A Humanized Monoclonal FSH Blocking Antibody for Alzheimer's Disease

治疗阿尔茨海默病的人源化单克隆 FSH 阻断抗体

基本信息

批准号：
10693288
负责人：
Tony Yuen
金额：
$ 165.48万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693288
关键词：
1 year old 18 year old 3xTg-AD mouse Acute Affect Affinity African Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Amino Acids Amyloid beta-Protein Precursor Antibodies Articulation Asparagine Binding Biotechnology Blocking Antibodies Body fat Brain Businesses Bypass Cercopithecus tantalus Cholesterol Clinical Clinical Trials Cognition Complement Complex Computer Models Coupled Cyclic GMP Data Dementia Development Discipline Disease Disparate Dose Drug Kinetics Elderly man Elderly woman Endocrinology Endopeptidases Energy Metabolism Epitopes Estrogen Replacements Estrogen decline Estrogens Evaluation Excretory function Fatty acid glycerol esters Female Follicle Stimulating Hormone Follicle Stimulating Hormone Receptor Formulation Frequencies Goals Gonadal structure Health Hazards Hippocampus Hormone use Hormones Human Impaired cognition In Vitro Label Lead Life Longitudinal Studies Medical Medicine Menopause Metabolism Monkeys Mus Neurosciences Obesity Organ Osteoporosis Ovariectomy Pathogenesis Perimenopause Personal Satisfaction Phase Physiology Pituitary Hormones Positron-Emission Tomography Prevention Prevention Protocols Production Property Public Health Research Risk Rodent Route Safety Science Serum Severities Structure Symptoms Testing Textbooks Therapeutic Therapeutic antibodies Thyroid Gland Thyrotropin Treatment Protocols Up-Regulation Woman Work absorption age related aged aging population bone bone loss bone mass cell bank design dosage efficacy evaluation efficacy testing energy balance first-in-human forest good laboratory practice humanized antibody humanized monoclonal antibodies humanized mouse hypercholesterolemia improved individual patient knock-down lead candidate loss of function male manufacture manufacturing scale-up men mild cognitive impairment mouse model novel novel therapeutics polyclonal antibody prevent receptor receptor binding safety study safety testing secretase small hairpin RNA tau Proteins transgenic model of alzheimer disease vervet

项目摘要

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.

项目摘要阿尔茨海默氏病（AD）在没有治愈的许多影响的疾病中脱颖而出实际上，老年男女，迫切需要进行新的疗法。还不清楚为什么更年期妇女的AD优势是明确的临床相关性与刺激骑马的植物水平的上升相关性（FSH）。我们已经确定FSH是几种衰老疾病的靶标 - 骨质疏松症，肥胖症，高胆固醇 - 现在是AD。抑制使用阻断抗体的FSH作用可减少体内脂肪，增加骨骼质量，降低血清胆固醇和从我们最新和最令人兴奋的结果来看，可以防止两种鼠标模型中的广告。我们设计了一本小说人源化的单克隆抗体Hu6，与接收器的结合域FSHβ中的一个小表位结合，这阻止了其对FSH受体（FSHR）的作用。我们的理想目标是将这种铅疗法用于至少是AD的所有四种疾病的疗法和预防。从30个新的池中选择合成的人源化抗体，HU6显示高亲和力与FSH（Kd〜7 nm），因此防止其对海马FSHR的作用，以改善AD小鼠的认知。这些观察以及其最佳药代动力学特征，为HU6进入早期发展的基础。在特定目标1中，我们提出扩大研究生产Hu6的提议；创建一个最佳公式；测试其物理特性;研究FSH：HU6复合物的结构；并制造用于CGMP级别的大型细胞库 Hu6。在特定的目标2中，我们将在“人性化”的TG32小鼠中进行药代动力学研究清除，以及非洲绿色的猴子猴子；确定最低有效剂量在预防和/或在3XTG小鼠中治疗AD；检查年轻和年龄3XTG小鼠的效率和安全性；并记录安全 Vervet猴子。这项工作将使用良好的实验室实践（GLP）标准进行西奈山，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由杰出顾问小组的支持，完成科学和医学专家，商业领导者和生物技术的企业家。有关剂量，路线和频率的确定信息有了早期的安全证明，应将我们推向后期的发展和首先 - 人类研究。