Metachromatic Leukodystrophy Enzyme Drug Development

异染性脑白质营养不良酶药物开发

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：过时的白细胞营养不良或MLD是一种遗传疾病，影响溶酶体酶A（ASA）（ASA）。患有MLD的人会在包括大脑在内的组织中形成广泛的溶酶体存储产品积累。 MLD的儿童患有多种脑部疾病，包括智力低下和生命早期的脑积水。 MLD临床试验中的当前疗法是与重组人酶ASA的酶替代疗法（ERT）。但是，ERT不会治疗MLD的大脑，因为ASA没有跨越血脑屏障（BBB）。目前的工作将继续致力于开发对MLD大脑的新治疗方法，MLD是一种基因设计的IgG-酶融合蛋白。 ASA酶融合到BBB分子木马马，这是一种基因设计的肽型单克隆抗体（MAB），针对内源性BBB肽受体，人类胰岛素受体（HIR）。人类ASA与Hirmab的重链融合在一起，以创建一个新的生物实体，即Hirmab-ASA融合蛋白，称为AGT-183。第一阶段的研究表明，Hirmab-ASA融合蛋白可以通过稳定转染的宿主细胞进行设计和表达。融合蛋白保留了高亲和力与HIR的高亲和力结合，保留了高ASA酶活性，将融合蛋白与MLD成纤维细胞的溶酶体区室分为三室，并在静脉内给药后迅速穿透恒河猴的BBB。拟议的第二阶段工作将制定一项制造计划，可以为将来的GMP制造复制。在II期生产的AGT-183将评估恒河猴的安全性，毒理学和药代动力学。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制造，以提交IND开始在MLD患者中开始治疗大脑。