Metachromatic Leukodystrophy Enzyme Drug Development

描述（由申请人提供）：异染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（阿萨）的遗传性疾病。患有MLD的人在组织（包括大脑）中形成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。目前临床试验中用于MLD的疗法是使用重组人酶阿萨的酶替代疗法（ERT）。然而，ERT不能治疗MLD的大脑，因为阿萨不能穿过血脑屏障（BBB）。目前的工作将继续发展一种新的治疗MLD的大脑，这是一种基因工程IgG-酶融合蛋白的工作。阿萨酶与BBB分子特洛伊木马融合，后者是一种针对内源性BBB肽受体（人胰岛素受体（HIR））的基因工程拟肽单克隆抗体（MAb）。将人阿萨融合到HIRMAb的重链上，以产生一种新的生物实体，即命名为AGT-183的HIRMAb-ASA融合蛋白。I期研究表明，HIRMAb-ASA融合蛋白可以被工程化并由稳定转染的宿主细胞表达。融合蛋白保留了与HIR的高亲和力结合，保留了高阿萨酶活性，被分流到MLD成纤维细胞的溶酶体隔室，并在静脉内给药后迅速穿透猕猴的BBB。拟定的第II阶段工作将制定可复制用于未来GMP生产的生产计划。将在恒河猴中评价第II阶段生产的AGT-183的安全性、毒理学和药代动力学。这项工作的完成将使AGT-183药物开发项目进入GLP毒理学和GMP生产，这是提交IND以开始治疗MLD患者的脑部所需的。

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.