SAN FRANCISCO, May 8, 2017 /PRNewswire/ -- Researchers at The Institute for Molecular Medicine (IMM) in Huntington Beach, CA, along with collaborators at the University of California at Irvine, Irvine, CA have created a therapeutic humanized monoclonal antibody that specifically targets misfolded Tau protein, a common pathological marker for several neurodegenerative disorders collectively referred to as tauopathies: Alzheimer's Disease (AD), Frontotemporal Dementia with Parkinsonism-17 (FTDP-17), Progressive Supranuclear Palsy (PSP), Amyotrophic Lateral Sclerosis (ALS), Pick's Disease (PiD) and others. This humanized monoclonal antibody, termed Armanezumab, inhibited seeding activity, reduced Tau proteins from the brains of mice bred to have tauopathy, and bound to the brains of human patients who had AD and other tauopathies. Therefore Armanezumab, after further development, may one day become useful for treating advanced stages of AD and other dementias associated with the accumulation of pathological Tau in the brain.
Today, AD is the most common cause of dementia. Immunotherapeutic strategies targeting two central pathological proteins, β-amyloid (Aβ) and Tau, have displayed strong positive effects in animal models of AD, leading to attempts by industry to use anti-Aβ or anti-Tau therapeutics in clinical trials. A primary focus has involved reducing Aβ levels in the brain. Anti-Aβ immunotherapy is considered one of the most promising AD treatments under investigation, and is currently being tested in many clinical trials. Unfortunately, none of the attempts reported to date have shown a positive clinical outcome in pivotal phase 3 trials.
However, there have been valuable lessons learned from these trials. First, to be effective anti-Aβ immunotherapy should be initiated before cognitive decline and severe pathological changes have occurred. Secondly, clearing Aβ in the late stages may be insufficient to halt the progression of AD. Rather, data from many prominent groups of scientists have suggested that it is not Aβ plaque burden but rather Tau pathology that correlates much better with the degree of dementia in AD. Thus, the development of a safe and effective immunotherapy targeting pathological Tau may be central to treating AD, FTDP-17, PSP and ALS.
"In this study our research team generated and characterized a monoclonal humanized antibody targeting the N-terminal region of Tau spanning amino acids 2-18. While this domain is normally hidden in a paperclip-like conformation in normal tau, it becomes exposed in aggregated pathological tau. Remarkably, Armanezumab recognized pathological, but not normal Tau, while preventing pathological Tau toxicity, aggregation, propagation, and reducing levels in mouse brains. A commercial-grade cell line producing 1.5 g/L of Armanezumab was developed based on these data," said Dr. Anahit Ghochikyan, Associate Professor at IMM and one of the senior authors of the study.
Another senior author, Dr. Michael Agadjanyan, Professor and Head of the Department of Immunology at IMM and faculty at the Institute for Memory Impairments and Neurological Disorders at UCI, added: "We are still at the early stages of immunotherapy for neurodegenerative disorders and the field is advancing methodically. Humanized monoclonal antibodies have become very effective in treating various cancers, and we hope that disorders of the brain will also yield to this approach. We believe that Armanezumab has the potential to be a safe and effective immunotherapeutic strategy for treating mid-stage Alzheimer's disease patients, as well as patients suffering from other tau-related disorders."
The composition of matter, formulation, and methods of use have been submitted to the US patent office and have been exclusively licensed to AGP Therapeutics, LLC. Study results appear in Molecular Neurodegeneration: https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-017-0172-1
About AGP Therapeutics, LLC
AGP Therapeutics, LLC is focused on bringing to the clinic passive vaccination strategies for multiple neurological disorders, in particular the following tauopathies: Alzheimer's Disease (AD), Frontotemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Pick's Disease (PiD), Progressive Supranuclear Palsy (PSP), Amyotrophic Lateral Sclerosis (ALS), Parkinsonism-Dementia Complex (PDC) of Guam, and Corticobasal Degeneration (CBD).
Guriq Basi, Ph.D.
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