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Affinity of tau antibodies for solubilized pathological tau species but not their immunogen or insoluble tau aggregates predicts in vivo and ex vivo efficacy


Year of Publication:
Contact PI Name:
Einar M. Sigurdsson
Contact PI Affiliation:
Departments of Neuroscience and Physiology, New York University School of Medicine, Medical Science Building, New York, New York, USA
Erin E. Congdon, Yan Lin, Hameetha B. Rajamohamedsait, Dov B. Shamir, Senthilkumar Krishnaswamy, Wajitha J. Rajamohamedsait, Suhail Rasool, Veronica Gonzalez, Josien Levenga, Jiaping Gu, Charles Hoeffer
Primary Reference (PubMED ID):
Funding Source:
Alzheimer's Association
Blas Frangione Foundation
National Institute on Aging (NIA)
National Institute of Neurological Disorders and Stroke (NINDS)
Study Goal and Principal Findings:

A few tau immunotherapies are now in clinical trials with several more likely to be initiated in the near future. A priori, it can be anticipated that an antibody which broadly recognizes various pathological tau aggregates with high affinity would have the ideal therapeutic properties. Tau antibodies 4E6 and 6B2, raised against the same epitope region but of varying specificity and affinity, were tested for acutely improving cognition and reducing tau pathology in transgenic tauopathy mice and neuronal cultures. Surprisingly, this study shows that one antibody, 4E6, which has low affinity for most forms of tau acutely improved cognition and reduced soluble phospho-tau, whereas another antibody, 6B2, which has high affinity for various tau species was ineffective. Concurrently, they confirmed and clarified these efficacy differences in an ex vivo model of tauopathy. Alzheimer’s paired helical filaments (PHF) were toxic to the neurons and increased tau levels in remaining neurons. Both toxicity and tau seeding were prevented by 4E6 but not by 6B2. Furthermore, 4E6 reduced PHF spreading between neurons. Interestingly, 4E6’s efficacy relates to its high affinity binding to solubilized PHF, whereas the ineffective 6B2 binds mainly to aggregated PHF. Blocking 4E6's uptake into neurons prevented its protective effects if the antibody was administered after PHF had been internalized. When 4E6 and PHF were administered at the same time, the antibody was protective extracellularly. Overall, these findings indicate that high antibody affinity for solubilized PHF predicts efficacy, and that acute antibody-mediated improvement in cognition relates to clearance of soluble phospho-tau. Importantly, both intra- and extracellular clearance pathways are in play. Together, these results have major implications for understanding the pathogenesis of tauopathies and for development of immunotherapies.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Immunotherapy(passive)
Therapeutic Agent:
4E6 (anti-Tau Mab)
Therapeutic Target:
Tau Protein
Therapy Type:
Biologic - Immunotherapy(passive)
Therapeutic Agent:
6B2 (anti-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
Closed Field Symmetrical Maze (CFSM)
Fear Conditioning Response
Motor Function
Locomotor Activity
Rotarod Test
Sarkosyl Soluble Tau
Sarkosyl Insoluble Tau
Tau Oligomers
Neuronal Marker NeuN
Total Tau Protein
Cell Biology
Tau Spreading
Target Engagement (Reduction Tau)