Over 5 million Americans suffer from Alzheimer's Disease (AD). The approved therapies available for AD onlytreat symptoms and do not address the underlying neurodegeneration. Importantly, disease-modifyingtherapeutics (DMT) to delay onset or progression of AD could reduce up to 50% of AD cases. However, themajor hurdle to developing DMTs for AD is the largely impermeable blood brain barrier (BBB). 98% of allsystemically administered therapeutics and virtually all antibodies fail to reach the brain, and thus are ineffectiveat 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 byusing its proprietary and innovative platform, Enabled Membrane ProteinTM (EMP), to develop single domainantibodies (sdAbs) that will latch onto transporters without altering their natural function, enter the BBB viaendocytosis, then into the brain via exocytosis. However, expression level of transporters and their efficiencywidely vary. Therefore, Abilita Bio will take a multi-target approach to identify a strong candidate. We haveidentified transporters from 4 different functional subfamilies to test as novel antibody targets to deliver ADtherapeutics 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 willuse our EMP platform to evolve the 4 targets to generate variants with enhanced properties while maintainingwildtype 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 conceptstudies using a microfluidic-based BBB model. This model provides more complexity than simple transwellsystems and will provide more relevant data to support future in vivo studies. Successful completion of this PhaseI program will develop potentially two candidates with in vitro efficacy. This data will inform in vivo efficacy andsafety studies in a Phase II program where we will combine our novel BBB transporter sdAb with Abilita Bio'sAD therapeutic that is currently under investigation. Ultimately, the development of this BBB transporter has thepotential to improve AD patient outcomes. NARRATIVE Alzheimer's Disease (AD) affects over 5 million people in the US and many therapeutics developed to treat the underlying neurodegeneration of AD are unable to reach the brain because of the largely impermeable blood- brain barrier (BBB). To address this unmet need, Abilita Bio is using its proprietary technology platform to develop an antibody against BBB transporters that can serve as a delivery system for AD therapeutics. This antibody has the potential to enable both previously unsuccessful and newly developed therapeutics to reach the brain and improve AD patient outcomes. 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