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The Murine Version of BAN2401 (mAb158) Selectively Reduces Amyloid-β Protofibrils in Brain and Cerebrospinal Fluid of tg-ArcSwe Mice
Abstract
Amyloid-β (Aβ) immunotherapy for Alzheimer's disease (AD) has good preclinical support from transgenic mouse models and clinical data suggesting that a long-term treatment effect is possible. Soluble Aβ protofibrils have been shown to exhibit neurotoxicity in vitro and in vivo, and constitute an attractive target for immunotherapy. Here, we demonstrate that the humanized antibody BAN2401 and its murine version mAb158 exhibit a strong binding preference for Aβ protofibrils over Aβ monomers. Further, we confirm the presence of the target by showing that both antibodies efficiently immunoprecipitate soluble Aβ aggregates in human AD brain extracts. mAb158 reached the brain and reduced the brain protofibril levels by 42% in an exposure-dependent manner both after long-term and short-term treatment in tg-ArcSwe mice. Notably, a 53% reduction of protofibrils/oligomers in cerebrospinal fluid (CSF) that correlated with reduced brain protofibril levels was observed after long-term treatment, suggesting that CSF protofibrils/oligomers could be used as a potential biomarker. No change in native monomeric Aβ 42 could be observed in brain TBS extracts after mAb158-treatment in tg-ArcSwe mice. By confirming the specific ability of mAb158 to selectively bind and reduce soluble Aβ protofibrils, with minimal binding to Aβ monomers, we provide further support in favor of its position as an attractive new candidate for AD immunotherapy. BAN2401 has undergone full phase 1 development, and available data indicate a favorable safety profile in AD patients.
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“the 30% plaque reduction in OL-Bace1cKO;AD mice falls in the range of effect sizes achieved by aducanumab24 and the FDA-approved lecanemab25 antibody therapies.”
From Oligodendrocytes produce amyloid-β and contribute to plaque formation alongside neurons in Alzheimer’s disease model mice (2024) · cites this paper as [25]
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Lecanemab in early Alzheimer's disease
van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., Kanekiyo, M., Li, D., Reyderman, L., Cohen, S., et al. (2023) · New England Journal of Medicine · doi:10.1056/nejmoa2212948 · Cited by 5,678
The Amyloid-β Pathway in Alzheimer’s Disease
Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S. H., Villemagne, V. L., Aisen, P., Vendruscolo, M., Iwatsubo, T., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01249-0 · Cited by 1,952
Self-citationLecanemab: Appropriate Use Recommendations
Cummings, J., Apostolova, L., Rabinovici, G. D., Atri, A., Aisen, P., Greenberg, S., Hendrix, S., Selkoe, D., Weiner, M., Petersen, R. C., et al. (2023) · The Journal of Prevention of Alzheimer's Disease · doi:10.14283/jpad.2023.30 · Cited by 961
“Lecanemab and mAb158 recognize soluble amyloid aggregates in human AD brain extracts (11, 12).”
BackgroundSwanson, C. J., Zhang, Y., Dhadda, S., Wang, J., Kaplow, J., Lai, R. Y. K., Lannfelt, L., Bradley, H., Rabe, M., Koyama, A., et al. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-021-00813-8 · Cited by 847
Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis
Viola, K. L., & Klein, W. L. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1386-3 · Cited by 628
“An antibody described as targeting protofibrillar AβOs, promoted by the Arctic mutation [74], reduced AβOs in the brains and CSF of the mouse model with no impact on Aβ monomers [169].”
Background
Metadata
- Authors
- Tucker, S., Möller, C., Tegerstedt, K., Lord, A., Laudon, H., Sjödahl, J., Söderberg, L., Spens, E., Sahlin, C., Waara, E. R., Satlin, A., Gellerfors, P., Osswald, G., & Lannfelt, L.
- Affiliations
- BioArctic Neuroscience (Sweden) (SE)
- Eisai (United States) (US)
- Uppsala University (SE)
- Venue
- Journal of Alzheimer’s Disease
- Publisher
- SAGE Publications
- Published
- 2014-11-21
- Volume
- 43
- Issue
- 2
- Pages
- 575-588
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W1664338907
- Cited by
- 272
- References
- 0
- Citations by year
- 2026: 21 · 2025: 47 · 2024: 41 · 2023: 55 · 2022: 19 · 2021: 21 · 2020: 15 · 2019: 12 · 2018: 15 · 2017: 9 · 2016: 10 · 2015: 6
- FWCI
- 5.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- MeSH terms
- Alzheimer Disease, Analysis of Variance, Animals, Antibodies, Monoclonal, Brain, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme-Linked Immunosorbent Assay, Humans, Immunologic Factors, Mice, Inbred C57BL, Mice, Transgenic, Protein Binding, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Immunoprecipitation, Mice, Presenilin-1, Plaque, Amyloid
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