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Efficacy and Mechanism of Action of Heavy-Chain α-Synuclein Antibody Fragments Derived from Llama

美洲驼重链α-突触核蛋白抗体片段的功效和作用机制

基本信息

批准号：
9762785
负责人：
Einar M Sigurdsson
金额：
$ 21.19万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762785
关键词：
Affinity Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Animal Model Antibodies Antibody Therapy Astrocytes Attention Attenuated B-Lymphocytes Binding Biological Assay Blood - brain barrier anatomy Brain Cell Culture Techniques Cell membrane Clinical Trials Data Deposition Diagnostic Disease Drosophila genus Drug Industry Endocytosis Engineering Epitopes Half-Life Human Image Immunize Immunoglobulin Fragments Immunoglobulin G Immunotherapy In Vitro Individual Intravenous Laboratories Length Lesion Lewy Bodies Lewy Body Dementia Libraries Llama Longevity Mediating Modeling Monitor Multiple System Atrophy Mus Mutation Neurons Parkinson Disease Pathogenesis Pathologic Pathology Penetration Peripheral Phage Display Phase II Clinical Trials Prions Proteins Public Health Publishing Reporting Research Signal Transduction Tauopathies Therapeutic Time Tissues Treatment Efficacy alpha synuclein base clinical development cost developmental toxicity fly improved in vivo insight interest intravenous injection mouse model nanobodies novel overexpression prevent protein aggregate protein aggregation protein misfolding receptor screening synucleinopathy tau Proteins tau aggregation uptake

项目摘要

Immunotherapies targeting various protein aggregates such as amyloid-β (Aβ), tau and α-synuclein (αsyn) are in different stages of clinical development, and collectively are the most common approach by the pharmaceutical industry to tackle diseases characterized by such depositions [1-3]. The majority of these potential therapies are whole antibodies. Much less attention has been paid to antibody fragments, which have certain advantages and their therapeutic and diagnostic potential should be explored further. Specifically, single domain antibodies (sdAbs) are of particular interest because their small size (13 kDa) improves tissue penetration, including through the blood-brain-barrier, allowing better access over antibodies (150 kDa) to the target molecule and its hidden epitopes. Importantly as well, they are high affinity, and easy to engineer and grow in large quantities. The Specific Aim is to determine the therapeutic potential of camelid single-domain heavy chain antibody fragments (sdAbs) against the αsyn protein. It is hypothesized that their small size will provide therapeutic benefits over whole antibodies, primarily because of greater access to the target, and to some extent due to their binding to novel epitopes that the larger antibodies cannot access. We have generated 51 clones of sdAbs, with unique complementary determining regions (CDRs), that recognize various forms of αsyn and propose to determine their therapeutic potential in different models, as well as to clarify their mechanism of action. For the initial screen, up to 30 of the individual sdAbs will be expressed globally in neurons of fruit fly models of synucleinopathy, and their ability to prevent/attenuate the αsyn pathology monitored. Subsequently, the 5 most efficacious sdAbs will be examined further in flies by expressing them in astrocytes or peripherally, and in cell culture models of synucleinopathy for mechanistic insight, and the most effective one from that study in an animal model. Our preliminary data support the feasibility of screening for therapeutic efficacy of antibody fragments targeting the tau protein in fly models. Specifically, we show that neuronal expression of an anti-tau single chain variable antibody fragment (scFv) prevents developmental toxicity of overexpression of human tau with or without a tauopathy mutation, and significantly extends the life span of the tauopathy flies. We expect that expressing sdAbs against αsyn in synucleinopathy flies will also provide therapeutic benefits. The proposed studies may identify a novel class of therapy candidates for Lewy Body Dementia, Parkinson's disease, Alzheimer's disease with Lewy Bodies, Multiple System Atrophy and for other synucleinopathies, with direct relevance to various other protein misfolding disorders.

针对各种蛋白聚集体的免疫疗法，如淀粉样蛋白-β (Aβ)， tau和α-突触核蛋白