title: 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 Aβ42 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.
authors.affiliation: BioArctic Neuroscience AB, Stockholm, Sweden.
authors.forename: Stina
authors.initials: S
authors.lastname: Tucker
authors.affiliation: BioArctic Neuroscience AB, Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Möller
authors.affiliation: BioArctic Neuroscience AB, Stockholm, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Tegerstedt
authors.affiliation: BioArctic Neuroscience AB, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Lord
authors.affiliation: BioArctic Neuroscience AB, Stockholm, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Laudon
authors.affiliation: BioArctic Neuroscience AB, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Sjödahl
authors.affiliation: BioArctic Neuroscience AB, Stockholm, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Söderberg
authors.affiliation: BioArctic Neuroscience AB, Stockholm, Sweden.
authors.forename: Erika
authors.initials: E
authors.lastname: Spens
authors.affiliation: BioArctic Neuroscience AB, Stockholm, Sweden.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Sahlin
authors.affiliation: BioArctic Neuroscience AB, Stockholm, Sweden.
authors.forename: Erik Rollman
authors.initials: ER
authors.lastname: Waara
authors.affiliation: Eisai Inc., Woodcliff Lake, NJ, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Satlin
authors.affiliation: BioArctic Neuroscience AB, Stockholm, Sweden.
authors.forename: Pär
authors.initials: P
authors.lastname: Gellerfors
authors.affiliation: BioArctic Neuroscience AB, Stockholm, Sweden.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Osswald
authors.affiliation: BioArctic Neuroscience AB, Stockholm, Sweden Department of Public Health/Geriatrics, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lannfelt
mesh_terms: D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000276:immunology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid; D053764:Presenilin-1 / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; D007155:Immunologic Factors; C508853:PSEN1 protein, human; D053764:Presenilin-1
keywords: Alzheimer's disease; BAN2401; amyloid-β; antibody; biomarker; cerebrospinal fluid; immunotherapy; mAb158; oligomer; protofibrils