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

基本信息

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
项目类别：
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

项目摘要

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.

项目概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，仅在美国就影响了大约 300 万人（每年约 20 万人）。 AMD 的特征是视网膜和黄斑下异常的血管生成，这是由血管生成引起的。为此，大多数治疗工作都集中在开发药物上。抑制 VEGF（抗 VEGF），目前已成为 FDA 批准的几种湿性 AMD 的标准治疗方法。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)，常规玻璃体内注射虽然有效，但必须玻璃体内注射抗 VEGF。每4-8周给药一次，导致继发感染、视网膜脱离等并发症，视网膜出血以及患者缺乏对治疗方案的依从性因此，仍然存在一个关键问题。需要开发这些挽救视力药物的长效制剂。长效制剂与低效的药物输送系统有关，而该系统存在缺陷导致有效负载变性、载药效率低、批次间分子变化重量（MW）和纯度、粘度高、体内酶促降解缺乏控制和不当为了解决这些限制，Delgen Biosciences Inc. 寻求调整其长效作用。缓释系统，通过与 FDA 批准的 VEGF 结合作为治疗湿性 AMD 的新药抑制剂雷珠单抗该技术基于新型分子刷聚合物 (MBP) 平台。北卡罗来纳大学教堂山分校尤伟博士实验室开发的技术在这个项目中，德尔根将重点关注基于 MBP 治疗性蛋白缀合物开发针对湿性 AMD 的长效眼部疗法。该应用程序的优势在于所提出方法的强大初步数据，包括（a）生成聚乙二醇化 MBP 的能力，水合半径 (RH) 高达前所未有的 10 nm 和 (b) 精确控制的 MBP 降解产生均匀的低分子量侧链聚合物。我们第一期 SBIR 的目标是分子开发与抗 VEGF 抗体结合的聚合物刷 (MBP) 片段（MBP-Fab），可以显着增强药物负载，减缓眼部清除，并延长 Fab 在眼睛中的半衰期，具体而言，我们打算进行关键的验证。合成和鉴定 MBP-Fab 先导制剂并证明其眼部耐受性的概念研究该项目的成功结果可以大大改善治疗效果。所提出的研究将为治疗湿性 AMD 的解决方案奠定基础。基于 MBP 的新型递送平台，可在眼科以外拥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。