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:
- 金额:$ 21.19万
- 依托单位:
- 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:
- 关键词:AffinityAlzheimer&aposs DiseaseAmyloidAmyloid beta-ProteinAnimal ModelAntibodiesAntibody TherapyAstrocytesAttentionAttenuatedB-LymphocytesBindingBiological AssayBlood - brain barrier anatomyBrainCell Culture TechniquesCell membraneClinical TrialsDataDepositionDiagnosticDiseaseDrosophila genusDrug IndustryEndocytosisEngineeringEpitopesHalf-LifeHumanImageImmunizeImmunoglobulin FragmentsImmunoglobulin GImmunotherapyIn VitroIndividualIntravenousLaboratoriesLengthLesionLewy BodiesLewy Body DementiaLibrariesLlamaLongevityMediatingModelingMonitorMultiple System AtrophyMusMutationNeuronsParkinson DiseasePathogenesisPathologicPathologyPenetrationPeripheralPhage DisplayPhase II Clinical TrialsPrionsProteinsPublic HealthPublishingReportingResearchSignal TransductionTauopathiesTherapeuticTimeTissuesTreatment Efficacyalpha synucleinbaseclinical developmentcostdevelopmental toxicityflyimprovedin vivoinsightinterestintravenous injectionmouse modelnanobodiesnoveloverexpressionpreventprotein aggregateprotein aggregationprotein misfoldingreceptorscreeningsynucleinopathytau Proteinstau aggregationuptake
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
项目成果
期刊论文数量(0)
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Einar M Sigurdsson其他文献
Einar M Sigurdsson的其他文献
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{{ truncateString('Einar M Sigurdsson', 18)}}的其他基金
Single domain antibodies for diagnosis and treatment of synucleinopathies
用于诊断和治疗突触核蛋白病的单域抗体
- 批准号:
10915130 - 财政年份:2023
- 资助金额:
$ 21.19万 - 项目类别:
Clearance and In Vivo Detection of Tau Pathology
Tau 病理学的清除和体内检测
- 批准号:
8673411 - 财政年份:2013
- 资助金额:
$ 21.19万 - 项目类别:
Epitope-Specific Targeting of Tau Aggregates.
Tau 聚集体的表位特异性靶向。
- 批准号:
8673382 - 财政年份:2013
- 资助金额:
$ 21.19万 - 项目类别:
Immune Therapy and Imaging in Mouse and Primate Models of Alzheimer's Disease.
阿尔茨海默病小鼠和灵长类动物模型的免疫治疗和成像。
- 批准号:
8676081 - 财政年份:2013
- 资助金额:
$ 21.19万 - 项目类别:
Epitope-Specific Targeting of Tau Aggregates
Tau 聚集体的表位特异性靶向
- 批准号:
10594553 - 财政年份:2011
- 资助金额:
$ 21.19万 - 项目类别:
Epitope-Specific Targeting of Tau Aggregates.
Tau 聚集体的表位特异性靶向。
- 批准号:
8230884 - 财政年份:2011
- 资助金额:
$ 21.19万 - 项目类别:
Epitope-Specific Targeting of Tau Aggregates.
Tau 聚集体的表位特异性靶向。
- 批准号:
8464819 - 财政年份:2011
- 资助金额:
$ 21.19万 - 项目类别:
Epitope-Specific Targeting of Tau Aggregates
Tau 聚集体的表位特异性靶向
- 批准号:
10467481 - 财政年份:2011
- 资助金额:
$ 21.19万 - 项目类别:
Epitope-Specific Targeting of Tau Aggregates.
Tau 聚集体的表位特异性靶向。
- 批准号:
8320099 - 财政年份:2011
- 资助金额:
$ 21.19万 - 项目类别:
Epitope-Specific Targeting of Tau Aggregates.
Tau 聚集体的表位特异性靶向。
- 批准号:
10187658 - 财政年份:2011
- 资助金额:
$ 21.19万 - 项目类别:














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