Tau antibody chimerization alters its charge and binding, thereby reducing its cellular uptake and efficacy
| Autor: | Jessica E. Chukwu, Hameetha B.R. Sait, Einar M. Sigurdsson, Xiang-Peng Kong, Erin E. Congdon, Jingjing Deng, Dov B. Shamir, Thomas A. Neubert, Devyani Ujla |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Research paper medicine.drug_class medicine.medical_treatment Tau protein tau Proteins Pharmacology Monoclonal antibody Antibodies Monoclonal Humanized Protein Aggregation Pathological General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Mice Protein Aggregates Structure-Activity Relationship 0302 clinical medicine Neuroblastoma medicine Animals Humans Binding site Neurons biology Chemistry Antibodies Monoclonal Biological Transport General Medicine Immunotherapy medicine.disease Immunohistochemistry Disease Models Animal 030104 developmental biology Tauopathies 030220 oncology & carcinogenesis Toxicity biology.protein Tauopathy Antibody Protein Multimerization Biomarkers Protein Binding |
| Zdroj: | EBioMedicine. 42 |
| ISSN: | 2352-3964 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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