| Popis: |
To evaluate the molecular, pharmacokinetic, and pharmacological properties of three anti-vascular endothelial growth factor (VEGF) agents-aflibercept, brolucizumab, and ranibizumab-and to provide a prediction of the optimal design of an intravitreal VEGF challenge in rabbits to assess the preclinical in vivo activity of the different anti-VEGF agents.Biochemical analyses and cellular and animal models of retinopathy were used to characterize anti-VEGF efficacy. Anti-VEGF biochemical binding affinity was determined through a kinetic exclusion assay. The in vitro potency was investigated by a calcium mobilization assay. Pharmacokinetic parameters were estimated for each drug to predict intraocular exposure relationships among the agents. The in silico modeling efforts informed the design of an in vivo rabbit model of VEGF-induced retinal hyperpermeability to determine the extent of VEGF neutralization in vivo. Consequently, data generated from the in vivo study enabled pharmacokinetic analysis and the generation of a logistical model describing the impact of the anti-VEGF agents on the VEGF-induced vascular leakage in rabbits.The three anti-VEGF agents ranked from most efficacious to least efficacious as aflibercept, brolucizumab, and ranibizumab, with results consistent and significant within each individual characterization experiment.This composite study demonstrated how the molecular properties of aflibercept, brolucizumab, and ranibizumab translate into differences of in vivo efficacy, with results in line with the reported literature.In silico, in vitro, and in vivo integrated studies provide information that enables the enhanced characterization of translational properties of anti-VEGF agents currently used for the treatment of retinal diseases. |
