A Humanized Monoclonal FSH Blocking Antibody for Alzheimer's Disease

项目概要 在影响健康的众多疾病中，阿尔茨海默病 (AD) 因无法治愈而引人注目。 老年男性和女性——从本质上讲，迫切需要一种新的疗法。也不清楚为什么 更年期妇女罹患 AD 的比例较高，虽然与雌激素下降有关，但 与卵泡刺激素（FSH）水平升高有明显的临床相关性。我们已将 FSH 确定为 治疗多种衰老疾病——骨质疏松症、肥胖症、高胆固醇血症——以及现在的AD。抑制 使用阻断抗体的 FSH 作用可减少体脂、增加骨量、降低血清胆固醇，并 根据我们最新、最令人兴奋的结果，两种小鼠模型都可以预防 AD。我们设计了一本小说 人源化单克隆抗体 Hu6 与 FSHβ 受体结合域内的小表位结合， 从而阻断其对 FSH 受体 (FSHR) 的作用。我们的理想目标是将这种领先疗法用于 所有四种疾病的治疗和预防——或者至少是AD。从30名新人中选出 合成人源化抗体后，Hu6 表现出与 FSH 的高亲和力结合 (KD ~7 nM)，从而阻止其 对海马 FSHR 的作用可改善 AD 小鼠的认知。这些观察结果及其最佳 药代动力学特征，为 Hu6 进入早期开发奠定基础。在具体目标 1 中，我们 建议扩大研究级Hu6的生产规模；创建最佳配方；测试其理化性质 属性；研究 FSH:Hu6 复合物的结构；并制造 cGMP 级主细胞库 胡6.在具体目标 2 中，我们将在 Tg32 小鼠“人源化”抗体中进行药代动力学研究 清除，以及非洲绿长尾猴；确定预防和/或预防的最低有效剂量 治疗 3xTg 小鼠的 AD；检查年轻和老年 3xTg 小鼠的功效和安全性；并记录安全 黑长尾猴。这项工作将按照良好实验室规范 (GLP) 标准进行，该标准建立于 西奈山、埃默里、维克森林和圣安东尼奥。我们还创建了跨职能研究团队 将得到由科学和医学专家、商业专家组成的杰出顾问小组的支持 生物技术领域的领导者和企业家。有关剂量、途径和频率的明确信息 早期的安全性证明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.