Metachromatic Leukodystrophy Enzyme Drug Development

异染性脑白质营养不良酶药物开发

• 批准号: 8643287
• 负责人: Ka-Wai Hui
• 金额: $ 58.33万
• 依托单位: ARMAGEN TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8643287
• 关键词: Active Biological Transport; Adult; Affect; Affinity; Affinity Chromatography; Anions; Antibodies; Arylsulfatases; Binding; Biochemical; Biological; Bioreactors; Blood; Blood - brain barrier anatomy; Brain; Brain Diseases; Cations; Cell membrane; Cells; Cerebrospinal Fluid; Child; Chimeric Proteins; Chinese Hamster; Chinese Hamster Ovary Cell; Chromatography; Clinical Trials; Defect; Development; Disease; Dose; Drug Kinetics; Engineering; Enzyme-Linked Immunosorbent Assay; Enzymes; Exhibits; Fibroblasts; Filtration; Future; Genes; Genetic Engineering; Growth; Hereditary Disease; Human; Human Engineering; Hydrocephalus; Immunoglobulin G; Inherited; Insulin Receptor; Life; Macaca mulatta; Measurement; Measures; Mediating; Membrane; Mental Retardation; Metachromatic Leukodystrophy; Monoclonal Antibodies; Mutate; Mutation; Names; Neuraxis; Neurons; Organ; Ovary; Patients; Peptide Receptor; Perfusion; Peripheral; Pharmaceutical Preparations; Phase; Plasma; Primates; Process; Production; Progress Reports; Protein Binding; Proteins; Recombinants; Research; Safety; Small Business Innovation Research Grant; Structure; Sulfoglycosphingolipids; Temperature; Testing; Tissues; Toxicology; Triage; Validation; Work; brain cell; design; drug development; enzyme activity; enzyme replacement therapy; human INSR protein; in vivo; intravenous administration; molecular trojan horse; nano; neuropathology; peptidomimetics; phase 1 study; programs; public health relevance; receptor; uptake

DESCRIPTION (provided by applicant): Metachromatic Leukodystrophy or MLD, is a genetic disease that affects the lysosomal enzyme, arylsulfatase A (ASA). People born with MLD develop extensive lysosomal storage product accumulation in tissues, including the brain. Children with MLD develop multiple brain disorders including mental retardation and hydrocephalus early in life. The current therapy in clinical trials for MLD is Enzyme Replacement Therapy (ERT) with the recombinant human enzyme, ASA. However, ERT does not treat the brain of MLD, because ASA does not cross the blood-brain barrier (BBB). The present work will continue work on the development of a new treatment of the brain of MLD, which is a genetically engineered IgG-enzyme fusion protein. The ASA enzyme is fused to a BBB molecular Trojan horse, which is a genetically engineered peptidomimetic monoclonal antibody (MAb) against an endogenous BBB peptide receptor, the human insulin receptor (HIR). The human ASA is fused to the heavy chain of the HIRMAb to create a new biological entity, the HIRMAb-ASA fusion protein named AGT-183. Phase I studies show the HIRMAb-ASA fusion protein could be engineered and expressed by stably transfected host cells. The fusion protein retained high affinity binding to the HIR, retained high ASA enzyme activity, was triaged to the lysosomal compartment of MLD fibroblasts, and rapidly penetrated the BBB in rhesus monkeys after intravenous administration. The proposed phase II work will develop a manufacturing plan that can be replicated for future GMP manufacturing. The AGT-183 produced in phase II will be evaluated for safety, toxicology and pharmacokinetics in Rhesus monkeys. The completion of this work will enable entry of the AGT-183 drug development program into GLP toxicology and GMP manufacturing required for submission of an IND to begin treatment of the brain in patients with MLD.

描述(申请人提供)：异色性脑白质营养不良，或MLD，是一种影响溶酶体酶，芳基硫酸酯酶A(AsA)的遗传病。患有MLD的人在包括大脑在内的组织中会产生大量的溶酶体储存产物。患有MLD的儿童在生命早期就会发展成多种脑部疾病，包括智力低下和脑积水。目前正在进行临床试验的MLD的治疗方法是使用重组人酶ASA的酶替代疗法(ERT)。然而，ERT不治疗MLD的大脑，因为ASA不能穿越血脑屏障(BBB)。目前的工作将继续开发一种新的治疗MLD大脑的方法，这是一种基因工程的免疫球蛋白-酶融合蛋白。将AsA酶与BBB分子特洛伊木马融合，后者是一种针对内源性BBB多肽受体--人胰岛素受体(HIR)的基因工程仿肽单抗(MAb)。人的AsA与HIRMAb的重链融合，产生一个新的生物实体，HIRMAb-AsA融合蛋白，命名为AGT-183。I期研究表明，HIRMAb-ASA融合蛋白可以在稳定表达的宿主细胞中进行工程和表达。融合蛋白与HIR具有高亲和力结合，具有较高的AsA酶活性，经静脉注射后可迅速进入恒河猴血脑屏障。拟议的第二阶段工作将制定一项制造计划，该计划可在未来的GMP制造中复制。在第二阶段生产的AGT-183将在恒河猴身上进行安全性、毒理学和药代动力学评估。这项工作的完成将使AGT-183药物开发计划进入GLP毒理学和GMP生产，这是提交IND以开始治疗MLD患者大脑所需的。