权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

总结