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

新型聚合物-抗体缀合物作为眼部疾病的长效治疗药物

• 批准号: 10760186
• 负责人: Fei Peng
• 金额: $ 35.01万
• 依托单位: DELGEN BIOSCIENCES INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10760186
• 关键词: 3-Dimensional; Address; Age related macular degeneration; Antibodies; Benchmarking; Biodegradation; Biological Assay; Biological Products; Biological Response Modifier Therapy; Biological Sciences; Blindness; Chemicals; Chemistry; Chronic; Clinical; Data; Development; Disulfides; Dose; Dropout; Drug Delivery Systems; Drug Kinetics; Encapsulated; Eye; Eye diseases; FDA approved; Fab Immunoglobulins; Formulation; Foundations; Frequencies; Goals; Growth; Growth Factor; Growth Factor Inhibition; Half-Life; Hyaluronic Acid; Hydration status; Immune response; Immunoglobulin Fragments; In Vitro; Individual; Inflammation; Injections; Lead; Legal patent; Link; Molecular; Molecular Structure; Molecular Weight; Nature; New Zealand; North Carolina; Oryctolagus cuniculus; Outcome; Patients; Persons; Pharmaceutical Preparations; Phase; Phosphorylcholine; Polyethylene Glycols; Polymers; Preparation; Proteins; Radial; Research; Retina; Retinal Detachment; Retinal Hemorrhage; Series; Side; Small Business Innovation Research Grant; Solubility; System; Technology; Testing; Therapeutic; Therapeutic Effect; Thick; Time; Toxic effect; Translating; Treatment Efficacy; Treatment Protocols; United States National Institutes of Health; Universities; Variant; Vascular Endothelial Growth Factors; Vertebral column; Viscosity; Vision; Water; angiogenesis; antibody and antigen binding; antibody conjugate; antibody inhibitor; biocompatible polymer; biomaterial compatibility; compliance behavior; delivery vehicle; drug action; drug efficacy; immunogenicity; improved; in vivo; inhibitor; inhibitor therapy; innovation; intravitreal injection; macula; manufacture; molecular size; novel; novel therapeutics; ophthalmic drug; ophthalmic examination; physical property; polymerization; protein degradation; ranibizumab; residence; retinal toxicity; scale up; secondary infection; standard care; standard of care; technology platform; therapeutic protein

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.

项目摘要 与年龄相关的黄斑变性（AMD）是一种慢性眼疾病，是 仅在美国，每年约有300万人（约200,000人）影响不可逆转的失明。湿的 AMD的特征是视网膜和黄斑下的异常血管生成，由血管诱导 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 抑制VEGF（抗VEGF），现在是湿AMD的标准处理。几个FDA批准 抗VEGF生物制剂包括针对VEGF蛋白的完整抗体和抗原结合片段（FAB） 尽管有效，但抗VEGF玻璃体内注射必须是 每4-8周一次管理一次，导致并发症，例如继发感染，残留脱离， 视网膜出血以及缺乏患者遵守治疗时间表。那仍然有关键 需要开发这些避免视觉药物的长效公式。发展的一个总体限制 长效公式已与效率低下的药物输送系统相关 导致有效载荷变性，药物负荷效率低，分子批次变化 重量（MW）和纯度，高粘度以及体内酶促降解中缺乏控制 蛋白质的降解。为了解决这些限制，Delgen Biosciences Inc.试图适应其长效 通过将其连接到FDA批准的VEGF，持续释放系统作为湿AMD的新药物 抑制剂Ranibizumab。该技术基于一种新型的分子刷聚合物（MBP）平台 Wei博士在UNC Chapel Hill的实验室开发的技术。在这个项目中，Delgen将专注于 基于MBP治疗蛋白结合物的湿AMD的长效眼疗法的开发。一个 该应用的强度是拟议方法的强大初步数据，包括（a） 证明能够以水合半径（RH）产生高乙二醇化的Mbps，直至前所未有的10 NM和（B）精确控制的Mbps降解会导致均匀的低MW侧链聚合物。目标 我们的I期SBIR是开发与抗VEGF抗体结合的分子聚合物刷（Mbps） 碎片（MBP-fabs），可以显着增强药物载荷，减慢眼清除率，并且 增加眼睛中晶圆厂的半衰期。特别是针对该建议，我们打算进行关键的证明 概念研究以合成和识别MBP-FAB铅公式并证明其眼部耐受性 并增加了体内半衰期。该项目的成功结果可能会大大改善治疗 治疗湿AMD的解决方案。拟议的研究将奠定发展的基础 基于MBP的新型输送平台，可以具有更广泛的生物药物应用 药物，最终有助于释放当今快速抗化的生物疗法的更大潜力。