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Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models


Year of Publication:
Contact PI Name:
Sethu Sankaranarayanan
Contact PI Affiliation:
Research and Development, Bristol-Myers Squibb, Wallingford, Connecticut, USA
Donna M. Barten, Laurel Vana, Nino Devidze, Ling Yang, Gregory Cadelina, Nina Hoque, Lynn DeCarr, Stefanie Keenan, et al.,
Primary Reference (PubMED ID):
Funding Source:
Bristol-Myers Squibb
National Institute on Aging (NIA)
Marian S. Ware Alzheimer Program
CurePSP Foundation
Karen Cohen Segal and Christopher S. Segal Alzheimer Drug Discovery Initiative Fund
Paula C. Schmerler Fund for Alzheimer's Research
Barrist Neurodegenerative Disease Research Fund
Eleanor Margaret Kurtz Endowed Fund
Mary Rasmus Endowed Fund for Alzheimer's Research
Study Goal and Principal Findings:

In Alzheimer's disease (AD), an extensive accumulation of extracellular amyloid plaques and intraneuronal tau tangles, along with neuronal loss, is evident in distinct brain regions. Staging of tau pathology by postmortem analysis of AD subjects suggests a sequence of initiation and subsequent spread of neurofibrillary tau tangles along defined brain anatomical pathways. Further, the severity of cognitive deficits correlates with the degree and extent of tau pathology. In this study, was demonstrated that phospho-tau (p-tau) antibodies, PHF6 and PHF13, can prevent the induction of tau pathology in primary neuron cultures. The impact of passive immunotherapy on the formation and spread of tau pathology, as well as functional deficits, was subsequently evaluated with these antibodies in two distinct transgenic mouse tauopathy models. The rTg4510 transgenic mouse is characterized by inducible over-expression of P301L mutant tau, and exhibits robust age-dependent brain tau pathology. Systemic treatment with PHF6 and PHF13 from 3 to 6 months of age led to a significant decline in brain and CSF p-tau levels. In a second model, injection of preformed tau fibrils (PFFs) comprised of recombinant tau protein encompassing the microtubule-repeat domains into the cortex and hippocampus of young P301S mutant tau over-expressing mice (PS19) led to robust tau pathology on the ipsilateral side with evidence of spread to distant sites, including the contralateral hippocampus and bilateral entorhinal cortex 4 weeks post-injection. Systemic treatment with PHF13 led to a significant decline in the spread of tau pathology in this model. The reduction in tau species after p-tau antibody treatment was associated with an improvement in novel-object recognition memory test in both models. These studies provide evidence supporting the use of tau immunotherapy as a potential treatment option for AD and other tauopathies.

Bibliographic Notes:
Full Author List: Sethu Sankaranarayanan, Donna M. Barten, Laurel Vana, Nino Devidze, Ling Yang, Gregory Cadelina, Nina Hoque, Lynn DeCarr, Stefanie Keenan, Alan Lin, Yang Cao, Bradley Snyder, Bin Zhang, Magdalena Nitla, Gregg Hirschfeld, Nestor Barrezueta, Craig Polson, Paul Wes, Vangipuram S. Rangan, Angela Cacace, Charles F. Albright, Jere Meredith, Jr., John Q. Trojanowski, Virginia M-Y. Lee, Kurt R. Brunden, Michael Ahlijanian.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Immunotherapy(passive)
Therapeutic Agent:
PHF13 (anti-pS396 Tau Mab)
Therapeutic Target:
Tau Protein
Therapy Type:
Biologic - Immunotherapy(passive)
Therapeutic Agent:
PHF6 (anti-pT231 Tau Mab)
Therapeutic Target:
Tau Protein

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Elevated Plus Maze
Novel Object Recognition Test (NORT)
Motor Function
Locomotor Activity
Tau Pathology
Sarkosyl Soluble Tau
Sarkosyl Insoluble Tau
CSF-Tau Protein
Total Tau Protein
Tau Protein
Ionized Calcium Binding Adaptor Molecule 1 (Iba1)
Glial Fibrillary Acidic Protein (GFAP)
Antibody Concentration-Plasma
Antibody Concentration-CSF
Antibody Concentration-ISF
Target Engagement (Reduction Tau)
Binding Affinity