A Highly Active Angiopoietin 1 Mimetic Potentiates Angiogenesis in Mouse Models of Choroidal Neovascularization.

Abstract

PURPOSE: The angiopoietin (ANGPT) pathway, comprised of the ANGPT ligands and their receptor Tie2, mediates angiogenesis and is a compelling target for neovascular age-related macular degeneration (nvAMD). Tie2 phosphorylation by ANGPT1 is associated with vascular stability and may be protective in nvAMD. In contrast, ANGPT2 potentiates angiogenesis and the bispecific ANGPT2/VEGF blocking antibody Faricimab has recently been approved for nvAMD. However, despite clear links between the ANGPT pathway and nvAMD and the success of Faricimab, poor characteristics of existing ANGPT1-based therapies have hindered their adoption as an alternate targeting strategy. METHODS: Hepta-ANGPT1 is an ANGPT1-mimetic fusion protein with improved activity, solubility, and half-life, addressing limitations of earlier mimetics. Here we used laser-induced and RNV3 (JR5558) models of mouse choroidal neovascularization (CNV) to investigate Hepta-ANGPT1 in CNV and explore its potential as a therapy for nvAMD. RESULTS: Hepta-ANGPT1 induced robust Tie2 phosphorylation in the choroid and did not lead to angiogenesis in healthy eyes. However, after laser CNV, we observed increased neovascularization in Hepta-ANGPT1-treated eyes, as well as increased number and size of neovascular lesions in treated RNV3 mice, indicating that Hepta-ANGPT1 potentiated angiogenesis. In contrast, CNV lesion size was smaller in Tie2 knockout mice, and no Hepta-ANGPT1-mediated increase was observed in knockout animals, confirming specificity. CONCLUSIONS: Although previous studies have found ANGPT1 to be protective in mouse CNV, Tie2 activation is pro-angiogenic in other tissues, including the cornea and iridocorneal angle. Hepta-ANGPT1 induced a similar effect in CNV, suggesting that under certain conditions, Tie2 activation can be detrimental in this disease. TRANSLATIONAL RELEVANCE: Understanding the contexts under which Tie2 activation is beneficial and where it is harmful will be critical to successful development of new Tie2-activating drugs for nvAMD.