title: Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer's disease: prelude to a clinical trial.
abstract: The Alzheimer's disease (AD) process is understood to involve the accumulation of amyloid plaques and tau tangles in the brain. However, attempts at targeting the main culprits, neurotoxic Aβ peptides, have thus far proven unsuccessful for improving cognitive function. Recent clinical trials with passively administrated anti-Aβ antibodies failed to slow cognitive decline in mild to moderate AD patients, but suggest that an immunotherapeutic approach could be effective in patients with mild AD. Using an AD mouse model (Tg2576), we tested the immunogenicity (cellular and humoral immune responses) and efficacy (AD-like pathology) of clinical grade Lu AF20513 vaccine. We found that Lu AF20513 induces robust "non-self" T-cell responses and the production of anti-Aβ antibodies that reduce AD-like pathology in the brains of Tg2576 mice without inducing microglial activation and enhancing astrocytosis or cerebral amyloid angiopathy. A single immunization with Lu AF20513 induced strong humoral immunity in mice with preexisting memory T-helper cells. In addition, Lu AF20513 induced strong humoral responses in guinea pigs and monkeys. These data support the translation of Lu AF20513 to the clinical setting with the aims of: (1) inducing therapeutically potent anti-Aβ antibody responses in patients with mild AD, particularly if they have memory T-helper cells generated after immunizations with conventional tetanus toxoid vaccine, and (2) preventing pathological autoreactive T-cell responses.
authors.affiliation: Department of Molecular Immunology, Institute for Molecular Medicine, Huntington Beach, California 92647, USA.
authors.forename: Hayk
authors.initials: H
authors.lastname: Davtyan
authors.forename: Anahit
authors.initials: A
authors.lastname: Ghochikyan
authors.forename: Irina
authors.initials: I
authors.lastname: Petrushina
authors.forename: Armine
authors.initials: A
authors.lastname: Hovakimyan
authors.forename: Arpine
authors.initials: A
authors.lastname: Davtyan
authors.forename: Anna
authors.initials: A
authors.lastname: Poghosyan
authors.forename: Annette M
authors.initials: AM
authors.lastname: Marleau
authors.forename: Nina
authors.initials: N
authors.lastname: Movsesyan
authors.forename: Anatoly
authors.initials: A
authors.lastname: Kiyatkin
authors.forename: Suhail
authors.initials: S
authors.lastname: Rasool
authors.forename: Anna Kirstine
authors.initials: AK
authors.lastname: Larsen
authors.forename: Peter Juul
authors.initials: PJ
authors.lastname: Madsen
authors.forename: Karen Malene
authors.initials: KM
authors.lastname: Wegener
authors.forename: Dorte Kornerup
authors.initials: DK
authors.lastname: Ditlevsen
authors.forename: David H
authors.initials: DH
authors.lastname: Cribbs
authors.forename: Lars Ostergaard
authors.initials: LO
authors.lastname: Pedersen
authors.forename: Michael G
authors.initials: MG
authors.lastname: Agadjanyan
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000097:blood / Q000494:pharmacology; D000917:Antibody Formation / Q000276:immunology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004306:Dose-Response Relationship, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D018985:Epitopes, B-Lymphocyte / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009457:Neuroglia / Q000187:drug effects / Q000276:immunology; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding / Q000276:immunology; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014611:Vaccination / Q000379:methods*; D014612:Vaccines / Q000276:immunology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000888:Antibodies, Anti-Idiotypic; D016207:Cytokines; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D010446:Peptide Fragments; D014612:Vaccines; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)