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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：
10279706
负责人：
Tony Yuen
金额：
$ 171.26万
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/10279706
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 Asparagine Binding Biotechnology Blocking Antibodies Body fat Brain Businesses Bypass Cercopithecus tantalus Cholesterol Cleaved cell Clinical Clinical Trials Cognition Complement Complex Computer Models Coupled Crystallization Cyclic GMP Data Dementia Development Discipline Disease Dose Drug Kinetics Elderly man Elderly woman Endocrinology Epitopes Estrogen Replacements Estrogens Evaluation Excretory function Fatty acid glycerol esters Female Follicle Stimulating Hormone Follicle Stimulating Hormone Receptor Formulation Frequencies Goals Gonadal structure Health Hazards Hippocampus (Brain)Hormone use Hormones Human Impaired cognition In Vitro Label Lead Life Longitudinal Studies Medical Medicine Menopause Metabolism Mus Neurosciences Obesity Organ Osteoporosis Ovariectomy Pathogenesis 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 base bone bone loss bone mass cell bank design dosage efficacy evaluation efficacy testing endopeptidase A energy balance first-in-human forest good laboratory practice humanized antibody humanized monoclonal antibodies hypercholesterolemia improved individual patient knock-down lead candidate loss of function male men mild cognitive impairment mouse model novel novel therapeutics polyclonal antibody prevent receptor receptor binding safety study safety testing scale up secretase small hairpin RNA tau Proteins transgenic model of alzheimer disease

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.

项目总结