Bibliographic
This study aims at testing the efficacy of the active Abeta immunotherapy CAD106 in the APP23 and APP24 transgenic mouse models of AD. CAD106 is comprised of the Aβ1-6 peptide coupled to the Qβ virus-like particle, and is designed to avoid meningoencephalitis thought to be mediated by inflammatory T-cells. Immunization with CAD106 induced efficacious Aβ antibody titers of different IgG subclasses mainly recognizing the Aβ3–6 epitope. CAD106 reduced brain beta amyloid accumulation in both APP transgenic mouse lines, and did so without evidence of unwanted side effects such as micro hemorrhages or an inflammatory response. Immunization with CAD106 did not activate Aβ-specific T-cells. Plaque number was a more sensitive readout than plaque area, followed by Abeta 42 and Abeta 40 levels. Inspection of brain sections from CAD106-treated animals indicated that vascular amyloid remained constant or even increased relative to controls.The Abeta antibodies observed to react with Abeta monomers and oligomers and blocked Abeta toxicity in cell culture. The antibodies stained amyloid deposits on tissue sections of mouse and human brain but did not label cellular structures containing APP. In fact, no cross-reactivity was observed with cellular APP or its metabolites, nor did CAD106 treatment alter the steady-state level of full-length APP or the metabolites sAPPβ and C99 containing the Aβ1–6 sequence. These observations argue against a significant interaction of the antibodies with APP and its primary metabolites in vivo. In rhesus monkeys, CAD106 induced a similar antibody response as in mice. CAD106 has entered clinical development as a potentially disease-modifying agent