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

基本信息

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
项目类别：
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

项目摘要

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）是治疗大脑血管疾病的潜在新药物，包括中风。但是，EPO是一种大分子药物，在大脑中不会跨越毛细血管内皮壁，该毛细血管壁构成血脑屏障（BBB）。目前的工作继续进行了重新设计的EPO形式的药物开发，其中EPO作为IgG融合蛋白产生。 IgG部分是针对人类胰岛素受体（HIR）的基因工程单克隆抗体（MAB）。 Hirmab-EPO融合蛋白的hirmab部分充当分子木马马，可通过内源性BBB胰岛素受体上的受体介导的转运在BBB穿越BBB的EPO。这项研究的SBIR前可行性阶段描述了Hirmab-Epo融合蛋白的恒河猴中的工程，表达，生化验证以及体内等离子体药代动力学和BBB转运。拟议的I期SBIR研究将开发一种生产Hirmab-EPO融合蛋白的制造计划。该制造业的设计旨在生产符合FDA规格的纯度，效能，安全性和杂质的治疗产品，以便在未来的GMP生产融合蛋白进行临床试验的GMP生产中复制制造。然后，在I期中产生的融合蛋白将在II期中用于恒河猴中的Hirmab- EPO融合蛋白的体内活性和毒理学。第二阶段的目的是产生功效/毒理学数据包，可以将其提交给FDA，以设计这种新的IgG-EPO融合蛋白的未来GLP毒理学。公共卫生相关性：促红细胞生成素（EPO）是一种组织保护剂，可以作为治疗大脑血管疾病（包括中风）的新药开发。但是，EPO在外周施用后无法穿透大脑，因为EPO不会跨越形成血脑屏障（BBB）的大脑内皮壁。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大脑血管疾病。