title: The second-generation active Aβ immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects.
abstract: Immunization against amyloid-β (Aβ) can reduce amyloid accumulation in vivo and is considered a potential therapeutic approach for Alzheimer's disease. However, it has been associated with meningoencephalitis thought to be mediated by inflammatory T-cells. With the aim of producing an immunogenic vaccine without this side effect, we designed CAD106 comprising Aβ1-6 coupled to the virus-like particle Qβ. Immunization with this vaccine did not activate Aβ-specific T-cells. In APP transgenic mice, CAD106 induced efficacious Aβ antibody titers of different IgG subclasses mainly recognizing the Aβ3-6 epitope. CAD106 reduced brain amyloid accumulation in two APP transgenic mouse lines. Plaque number was a more sensitive readout than plaque area, followed by Aβ42 and Aβ40 levels. Studies with very strong overall amyloid reduction showed an increase in vascular Aβ, which atypically was nonfibrillar. The efficacy of Aβ immunotherapy depended on the Aβ levels and thus differed between animal models, brain regions, and stage of amyloid deposition. Therefore, animal studies may not quantitatively predict the effect in human Alzheimer's disease. Our studies provided no evidence for increased microhemorrhages or inflammatory reactions in amyloid-containing brain. In rhesus monkeys, CAD106 induced a similar antibody response as in mice. The antibodies stained amyloid deposits on tissue sections of mouse and human brain but did not label cellular structures containing APP. They reacted with Aβ monomers and oligomers and blocked Aβ toxicity in cell culture. We conclude that CAD106 immunization is suited to interfere with Aβ aggregation and its downstream detrimental effects.
authors.affiliation: Novartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wiessner
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Wiederhold
authors.forename: Alain C
authors.initials: AC
authors.lastname: Tissot
authors.forename: Peter
authors.initials: P
authors.lastname: Frey
authors.forename: Simone
authors.initials: S
authors.lastname: Danner
authors.forename: Laura H
authors.initials: LH
authors.lastname: Jacobson
authors.forename: Gary T
authors.initials: GT
authors.lastname: Jennings
authors.forename: Rainer
authors.initials: R
authors.lastname: Lüönd
authors.forename: Rainer
authors.initials: R
authors.lastname: Ortmann
authors.forename: Julia
authors.initials: J
authors.lastname: Reichwald
authors.forename: Mauro
authors.initials: M
authors.lastname: Zurini
authors.forename: Anis
authors.initials: A
authors.lastname: Mir
authors.forename: Martin F
authors.initials: MF
authors.lastname: Bachmann
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology; D016229:Amyloid beta-Peptides / Q000009:adverse effects / Q000627:therapeutic use*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000276:immunology*; D000818:Animals; D002478:Cells, Cultured; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D016896:Treatment Outcome
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor