Abstract
The Notch signaling pathway has been implicated in cell fate determination and differentiation in many tissues. Accumulating evidence points toward a pivotal role in blood vessel formation, and the importance of the Delta-like ligand (Dll) 4-Notch1 ligand-receptor interaction has been shown in both physiological and tumor angiogenesis. Disruption of this interaction leads to a reduction in tumor growth as a result of an increase in nonfunctional vasculature leading to poor perfusion of the tumor. MEDI0639 is an investigational human therapeutic antibody that targets Dll4 to inhibit the interaction between Dll4 and Notch1. The antibody cross-reacts to cynomolgus monkey but not mouse species orthologues. In vitro MEDI0639 inhibits the binding of Notch1 to Dll4, interacting via a novel epitope that has not been previously described. Binding to this epitope translates into MEDI0639 reversing Notch1-mediated suppression of human umbilical vein endothelial cell growth in vitro. MEDI0639 administration resulted in stimulation of tubule formation in a three-dimensional (3D) endothelial cell outgrowth assay, a phenotype driven by disruption of the Dll4-Notch signaling axis. In contrast, in a two-dimensional endothelial cell-fibroblast coculture model, MEDI0639 is a potent inhibitor of tubule formation. In vivo, MEDI0639 shows activity in a human endothelial cell angiogenesis assay promoting human vessel formation and reducing the number of vessels with smooth muscle actin-positive mural cells coverage. Collectively, the data show that MEDI0639 is a potent modulator of Dll4-Notch signaling pathway.
Highlights
The Notch signaling cascade is an evolutionarily conserved pathway that has been implicated in cell fate determination, stem cell maintenance, and differentiation in many tissues during development [1, 2]
This effect is consistent with previously published studies that highlight the role of Dll4 as a negative regulator of angiogenesis and the phenotypic consequence of inhibition being an increase in vessel branching due to an increase in the number of tip cells [18, 19, 30]
MEDI0639 was evaluated in a 2D coculture assay, in which endothelial tubes form on top of a fibroblast monolayer
Summary
The Notch signaling cascade is an evolutionarily conserved pathway that has been implicated in cell fate determination, stem cell maintenance, and differentiation in many tissues during development [1, 2]. Deletion of a single allele of Dll, which is the only Notch ligand expressed predominantly in the endothelium, results in embryonic lethality with severe vascular defects in most genetic backgrounds in mice [6,7,8]. This phenotype has only previously been reported for VEGF-A and suggests. The effect of blocking Dll signaling on tumor growth has been evaluated in several preclinical xenograft models of human cancer in which either tumor cell lines or primary human tumors are grown subcutaneously in immunodeficient mice [17, 19, 20] In these studies, reductions in tumor growth have been reported. We describe the in vitro and in vivo characterization of a human antiDll4–specific monoclonal antibody, MEDI0639, which targets a novel epitope on Dll and is a potent modulator of Dll4-Notch signaling
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