Antibody response and plasma Abeta1-40 levels in young Microcebus murinus primates immunized with Abeta1-42 and its derivatives
Résumé
We have been developing Abeta derivative vaccines with the objective to improve the safety of Abeta targeting immunotherapy. Our Abeta homologs are designed to have less direct toxicity and to produce a modified immune response compared to Abeta. 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 in young lemur primates (n=25) that with age develop Abeta 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-Abeta IgM response. Abeta1-42, K6Abeta1-30 and K6Abeta1-30[E(18)E(19)] resulted in a high anti-Abeta IgG response, whereas Abeta1-30[E(18)E(19)] 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 Abeta1-42 treated primates maintained a moderate IgG titer. The increase in antibodies that recognized Abeta1-40 often correlated with increase in Abeta1-40 in plasma, which suggests that the antibodies were binding to Abeta in vivo. Interestingly, significant transient weight gain was observed (K6Abeta1-30-, Abeta1-30[E(18)E(19)]- and Abeta1-42-treated) or a trend in the same direction (K6Abeta1-30[E(18)E(19)]-treated, adjuvant controls) following the injections. Based on these findings, we have chosen K6Abeta1-30 for immunizations in old primates as the antibody response to this vaccine was less variable compared to other Abeta derivatives. Our present findings indicate that most of our Abeta derivatives elicit a substantial antibody response in primates, and importantly this effect is reversible which enhances the safety profile of our approach.