Discovery of Novel Blood-Brain Barrier Targeting Antibodies for the Treatment of Alzheimer's Disease
发现用于治疗阿尔茨海默病的新型血脑屏障靶向抗体
基本信息
- 批准号:10254514
- 负责人:
- 金额:$ 43.29万
- 依托单位:
- 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:2021-09-15 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAcademiaAddressAffectAffinityAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAlzheimer&aposs disease therapeuticAmericanAntibodiesAntibody TherapyBacteriophagesBindingBlood - brain barrier anatomyBlood CirculationBrainCarrier ProteinsCellsChemicalsClinicCoculture TechniquesDataDevelopmentDiseaseDisease OutcomeEndocytosisEndothelial CellsEndotheliumEnvironmentEnzyme-Linked Immunosorbent AssayExocytosisFDA approvedFamilyFc ReceptorFlow CytometryFormulationFutureGene LibraryGoalsImmunizationImmunizeIn VitroIndustryInvestigationLlamaMeasurementMeasuresMediatingMedical DeviceMembraneMembrane ProteinsMicrofluidicsModelingNerve DegenerationPatient-Focused OutcomesPharmaceutical PreparationsPhasePropertyProteinsProteomicsResearchRiskSLC2A1 geneSignal TransductionSmall Business Innovation Research GrantSpecificitySystemTechnologyTestingTherapeuticToxic effectValidationVariantbaseblood-brain barrier functioncerebral capillarydrug candidateefficacy studyimprovedimproved outcomein vitro testingin vivoinnovationmembernanobodiesnanoparticlenovelprogramsreduce symptomsresponsesafety studysolutesymptom treatmenttargeted deliverytherapeutic proteintraffickingtranscytosisvalidation studiesvirtual
项目摘要
SUMMARY
Over 5 million Americans suffer from Alzheimer’s Disease (AD). The approved therapies available for AD only
treat symptoms and do not address the underlying neurodegeneration. Importantly, disease-modifying
therapeutics (DMT) to delay onset or progression of AD could reduce up to 50% of AD cases. However, the
major hurdle to developing DMTs for AD is the largely impermeable blood brain barrier (BBB). 98% of all
systemically administered therapeutics and virtually all antibodies fail to reach the brain, and thus are ineffective
at treating AD. Members of BBB transporters have been previously used to transport nanoparticle formulations,
but are associated with significant scientific complexity and toxicity risk. Abilita Bio will circumvent these risks by
using its proprietary and innovative platform, Enabled Membrane ProteinTM (EMP), to develop single domain
antibodies (sdAbs) that will latch onto transporters without altering their natural function, enter the BBB via
endocytosis, then into the brain via exocytosis. However, expression level of transporters and their efficiency
widely vary. Therefore, Abilita Bio will take a multi-target approach to identify a strong candidate. We have
identified transporters from 4 different functional subfamilies to test as novel antibody targets to deliver AD
therapeutics through the BBB.
The goal of this Phase I SBIR proposal is to develop sdAbs of our 4 identified targets and perform proof-of-
concept of BBB transport in vitro. This will be accomplished through the execution of 3 aims. In Aim 1, we will
use our EMP platform to evolve the 4 targets to generate variants with enhanced properties while maintaining
wildtype function. In Aim 2, we will immunize llamas with our EMP variants to develop sdAbs against each target.
We will test sdAb hits for specificity and affinity. With our two top hits, we will perform in vitro proof of concept
studies using a microfluidic-based BBB model. This model provides more complexity than simple transwell
systems and will provide more relevant data to support future in vivo studies. Successful completion of this Phase
I program will develop potentially two candidates with in vitro efficacy. This data will inform in vivo efficacy and
safety studies in a Phase II program where we will combine our novel BBB transporter sdAb with Abilita Bio’s
AD therapeutic that is currently under investigation. Ultimately, the development of this BBB transporter has the
potential to improve AD patient outcomes.
概括
超过 500 万美国人患有阿尔茨海默病 (AD)。批准的疗法仅适用于 AD
治疗症状而不是解决潜在的神经退行性变。重要的是,改变疾病
延缓 AD 发病或进展的治疗 (DMT) 可以减少多达 50% 的 AD 病例。然而,
开发用于 AD 的 DMT 的主要障碍是基本上不可渗透的血脑屏障 (BBB)。 98% 全部
全身给药的治疗方法几乎所有抗体都无法到达大脑,因此无效
在治疗 AD 时。 BBB 转运蛋白的成员以前曾被用来转运纳米颗粒制剂,
但与显着的科学复杂性和毒性风险相关。 Abilita Bio 将通过以下方式规避这些风险
使用其专有的创新平台 Enabled Membrane ProteinTM (EMP) 开发单域
抗体 (sdAb) 将锁定转运蛋白而不改变其自然功能,通过
内吞作用,然后通过胞吐作用进入大脑。然而,转运蛋白的表达水平及其效率
差异很大。因此,Abilita Bio 将采取多目标方法来寻找强有力的候选者。我们有
确定了来自 4 个不同功能亚家族的转运蛋白,作为传递 AD 的新抗体靶标进行测试
通过 BBB 进行治疗。
第一阶段 SBIR 提案的目标是开发我们 4 个已确定目标的 sdAb,并进行证明-
体外 BBB 转运的概念。这将通过执行 3 个目标来实现。在目标 1 中,我们将
使用我们的 EMP 平台进化 4 个目标,以生成具有增强特性的变体,同时保持
野生型功能。在目标 2 中,我们将使用我们的 EMP 变体对美洲驼进行免疫,以开发针对每个目标的 sdAb。
我们将测试 sdAb 命中的特异性和亲和力。凭借我们的两个热门产品,我们将进行体外概念验证
使用基于微流体的 BBB 模型进行研究。该模型比简单的 transwell 提供了更多的复杂性
系统并将提供更多相关数据来支持未来的体内研究。本阶段顺利完成
我的计划将开发两种具有体外功效的潜在候选药物。该数据将告知体内功效和
在第二阶段计划中进行安全性研究,我们将把我们的新型 BBB 转运蛋白 sdAb 与 Abilita Bio 的结合起来
AD疗法目前正在研究中。最终,这种 BBB 转运蛋白的开发
改善 AD 患者预后的潜力。
项目成果
期刊论文数量(0)
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Mauro Mileni其他文献
Mauro Mileni的其他文献
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{{ truncateString('Mauro Mileni', 18)}}的其他基金
Novel Anti-CCR8 VHH for the Treatment of NSCLC
用于治疗 NSCLC 的新型抗 CCR8 VHH
- 批准号:
10760140 - 财政年份:2023
- 资助金额:
$ 43.29万 - 项目类别:
Discovery of therapeutic nanobodies targeting the G protein-coupled receptors in the brain for the treatment of Alzheimer Disease
发现针对大脑中 G 蛋白偶联受体的治疗性纳米抗体可用于治疗阿尔茨海默病
- 批准号:
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Discovery of therapeutic antibodies targeting breast cancer metastasis using Enabled G-Protein-Coupled Receptors
使用启用的 G 蛋白偶联受体发现针对乳腺癌转移的治疗抗体
- 批准号:
9256138 - 财政年份:2016
- 资助金额:
$ 43.29万 - 项目类别:
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