Novel Polymer-antibody Conjugates as Long-acting Therapeutics for Ocular Diseases

项目总结

PROJECT SUMMARY Wet age-related macular degeneration (AMD), a chronic eye disorder, is one of the leading causes of irreversible blindness and impacts approximately 3 million people (~200,000 each year) in the US alone. Wet AMD is characterized by aberrant angiogenesis under the retina and macular, which is induced by vascular endothelial growth factors (VEGFs). To this end, most therapeutic efforts have focused on developing drugs that inhibit VEGFs (anti-VEGFs), which are now the standard treatment for wet AMD. Several FDA-approved anti-VEGF biologics include full antibodies and antigen-binding fragments (Fab) against the VEGF protein that are delivered intravitreally on a routine basis. Although effective, anti-VEGF intravitreal injections must be administered every 4-8 weeks, resulting in complications such as secondary infections, retinal detachment, retinal hemorrhage as well as lack of patient adherence to a treatment schedule. Thus, there remains a critical need to develop long-acting formulations of these vision-saving drugs. One overarching limitation to developing long-acting formulations has been tied to inefficient drug delivery systems, which are plagued by shortcomings that lead to denaturation of the payloads, low drug loading efficiency, batch-to-batch variations in molecular weight (MW) and purity, high viscosity, and lack of control in the enzymatic degradation in vivo and improper degradation of the protein. To address these limitations, Delgen Biosciences Inc. seeks to adapt its long-acting and sustained release system as a novel drug for wet AMD by conjugating it to the FDA-approved VEGF inhibitor, ranibizumab. This technology is based on a novel Molecular Brush Polymer (MBP) platform technology developed in Dr. Wei You’s lab at UNC Chapel Hill. In this project, Delgen will focus on the development of long-acting ocular therapeutics for wet AMD based on MBP-therapeutic protein conjugates. A strength of this application is the strong preliminary data for the proposed approach, including (a) demonstrated ability to generate PEGylated MBPs with a radius of hydration (RH) up to an unprecedented 10 nm and (b) precisely controlled degradation of MBPs results in uniform low-MW side chain polymers. The goal of our Phase I SBIR is to develop molecular polymer brushes (MBPs) conjugated with anti-VEGF antibody fragments (MBP-Fabs), which can significantly enhance drug loading, slow down ocular clearance, and increase the half-life of Fab in the eye. Specifically for this proposal, we intend to conduct critical proof-of- concept studies to synthesize and identify an MBP-Fab lead formulation and demonstrate its ocular tolerance and increased half-life in vivo. Successful outcomes of the project can lead to greatly improved therapeutic solutions for the treatment of wet AMD. The proposed research will lay the foundation for the development of novel MBP based delivery platforms that can have broader biopharmaceutical applications beyond ophthalmic drugs and ultimately help unleash the greater potential of today’s fast-advancing biological therapeutics.