title: Novel Phospho-Tau Monoclonal Antibody Generated Using a Liposomal Vaccine, with Enhanced Recognition of a Conformational Tauopathy Epitope.
abstract: The microtubule-associated protein Tau is an intrinsically unfolded, very soluble neuronal protein. Under still unknown circumstances, Tau protein forms soluble oligomers and insoluble aggregates that are closely linked to the cause and progression of various brain pathologies, including Alzheimer's disease. Previously we reported the development of liposome-based vaccines and their efficacy and safety in preclinical mouse models for tauopathy. Here we report the use of a liposomal vaccine for the generation of a monoclonal antibody with particular characteristics that makes it a valuable tool for fundamental studies as well as a candidate antibody for diagnostic and therapeutic applications. The specificity and affinity of antibody ACI-5400 were characterized by a panel of methods: (i) measuring the selectivity for a specific phospho-Tau epitope known to be associated with tauopathy, (ii) performing a combination of peptide and protein binding assays, (iii) staining of brain sections from mouse preclinical tauopathy models and from human subjects representing six different tauopathies, and (iv) evaluating the selective binding to pathological epitopes on extracts from tauopathy brains in non-denaturing sandwich assays. We conclude that the ACI-5400 antibody binds to protein Tau phosphorylated at S396 and favors a conformation that is typically present in the brain of tauopathy patients, including Alzheimer's disease.
authors.affiliation: Experimental Genetics Group - LEGTEGG, Department of Human Genetics, KULeuven, Leuven, Belgium.
authors.forename: Clara
authors.initials: C
authors.lastname: Theunis
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, Lausanne, Switzerland.
authors.forename: Oskar
authors.initials: O
authors.lastname: Adolfsson
authors.affiliation: Experimental Genetics Group - LEGTEGG, Department of Human Genetics, KULeuven, Leuven, Belgium.
authors.forename: Natalia
authors.initials: N
authors.lastname: Crespo-Biel
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, Lausanne, Switzerland.
authors.forename: Kasia
authors.initials: K
authors.lastname: Piorkowska
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, Lausanne, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Pihlgren
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, Lausanne, Switzerland.
authors.forename: David T
authors.initials: DT
authors.lastname: Hickman
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, Lausanne, Switzerland.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gafner
authors.affiliation: Experimental Genetics Group - LEGTEGG, Department of Human Genetics, KULeuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Borghgraef
authors.affiliation: Experimental Genetics Group - LEGTEGG, Department of Human Genetics, KULeuven, Leuven, Belgium.
authors.forename: Herman
authors.initials: H
authors.lastname: Devijver
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, Lausanne, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pfeifer
authors.affiliation: Experimental Genetics Group - LEGTEGG, Department of Human Genetics, KULeuven, Leuven, Belgium.
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
authors.affiliation: AC Immune SA, EPFL Innovation Park, Building B, Lausanne, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Muhs
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000915:Antibody Affinity; D000918:Antibody Specificity; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D000939:Epitopes; D006801:Humans; D006825:Hybridomas; D008081:Liposomes; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D019600:Neuropil Threads / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D011994:Recombinant Proteins / Q000276:immunology; D024801:Tauopathies / Q000175:diagnosis* / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D014612:Vaccines; D016875:tau Proteins / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000939:Epitopes; D008081:Liposomes; C054369:MAPT protein, human; D011994:Recombinant Proteins; D014612:Vaccines; D016875:tau Proteins
keywords: Alzheimer’s disease; Antibody binding sites; monoclonal antibody; protein conformation; tauopathies