Direct Tie2 Agonists Stabilize Vasculature for the Treatment of Diabetic Macular Edema

Abstract

Purpose Diabetic macular edema (DME) is the leading cause of vision loss and blindness among working-age adults. Although current intravitreal anti-vascular endothelial growth factor (VEGF) therapies improve vision for many patients with DME, approximately half do not achieve the visual acuity required to drive. We therefore sought additional approaches to resolve edema and improve vision for these patients. Methods We explored direct agonists of Tie2, a receptor known to stabilize vasculature and prevent leakage. We identified a multivalent PEG–Fab conjugate, Tie2.1-hexamer, that oligomerizes Tie2 and drives receptor activation and characterized its activities in vitro and in vivo. Results Tie2.1-hexamer normalized and stabilized intercellular junctions of stressed endothelial cell monolayers in vitro, suppressed vascular leak in mice under conditions where anti-VEGF alone was ineffective, and demonstrated extended ocular exposure and robust pharmacodynamic responses in non-human primates. Conclusions Tie2.1-hexamer directly activates the Tie2 pathway, reduces vascular leak, and is persistent within the vitreal humor. Translational Relevance Our study presents a promising potential therapeutic for the treatment of DME.

Translatability of In Vitro Stress for Predicting Deamidation and Oxidation Biotransformation on Biotherapeutics

“…(a) Plot reflecting in vivo oxidation progression on Molecule W ( n = 2) obtained from rabbit vitreous humor over a 3-week pharmacokinetic study (collection points at day 0, 14, and 21). A similar result (up to 40% oxidation over 14 days) was observed by our group in cynomolgus monkey vitreous humor . (b) Plot depicting the progressive increase of deamidation observed on Molecule Y, from serum samples, that was intravenously dosed in cynomolgus monkey (triplicate biological replicates, at time points 0.01, 0.08, 0.25, 2, 6, 1, 2, 4, 7, 10, and 14 days.…”

“…Notably, oxidation increased consistently by up to 40% (absolute percentage basis) over a 3-week period in both eyes. Note that we also observed up to 40% oxidation for this molecule at the same amino acid residue in cynomologus monkey vitreous humor …”

Microvascular destabilization and intricated network of the cytokines in diabetic retinopathy: from the perspective of cellular and molecular components

“…In diabetic rat retinas, Ang-2 expression was increased significantly (about 30-fold and more); and the pericyte loss was detected in the retinas [ 206 ]. A direct Tie2 agonist, Tie2.1-hexamer, was reported to stabilize the retinal vessel both in vitro and in vivo [ 207 ]. Ang-2 was increased in the intraocular samples of the patients with DR and other retinal or choroidal vascular diseases [ 208 , 209 ].…”

A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future

“…Higher valency and higher density, altered by the length and number of PEG arms, led to increased in vitro activity in cellular assays. Treatment with the anti-Tie2 hexamer resulted in a bell-shaped activity curve, suggesting that clustering of the cell-surface Tie2 receptor drives downstream signaling [ 299 ].…”