Abstract 207: Dual targeting of DLL4 and VEGF signaling by a novel bispecific antibody inhibits tumor growth and reduces cancer stem cell frequency

Both Notch/Delta-like ligand 4 (DLL4) and vascular endothelial growth factor (VEGF) pathways play a critical role in angiogenesis and tumor growth. Due to differential regulatory effects of VEGF and DLL4 on the vasculature, inhibition of DLL4 or VEGF inhibits tumor growth by distinct mechanisms: anti-DLL4 treatment induces an abnormal increase of poorly perfused blood vessels, which results in a nonproductive angiogenesis unable to support tumor growth, whereas the anti-VEGF therapy significantly decreases vasculature reducing the blood supply to tumors. We have recently developed a high binding affinity bispecific monoclonal antibodythat targets both human DLL4 and human VEGF. In vitro, this antibody exhibited nanomolar affinity to hVEGF and hDLL4, and reduced HUVEC proliferation induced by VEGF. The bispecific antibody demonstrated significant in vivo anti-tumor efficacy in various solid tumors, delayed tumor recurrence following termination of chemotherapy, and decreased the frequency of tumor initiatingcells. Analysis of tumor vasculature after treatment with anti-DLL4/VEGF revealed inhibition of vascular gene expression and endothelial cell proliferation, indicating that the anti-VEGF effect on the vasculature is dominant over the anti-DLL4 effect. Notably, at doses where both anti-DLL4 and anti-VEGF alone produced suboptimal anti-tumor effect, dual targeting resulted in additive tumor growth inhibition. These results indicate that our bispecific anti-DLL4/VEGF is broadly efficacious and may be useful for treatment of a variety of solid tumors. Citation Format: Wan-Ching Yen, Fumiko Axelrod, Chris Bond, Jennifer Cain, Cecile Chartier, Marcus Fischer, Shirley Ma, Rene Meisner, Janak Raval, Jalpa Shah, Austin Gurney, John Lewicki, Timothy Hoey. Dual targeting of DLL4 and VEGF signaling by a novel bispecific antibody inhibits tumor growth and reduces cancer stem cell frequency. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 207. doi:10.1158/1538-7445.AM2014-207