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.
抽象的
针对淀粉样蛋白-β (Aβ)、tau 和 α-突触核蛋白 (αsyn) 聚集体的免疫疗法是最常见的
针对以此类沉积物为特征的疾病的常见实验方法。这些潜力中的大部分
疗法是完整抗体。抗体片段与抗体相比具有一定的优势,但它们
诊断和治疗潜力尚未得到充分开发。五种抗 αsyn IgG 抗体和一种 αsyn
疫苗正在进行 1-2 期临床试验,并且一种 Aβ 抗体最近在 3 期试验中显示出临床益处,
强烈支持这种治疗方法。关于抗体片段,几种抗αsyn单
链可变片段(scFv)在培养和体内均有效,并且两个抗αsyn单结构域
抗体 (sdAb) 已通过结合测定进行了表征,但其治疗功效或诊断效果
成像潜力尚未见报道。 SdAb 比 scFv 具有多个优势,包括更高的
亲和力、与隐秘表位的结合以及更简单的工程设计。它们也更适合基因治疗
由于不复杂的表达和可预测的蛋白质折叠,考虑到它们的单一结构域,导致
高溶解度。
我们通过噬菌体筛选开发了 58 个具有独特结合区域的抗 αsyn sdAb 克隆
显示用 αsyn 免疫的美洲驼 B 细胞生成的文库。提出三个目标以澄清
它们在体内检测和清除 αsyn 的潜力。目标 1 将确定 sdAb 的体内成像潜力
靶向αsyn。目标 2 将阐明 αsyn 清除潜力以及针对 αsyn 的 sdAb 的作用机制,
Aim 3将探索针对αsyn的sdAb基因治疗的可行性。
初步研究结果表明,sdAbs:1)以高亲和力识别各种形式的αsyn; 2)
清除αsyn并防止其在培养模型中的毒性; 3)从αsyn小鼠脑间质液中清除αsyn; 4)
静脉注射后与 αsyn 小鼠大脑中的 αsyn 结合,与体内脑信号相关性良好
有αsyn脑负担; 5) 静脉注射sdAb后从大脑中清除αsyn,改善
通过其 PROTAC 衍生物进行清除,以及; 6)静脉注射sdAb基因治疗后清除大脑中的αsyn。它
假设小尺寸的 sdAb 将提供比整体更好的诊断和治疗益处
抗体,主要是因为更容易进入大脑和目标,基因治疗的正确折叠,
在某种程度上,由于它们与较大抗体无法访问的新表位结合。
总体而言,拟议的研究可能有助于阐明 αsyn 发病机制,破译其机制
sdAbs 的作用,并确定有前途的诊断和治疗性 sdAbs 用于临床试验
突触核蛋白病,例如路易体痴呆、帕金森病、路易体阿尔茨海默氏病、
和多系统萎缩。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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:














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