Development of a Ranibizumab Biosimilar using Bovine Milk-Derived Exosomes for the Inhibition of Corneal Neovascularization

Introduction: Corneal neovascularization disease is an important clinical symptom of many ocular surface disorders, and the use of anti-vascular endothelial growth factor (anti-VEGF) drugs is considered the most promising treatment method. Method: Ranibizumab (RB) is one of the few anti-VEGF drugs approved by the FDA in the treatment of ophthalmic diseases, but the special synthetic route leads to a short biological half-life, and therapeutic concentration cannot be maintained for a long time in clinical treatment. Therefore, we aim to develop a low immunogenicity sustained release system to improve the bioavailability of RB. RB was loaded on bovine milk-derived exosomes (MEXOs), and the in vitro release profile and pharmacokinetic characteristics were detected. RB was continuously release from the MEXOs (2 days, 60 h). The tubular network formation experiment of human umbilical vein endothelial cells showed that the MEXOs enhanced the inhibitory effects of RB on VEGF-induced tube formation, as confirmed by a cell proliferation experiment. Results: In vivo experiments showed that RB-loaded bovine milk-derived exosomes (RB-MEXOs) increased the precorneal residence time and half-life period of RB in New Zealand white rabbits. Conclusion: These results suggested that RB-MEXOs is conducive to the maintenance of effective RB concentration in vivo, and their use is potential strategy for treating corneal vascularization.