Abilita Bio, an innovation-driven biotechnology company, is seeking SBIR Phase I funding for the discovery of novel therapeutic nanobodies targeting the orphan G protein-coupled receptors GPR17 and GPR37, to address the neuropathology of Alzheimers disease. More than 5 million Americans suffer from this debilitating disease, which causes memory loss and the progressive impairment of cognitive functions. Despite an abundance of evidence supporting the role of amyloid-? and tau in Alzheimers disease etiopathology, amyloid-? targeted clinical efforts have generated little evidence of improvement in cognitive or functional outcomes, which emphasizes the unmet need for novel targets and therapeutic strategies. Recent imaging studies have demonstrated that white matter structural changes and underlying myelin abnormalities are significant components of Alzheimers disease and may precede overt amyloid and tau pathologies. Due to the association of white matter changes and myelin loss with the clinical progression of Alzheimers disease, the glial cells responsible for the production and repair of myelin, oligodendrocytes, may be critically affected. Therefore, drugs that promote oligodendrocyte maturation and remyelination may represent promising new treatments for Alzheimers and other neurodegenerative diseases. Recently, it has been found that two orphan G protein-coupled receptors, GPR17 and GPR37, act to negatively regulate oligodendrocyte development as they mature to myelinating cells, which and ultimately affects their capacity to repair damaged axons. Selective antagonists of GPR17 and GPR37 signaling may unblock oligodendrocyte checkpoints to promote their differentiation and remyelinating activity, which presents an opportunity to repair the pathological damage caused by Alzheimers. Despite the potential of GPR17 and GPR37, no specific pharmacological agents are available that can be used to validate the targets in Alzheimers disease, or serve as therapeutic leads, which we will address in the proposed research. GPR17 and GPR37 have been exceedingly difficult to drug due to their poorly defined binding pockets, poor functional folding and high constitutively activity, which is typical for orphan receptors. We will address the need for selective target modulators by using a novel approach, where we will use our innovative directed evolution-based protein stabilization technology to optimize GPR17 and GPR37 for use in llama immunization and phage library screening for the discovery of camelid single chain antibodies (nanobodies). Nanobodies 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 development. We plan to discover both agonistic and antagonistic nanobodies that will be pharmacologically characterized and tested for their ability to stimulate oligodendrocyte maturation and myelination activity. Nanobodies verified to exhibit potency and selectivity in these assays will be taken forward to in vivo validation in Alzheimers Disease models in a future Phase II SBIR effort, with the aim of clinical development.
Public Health Relevance Statement: 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 receptors (GPCRs) antigens that are needed to enable therapeutic antibody discovery and their development. Abilita Bios unique approach, is based on directed evolution to obtain radically improved variants of the natural GPCR target, and has allowed the identification of variants with exceptional stability and homogeneity that we call EMPsTM (Enabled Membrane Proteins). The availability of such enhanced variants will enable the discovery and development of small single-chain antibodies (nanobodies) therapeutics designed to be used in monotherapy or in combination with current therapies to control the burden of Alzheimers disease, a predominant degenerative neurological disease in the aging population, using a potentially transformative approach aiming at slowing and/or possibly reversing the course of the disease.
Project Terms: Address; Affect; aging population; Agonist; Alzheimer's Disease; Alzheimer's disease model; American; Amyloid; Amyloid beta-Protein; Antibodies; Antigen Receptors; Antigens; Axon; axon injury; Bacteriophages; base; Binding; Biological Assay; Biotechnology; Brain; Brain Diseases; Cells; Clinical; clinical development; Cognitive; cognitive function; Demyelinations; design; Development; Directed Molecular Evolution; Disease; Drug Targeting; Elements; Evolution; Exhibits; Failure; functional outcomes; Funding; Future; Future Generations; G-Protein-Coupled Receptors; G-substrate; GPR17 gene; gray matter; imaging study; Immunization; Impaired cognition; improved; in vitro Model; in vivo; innovation; Libraries; Llama; Membrane Proteins; Memory Loss; Molecular Conformation; Morphology; Mutation; Myelin; myelination; nanobodies; Neurodegenerative Disorders; Neuroglia; neuroimaging; neuropathology; novel; novel strategies; novel therapeutics; oligodendrocyte progenitor; Oligodendroglia; Orphan; Pathogenicity; Pathologic; Pathology; Patients; Phage Display; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; preclinical development; Process; Production; Property; Proteins; receptor; receptor binding; remyelination; repaired; Reporting; Research; Risk; Role; screening; Senile Plaques; Signal Transduction; Small Business Innovation Research Grant; Structural defect; Structure; targeted treatment; tau aggregation; tau Proteins; Technology; Testing; Therapeutic; Therapeutic antibodies; therapeutic development; tool; United States; Validation; Variant; white matter
