Abstract
Purpose :
Tie2 receptor is mainly expressed in endothelial cells that modulates angiogenesis with angiopoietins (Ang) binding. VEGF neutralizing molecules were approved to treat neovascular ocular diseases but there still is a great need to develop therapeutic agents to treat the patients who do not respond well to anti-VEGF drugs. We recently isolated a Tie2 activating antibody, PMC-403 and are evaluated its potential therapeutic potential to treat neovascular diseases.
Methods :
Experimental CNV was induced by laser photocoagulation in C57BL/6 mice and in rhesus monkeys. The animals received IVT administration of aflibercept or PMC-403 and the dose dependent responses were measured in multiple assays: 1) FFA, OCT and ERG were evaluated. 2) The number of leakage spots, the percent changes of leakage area, and the maximum retinal thickness of laser-burned spots were evaluated. 3) In the monkey CNV model, the level of mRNA expression of 10 genes related to angiogenesis and inflammation was measured.
Results :
In similar to Ang1, PMC-403 activated Foxo-1 phosphorylation, inhibited VEGFR-2 phosphorylation, and reduced the Survivin expression in HUVEC cells. In a mouse CNV model, PMC-403 reduced the thickness and the leakage of retinal blood vessels comparable to aflibercept in accompanied with improvement of the sensitivity of optic nerves. In a monkey CNV models, PMC-403 improved retina thickness and vessel leakage but the response rate was slower in comparison to aflibercept. Interestingly, PMC-403 showed better responses in sensitivity of optic nerves than aflibercept with decreased level of pro-angiogenesis genes such as Ang2, VEGF, PlGF, and PDGF. In addition, the level of pericyte in retina was dramatically increased by PMC-403 without inflammation.
Conclusions :
PMC-403 improved sensitivity of optic neurons in animal CNV models through a normalization of leaky blood vessels. These data strongly support the notion that PMC-403 stabilizes retinal and choroidal blood vessels and it can be developed as an effective therapeutic agent to treat a wide variety of retinal and choroidal vascular disorders.
This is a 2021 ARVO Annual Meeting abstract.