Abstract 5098: A mouse DLL4 cross-reactive variant of MEDI0639 disrupts functional vessel formation and inhibits tumor growth in preclinical models.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Delta-like ligand 4 (DLL4) is a membrane bound ligand for Notch receptors essential for functional vessel formation during development and angiogenesis. We have shown previously that MEDI0639, a human anti-DLL4 antibody, has potent in vitro and in vivo activity in blocking DLL4-Notch interaction. However, because MEDI0639 has low binding affinity to mouse DLL4, to enable in vivo pharmacology studies using xenograft tumor models in mice, MEDI0639 was engineered to bind more strongly to mouse DLL4. The resulting affinity-optimized variant antibody (anti-mDLL4 mAb) bound with high affinity to both human and mouse DLL4 and maintained binding specificity to DLL4. In a number of human cancer xenograft models in nude mice, the MEDI0639 variant antibody markedly inhibited the growth of tumors. qRT-PCR analysis using the Fluidigm platform showed decreases in mouse genes downstream of the Notch signaling pathway at efficacious doses, indicating on-target antibody effect on tumor vasculature. In addition, IHC and imaging analysis of xenograft tumors from the anti-DLL4 mAb dosed animals showed a dose-dependent increase in microvessel density and decrease in tumor perfusion compared to the control groups. In summary, we describe here the generation of mouse and human DLL4 cross-reactive antibody and the utilization of this antibody in demonstrating a positive correlation between the anticipated mechanism of action of DLL4 blockade on vasculature and inhibition of tumor growth. Citation Format: Song H. Cho, David W. Jenkins, Patrick Strout, Martin Korade, Haihong Zhong, Ching Ching Leow, Shannon Breen, Jon Chesebrough, Nicholas Holoweckyj, Ivan Inigo, Gennady Gololobov, Ping Tsui, Kimberly Cook, Melissa Damschroder, Meggan Czapiga, Philip Brohawn, Jiaqi Huang, Sally-Ann Ricketts, Juliana Maynard, Adeela Kamal. A mouse DLL4 cross-reactive variant of MEDI0639 disrupts functional vessel formation and inhibits tumor growth in preclinical 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 5098. doi:10.1158/1538-7445.AM2013-5098