Abstract C164: Dual targeting of the DLL4 and VEGF pathways with a bispecific monoclonal antibody inhibits tumor growth and reduces cancer stem cell frequency

Abstract

Abstract 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, blockade of DLL4 or VEGF signaling inhibits tumor growth by distinct mechanisms: anti-DLL4 treatment induces an abnormal increase of poorly perfused blood vessels, which results in nonproductive angiogenesis unable to support tumor growth, whereas anti-VEGF therapy significantly decreases vasculature reducing the blood supply to tumors. In addition, DLL4-Notch signaling plays a key role in the maintenance of cancer stem cells. We have recently developed a bispecific monoclonal antibody that targets both human DLL4 and human VEGF (OMP-305B83). In vitro, this antibody exhibited low nanomolar binding affinity to hVEGF and hDLL4, and reduced human endothelial cell proliferation induced by VEGF. The bispecific antibody demonstrated significant in vivo anti-tumor efficacy in various solid tumors, induced tumor regression, decreased the frequency of tumor initiating cells, and delayed tumor recurrence following termination of chemotherapy. 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 produces suboptimal anti-tumor effect, dual targeting resulted in additive tumor growth inhibition. The combination of anti-DLL4 and anti-VEGF resulted in broad spectrum efficacy in many different solid tumor types including breast, colon, ovarian and pancreatic tumors. Notably, serial transplantation studies indicated that the anti-cancer stem cell activity of anti-DLL4 was retained with the bispecific. In safety studies, OMP-305B83 demonstrated an improved cardiac profile in cynomolgus monkeys compared to anti-DLL4 with reduction of endothelial hyperplasia and suppression of vascular-related gene upregulation in the heart. These results indicate that our bispecific anti-DLL4/VEGF is broadly efficacious and may be useful for treatment of a variety of tumor types. We are currently enrolling patients with advanced refractory solid tumors in a Phase 1a clinical trial. Citation Format: Wan-Ching Yen, Marcus M. Fischer, Gretchen Argast, Breanna Wallace, Min Wang, Rene Meisner, John Lewicki, Ann M. Kapoun, Austin Gurney, Timothy Hoey. Dual targeting of the DLL4 and VEGF pathways with a bispecific monoclonal antibody inhibits tumor growth and reduces cancer stem cell frequency. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C164.