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Clinical anti-vascular epithelial growth factor (VEGF) therapy trials faced a major challenge due to upregulated expression of other pro-angiogenic factors, such as fibroblast growth factor-2 (FGF-2). RC28, a novel recombinant dual decoy receptor IgG1 Fc-fusion protein, can block VEGFA and FGF-2 simultaneously. It is designed for the treatment of neovascular age-related macular degeneration and other pathological ocular neovascularization. The present study investigated the prevention efficacy of RC28 on choroidal neovascularization (CNV) in a monkey model and compared to the other mono VEGF antagonists; biodistribution and pharmacokinetics performance were also investigated.ELISA and endothelial cell proliferation, migration, and tubule formation assay evaluated the bioactivity of RC28 in vitro, and an initial comparison was made among the mono target antagonists, Bevacizumab (Avastin), Ranibizumab (Lucentis), Aflibercept (EYLEA), Conbercept (KH902), and Ranibizumab (Lucentis). Laser-induced CNV in monkeys, and both VEGF and FGF-2 serum levels were detected in animals before and after the CNV model were induced. RC28 prevention efficacy was compared to other VEGF antagonists on CNV with respect to the incidence of CNV and several ophthalmic examinations. Ocular and systemic levels of RC28 were analyzed by 89Zr-labeled RC28 after single intravitreal administration for the biodistribution and pharmacokinetic profiles.RC28 is a unique fusion protein with high affinity to both VEGF and FGF-2, and beneficial to in vitro and in vivo bioactivity. The in vivo pharmacological studies demonstrated that the incidence of CNV formation was largely reduced in RC28 treatment groups with a low dosage as compared to other VEGF antagonist control groups. Furthermore, traces of RC28 were detected as dispersing from eyeballs to the liver after 20 days, and a prolonged half-time pharmacokinetic profile was exhibited.