Abstract LB-97: A novel anticancer bispecific antibody targeting VEGF and Dll4 inhibits tumor progression in lung and gastric cancer xenograft models

Abstract

Abstract Several angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathway have been used for cancer treatment. However, VEGF inhibitors alone can promote tumor invasion and metastasis by increase of intratumoral hypoxia in some preclinical models. Emerging reports regarding angiogenesis suggest Delta-like-ligand 4 (Dll4) is a promising target to augment the effects of VEGF inhibitors. Dll4 blockade inhibits tumor progression by increasing nonproductive angiogenesis whereas VEGF blockade inhibits tumor progression by decreasing angiogenesis. To evaluate the effect by inhibiting both VEGF and Dll4 on tumor angiogenesis, we have developed HD105, a novel bispecific antibody targeting VEGF and Dll4, as the format of VEGF-binding IgG linked with Dll4-binding single-chain Fv. The bispecific antibody showed potent binding affinity against VEGF (KD: 3.4 x 10-12 M) and Dll4 (KD: 4.2 x 10-8 M), which are comparable with KD values of anti-VEGF antibody (9.8 x 10-10 M) and Dll4 single targeting antibody (5.5 x 10-9 M). The HD105 bispecific antibody also inhibited interaction of Dll4 and its receptor, Notch 1 (IC50: 1 nM ± 0.2). By using in vitro cell-based assays, the HD105 effectively blocked Dll4 as well as VEGF signaling pathways in endothelial cells, resulting in downregulation of Notch intracellular domain (NICD) and VEGFR-2/extracellular-signal-regulated kinase (ERK) phosphorylation. In addition, the HD105 more efficiently inhibited tumor progression than each single-targeting antibody in A549 human lung cancer and SCH human gastric cancer xenograft models. In conclusion, the novel bispecific antibody could be potentially developed as a clinically more efficacious therapeutic antibody. Citation Format: Weon-Kyoo You, Dongheon Lee, Yu Bin Choi, Kyung Jae Kang, Dong In Kim, Jin-Hyung Ahn, Jinwon Jung, Eun-Sil Sung, Jun Seo Goo, Hyun Sook Jang, Kyung Duk Moon, Sang Hooon Lee. A novel anticancer bispecific antibody targeting VEGF and Dll4 inhibits tumor progression in lung and gastric cancer xenograft models. [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 LB-97. doi:10.1158/1538-7445.AM2014-LB-97