ArticleEBioMedicine2019
Tau antibody chimerization alters its charge and binding, thereby reducing its cellular uptake and efficacy.
Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers, 1 of them a synthesis that pooled it.
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Who cites it
30 citing papers in PubMed, 1 synthesis or guideline pooled it, 61 citations in OpenAlex.
- Similarities and Differences in the Pattern of Tau Hyperphosphorylation in Physiological and Pathological Conditions: Impacts on the Elaboration of Therapies to Prevent Tau Pathology.Frontiers in neurology · 2020Pooled it
- Advances in Alzheimer's disease: mechanistic insights and therapeutic targets.Science China. Life sciences · 2026Review
- A single-domain antibody targets aggregation-prone region of α-synuclein to reduce synucleinopathy, rescue neurodegeneration and improve function.bioRxiv : the preprint server for biology · 2026Article
- Tau pSer396 and pSer404 Define Distinct Epitope Regions Linked to Different Antibody Functions.bioRxiv : the preprint server for biology · 2026Article
- Tau-targeting active immunotherapy slows progression and reduces pathology in mouse models of tauopathy.Brain pathology (Zurich, Switzerland) · 2026Article
- Clearing truncated tau protein restores neuronal function and prevents microglia activation in tauopathy mice.Cell reports · 2025Article
- Immunization targeting diseased proteins in synucleinopathy and tauopathy: insights from clinical trials.Translational neurodegeneration · 2025Review
- Optimization and Validation of the Cationization Method for the Fab' Fragment of Antibody Rituximab.ACS omega · 2025Article
- Isoelectric point, net charge and amino acid analysis of experimentally validated therapeutic antibodies.In silico pharmacology · 2025Article
- Co-opting templated aggregation to degrade pathogenic tau assemblies and improve motor function.Cell · 2024Article
- Single-domain antibody-based protein degrader for synucleinopathies.Molecular neurodegeneration · 2024Article
- Single-Domain Antibody-Based Protein Degrader for Synucleinopathies.bioRxiv : the preprint server for biology · 2024Article
- Tau Immunotherapies for Alzheimer's Disease and Related Tauopathies: Status of Trials and Insights from Preclinical Studies.Journal of Alzheimer's disease : JAD · 2024Review
- Messenger RNA-encoded antibody approach for targeting extracellular and intracellular tau.Brain communications · 2024Article
- The functionality of a therapeutic antibody candidate restored by a single mutation from proline to threonine in the variable region.Human vaccines & immunotherapeutics · 2023Article
- Tau-targeting therapies for Alzheimer disease: current status and future directions.Nature reviews. Neurology · 2023Review
- Single-domain antibody-based noninvasive in vivo imaging of α-synuclein or tau pathology.Science advances · 2023Article
- New insight into tau immunotherapy.Aging brain · 2023Article
- Targeting tau only extracellularly is likely to be less efficacious than targeting it both intra- and extracellularly.Seminars in cell & developmental biology · 2022Review
- Microtubule-modulating Agents in the Fight Against Neurodegeneration: Will it ever Work?Current neuropharmacology · 2022Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundBringing 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.
methodsInitially, 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.
findingsNeuronal 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.
conclusionsThese 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.