Epitopes described in "The second-generation active Aβ immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects."

Article Authors:Christoph Wiessner; Karl-Heinz Wiederhold; Alain C Tissot; Peter Frey; Simone Danner; Laura H Jacobson; Gary T Jennings; Rainer Lüönd; Rainer Ortmann; Julia Reichwald; Mauro Zurini; Anis Mir; Martin F Bachmann; Matthias Staufenbiel
Article Title:The second-generation active Aβ immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects.
Reference Detail
Reference ID:1022209
Abstract:Immunization against amyloid- (A) 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 A1-6 coupled to the virus-like particle Q. Immunization with this vaccine did not activate A-specific T-cells. In APP transgenic mice, CAD106 induced efficacious A antibody titers of different IgG subclasses mainly recognizing the A3-6 epitope. CAD106 reduced brain amyloid accumulation in two APP transgenic mouse lines. Plaque number was a more sensitive readout than plaque area, followed by A42 and A40 levels. Studies with very strong overall amyloid reduction showed an increase in vascular A, which atypically was nonfibrillar. The efficacy of A immunotherapy depended on the A 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 A monomers and oligomers and blocked A toxicity in cell culture. We conclude that CAD106 immunization is suited to interfere with A aggregation and its downstream detrimental effects.
Affiliations:Novartis Institutes for Biomedical Research, CH-4056 Basel, Switzerland.
Reference Type:Literature
PubMed ID:21697382
Journal:J Neurosci
Journal Volume:31
Article Pages:9323-31
Journal ISSN:1529-2401
Article Chemical List:Amyloid beta-Peptides;Amyloid beta-Protein Precursor
Article MeSH List:Alzheimer Disease(drug therapy; immunology); Amyloid beta-Peptides(adverse effects; therapeutic use); Amyloid beta-Protein Precursor(genetics; immunology); Animals; Cells, Cultured; Immunotherapy(methods); Mice; Mice, Transgenic; Treatment Outcome
Curation Last Updated:2016-04-05 22:57:45