Abstract
Current anti-VEGF drugs for patients with diabetic retinopathy suffer from short residence time in the vitreous of the eye. In order to maintain biologically effective doses of drug for inhibiting retinal neovascularization, patients are required to receive regular monthly injections of drug, which often results in low patient compliance and progression of the disease. To improve the intravitreal residence time of anti-VEGF drugs, we have synthesized multivalent bioconjugates of an anti-VEGF protein, soluble fms-like tyrosine kinase-1 (sFlt) that is covalently grafted to chains of hyaluronic acid (HyA), conjugates that are termed mvsFlt. Using a mouse corneal angiogenesis assay, we demonstrate that covalent conjugation to HyA chains does not decrease the bioactivity of sFlt and that mvsFlt is equivalent to sFlt at inhibiting corneal angiogenesis. In a rat vitreous model, we observed that mvsFlt had significantly increased intravitreal residence time compared to the unconjugated sFlt after 2 days. The calculated intravitreal half-lives for sFlt and mvsFlt were 3.3 and 35 hours, respectively. Furthermore, we show that mvsFlt is more effective than the unconjugated form at inhibiting retinal neovascularization in an oxygen-induced retinopathy model, an effect that is most likely due to the longer half-life of mvsFlt in the vitreous. Taken together, our results indicate that conjugation of sFlt to HyA does not affect its affinity for VEGF and this conjugation significantly improves drug half-life. These in vivo results suggest that our strategy of multivalent conjugation could substantially improve upon drug half-life, and thus the efficacy of currently available drugs that are used in diseases such as diabetic retinopathy, thereby improving patient quality of life.
Highlights
Diabetes affects 285 million adults worldwide, which accounts for 6.4% of the world’s population
The overall goal of this study was to determine whether increasing soluble fms-like tyrosine kinase-1 (sFlt) molecular size through conjugation to hyaluronic acid (HyA) would increase drug half-life in the vitreous and to investigate the ability of the multivalent sFlt bioconjugate to inhibit in vivo angiogenesis
In contrast to other drugs that are currently used for treating diabetic retinopathy that suffer from short half-lives, we have developed large macromolecules of multivalent protein bioconjugates that maintain their ability in inhibiting vascular endothelial growth factor (VEGF)-driven angiogenesis in vivo and show significantly longer residence time in the vitreous
Summary
Diabetes affects 285 million adults worldwide, which accounts for 6.4% of the world’s population. Anti-VEGF therapeutics such as Lucentis (ranibizumab, Genentech, 48 kDa humanized antibody fragment), Avastin (bevacizumab, Genentech, a 150 kDa humanized antibody) and Eylea (aflibercept, Regeneron, a 110 kDa VEGF-receptor fusion protein) are the clinically used drugs for treating diabetic retinopathy in the clinic. These therapeutics suffer from short drug half-lives as a result of small molecular size and single injections of these drugs provide limited therapeutic effect over a finite period of time [8]. Such approaches will help to reduce the frequency at which patients are required to receive injections thereby improving quality of life as well as long term visual potential
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
