A Humanized Monoclonal FSH Blocking Antibody for Alzheimer's Disease

项目摘要 阿尔茨海默氏病（AD）在许多影响阿尔茨海默氏症的疾病中脱颖而出， 老年男女--本质上，迫切需要一种新的治疗方法。原因也不清楚 绝经期妇女AD占优势，虽然雌激素下降与AD有关， 与促卵泡激素（FSH）水平升高有明确的临床相关性。我们已经确定FSH是一种 针对几种衰老疾病--骨质疏松症，肥胖症，高脂血症--现在，AD。抑制 FSH使用封闭抗体的作用减少体脂，增加骨量，降低血清胆固醇， 从我们最新和最令人兴奋的结果，防止AD在两个小鼠模型。我们设计了一部小说 人源化单克隆抗体Hu 6，其与FSHβ受体结合结构域内的小表位结合， 从而阻断其对FSH受体（FSHR）的作用。我们的理想目标是使用这种铅治疗， 治疗和预防所有四种疾病--或者至少是AD。从30个新的游泳池中选出 在合成的人源化抗体中，Hu 6显示出与FSH的高亲和力结合（KD ~7 nM），从而阻止其与FSH的结合。 作用于海马FSHR以改善AD小鼠的认知。这些观察，连同其最佳的 药代动力学特征，为Hu 6进入早期开发阶段奠定基础。在具体目标1中， 建议扩大研究级Hu 6的生产规模;创建最佳配方;测试其理化性质 性质;研究FSH：Hu 6复合物的结构;并生产cGMP级主细胞库 胡六。在特定目标2中，我们将在Tg 32小鼠中进行抗体的“人源化”药代动力学研究。 清除率和非洲绿色长尾猴;确定预防和/或 在3xTg小鼠中治疗AD;检查在年轻和老年3xTg小鼠中的功效和安全性;并在3xTg小鼠中记录安全性。 长尾猴本工作将按照药物非临床研究质量管理规范（GLP）标准进行， 西奈山，埃默里，维克森林和圣安东尼奥。我们还建立了跨职能研究团队， 将得到一个杰出的顾问小组的支持，该小组由科学和医学专家，商业 生物技术领域的领导者和企业家。关于剂量、途径和频率的连续信息， 安全性的早期证据应该会推动我们进入后期开发和首次人体研究。

PROJECT SUMMARY Alzheimer’s disease (AD) stands out as notable in not having a cure among many diseases that affect elderly men and women––in essence, creating an urgent need for a new therapy. It is also unclear why menopausal women have a preponderance of AD, and, while declining estrogen bas been implicated, there is clear clinical correlation with rising levels of follicle stimulating hormone (FSH). We have identified FSH as a target for several aging disorders––osteoporosis, obesity, hypercholesteremia––and now, AD. Inhibiting the action of FSH using blocking antibodies reduces body fat, increases bone mass, lowers serum cholesterol, and from our newest and most exciting results, prevents AD in two mouse models. We have designed a novel humanized monoclonal antibody, Hu6, that binds to a small epitope within the receptor–binding domain of FSHβ, thus blocking its action on the FSH receptor (FSHR). Our aspirational goal is to use this lead therapeutic for the therapy and prevention of all four disorders––or, at the very least, AD. Selected from a pool of 30 newly synthesized humanized antibodies, Hu6 displays high–affinity binding to FSH (KD ~7 nM) and thus prevents its action on hippocampal FSHRs to improve cognition in AD mice. These observations, together with its optimal pharmacokinetic profile, lay the groundwork for Hu6 to enter early stage development. In Specific Aim 1, we propose to scale up production of research–grade Hu6; create an optimal formulation; test its physicochemical properties; study the structure of the FSH:Hu6 complex; and manufacture a master cell bank for cGMP–grade Hu6. In Specific Aim 2, we will perform pharmacokinetic studies in Tg32 mice ‘humanized’ for antibody clearance, and in African green vervet monkeys; determine minimum effective dose(s) in preventing and/or treating AD in 3xTg mice; examine efficacy and safety in young and aged 3xTg mice; and document safety in vervet monkeys. The work will be conducted using Good Laboratory Practice (GLP) standards established at Mount Sinai, Emory, Wake Forest and San Antonio. We have also created cross–functional research teams that will be supported by a distinguished panel of advisors, comprising science and medicine experts, business leaders, and entrepreneurs in biotechnology. Definitive information on dosage, route and frequency, together with early proof of safety should propel us into late stage development and first–in–human studies.