Our goal is to develop a novel neuron-penetrating bispecific antibody that promotes neuronal integrity and neurogenesis for the treatment of AD. In the US alone, over 6 million Americans are currently living with AD, with total economic costs around $355 billion in 20211. Despite the staggering cost, only a few mildly effective AD symptom-treating drugs exist. As a result, treating and even reversing the effects of AD remains a significant unmet need. Pathologically, AD is characterized by the presence of neuritic plaques and neurofibrillary tangles in the brain. The primary component of the extracellular neuritic plaques is the ß-amyloid protein (Aß), an approximately 4 kDa fragment proteolytically derived from the larger amyloid precursor protein (APP)2. A vast amount of literature has implicated Aß accumulation as being central to the progression of AD, and inhibiting Aß production represents a promising strategy for treating AD. We have generated two single-chain variable domain antibody fragments (scFv), Asec and Bsec, which respectively promote a-secretase activity and block ß-secretase activity toward amyloid precursor protein (APP) by binding to APP at either the a-site or the ß-site3-5. Next, we generated a tandem bispecific antibody that combines the Asec and Bsec scFvs and showed that it elevates levels of sAPPa, a soluble a-secretase- associated APP fragment, and decreases levels of Aß and sAPPß, a soluble ß-secretase-associated fragment in cell models of AD6. An ApoB tag was added to the bispecific antibody (called VTC-939), which can facilitate transfer across the blood-brain barrier (BBB)6-8 and neuronal targeting. Using recombinant human adeno- associated virus (rAAV) as a vector infective to hepatic cells, VTC-939 could be secreted into the blood and brain at high levels. When VTC-939 was tested as a therapeutic in an APP/PS1 AD mouse model, VTC-939 increased levels of sAPPa, while decreasing Aß deposits and oligomeric Aß levels. In addition, VTC-939 treatment increased neuronal health, substantially increased hippocampal neurogenesis and significantly increased survival rates compared with untreated mice9. These results indicate that altering APP processing to inhibit toxic amyloidogenic ß-site activity while simultaneously promoting neuroprotective a-secretase processing provides increased neuronal benefits and represents a promising new therapeutic approach for treating, and potentially reversing AD. Building from this work, our objective is to develop VTC-939 as a novel neuron-penetrating antibody that restores neuronal integrity and promotes neurogenesis for the treatment of AD. The specific aims are to: 1) produce antibody constructs and establish quality control assays, 2) determine the optimal effective dose of VTC-939 to promote neuronal integrity, neurogenesis and longevity in the APP/PS1 AD mouse model, and 3) generate acute toxicology and biodistribution profiles for VTC-939 in normal healthy mice. A therapy that can safely and effectively promote neuronal integrity and neurogenesis would provide a significant advancement for a clear unmet medical need.
Public Health Relevance Statement: Project Narrative In the US alone, over 6 million Americans are currently living with Alzheimer's disease (AD), with total economic costs around $355 billion in 20211. This project is focused on developing a novel neuron-penetrating bispecific antibody that restores neuronal integrity and promotes neurogenesis in an AD mouse model. A therapeutic that can effectively and safely promote neuronal integrity and neurogenesis while preventing AD disease would provide a significant advancement for a clear unmet medical need.
Project Terms: Dependovirus; Adeno-Associated Viruses; Dependoparvovirus; adeno associated virus group; Alzheimer's Disease; AD dementia; Alzheimer; Alzheimer Type Dementia; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's disease dementia; Alzheimers Dementia; Alzheimers disease; Primary Senile Degenerative Dementia; dementia of the Alzheimer type; primary degenerative dementia; senile dementia of the Alzheimer type; Animals; Antibodies; Apolipoproteins B; Apo-B; ApoB; Autopsy; necropsy; postmortem; Behavior; Biological Assay; Assay; Bioassay; Biologic Assays; Blood; Blood Reticuloendothelial System; Blood Chemical Analysis; Blood Chemical Analyses; blood chemistry; Blood - brain barrier anatomy; Blood-Brain Barrier; Hemato-Encephalic Barrier; bloodbrain barrier; Brain; Brain Nervous System; Encephalon; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Engineering; Enzyme-Linked Immunosorbent Assay; ELISA; enzyme linked immunoassay; Goals; Health; Hematology; Hippocampus (Brain); Ammon Horn; Cornu Ammonis; Hippocampus; hippocampal; Human; Modern Man; Immunoglobulin Fragments; Antibody Fragments; Literature; Longevity; Length of Life; life span; lifespan; Mus; Mice; Mice Mammals; Murine; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Neurons; Esteroproteases; Peptidases; Protease Gene; Proteases; Proteinases; Proteolytic Enzymes; Peptide Hydrolases; Peptides; Pharmacokinetics; Drug Kinetics; Proteins; Quality Control; Survival Rate; Testing; Tissues; Body Tissues; Toxicology; Viral Proteins; Viral Gene Products; Viral Gene Proteins; virus protein; Weight; Work; Amyloid beta-Protein; Alzheimer beta-Protein; Alzheimer's Amyloid beta-Protein; Alzheimer's amyloid; Amyloid Alzheimer's Dementia Amyloid Protein; Amyloid Beta-Peptide; Amyloid Protein A4; Amyloid ß; Amyloid ß-Peptide; Amyloid ß-Protein; Aß; a beta peptide; abeta; amyloid beta; amyloid-b protein; beta amyloid fibril; soluble amyloid precursor protein; Amyloid beta-Protein Precursor; Amyloid A4 Protein Precursor; Amyloid Protein Precursor; Amyloid ß-Protein Precursor; amyloid precursor protein; Neurofibrillary Tangles; neurofibrillary degeneration; neurofibrillary lesion; neurofibrillary pathology; tangle; secretase; Site; Acute; Phase; Medical; Bispecific Antibodies; Bi-specific antibodies; Bifunctional Antibodies; bsAb; Hepatic Cells; Hepatic Parenchymal Cell; Liver Cells; Hepatocyte; Ligand Binding Protein; Ligand Binding Protein Gene; Protein Binding; bound protein; Binding Proteins; Therapeutic; Amyloid Plaques; Neuritic Plaques; amyloid beta plaque; amyloid-b plaque; aß plaques; cored plaque; diffuse plaque; Senile Plaques; Deposit; Deposition; a-secretase; alpha secretase; subdermal; subcutaneous; extracellular; Cell Protection; Cytoprotection; American; membrane structure; Membrane; Histopathology; novel; economic cost; neurogenesis; Pharmacodynamics; Molecular Interaction; Binding; preventing; prevent; Protein Fragment; Dose; ß-secretase; beta secretase; Data; Recombinants; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Pathologic; Process; Development; developmental; vector; cost; Abeta synthesis; Amyloid ß production; Amyloid ß synthesis; Aß production; Aß synthesis; abeta production; amyloid beta production; amyloid beta synthesis; Biodistribution; C-terminal; Cell model; Cellular model; abeta accumulation; abeta aggregation; amyloid beta accumulation; amyloid beta aggregation; amyloid ß accumulation; amyloid ß aggregation; aß accumulation; aß aggregation; mouse model; murine model; amyloid precursor protein processing; APP processing; novel therapeutic intervention; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; inflammatory marker; inflammation marker; regenerative; cognitive performance; symptom treatment; symptomatic treatment; treat symptom; side effect
