Eye Drop Development of Anti-VEGF Therapeutics by Ocular Penetrating Carrier to the Posterior Region of the Eye

Purpose: To develop an eye drop to deliver therapeutic antibodies, such as aflibercept, into the eye to avoid invasive intravitreal injection (IVT). Methods: We modified and screened cell penetrating peptides (CPPs) for enhanced ocular penetration of large molecule anti-VEGF drugs via eye drop. Modifications to make ocular penetrating carriers (OPCs) included amino acid substitutions, deletions, and multimerization. OPC activity was determined by measuring intraocular levels of aflibercept alone or with anti-Ang2 after formulation with OPC and eye drop application onto mouse eyes. To determine if the aflibercept/OPC eye drop can penetrate large animal eyes in vivo, we applied 50 µg eye drops onto pig eyes. The efficacy of aflibercept/OPC eye drop (20 µg, five drops per day) was determined in a mouse model of laser induced choroidal neovascularization (CNV) and compared to IVT injection of aflibercept. Results: OPC-formulated eye drops improved intraocular delivery of aflibercept up to sixfold in mouse eyes compared to a previously published CPP. In a mouse model of CNV, aflibercept/OPC eye drop treatment decreased vascular leakage, lesion volume, and CNV area by 20% to 50%. The efficacy of aflibercept/OPC eye drop treatment was similar to IVT injection of aflibercept (20 µg). Intraocular penetration of select OPCs was confirmed in pig eyes. Additionally, we demonstrated that a single OPC eye drop can deliver two different protein therapeutics into the eye. Conclusions: Aflibercept/OPC application demonstrates efficacy comparable to IVT injections in a mouse CNV model, supporting its potential as an alternative non-invasive delivery method into the posterior segment. Translational Relevance: OPC eye drop delivery of large molecule therapeutics for AMD, DR, and DME is a noninvasive delivery method that could improve patient adherence.