Abstract
Purpose :
Vascular dysfunction, deposition of blood-derived fibrin and subsequent activation of innate Immune cells is a central mechanism underlying neurodegenerative ocular diseases, including diabetic retinopathy (DR), diabetic macular edema (DME) and age-related macular edema (AMD). Conversion of the blood coagulation protein fibrinogen to fibrin by thrombin exposes the epitope, P2, that is cryptic on soluble fibrinogen. Fibrin P2 is an activating ligand for CD11b/CD11c found on microglia and macrophages. The sustained presence of fibrin P2 results in chronic inflammation. We developed a first-in-class humanized anti-fibrin P2 antibody, THN3391, to treat toxic inflammation in neurodegenerative disease and tested it in animal models of ocular diseases
Methods :
We evaluated THN391 in a rat laser-induced choroidal neovascularization (LCNV) model that is used to assess wet AMD. Rats were lasered on Day 0 and injected with THN391, isotype control, or VEGF antagonists (VO-CRO, Nashville, TN). Lesion permeability was assessed by non-invasive quantitative fluorescein angiography (qFA). The extent of CNV was measured post-mortem using image analysis of isolectin-B4-stained choroidal flat-mounts. We evaluated THN393 (mouse chimeric THN391) in a murine STZ model of DR. Diabetes was induced with daily STZ injections, Weekly IP injections were given to 3 groups: 1) nondiabetic, isotype control, 2) diabetic, isotype control and 3) diabetic.
Results :
THN391 shows efficacy in the LCNV model, reducing both CNV area and the permeability of the laser-induced neovascular lesions, measured non-invasively by qFA. qFA was performed longitudinally at 7-, 14- and 28-days post-laser. On Day 7 and Day 14, THN391 and control VEGF antagonists (aflibercept and bevacizumab) significantly reduced lesion permeability. Lesions show recovery on their own by Day 28. In the STZ model, chimeric mouse THN391 (THN393) results were directionally similar as measured by qFA although, but not reaching statistical significance.
Conclusions :
Our results support further clinical development of THN391 to treat neurodegenerative ocular diseases. The role of macrophages may contribute to the resistance and/or loss of efficacy of the VEGF antagonists in retinal diseases. TH391 alone, or in combination with VEGF antagonists, has the potential to treat these diseases and overcome a key resistance mechanism.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.