Discovery of therapeutic nanobodies targeting the G protein-coupled receptors in the brain for the treatment of Alzheimer Disease

Project Summary Abstract Abilita Bioan innovation driven biotechnology companyis seeking SBIR Phase I funding for the discovery of novel therapeutic nanobodies targeting the orphan G protein coupled receptors GPRand GPRto address the neuropathology of Alzheimer s diseaseMore thanmillion Americans suffer from this debilitating diseasewhich causes memory loss and the progressive impairment of cognitive functionsDespite an abundance of evidence supporting the role of amyloidand tau in Alzheimer s disease etiopathologyamyloidtargeted clinical efforts have generated little evidence of improvement in cognitive or functional outcomeswhich emphasizes the unmet need for novel targets and therapeutic strategiesRecent imaging studies have demonstrated that white matter structural changes and underlying myelin abnormalities are significant components of Alzheimer s disease and may precede overt amyloid and tau pathologiesDue to the association of white matter changes and myelin loss with the clinical progression of Alzheimer s diseasethe glial cells responsible for the production and repair of myelinoligodendrocytesmay be critically affectedThereforedrugs that promote oligodendrocyte maturation and remyelination may represent promising new treatments for Alzheimer s and other neurodegenerative diseasesRecentlyit has been found that two orphan G protein coupled receptorsGPRand GPRact to negatively regulate oligodendrocyte development as they mature to myelinating cellswhich and ultimately affects their capacity to repair damaged axonsSelective antagonists of GPRand GPRsignaling may unblock oligodendrocyte checkpoints to promote their differentiation and remyelinating activitywhich presents an opportunity to repair the pathological damage caused by Alzheimer sDespite the potential of GPRand GPRno specific pharmacological agents are available that can be used to validate the targets in Alzheimer s diseaseor serve as therapeutic leadswhich we will address in the proposed researchGPRand GPRhave been exceedingly difficult to drug due to their poorly defined binding pocketspoor functional folding and high constitutively activitywhich is typical for orphan receptorsWe will address the need for selective target modulators by using a novel approachwhere we will use our innovative directed evolution based protein stabilization technology to optimize GPRand GPRfor use in llama immunization and phage library screening for the discovery of camelid single chain antibodiesnanobodiesNanobodies have unique properties that enable the recognition of receptor binding pockets and structural elements critical for the functional modulation of G protein coupled receptors and have been validated by successful clinical developmentWe plan to discover both agonistic and antagonistic nanobodies that will be pharmacologically characterized and tested for their ability to stimulate oligodendrocyte maturation and myelination activityNanobodies verified to exhibit potency and selectivity in these assays will be taken forward to in vivo validation in Alzheimer s Disease models in a future Phase II SBIR effortwith the aim of clinical development Project Narrative The proposed study focuses on addressing technical hurdles that have so far limited the ability to produce high quality and stable whole protein G protein coupled receptorsGPCRsantigens that are needed to enable therapeutic antibody discovery and their developmentAbilita Bio s unique approachis based on directed evolution to obtain radically improved variants of the natural GPCR targetand has allowed the identification of variants with exceptional stability and homogeneity that we call EMPsTMEnabled Membrane ProteinsThe availability of such enhanced variants will enable the discovery and development of small single chain antibodiesnanobodiestherapeutics designed to be used in monotherapy or in combination with current therapies to control the burden of Alzheimer s diseasea predominant degenerative neurological disease in the aging populationusing a potentially transformative approach aiming at slowing and or possibly reversing the course of the disease