The Second-Generation Active Aβ Immunotherapy CAD106 Reduces Amyloid Accumulation in APP Transgenic Mice While Minimizing Potential Side Effects

Immunization against amyloid-beta (A beta) 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 A beta 1-6 coupled to the virus-like particle Q beta. Immunization with this vaccine did not activate A beta-specific T-cells. In APP transgenic mice, CAD106 induced efficacious A beta antibody titers of different IgG subclasses mainly recognizing the A beta 3-6 epitope. CAD106 reduced brain amyloid accumulation in two APP transgenic mouse lines. Plaque number was a more sensitive readout than plaque area, followed by A beta 42 and A beta 40 levels. Studies with very strong overall amyloid reduction showed an increase in vascular A beta, which atypically was nonfibrillar. The efficacy of A beta immunotherapy depended on the A beta 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 beta monomers and oligomers and blocked A beta toxicity in cell culture. We conclude that CAD106 immunization is suited to interfere with A beta aggregation and its downstream detrimental effects.