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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：
Mauro Mileni
金额：
$ 43.29万
依托单位：
ABILITA BIO, INC.
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：
https://reporter.nih.gov/project-details/10254514
关键词：
3-Dimensional Academia Address Affect Affinity Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic American Antibodies Antibody Therapy Bacteriophages Binding Blood - brain barrier anatomy Blood Circulation Brain Carrier Proteins Cells Chemicals Clinic Coculture Techniques Data Development Disease Disease Outcome Endocytosis Endothelial Cells Endothelium Environment Enzyme-Linked Immunosorbent Assay Exocytosis FDA approved Family Fc Receptor Flow Cytometry Formulation Future Gene Library Goals Immunization Immunize In Vitro Industry Investigation Llama Measurement Measures Mediating Medical Device Membrane Membrane Proteins Microfluidics Modeling Nerve Degeneration Patient-Focused Outcomes Pharmaceutical Preparations Phase Property Proteins Proteomics Research Risk SLC2A1 gene Signal Transduction Small Business Innovation Research Grant Specificity System Technology Testing Therapeutic Toxic effect Validation Variant base blood-brain barrier function cerebral capillary drug candidate efficacy study improved improved outcome in vitro testing in vivo innovation member nanobodies nanoparticle novel programs reduce symptoms response safety study solute symptom treatment targeted delivery therapeutic protein trafficking transcytosis validation studies virtual

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。