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

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.