Antibody Response And Plasma A Beta 1-40 Levels In Young Microcebus Murinus Primates Immunized With A Beta 1-42 And Its Derivatives

We have been developing A beta derivative vaccines with the objective to improve the safety of A beta targeting immunotherapy. Our A beta homologs are designed to have less direct toxicity and to produce a modified immune response compared to A beta. In extensive mouse Studies, all Our vaccines have improved cognition in transgenic mice while eliciting different immune responses and reducing brain amyloid burden to a variable degree. While we are continuing to characterize these vaccines in mice, in preparation for Studies in old primates and for human trials we assessed their effect ill Young lemur primates (n = 25) that with age develop A beta plaques and tau aggregates as seen in Alzheimer's disease. In the primates, all the peptides administered with alum adjuvant elicited a moderate to robust anti-A beta IgM response. A beta 1-42, K6A beta 1-30 and K6A beta 1-30[E18E19] resulted in a high anti-A beta IgG response, whereas A beta 1-30[E18E19] produced a weaker more variable IgG titer. Notably, 22 weeks after the 3rd immunization, IgM and IgG levels in derivative-vaccinated primates were similar to preimmune values whereas A beta 1-42 treated primates maintained a moderate IgG titer. The increase in antibodies that recognized A beta 1-40 often correlated with increase in A beta 1-40 in plasma, which suggests that the antibodies were binding to A beta in vivo. Interestingly, significant transient weight gain was observed (K6A beta 1-30-, A beta 1-30[E18E19]- and A beta 1-42-treated) or a trend in the same direction (K6A beta 1-30[E18E19]-treated. adjuvant controls) following the injections. Based on these findings, we have chosen K6A beta 1-30 for immunizations in old primates as the antibody response to this vaccine was less variable compared to other A derivatives. Our present findings indicate that most of our A beta derivatives elicit a substantial antibody response in primates, and importantly this effect is reversible which enhances the safety profile of our approach. (C) 2008 Elsevier Ltd. All rights reserved.