Angiopoietin-2 (Ang2), a member of the angiopoietin family, is a glycoprotein critical in regulating vascular development and inflammation. It binds to the Tie2 receptor, primarily expressed on endothelial cells, but unlike its stabilizing counterpart Angiopoietin-1 (Ang1), Ang2 acts as a context-dependent agonist/antagonist. Under pathological conditions like hypoxia or inflammation, Ang2 is upregulated, disrupting vascular integrity by competing with Ang1 for Tie2 binding. This promotes endothelial activation, vascular leakage, and pathological angiogenesis, making it a key player in diseases such as cancer, diabetic retinopathy, and inflammatory disorders.
Ang2-targeting antibodies are designed to inhibit its detrimental effects. These antibodies block Ang2/Tie2 signaling, thereby stabilizing vessels, reducing inflammation, and suppressing tumor growth or abnormal angiogenesis. Preclinical studies highlight their potential in combination therapies, particularly with VEGF inhibitors, to overcome resistance in cancers or retinal diseases. For example, faricimab, a bispecific antibody targeting both Ang2 and VEGF-A, has shown efficacy in clinical trials for age-related macular degeneration and diabetic macular edema.
Despite promise, challenges remain, including understanding tissue-specific Ang2 roles and managing off-target effects. Research continues to optimize antibody design (e.g., bispecific formats) and identify biomarkers for patient stratification. Ang2 antibodies thus represent a versatile therapeutic avenue, bridging vascular biology and immune modulation in complex diseases.