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
基本信息
- 批准号:10915130
- 负责人:
- 金额:$ 71.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-30 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAlzheimer&aposs DiseaseAmyloidAmyloid beta-ProteinAntibodiesAttentionB-LymphocytesBindingBiological AssayBlood - brain barrier anatomyBrainCell membraneClinicalClinical TrialsDataDepositionDiagnosisDiagnosticDiagnostic ImagingDiseaseDrug or chemical Tissue DistributionEndocytosisEngineeringEpitopesFDA approvedHalf-LifeImageImmunizeImmunoglobulin FragmentsImmunoglobulin GImmunotherapyIn VitroIntercellular FluidIntravenousLengthLesionLewy BodiesLewy Body DementiaLibrariesLlamaMediatingModelingMultiple System AtrophyMusNeuronsParkinson DiseasePathogenesisPathologicPenetrationPhage DisplayPhasePost-Translational Protein ProcessingPrionsProteinsPublic HealthPublishingReportingResearchSignal TransductionSolubilityTauopathiesTherapeuticThrombocytopeniaTissuesToxic effectTreatment EfficacyVaccinesabeta accumulationalpha synucleinbeta pleated sheetgene therapyimaging potentialimaging probeimprovedin vivoin vivo imagingintravenous administrationintravenous injectionmouse synuclein alphananobodiesnovelphase III trialpreventprotein foldingreceptorsmall moleculesynucleinopathytargeted imagingtargeted treatmenttau Proteinstau aggregationuptake
项目摘要
Abstract
Immunotherapies targeting aggregates of amyloid-β (Aβ), tau and α-synuclein (αsyn) are the most
common experimental approach for diseases characterized by such depositions. Most of these potential
therapies are whole antibodies. Antibody fragments have certain advantages over antibodies but their
diagnostic and therapeutic potential has not been well explored. Five anti-αsyn IgG antibodies and one αsyn
vaccine are in Phase 1-2 clinical trials, and one Aβ antibody recently showed clinical benefit in a Phase 3 trial,
which strongly supports this therapeutic approach. Regarding antibody fragments, several anti-αsyn single
chain variable fragments (scFvs) are effective in culture and in vivo, and two anti-αsyn single domain
antibodies (sdAbs) have been characterized in a binding assay but their therapeutic efficacy or diagnostic
imaging potential have not been reported. SdAbs have several advantages over scFvs, including higher
affinity, binding to cryptic epitopes and simpler engineering. They are also more suitable for gene therapy
because of uncomplicated expression and predictable protein folding, given their single domain, resulting in
high solubility.
We have developed 58 anti-αsyn sdAb clones with unique binding regions from a screen of phage
display libraries generated from B-cells of a llama immunized with αsyn. Three aims are proposed to clarify
their potential to detect and clear αsyn in vivo. Aim 1 will determine the in vivo imaging potential of sdAbs
targeting αsyn. Aim 2 will clarify αsyn clearance potential and mechanism of action of sdAbs targeting αsyn,
and Aim 3 will explore the feasibility of sdAb gene therapy targeting αsyn.
Preliminary findings indicate that the sdAbs: 1) recognize various forms of αsyn with high affinity; 2)
clear αsyn and prevent its toxicity in culture models; 3) clear αsyn from brain interstitial fluid in αsyn mice; 4)
bind to αsyn in the brain of αsyn mice after intravenous injection with in vivo brain signal that correlates well
with αsyn brain burden; 5) clear αsyn from the brain after intravenous injection of sdAb with improved
clearance by its PROTAC derivative, and; 6) clear αsyn from the brain after intravenous sdAb gene therapy. It
is hypothesized that the small size of the sdAbs will provide diagnostic and therapeutic benefits over whole
antibodies, primarily because of greater access into the brain and to the target, proper folding for gene therapy,
and to some extent due to their binding to novel epitopes that the larger antibodies cannot access.
Overall, the proposed studies are likely to aid in clarifying αsyn pathogenesis, decipher the mechanism
of action of the sdAbs, and identify promising diagnostic and therapeutic sdAbs for clinical trials on
synucleinopathies such as Lewy Body Dementia, Parkinson's disease, Alzheimer's disease with Lewy Bodies,
and Multiple System Atrophy.
摘要
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
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
- 批准号:
9762785 - 财政年份:2018
- 资助金额:
$ 71.75万 - 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:
$ 71.75万 - 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:
$ 71.75万 - 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:
$ 71.75万 - 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:
$ 71.75万 - 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:
$ 71.75万 - 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:
$ 71.75万 - 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:
$ 71.75万 - 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:
$ 71.75万 - 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:
$ 71.75万 - 项目类别: