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

项目总结 湿性老年性黄斑变性(AMD)是一种慢性眼病，是导致 不可逆转的失明，仅在美国就影响了大约300万人(每年约20万人)。湿的 AMD的特征是视网膜和黄斑下异常的血管生成，这是由血管引起的 内皮生长因子(VEGFs)。为此，大多数治疗努力都集中在开发药物上。 这抑制了VEGFs(抗VEGFs)，后者现在是湿性AMD的标准治疗方法。几个FDA批准的 抗血管内皮生长因子生物制品包括针对血管内皮生长因子蛋白的完整抗体和抗原结合片段(FAB)， 是常规的玻璃体内注射。尽管有效，但抗血管内皮生长因子玻璃体内注射必须 每4-8周给药一次，导致继发感染、视网膜脱离、 视网膜出血以及患者不遵守治疗计划。因此，仍然存在一个关键的 需要开发这些挽救视力的药物的长效配方。开发的一个主要限制 长效制剂一直与低效的药物输送系统捆绑在一起，该系统存在缺陷。 这会导致有效载荷的变性、药物载药率低、分子的批次间差异 重量(MW)和纯度高，粘度高，在体内的酶降解缺乏控制和不当 蛋白质的降解。为了解决这些限制，德尔根生物科学公司试图调整其长期发挥作用的 将缓释系统与FDA批准的血管内皮生长因子偶联，作为治疗湿性AMD的新药 抑制剂，雷尼比珠单抗。这项技术基于一种新型的分子刷聚合物(MBP)平台 这项技术是在北卡罗来纳大学教堂山分校魏友博士的实验室里开发的。在这个项目中，Delgen将专注于 基于MBP-治疗性蛋白结合物的湿性AMD长效眼科疗法的研究进展。一个 本申请的优点是为拟议的方法提供了强有力的初步数据，包括(A) 展示了生成聚乙二醇化Mbps的能力，水化半径(RH)高达前所未有的10 NM和(B)Mbps的精确可控降解可得到均匀的低分子量侧链聚合物。目标是 我们第一阶段的SBIR是开发与抗血管内皮生长因子抗体偶联的分子聚合物刷(MBPS) 碎片(MBP-Fabs)，可显著提高药物载量，减缓眼部清除，以及 增加Fab在眼睛中的半衰期。具体来说，对于这项提案，我们打算进行关键的证据- MBP-Fab铅制剂的合成和鉴定及其眼耐受性的概念性研究 并增加了体内半衰期。该项目的成功结果可以极大地改善治疗 湿性AMD的治疗方案。所提出的研究将为开发 基于MBP的新型给药平台，可在眼科以外具有更广泛的生物制药应用 药物，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.