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Bioengineering of a New Decoy Receptor Drug Delivery Technology

新型诱饵受体药物输送技术的生物工程

基本信息

批准号：
7742393
负责人：
Ka-Wai Hui
金额：
$ 11.2万
依托单位：
ARMAGEN TECHNOLOGIES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7742393
关键词：
AGT gene Acute Adult Affinity Affinity Chromatography Animal Testing Anions Applications Grants Binding Biological Assay Biomedical Engineering Bioreactors Blood Blood - brain barrier anatomy Blood capillaries Brain Brain Diseases Brain Injuries COS Cells Carbohydrates Cations Cell Line Cells Chemistry Chimeric Proteins Chinese Hamster Chinese Hamster Ovary Cell Chromatography Clinical Trials Clinical trial protocol document Cloning Complementary DNA DNA DNA Sequence Data Development Dihydrofolate Reductase Dose Drug Delivery Systems Drug Kinetics Drug Receptors Electroporation Engineering Enzyme-Linked Immunosorbent Assay Equipment Equus caballus Etanercept Extracellular Domain FDA approved Filtration Future Gene Amplification Gene Fusion Generations Genes Genetic Genetic Engineering Goals Human Hypoxanthines IgG1 Immunoglobulin G Inflammatory Insulin Insulin Receptor Ischemic Stroke Isoelectric Focusing Lead Light Liquid substance Macaca mulatta Mass Spectrum Analysis Measures Mediating Methods Methotrexate Modeling Molecular Sieve Chromatography Monoclonal Antibodies Neomycin resistance gene Nerve Degeneration Neuroglia Ovary Peripheral Pharmaceutical Preparations Pharmacologic Substance Pharmacology and Toxicology Phase Plasma Plasmids Polyacrylamide Gel Electrophoresis Primates Process Production Protein Binding Proteins RNA Recombinant Fusion Proteins Recombinant Proteins Research Research Contracts Robotics Rodent Running Serum Serum-Free Culture Media Site Small Business Innovation Research Grant Sodium Dodecyl Sulfate Specificity Spinal cord injury Sterility Stroke Structure TNFR-Fc fusion protein Technology Temperature Testing Therapeutic Thymidine Transfection Transgenes Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Tumor Necrosis Factors Western Blotting Work antibiotic G 418 base capillary cell bank cytokine design dimer drug development expression vector extracellular fusion gene good laboratory practice human INSR protein human TNF protein humanized monoclonal antibodies in vivo meetings milligram molecular trojan horse neurotechnology neurotrophic factor new technology novel novel strategies peptide permease pre-clinical public health relevance receptor receptor binding research and development transcytosis vector

项目摘要

DESCRIPTION (provided by applicant): Decoy receptors are potential new pharmaceuticals to treat brain diseases, such as brain injury, spinal cord injury, stroke, or neurodegeneration. However, decoy receptor drugs are large molecule pharmaceuticals that do not cross the blood-brain barrier (BBB). The present work will produce a novel recombinant fusion protein that is able to both (a) bind a human BBB receptor to trigger transport into the brain, and (b) bind human tumor necrosis factor (TNF)-1, to block cytoxic effects of this inflammatory cytokine. A new approach to the BBB delivery of large molecules such decoy receptors is the molecular Trojan horse technology. A bi-functional fusion protein is produced with genetic engineering, wherein the decoy receptor extracellular domain (ECD) is fused to a BBB molecular Trojan horse. The latter is a genetically engineered monoclonal antibody (MAb) that is able to cross the human BBB by receptor-mediated transcytosis on endogenous BBB peptide transport systems. The present work will produce a novel fusion gene encoding the ECD of the human TNF receptor type II and a genetically engineered MAB molecular Trojan horse, which will allow the production of the corresponding fusion protein, AGT-110. The fusion protein genes will be incorporated in a eukaryotic expression vector followed by permanent transfection of host cells. These phase I SBIR studies will enable production of a permanently transfected host cell line for future manufacturing of AGT-110. PUBLIC HEALTH RELEVANCE: Decoy receptors are potential new pharmaceuticals to treat brain diseases, such as brain injury, spinal cord injury, stroke, or neurodegeneration. However, decoy receptor drugs are large molecule pharmaceuticals that do not cross the blood-brain barrier (BBB). The present work will produce a novel recombinant fusion protein that is able to both (a) bind a human BBB receptor to trigger transport into the brain, and (b) bind human tumor necrosis factor-alpha, to block cytoxic effects of this inflammatory cytokine.

描述（由申请人提供）：诱饵受体是治疗脑疾病的潜在新药，如脑损伤、脊髓损伤、中风或神经变性。然而，诱骗受体药物是大分子药物，不能穿过血脑屏障（BBB）。目前的工作将产生一种新的重组融合蛋白，它能够(a)结合人血脑屏障受体触发转运进入大脑，(b)结合人肿瘤坏死因子(TNF)-1，阻断这种炎症细胞因子的细胞毒性作用。分子特洛伊木马技术是一种用于血脑屏障递送大分子诱饵受体的新方法。利用基因工程技术制备了一种双功能融合蛋白，其中诱骗受体细胞外结构域（ECD）与血脑屏障分子特洛伊木马融合。后者是一种基因工程单克隆抗体（MAb），能够通过受体介导的内源性血脑屏障肽转运系统的胞吞作用穿过人血脑屏障。目前的工作将产生一种新的融合基因，编码人类TNF受体II型的ECD和一种基因工程MAB分子特洛伊木马，这将允许产生相应的融合蛋白AGT-110。融合蛋白基因将被纳入真核表达载体，然后永久转染宿主细胞。这些I期SBIR研究将为AGT-110的未来生产提供永久转染的宿主细胞系。