(157x) Engineering Superior VEGF Antagonists to Treat Retinal Diseases | AIChE

(157x) Engineering Superior VEGF Antagonists to Treat Retinal Diseases

Authors 

Sargunas, P. - Presenter, Johns Hopkins University
Spangler, J., Johns Hopkins University
Kureshi, R., Johns Hopkins University
Neovascularization in the eye drives the pathogenesis of diseases including age-related macular degeneration and diabetic retinopathy, two of the leading causes of blindness in adults. Obstruction of the interaction between vascular endothelial growth factor (VEGF) ligands and their cognate receptors (VEGFR) shows clinical benefit in the treatment of retinal diseases. However, effective suppression of VEGF signaling and achieving sustained ocular delivery present major unmet medical challenges. The FDA-approved drug aflibercept, an Fc-fused fusion protein chimera of VEGFR that acts as a VEGF decoy, provides a good starting point for VEGF neutralization, but requires further improvements. The affinity of aflibercept for VEGF ligands is equal to that of surface-bound receptors, limiting its potency as an antagonist. Moreover, although aflibercept binds VEGF-A with high affinity, it does not interact with VEGF-C isoforms, which are often upregulated in a compensatory mechanism that leads to drug resistance. Utilizing crystallographic data of VEGF/VEGFR complexes and molecular evolution platforms, we engineered the binding domains of VEGFR to isolate high-affinity aflibercept variants that cross-react with both VEGF-A and VEGF-C isoforms. We characterized the biophysical and functional properties of these engineered variants and demonstrated their therapeutic potential in rodent models of age-related macular degeneration. Overall, our results indicate that these novel antagonists could act as superior therapeutics for the treatment of retinal diseases.