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 aducanumab and the FDA-approved lecanemab antibody therapies.
“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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“A comparison of the binding characteristics of various anti-Aβ mAbs to naturally occurring oAβ has not been published, though the murine precursor of lecanemab mAb158, designed to bind to synthetic protofibrils, has been shown to immunoprecipitate oAβ from soluble AD brain extracts [143].”
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Schilling, S., Rahfeld, J., Lues, I., & Lemere, C. A. (2018) · Molecules · doi:10.3390/molecules23051068 · Cited by 45 · see citing works
Therapeutic Strategies to Reduce the Toxicity of Misfolded Protein Oligomers
Kreiser, R. P., Wright, A. K., Block, N. R., Hollows, J. E., Nguyen, L. T., LeForte, K., Mannini, B., Vendruscolo, M., & Limbocker, R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21228651 · Cited by 47 · see citing works
“Similarly to aducanumab, BAN2401, which is a humanized version of an antibody raised in mice immunized with Aβ42 protofibrils [79] and is in Phase 3 clinical trials, has the ability to potently inhibit Aβ protofibril accumulation in AD mice [80].”
BackgroundClarity AD: Asian regional analysis of a phase III trial of lecanemab in early Alzheimer's disease
Chen, C., Katayama, S., Lee, J. H., Lee, J.-Y., Nakagawa, M., Torii, K., Ogawa, T., Dash, A., Irizarry, M. C., Dhadda, S., et al. (2025) · The Journal of Prevention of Alzheimer s Disease · doi:10.1016/j.tjpad.2025.100160 · Cited by 52 · see citing works
“Lecanemab is an anti-amyloid monoclonal antibody that binds with the highest affinity to soluble A 𝛽 protofibrils, which are more toxic than monomers or insoluble fibrils/plaque [ 11 , 18–26 ].”
van Dyck, C. H., Sperling, R. A., Johnson, K. A., Dhadda, S., Kanekiyo, M., Li, D., Gee, M., Hersch, S. M., Irizarry, M. C., & Kramer, L. D. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70905 · Cited by 54 · see citing works
The biogenesis and biology of amyloid β oligomers in the brain
Ashe, K. H. (2020) · Alzheimer s & Dementia · doi:10.1002/alz.12084 · Cited by 45 · see citing works
Recent advancements toward therapeutic vaccines against Alzheimer’s disease
Herline, K., Drummond, E., & Wısnıewskı, T. (2018) · Expert Review of Vaccines · doi:10.1080/14760584.2018.1500905 · Cited by 44 · see citing works
Alzheimer’s Disease: Drug Discovery
Huang, X. (2020) · Exon Publications eBooks · doi:10.36255/exonpublications.alzheimersdisease.2020 · Cited by 45 · see citing works
Brain tissue Aβ42 levels are linked to shunt response in idiopathic normal pressure hydrocephalus
Hamdeh, S. A., Virhammar, J., Sehlin, D., Alafuzoff, I. I., Cesarini, K. G., & Marklund, N. (2018) · Journal of neurosurgery · doi:10.3171/2017.7.jns171005 · Cited by 41 · see citing works
Aptamers targeting amyloidogenic proteins and their emerging role in neurodegenerative diseases
Murakami, K., Izuo, N., & Bitan, G. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101478 · Cited by 42 · see citing works
“Followup studies have generated antibodies against these assemblies, including mAb158 (36) and NU-1 (37), which bind protofibrils and ADDLs, respectively.”
BackgroundRapid amyloid‐β oligomer and protofibril accumulation in traumatic brain injury
Hamdeh, S. A., Waara, E. R., Möller, C., Söderberg, L., Basun, H., Alafuzoff, I. I., Hillered, L., Lannfelt, L., Ingelsson, M., & Marklund, N. (2017) · Brain Pathology · doi:10.1111/bpa.12532 · Cited by 41 · see citing works
“The mAb82E1 assay measures smaller oligomeric Ab species as well as larger protofibrils and has been frequently used both for samples from transgenic mice overexpressing human AbPP and AD brains (16, 47).”
BackgroundSelf-citationPassive Immunotherapies Targeting Amyloid Beta and Tau Oligomers in Alzheimer’s Disease
Zanden, C. M. V., & Chi, E. Y. (2019) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2019.10.024 · Cited by 40 · see citing works
Hayato, S., Takenaka, O., Reddy, S. H. S., Landry, I. S., Reyderman, L., Koyama, A., Swanson, C. J., Yasuda, S., & Hussein, Z. (2022) · CPT Pharmacometrics & Systems Pharmacology · doi:10.1002/psp4.12862 · Cited by 41 · see citing works
Dhadda, S., Kanekiyo, M., Li, D. X., Swanson, C. J., Irizarry, M. C., Berry, S. M., Kramer, L. D., & Berry, D. A. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-01129-x · Cited by 39 · see citing works
“In animal models, the reduction of Aβ protofibrils and Aβ plaque, as well as prevention of Aβ deposition before plaques develop, has been demonstrated using the murine version of lecanemab [1, 2].”
