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Manufacturing of Trojan Horse-TNFR Decoy Receptor Fusion Protein

特洛伊木马-TNFR诱饵受体融合蛋白的制造

基本信息

批准号：
8307104
负责人：
RUBEN J. BOADO
金额：
$ 14.85万
依托单位：
ARMAGEN TECHNOLOGIES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2012-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8307104
关键词：
A Mouse Affinity Affinity Chromatography Alzheimer&apos s Disease Anions Binding Binding Sites Biochemical Bioreactors Blood - brain barrier anatomy Brain Brain Diseases Cations Cell Line Cells Cerebrum Chimeric Proteins Chinese Hamster Chinese Hamster Ovary Cell Chromatography Clinical Trials Cloning Development Dose Drug Kinetics Engineering Epitopes Equus caballus Etanercept Extracellular Domain Future Goals Human Human Engineering Immunoglobulin G Inflammatory Insulin Insulin Receptor Macaca mulatta Mediating Mental Depression Methodology Monoclonal Antibodies Ovary Parkinson Disease Peripheral Pharmaceutical Preparations Pharmacology Phase Plasma Play Primates Production Proteins Receptors, Tumor Necrosis Factor, Type II Research Role Safety Scheme Sepharose Serum-Free Culture Media Small Business Innovation Research Grant Staging Structure Surface Plasmon Resonance TNF gene Testing Therapeutic Tissues Toxicology Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Validation Work cytokine design drug development human INSR protein human TNF protein in vivo inhibitor/antagonist intravenous administration meetings molecular trojan horse mouse model novel receptor receptor binding scale up small molecule uptake

项目摘要

DESCRIPTION (provided by applicant): Tumor necrosis factor (TNF)-¿ plays a pro-inflammatory role in brain diseases. The biologic TNF inhibitors (TNFI), such as the TNF decoy receptor cannot be developed for brain diseases, because the TNFIs are large molecules that do not cross the blood-brain barrier (BBB). The present work continues the drug development of a re-engineered form of the human type II TNF receptor (TNFR), wherein the TNFR 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-TNFR fusion protein acts as a molecular Trojan horse to ferry the fused decoy receptor 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-TNFR fusion protein. The proposed phase I SBIR research will develop a manufacturing scheme for production of the HIRMAb-TNFR 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 small scale manufacturing methodology developed in phase I will then be scaled up in phase II to the 50L bioreactor stage for manufacturing of the HIRMAb-TNFR fusion protein at production levels that can support future clinical trials. PUBLIC HEALTH RELEVANCE: Biologic tumor necrosis factor inhibitors (TNFI), such as the tumor necrosis factor (TNF) decoy receptor, cannot be developed for brain diseases, because these large molecule drugs do not cross the blood-brain barrier (BBB). The present research will re-engineer the human type II TNF receptor (TNFR) as an IgG-TNFR fusion protein, where the IgG part is a genetically engineered monoclonal antibody that crosses the BBB via transport on the endogenous insulin receptor. The IgG acts as a molecular Trojan horse to ferry across the BBB the TNFI.

描述（由申请人提供）：肿瘤坏死因子（TNF）-<$在脑部疾病中起促炎作用。生物TNF抑制剂（TNFI），如TNF诱饵受体，不能用于脑部疾病，因为TNFI是不能穿过血脑屏障（BBB）的大分子。本工作继续人II型TNF受体（TNFR）的再工程化形式的药物开发，其中TNFR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-TNFR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诱饵受体运送穿过BBB。本研究的前SBIR可行性阶段描述了HIRMAb-TNFR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。拟议的第一阶段SBIR研究将开发生产HIRMAb-TNFR融合蛋白的制造方案。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。然后将在第I阶段开发的小规模生产方法在第II阶段扩大至50 L生物反应器阶段，以支持未来临床试验的生产水平生产HIRMAb-TNFR融合蛋白。公共卫生相关性：生物肿瘤坏死因子抑制剂（TNFI），如肿瘤坏死因子（TNF）诱饵受体，不能开发用于脑部疾病，因为这些大分子药物不能穿过血脑屏障（BBB）。本研究将人II型TNF受体（TNFR）重新设计为IgG-TNFR融合蛋白，其中IgG部分是基因工程单克隆抗体，其通过内源性胰岛素受体上的转运穿过BBB。IgG充当分子特洛伊木马以将TNFI运送穿过BBB。