(27v) Engineering Bispecific Receptor Decoy Antagonists to Treat Neovascular Eye Diseases

Vision loss is a global public health issue that profoundly hinders patient quality of life and poses a substantial economic burden on healthcare systems. Two leading causes of vision impairment in adults are age-related macular degeneration (AMD) and diabetic retinopathy (DR), which are driven by ocular neovascularization, the growth of abnormal blood vessels in the eye. Vascular endothelial growth factor (VEGF) ligands are one of the primary drivers of neovascularization; thus, blocking the interaction of these ligands with their cognate receptors (VEGFRs) has become a clinically promising approach for the treatment of AMD and DR. Current FDA-approved therapies targeting the VEGF pathway mainly inhibit signaling of VEGF-A, which is the most well-known promoter of blood vessel formation. However, VEGF-C can also be a potent driver of neovascularization and is known to be upregulated to compensate for VEGF-A inhibition, which often results in therapeutic resistance. No current therapies exist that target both VEGF-A and VEGF-C to more comprehensively inhibit neovascularization. We designed bispecific receptor decoy fusion proteins comprised of the binding domains of VEGFR-1 and VEGFR-2 fused to a dimerizing human Fc to create novel antagonists capable of binding both VEGF-A and VEGF-C simultaneously. We have characterized the binding of these proteins and conducted functional assays to explore their efficacy as inhibitors of VEGF ligand signaling and angiogenesis. Our novel antagonist format could lead to superior therapeutics that completely inhibit ocular neovascularization and overcome therapeutic resistance to VEGF-targeted therapies.