Ocular Kinetics, Distribution, and Effects of Human VEGF Isoforms 121 and 165: Implications for Therapeutic...

Targeting VEGF is an established therapeutic strategy for several retinal diseases; however, gaps in understanding the kinetic behavior of VEGF in the eye hinder the interpretation of anti-VEGF pharmacokinetic/pharmacodynamic data. This study aimed to investigate the ocular kinetics, biodistribution, and biological effects of human VEGF isoforms 121 and 165. Thirty rabbits received single intravitreal injections across a 100-fold dose range (0.5-50 μg/eye) for each isoform, followed by a 4-week monitoring period that included ocular examination, imaging, and histopathological assessment. Serial aqueous humor and terminal vitreous humor samples were collected for bioanalytical quantitation. Pharmacokinetic modeling was employed to analyze elimination patterns, and molecular diffusivity was assessed in vitro using fluorescence correlation spectroscopy. Results revealed concentration-dependent elimination for both VEGF isoforms. At aqueous humor concentrations above 100 ng/mL, elimination followed linear kinetics with a half-life of 3.71 days, consistent with diffusion-controlled processes. However, rapid elimination at lower concentrations suggests the involvement of a saturable clearance mechanism, potentially mediated by VEGF receptors at the vitreoretinal interface. Both VEGF121 and VEGF165 induced dose-dependent retinal and iridal neovascularization, along with retinal vessel congestion, tortuosity, leakage, and increased retinal thickness, with no significant differentiation between the two isoforms. The low incidence of antihuman VEGF antibodies indicated minimal immune interference. These findings highlight the importance of accounting for receptor-mediated elimination and VEGF accumulation in designing VEGF-targeted therapies for ocular diseases.