Re-Engineering Blood-Borne Erythropoietin for Targeted Delivery

重新设计血源性促红细胞生成素以实现靶向递送

• 批准号: 8121023
• 负责人: RUBEN J. BOADO
• 金额: $ 14.98万
• 依托单位: ARMAGEN TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121023
• 关键词: Affinity; Affinity Chromatography; Animals; Anions; Binding; Biochemical; Bioreactors; Blood; Blood - brain barrier anatomy; Blood capillaries; Brain; Brain Diseases; Cations; Cerebrovascular Disorders; Cerebrum; Chimeric Proteins; Chinese Hamster Ovary Cell; Chromatography; Clinical Trials; Collaborations; Conditioned Culture Media; Data; Dose; Drug Kinetics; Engineering; Erythropoietin; Erythropoietin Receptor; Event; Failure; Filtration; Future; German population; Germany; Goals; Health Sciences; Hour; Human; Immunoglobulin G; Injection of therapeutic agent; Insulin Receptor; Intravenous; Isoelectric Point; Laboratories; Letters; Liquid substance; Macaca mulatta; Mediating; Methods; Middle Cerebral Artery Occlusion; Modeling; Monoclonal Antibodies; Neuroprotective Agents; Oregon; Patients; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Plasma; Primates; Production; Protective Agents; Proteins; Publications; Radiolabeled; Rattus; Recombinant Erythropoietin; Research; Safety; Scheme; Sepharose; Serum-Free Culture Media; Small Business Innovation Research Grant; Staging; Sterility; Stroke; Stroke Volume; Structure; Testing; Therapeutic; Tissues; Toxicology; Validation; Vascular Diseases; Vial device; Work; base; brain cell; capillary; design; drug development; glycosylation; human INSR protein; in vivo; meetings; molecular trojan horse; nano; neuroprotection; neurotrophic factor; radiotracer; receptor; targeted delivery

DESCRIPTION (provided by applicant): Erythropoietin (EPO) is a potential new pharmaceutical to treat vascular disease of the brain, including stroke. However, EPO is a large molecule pharmaceutical that does not cross the capillary endothelial wall in brain, which forms the blood-brain barrier (BBB). The present work continues the drug development of a re-engineered form of EPO, wherein the EPO is produced as an IgG fusion protein. The IgG part is a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb part of the HIRMAb-EPO fusion protein acts as a molecular Trojan horse to ferry the fused EPO across the BBB via receptor-mediated transport on the endogenous BBB insulin receptor. The pre-SBIR feasibility stage of this research describes the engineering, expression, biochemical validation, and in vivo plasma pharmacokinetics and BBB transport in the Rhesus monkey of the HIRMAb-EPO fusion protein. The proposed phase I SBIR research will develop a manufacturing scheme for production of the HIRMAb-EPO fusion protein. This manufacturing will be designed to produce a therapeutic product that meets FDA specifications with regard to purity, potency, safety, and impurities, so that the manufacturing can be replicated in future GMP production of the fusion protein for clinical trials. The fusion protein produced in phase I will then be used in phase II for in vivo activity and toxicology of the HIRMAb- EPO fusion protein in Rhesus monkeys. The goal of phase II is to produce an efficacy/toxicology data package that can be presented to the FDA for design of future GLP toxicology of this new IgG-EPO fusion protein. PUBLIC HEALTH RELEVANCE: Erythropoietin (EPO) is a tissue-protective agent that could be developed as a new drug for the treatment of vascular disorders of the brain, including stroke. However, EPO cannot penetrate the brain following peripheral administration, because EPO does not cross the endothelial wall in brain, which forms the blood-brain barrier (BBB). This research will develop a new IgG-EPO fusion protein for the treatment of vascular disease of the brain including stroke.

描述（由申请人提供）：促红细胞生成素（EPO）是一种治疗脑血管疾病（包括中风）的潜在新药。然而，EPO是一种大分子药物，不能穿过形成血脑屏障（BBB）的脑内毛细血管内皮壁。本工作继续EPO的再工程形式的药物开发，其中EPO作为IgG融合蛋白产生。IgG部分是针对人胰岛素受体（HIR）的基因工程单克隆抗体（MAb）。HIRMAb-EPO融合蛋白的HIRMAb部分充当分子特洛伊木马，通过内源性BBB胰岛素受体上的受体介导的转运将融合的EPO运送穿过BBB。本研究的前SBIR可行性阶段描述了HIRMAb-EPO融合蛋白的工程化、表达、生物化学验证以及在恒河猴中的体内血浆药代动力学和BBB转运。拟议的I期SBIR研究将开发用于生产HIRMAb-EPO融合蛋白的生产方案。该生产将被设计为生产符合FDA关于纯度、效力、安全性和杂质的质量标准的治疗产品，使得该生产可以在用于临床试验的融合蛋白的未来GMP生产中复制。然后将在阶段I中产生的融合蛋白用于阶段II中，用于HIRMAb-EPO融合蛋白在恒河猴中的体内活性和毒理学。第二阶段的目标是产生一个疗效/毒理学数据包，可以提交给FDA，用于设计这种新的IgG-EPO融合蛋白的未来GLP毒理学。 公共卫生关系：促红细胞生成素（EPO）是一种组织保护剂，可开发为治疗脑血管疾病（包括中风）的新药。然而，EPO在外周给药后不能穿透脑，因为EPO不能穿过脑内形成血脑屏障（BBB）的内皮壁。这项研究将开发一种新的IgG-EPO融合蛋白，用于治疗包括中风在内的脑血管疾病。