Bispecific brain-penetrant antibodies for treatment of Alzheimer's disease.

1. J Prev Alzheimers Dis. 2025 Sep;12(8):100214. doi: 10.1016/j.tjpad.2025.100214. Epub 2025 May 26. Bispecific brain-penetrant antibodies for treatment of Alzheimer's disease. Sehlin D(1), Hultqvist G(2), Michno W(3), Aguilar X(1), Dahlén AD(1), Cerilli E(1), Bucher NM(1), Lopes van den Broek S(1), Syvänen S(4). Author information: (1)Department of Public Health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, Uppsala 751 85, Sweden. (2)Department of Pharmacy, Uppsala University, Uppsala, Sweden. (3)Department of Public Health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, Uppsala 751 85, Sweden; Science for Life Laboratory, Uppsala University, Uppsala, Sweden. (4)Department of Public Health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, Uppsala 751 85, Sweden. Electronic address: stina.syvanen@uu.se. The emerging class of bispecific antibodies represents a significant advancement in Alzheimer's disease (AD) immunotherapy by addressing the limited brain concentrations achieved with conventional monoclonal antibodies. The majority of bispecific antibodies developed for AD treatment utilize transferrin receptor (TfR1)-mediated transcytosis to enhance blood-brain barrier (BBB) penetration, resulting in higher and more uniform brain concentrations compared to conventional antibodies. This improved delivery has demonstrated superior efficacy in reducing brain amyloid-beta (Aβ) burden. Additionally, TfR1-mediated delivery may help mitigate adverse effects such as amyloid-related imaging abnormalities (ARIA). This is likely achieved by a reduction in antibody accumulation at vascular Aβ deposits, resulting from the combined effects of lower dosing and a different brain entry route when using bispecific antibodies. Besides targeting Aβ, bispecific antibodies have been engineered to address other key pathological features of AD, including tau pathology and neuroinflammatory targets, which are critical drivers of disease progression. These antibodies also show promise in diagnostic applications, particularly as radioligands for antibody-based positron emission tomography (immunoPET), leveraging their rapid brain delivery and efficient and specific target engagement. Moreover, the principles of bispecific antibody technology have been adapted for use beyond immunotherapy. The incorporation of TfR1-binding domains into enzymes, antisense oligonucleotides, or viral vectors such as adeno-associated viruses broadens their therapeutic potential. These approaches may enable more efficient treatment strategies, not only for AD but also for other neurological disorders, by facilitating the delivery of diverse therapeutic agents across the BBB. Copyright © 2025 The Author(s). Published by Elsevier Masson SAS.. All rights reserved. DOI: 10.1016/j.tjpad.2025.100214 PMCID: PMC12413732 PMID: 40425446 [Indexed for MEDLINE] Conflict of interest statement: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Stina Syvanen reports financial support was provided by Swedish Research Council. Stina Syvanen reports financial support was provided by Swedish Brain Foundation (Hjärnfonden). Stina Syvanen reports financial support was provided by Swedish Alzheimer Foundation (Alzheimerfonden). Dag Sehlin reports financial support was provided by Swedish Research Council. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.