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

• 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
• 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' s Disease; Alzheimer' s disease patient; Alzheimer' 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

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.

总结 超过500万美国人患有阿尔茨海默病（AD）。已批准的治疗仅适用于AD 治疗症状，但不解决潜在的神经退行性疾病。重要的是， 因此，联合应用治疗剂（DMT）来延迟AD的发作或进展可以减少高达50%的AD病例。但 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%的 全身给予治疗，几乎所有抗体都无法到达大脑，因此无效 治疗AD BBB转运蛋白的成员先前已用于转运纳米颗粒制剂， 但与重大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： 利用其专有和创新的平台，使能膜蛋白TM（EMP），开发单域 抗体（sdAb）将锁定转运蛋白而不改变其天然功能，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 差别很大因此，Abilita Bio将采取多目标的方法来确定强有力的候选人。我们有 鉴定了来自4个不同功能亚家族的转运蛋白，以测试其作为递送AD的新抗体靶标 通过血脑屏障进行治疗。 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 体外血脑屏障转运的概念。这将通过实现三个目标来实现。在目标1中，我们 使用我们的EMP平台来进化4个目标，以生成具有增强特性的变体，同时保持 wildtype函数在目标2中，我们将用我们的EMP变体免疫美洲驼，以开发针对每个靶标的sdAb。 我们将测试sdAb命中的特异性和亲和力。在我们的两首热门歌曲中，我们将在体外进行概念验证 使用基于微流体的BBB模型的研究。该模型提供了比简单transwell更复杂的 系统，并将提供更多的相关数据，以支持未来的体内研究。成功完成本阶段 我计划将开发两种具有体外疗效的潜在候选药物。该数据将告知体内功效， 在II期项目中，我们将联合收割机将我们的新型BBB转运蛋白sdAb与Abilita Bio的 目前正在研究的AD治疗剂。最终，这种BBB转运蛋白的开发具有 改善AD患者预后的潜力。