Angiopoietin-2 Antagonists for Anti-Angiogenic Therapy

Abstract

Interactions between Tie2, an endothelial cell-specific receptor tyrosine kinase, and its ligands the angiopoietins have been shown to play critical roles in multiple steps of angiogenesis and vascular remodeling. These include the stabilization of immature vessels, the destabilization of mature vessels, and endothelial cell migration and survival. Angiopoietin 1 has been shown to be a Tie2 agonist, stimulating autophosphorylation and the activation of downstream signaling pathways responsible for the maturation and stabilization of the developing vasculature. In contrast, angiopoietin 2 is largely thought to function as a contextdependent antagonist of Tie2 signaling, inducing vascular plasticity and sensitivity to pro-angiogenic factors such as VEGF-A. Furthermore, Ang2 exhibits broad expression in the vasculature of human tumors but limited expression in normal tissues, suggesting it could be an attractive target for safe and effective anti-angiogenic therapy. Potent and specific antibodies and peptideFc fusion proteins neutralizing the interaction between Ang2 and Tie2 have now been developed. In a variety of nonclinical studies in rodents, treatment with these agents resulted in an inhibition of the growth of human tumor xenografts and an inhibition of VEGF-stimulated corneal angiogenesis. In addition, mechanism of action studies suggest that Ang2 antagonists achieve efficacy by targeting the tumor vasculature. Data in support of the clinical utility of Ang2 inhibition in the oncology setting is currently being collected, with AMG 386, an Ang2 inhibitor, having been advanced into phase I oncology clinical trials in patients with solid tumors.