Presenter of 2 Presentations
Discussants
DEVELOPMENT OF DUAL AΒ-TAU VACCINES FOR THE TREATMENT AND PREVENTION OF ALZHEIMER’S DISEASE
Abstract
Aims
Alzheimer’s disease (AD) is characterized by two pathological hallmarks: Aβ plaques and tau tangles. Several Aβ pathology-targeting antibodies have exhibited signs of slowing cognitive decline in AD, while tau-targeting antibodies and vaccines against either Aβ or tau are in earlier clinical development stages. Since Aβ and tau may act synergistically in the cause and/or progression of disease, targeting both may lead to better efficacy towards AD treatment and prevention. Prothena developed two dual Aβ-tau vaccines for AD targeting clearance of pathogenic Aβ and inhibition of tau neuronal cell-to-cell transmission.
Methods
Aβ-tau immunogen constructs were evaluated in multiple species. Sera from these animals were assessed for high and balanced titers, immunoreactivity against pathological Aβ and tau, and binding avidity to aggregates of Aβ and tau. In vitro models of Aβ phagocytosis, Aβ neuronal toxicity, and tau cellular uptake were also developed and utilized to evaluate sera from immunized animals.
Results
Prothena’s dual vaccines generated robust and balanced immunogenic responses against Aβ and tau proteins in multiple animal species. Immunized sera was shown to bind Aβ plaques and tau tangles in human AD brain sections at titers expected to be achieved in the CNS in vivo. Immunized sera also inhibited the binding of soluble Aβ aggregates to cultured hippocampal neurons. In vitro models demonstrated the sera induced phagocytosis of Aβ aggregates and blocked tau binding to heparin a model of cellular uptake.
Conclusions
Prothena’s dual Aβ-tau vaccines may lead to a disease modifying treatment and/or prevention of AD with improved efficacy over other monotherapies.