Metachromatic Leukodystrophy Enzyme Drug Development

描述（由申请人提供）：异色性脑白质营养不良症（MLD）是一种影响溶酶体酶芳基硫酸酯酶a （ASA）的遗传性疾病。出生时患有MLD的人在包括大脑在内的组织中会产生广泛的溶酶体储存产物积累。患有MLD的儿童在生命早期会出现多种脑部疾病，包括智力迟钝和脑积水。目前在临床试验中的治疗MLD是酶替代疗法（ERT）与重组人酶，ASA。然而，ERT不能治疗MLD的大脑，因为ASA不能穿过血脑屏障（BBB）。目前的工作将继续致力于开发一种治疗MLD大脑的新方法，这是一种基因工程的igg酶融合蛋白。ASA酶与血脑屏障分子特洛伊木马融合，这是一种针对内源性血脑屏障肽受体，人胰岛素受体（HIR）的基因工程拟肽单克隆抗体（MAb）。人ASA与HIRMAb重链融合，形成新的生物实体，HIRMAb-ASA融合蛋白，命名为AGT-183。I期研究表明，HIRMAb-ASA融合蛋白可以通过稳定转染的宿主细胞进行工程化和表达。融合蛋白与HIR保持高亲和力结合，保持高ASA酶活性，被分类到MLD成纤维细胞的溶酶体室，并在静脉给药后迅速穿透恒河猴血脑屏障。拟议的第二阶段工作将制定一个生产计划，可用于未来的GMP生产。II期生产的AGT-183将在恒河猴体内进行安全性、毒理学和药代动力学评估。这项工作的完成将使AGT-183药物开发项目进入GLP毒理学和GMP生产，这是提交IND以开始对MLD患者进行脑部治疗所必需的。

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.