Abstract 4424: Nonclinical safety evaluation of MEDI0639 (Anti-DLL4 Mab) to support first time In human: linking DLL4-notch signaling blockade to exaggerated pharmacology effects in cynomolgus monkeys.
Authors: Ryan Patricia C. , Huang Jiaqi , Bao Haifeng , Cho Song , Brohawn Philip , Burke Patricia , Lehmann Kim , Pilataxi Fernanda , Yao Yihong , McKeever Kathleen , Dixit Rakesh 
Published: August 2014

Delta-like ligand 4 (DLL4)-Notch signaling regulates several key stages of angiogenesis. MEDI0639 is a human IgG1 antibody that blocks the binding of DLL4 to the Notch receptor and is being developed as a potential anticancer therapy for patients with solid tumors. Cynomolgus monkeys were selected as a pharmacologically relevant species for toxicologic evaluations of MEDI0639. The results of these studies showed dose-dependent MEDI0639-related serious adverse effects associated with possible gastrointestinal bleeding and heart failure. In general, these adverse effects were monitorable, reversible and consistent with the likely pharmacologic effects on vascular homeostasis. Pathologic changes were observed in liver, heart, lung, and thymus. Changes in clinical pathology parameters, such as decreased red blood cell (RBC) mass, were consistent with possible blood loss and responsive erythropoiesis. Elevations in levels of liver enzymes were indicative of hepatocellular injury and were consistent with histopathologic findings in liver. Due to the adverse cardiovascular (CV) findings from repeat-dose toxicity studies, the effects of MEDI0639 on the CV system were characterized in a dedicated CV safety pharmacology study in cynomolgus monkeys. Notable findings from this study were increased levels of C-reactive protein (CRP), blood pressure (BP), and heart rate (HR) which tended to return to baseline levels during an 8-week dose-free recovery period.

In addition to the evaluation of these toxicity parameters, the potential pharmacodynamic (PD) effects of MEDI0639 on circulating endothelial cells (CECs) in whole blood and on RNA expression levels of selected genes in the DLL4 and angiogenesis pathways in samples of colon tissue were assessed. Results showed that mRNA expressions levels of DLL4 and Notch4 were up-regulated when normalized to housekeeping genes while expression levels of Jagged1, Hey1, and Hes1 were down regulated when normalized to the EC surface marker PECAM (CD31) in all MEDI0639-treated groups. The effects of MEDI0639 on EC were confirmed by the observed increase in expression of PECAM in colon tissue and the increased numbers of total, proliferating, and apoptotic CECs in whole blood of MEDI0639-treated animals.

Overall, MEDI0639-related adverse effects were monitorable, reversible and consistent with exaggerated pharmacology effects - that is DLL4 blockade is expected to lead to the formation of immature, disorganized blood vessels with inadequate mural cell coverage. This data was used to determine an appropriate starting dose for a FTIH Phase 1 clinical study of MEDI0639 in cancer patients.

Citation Format: Patricia C. Ryan, Jiaqi Huang, Haifeng Bao, Song Cho, Philip Brohawn, Patricia Burke, Kim Lehmann, Fernanda Pilataxi, Yihong Yao, Kathleen McKeever, Rakesh Dixit. Nonclinical safety evaluation of MEDI0639 (Anti-DLL4 Mab) to support first time In human: linking DLL4-notch signaling blockade to exaggerated pharmacology effects in cynomolgus monkeys. [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 4424. doi:10.1158/1538-7445.AM2013-4424