Antibody semorinemab reduces tau pathology in a transgenic mouse model and engages tau in patients with Alzheimer’s disease
| Autor: | Gautham K. Rao, Stephen P. Schauer, Edmond Teng, Joseph Bravo, Reina N. Fuji, Andrea Pfeifer, Yong Ying, Kimberly Scearce-Levie, Jessica Couch, Hilda Solanoy, Paul T. Manser, Andreas Muhs, Han Lin, Daniela Bumbaca Yadav, Oded Foreman, Dongping He, James A. Ernst, Flavia Brunstein, Hai Ngu, Michael C. M. Kwok, Maria Pihlgren, Oskar Adolfsson, Mira Blendstrup, William B. Smith, Priya Chandra, Akash Datwani, Michael Keeley, Danielle DiCara, Robert Brendza, Yanmei Lu, Julien Lafrance-Vanasse, Corinne Foo-Atkins, Jasvinder K. Atwal, Isidro Hötzel, Seung-Hye Lee, Kristin R. Wildsmith, Ruby Chan, Helen Booler, Rich Erickson, Barthélemy Demeule, Geoffrey A. Kerchner, Wilman Luk, Gai Ayalon |
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| Rok vydání: | 2021 |
| Předmět: |
Genetically modified mouse
medicine.drug_class receptor Mice Transgenic tau Proteins Monoclonal antibody in-vivo diversity Mice Alzheimer Disease In vivo propagation medicine brain interstitial fluid Animals Humans oligomers a-beta Microglia biology business.industry Immunization Passive Neurotoxicity Brain General Medicine trial medicine.disease Isotype amyloid-beta cerebrospinal-fluid Disease Models Animal medicine.anatomical_structure Tauopathies Immunology biology.protein Tauopathy Antibody business |
| Zdroj: | Science Translational Medicine. 13 |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.abb2639 |
| Popis: | Tau has become an attractive alternative target for passive immunotherapy efforts for Alzheimer's disease (AD). The anatomical distribution and extent of tau pathology correlate with disease course and severity better than other disease markers to date. We describe here the generation, preclinical characterization, and phase 1 clinical characterization of semorinemab, a humanized anti-tau monoclonal antibody with an immunoglobulin G4 (igG4) isotype backbone. Semorinemab binds all six human tau isoforms and protects neurons against tau oligomer neurotoxicity in cocultures of neurons and microglia. In addition, when administered intraperitoneally once weekly for 13 weeks, murine versions of semorinemab reduced the accumulation of tau pathology in a transgenic mouse model of tauopathy, independent of antibody effector function status. Semorinemab also showed clear evidence of target engagement in vivo, with increases in systemic tau concentrations observed in tau transgenic mice, nonhuman primates, and humans. Higher concentrations of systemic tau were observed after dosing in AD participants compared to healthy control participants. No concerning safety signals were observed in the phase 1 clinical trial at single doses up to 16,800 mg and multiple doses totaling 33,600 mg in a month. |
| Databáze: | OpenAIRE |
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