Antibody-based therapies have emerged as an important treatment for many eye diseases with pathological blood vessel formation, including the wet form of aged related macular degeneration (AMD), proliferative diabetic retinopathy, and choroidal neovascularization. Avastin (bevacizumab) and Lucentis (ranibizumab) are humanized antibody and its Fab fragments, respectively, that prevent angiogenesis by blocking VEGF. They have shown remarkable clinical response in treating these eye diseases; however current therapeutic regimens require monthly intravitreal injections because of fast diffusion-mediated clearance of drugs from the eye. Frequent injections result in severe patient burden in terms of increased risk of infection and repeated stress and pain associated with the injection. Prolonging the activity of antibody in the eye would greatly improve the therapeutic utility and efficacy, and decrease toxicity. The overall objective of this application is to develop ranibizumab (Ran) derivatives that can engage the extracellular matrix of the vitreous with high affinity, particularly through engineering peptide conjugates that can interact with type II collagen (Coll) and hyaluronan (HA). The long-term goal is to explore their sustained delivery for treating macular degeneration and other disease of the posterior eye. The central hypothesis is that the Ran derivatives which interact with the vitreous ECM will have significantly extended duration and improved therapeutic activity after intravitreal injection. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims. The focus of Aim 1 is to synthesize peptide-Ran conjugates that can bind to type II collagen or hyaluronan (HA) while maintaining their anti-VEGF activity. The conjugates will be tested for ECM binding affinity and VEGF inhibiting activity using in vitro molecular- and cell-level assays.
Aim 1 also includes plans to develop self-assembled peptide nanofibers that can be co-injected with peptide-Ran conjugates for high level of drug loading particularly for patients with low level of ECM in the vitreous.
Aim 2 focuses on testing the sustained delivery of the Ran formulation and ultimately the long-term efficacy in delaying the neovasculature formation using induced choroidal neovascularization (CNV) model in rabbit.
Aim 2 also includes the long-term biocompatibility study of the Ran formulations. The proposal is significant because localization and sustained release of antibody drugs made possible by ECM binding and ECM-like nanofibers can be applied to other pathologic conditions in the skin and joints which are rich in collagen and HA.
The proposed research is aimed at developing sustained antibody delivery system that can benefit patients with macular degeneration and other posterior eye diseases involving pathologic neovasculature formation.