BackgroundLiu, N., Liang, X., Chen, Y., & Xie, L. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102199 · Cited by 41 · see citing works
Lessons from Anti-Amyloid-β Immunotherapies in Alzheimer Disease: Aiming at a Moving Target
Wang, Y., Yan, T., Lu, H., Yin, W., Lin, B., Fan, W., Zhang, X., & Fernández-Fúnez, P. (2017) · Neurodegenerative Diseases · doi:10.1159/000478741 · Cited by 38 · see citing works
Dendrimers and Derivatives as Multifunctional Nanotherapeutics for Alzheimer’s Disease
Moreira, D. A., Santos, S. D., Leiro, V., & Pêgo, A. P. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15041054 · Cited by 39 · see citing works
“oligomers/protofibrils (lecanemab) [55] or fibrils (aducanumab) [56].”
BackgroundAβ-Immunotherapeutic strategies: a wide range of approaches for Alzheimer's disease treatment
Montoliu‐Gaya, L., & Villegas, S. (2016) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2016.11 · Cited by 37 · see citing works
Cationization increases brain distribution of an amyloid-beta protofibril selective F(ab’)2 fragment
Syvänen, S., Edén, D., & Sehlin, D. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.09.065 · Cited by 36 · see citing works
“A humanized variant of the mouse monoclonal antibody mAb158, selectively binding to Ab protofibrils [17,18] was enzymatically cleaved with the enzyme IdeS, specifically cleaving just below the hinge region [19], according to a previously published method, to generate F(ab’)2-h158 [20].”
MethodCytotoxic species in amyloid-associated diseases: Oligomers or mature fibrils
Siddiqi, M. K., Malik, S., Majid, N., Alam, P., & Khan, R. H. (2019) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2019.06.001 · Cited by 37 · see citing works
Factors affecting the GABAergic synapse function in Alzheimer’s disease: Focus on microRNAs
Rivera, J., Sharma, B., Torres, M. M., & Kumar, S. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102123 · Cited by 36 · see citing works
Unraveling Alzheimer’s: the promise of aducanumab, lecanemab, and donanemab
Ameen, T. B., Kashif, S. N., Abbas, S. M. I., Babar, K., Ali, S. M. S., & Raheem, A. (2024) · The Egyptian Journal of Neurology Psychiatry and Neurosurgery · doi:10.1186/s41983-024-00845-5 · Cited by 37 · see citing works
“Put simply, the treatment appeared to be effective in reducing or impeding amyloid buildup in the brain among these participants [50, 58–62].”
BackgroundAlbertini, G., Zielonka, M., Cuypers, M., Snellinx, A., Xu, C., Poovathingal, S. K., Wojno, M., Davie, K., van Lieshout, V., Craessaerts, K., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-02125-8 · Cited by 47 · see citing works
Lessons from antiamyloid-β immunotherapies in Alzheimer's disease
Plascencia‐Villa, G., & Perry, G. L. (2023) · Handbook of clinical neurology · doi:10.1016/b978-0-323-85555-6.00019-9 · Cited by 34 · see citing works
Gustavsson, T., Metzendorf, N. G., Wik, E., Roshanbin, S., Julku, U. H., Chourlia, A., Nilsson, P., Andersson, K. G., Laudon, H., Hultqvist, G., et al. (2023) · Alzheimer s Research & Therapy · doi:10.1186/s13195-023-01236-3 · Cited by 35 · see citing works
Self-citationCurrent strategies of detecting Aβ species and inhibiting Aβ aggregation: Status and prospects
Li, J., Liao, W., Huang, D., Ou, M., Chen, T., Wang, X., Zhao, R., Zhang, L., Mei, L., Liu, J., et al. (2023) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2023.215375 · Cited by 36 · see citing works
A possible mechanism for the enhanced toxicity of beta-amyloid protofibrils in Alzheimer’s disease
Chen, Z., Singh, P. K., Calvano, M., Norris, E. H., & Strickland, S. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2309389120 · Cited by 34 · see citing works
“An antibody that binds preferentially to A β protofibrils was developed in mice (3) and adapted for human use.”
Structure and function of therapeutic antibodies approved by the US FDA in 2023
Strohl, W. R. (2024) · Antibody Therapeutics · doi:10.1093/abt/tbae007 · Cited by 35 · see citing works
“Eisai licensed the antibody and humanized it under the name BAN2401 [82].”
BackgroundElevated soluble amyloid beta protofibrils in Down syndrome and Alzheimer's disease
Johannesson, M., Sahlin, C., Söderberg, L., Basun, H., Fälting, J. M., Möller, C., Zachrisson, O., Sunnemark, D., Svensson, A., Odergren, T., et al. (2021) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2021.103641 · Cited by 32 · see citing works
Self-citationAilioaie, L. M., Ailioaie, C., & Litscher, G. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15030916 · Cited by 37 · see citing works
“Preclinical research showed that mAb158 significantly reduced Aβ protofibrils in the brain and CSF of Tg-ArcSwe mice [141], and further research in mouse neuron-glial cultures showed that mAb158 can reduce the toxicity of Aβ protofibrils by preventing pathological accumulation in astrocytes, because in human brain tis…”
Background
- 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
- Health Sciences › Medicine › Physiology › 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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