O1-06-06

Alzheimer's disease is characterized by the deposition of insoluble plaques of amyloid–β peptide in the brain of patients. A conformational change occurs in the amyloid–β peptide upon aggregation of soluble monomers into insoluble fibers with the transition of α–helixes or random coil conformation into β–sheets. The objective of this study was to use AC Immune's supramolecular technology to generate conformational sensitive antibodies targeting specifically the β–sheets of amyloidβ1–42. AC Immune's monoclonal antibody ACI–01–Ab7 was generated following immunization of mice with pegylated amyloidβ1–16peptide integrated into liposomes containing Lipid A. The functionality of the antibody was characterized in vitro by several different methods and the in vivo efficacy of the antibody was evaluated in amyloid precursor protein (APP) transgenic mice. The ACI–01–Ab7 binds amyloidβ1–42monomers with an affinity of 3x10–7 and to amyloidβ1–42 fibers with an even higher affinity of 4x10–8, as demonstrated by surface plasmon resonance. Using density gradient ultracentrifugation, we were able to establish the functional capacity of ACI–01–Ab7 monoclonal antibody to inhibit the aggregation of amyloidβ1–42 into amyloid fibers. Moreover, preformed amyloid fibrils disaggregate in the presence of ACI–01–Ab7. To investigate by which mechanism ACI–01–Ab7 inhibits the aggregation of amyloid fibers and disaggregate preformed fibers in vitro, we used Electron Microscopy and Solid state NMR spectroscopy. ACI–01–Ab7 binds to some, but not to all branches of amyloid fibers, suggesting specificity for a given secondary structure of amyloidβ1–42fibers. NMR studies directly demonstrated the induction of amyloidβ–peptide transition from β–sheets into random coil by our monoclonal antibody. Finally, in vivo administration of ACI–01–Ab7 into APP transgenic mice decreased the level of soluble amyloidβ1–40in the brain and significantly increased the cognitive memory capacity of these mice. The present results indicate that our monoclonal antibody ACI–01–Ab7 solubilizes amyloid fibers both in vitro and in vivo by inducing a conformation shift of amyloid–β from β–sheets to random coil. ACI–01–Ab7 therefore represents a promising approach for β–amyloid immune therapy of early and late stages of Alzheimer's Disease.