similar anti-tumor effects were observed by strictly targeting stromal Dll4 with a mouse Dll4-specific surrogate antibody REGN1035 in SCID mice bearing OVCAR3 tumors. In contrast, the specific blockade of tumor cell-expressed human Dll4 did not exhibit any appreciable anti-tumor activity, indicating the lack of tumor growth-promoting autocrine Dll4-Notch tumor cell signaling in these models. Finally, the combined treatment of Dll4 antibody with the anti-VEGF agent ziv-aflibercept (VEGF Trap) resulted in enhanced anti-tumor effects and virtually the complete suppression of intraperitoneal A2780 tumor growth, suggesting clinical benefit for the combined blockade of VEGF and Dll4 in ovarian cancer. These studies lend further support for the therapeutic targeting of Dll4 as a promising new angiogenesis-based anticancer strategy in ovarian cancer, both as a single agent and in combination with anti-VEGF agents. Citation Format: Frank Kuhnert, Guoying Chen, Gavin Thurston. Potent anti-tumor activity of blocking stromal Dll4 in ovarian xenograft models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5091. doi:10.1158/1538-7445.AM2013-5091