Pathologic neovascularization and vessel leakage are key drivers for vision loss in several back-of-the-eye diseases, such as diabetic retinopathy and age-related macular degeneration. In the eye, integrin receptors play an important role in (pathological) angiogenesis and vascular leakage. Blocking integrin receptors has the potential to inhibit these processes, independent of anti-VEGF responsiveness. In this study, we evaluated the integrin-blocking and anti-angiogenic properties of THR-687, a novel small molecule integrin antagonist.
Competition ELISA assays were used to assess the ability of THR-687 to compete with the binding of integrin receptors to their natural ligands. The inhibitory effect of THR-687 on the migration of human umbilical vein endothelial cells (HUVECs) was evaluated in the ORISTM cell migration assay. The effect of THR-687 on blood vessel outgrowth was evaluated in an ex vivo mouse choroidal explant model as well as in an in vivo cynomolgus choroidal neovascularization model (CNV) model. The safety profile of THR-687 was evaluated in (non)-GLP toxicology studies, including cytotoxicity, genotoxicity, safety pharmacology, ocular and systemic toxicity.
THR-687 was found to inhibit multiple integrin receptors belonging to the RGD class with IC50 values in the low nanomolar range, including, but not limited to, αvβ3, αvβ5 and α5β1. THR-687 inhibited the migration of HUVECs in the ORISTM system (IC50 of 258 ± 65nM) as well as ex vivo choroidal vessel sprouting (IC50 of 176 ± 67nM). Moreover, THR-687 potently inhibited angiogenesis-induced leakage in the cynomolgus CNV model even with the lowest dose tested (0.45 mg/eye). No cytotoxicity or genotoxicity was observed and THR-687 was found to be very well tolerated in safety pharmacology studies. Ocular and systemic toxicity indicate a good safety profile of the compound.
THR-687 is a potent and safe RGD integrin antagonist for the treatment of diabetic eye disease.