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

项目摘要 湿性年龄相关性黄斑变性（AMD）是一种慢性眼部疾病，是导致老年性黄斑变性的主要原因之一。 不可逆转的失明，仅在美国就影响约300万人（每年约20万人）。湿 AMD的特征在于视网膜和黄斑下的异常血管生成，这是由血管生成诱导的。 内皮生长因子（VEGF）。为此，大多数治疗努力都集中在开发药物上 抑制VEGF（抗VEGF），现在是湿性AMD的标准治疗方法。几个FDA批准的 抗VEGF生物制剂包括抗VEGF蛋白的完整抗体和抗原结合片段（Fab）， 都是常规的玻璃体内注射虽然有效，但抗VEGF玻璃体内注射必须 每4-8周给药一次，导致并发症如继发性感染，视网膜脱落， 视网膜出血以及患者缺乏对治疗方案的依从性。因此，仍然存在一个关键的 我们需要开发这些视力保护药物的长效配方。发展的一个首要限制是， 长效制剂与低效的药物输送系统有关，该系统存在缺陷 这导致有效载荷的变性、低的药物装载效率、批次间的分子差异， 重量（MW）和纯度，粘度高，缺乏控制，在体内酶降解和不当 蛋白质的降解。为了解决这些局限性，Delgen Biosciences Inc.试图将其长效的 并通过将其与FDA批准的VEGF结合， 抑制剂，雷珠单抗。该技术基于一种新型的分子刷聚合物（MBP）平台 这项技术是由魏佑博士在查佩尔山的实验室开发的。在这个项目中，Delgen将专注于 基于MBP-治疗性蛋白缀合物的湿性AMD的长效眼部治疗剂的开发。一 这种应用的优势是所提出的方法的强有力的初步数据，包括（a） 证明了产生PEG化MBP的能力，其水合半径（RH）高达前所未有的10 nm和（B）精确控制的MBP降解产生均匀的低MW侧链聚合物。目标 我们的第一阶段SBIR是开发与抗VEGF抗体缀合的分子聚合物刷（MBP 片段（MBP-Fab），其可以显著增强药物负载，减缓眼部清除，以及 增加Fab在眼睛中的半衰期。针对这一建议，我们打算进行关键的证明- 合成和鉴定MBP-Fab先导制剂并证明其眼耐受性的概念研究 并增加体内半衰期。该项目的成功结果可以大大改善治疗效果。 治疗湿性AMD的解决方案。该研究将为开发 新型的基于MBP的递送平台，其可以具有除眼科之外的更广泛的生物制药应用， 并最终帮助释放当今快速发展的生物疗法的更大潜力。

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.