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EBioMedicine. 2019 Apr;42:157-173. doi: 10.1016/j.ebiom.2019.03.033. Epub 2019 Mar 22.

Tau antibody chimerization alters its charge and binding, thereby reducing its cellular uptake and efficacy.

Author information

1
New York University School of Medicine, Department of Neuroscience and Physiology, and The Neuroscience Institute, 435 E 30th St. SB1123, New York, NY 10016, United States of America.
2
New York University School of Medicine, Department of Biochemistry and Molecular Pharmacology, 550 First Ave, MSB 398, New York, NY 10016, United States of America.
3
New York University School of Medicine, Department of Cell Biology, 540 First Avenue, Skirball Institute Lab 5-18, New York, NY 10016, United States of America.
4
New York University School of Medicine, Department of Neuroscience and Physiology, and The Neuroscience Institute, 435 E 30th St. SB1123, New York, NY 10016, United States of America; New York University School of Medicine, Department of Psychiatry, 435 E 30th St. Science Building SB1115, New York, NY 10016, United States of America. Electronic address: einar.sigurdsson@med.nyu.edu.

Abstract

BACKGROUND:

Bringing antibodies from pre-clinical studies to human trials requires humanization, but this process may alter properties that are crucial for efficacy. Since pathological tau protein is primarily intraneuronal in Alzheimer's disease, the most efficacious antibodies should work both intra- and extracellularly. Thus, changes which impact uptake or antibody binding will affect antibody efficacy.

METHODS:

Initially, we examined four tau mouse monoclonal antibodies with naturally differing charges. We quantified their neuronal uptake, and efficacy in preventing toxicity and pathological seeding induced by human-derived pathological tau. Later, we generated a human chimeric 4E6 (h4E6), an antibody with well documented efficacy in multiple tauopathy models. We compared the uptake and efficacy of unmodified and chimeric antibodies in neuronal and differentiated neuroblastoma cultures. Further, we analyzed tau binding using ELISA assays.

FINDINGS:

Neuronal uptake of tau antibodies and their efficacy strongly depends on antibody charge. Additionally, their ability to prevent tau toxicity and seeding of tau pathology does not necessarily go together. Particularly, chimerization of 4E6 increased its charge from 6.5 to 9.6, which blocked its uptake into human and mouse cells. Furthermore, h4E6 had altered binding characteristics despite intact binding sites, compared to the mouse antibody. Importantly, these changes in uptake and binding substantially decreased its efficacy in preventing tau toxicity, although under certain conditions it did prevent pathological seeding of tau.

CONCLUSIONS:

These results indicate that efficacy of chimeric/humanized tau antibodies should be thoroughly characterized prior to clinical trials, which may require further engineering to maintain or improve their therapeutic potential. FUND: National Institutes of Health (NS077239, AG032611, R24OD18340, R24OD018339 and RR027990, Alzheimer's Association (2016-NIRG-397228) and Blas Frangione Foundation.

KEYWORDS:

Alzheimer's disease; Antibody engineering; Immunotherapy; Neuroblastoma; Neuron; Tau protein; Vaccine development

PMID:
30910484
PMCID:
PMC6492224
DOI:
10.1016/j.ebiom.2019.03.033
[Indexed for MEDLINE]
Free PMC Article

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