Immunogenicity, Efficacy, Safety, and Mechanism of Action of Epitope Vaccine (Lu AF20513) for Alzheimer's Disease: Prelude to a Clinical Trial

Abstract

Alzheimer’s disease (AD) process is understood to involve the accumulation of amyloid plaques and tau tangles in the brain. However, attempts at targeting the main culprits, neurotoxic Aβ peptides, have thus far proven unsuccessful for improving cognitive function. Recent clinical trials with passively administrated anti-Aβ antibodies failed to slow cognitive decline in mild-moderate AD patients, but suggest that an immunotherapeutic approach could be effective in patients with mild AD. In an AD mouse model (Tg2576) we tested the immunogenicity (cellular and humoral immune responses) and efficacy (AD-like pathology) of clinical grade Lu AF20513 vaccine. Lu AF20513 induces robust “non-self” T cell responses and production of anti-Aβ antibodies that reduce AD-like pathology in the brains of Tg2576 mice without inducing microglial activation and enhancing astrocytosis or CAA. Importantly, a single immunization with Lu AF20513 induces strong humoral immunity in mice with pre-existing memory Th cells. In addition, Lu AF20513 induces strong humoral responses in guinea pigs and monkeys. Collectively, these data suggest translation of Lu AF20513 to clinical setting with aims to (i) induce therapeutically potent anti-Aβ antibody responses in patients with mild AD, particularly if they have memory Th cells generated after immunizations with conventional Tetanus Toxoid vaccine; (ii) exclude likely pathological autoreactive T cell responses.

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

“…The various EV designs all induced high levels of anti-Ab antibodies without activation of potentially harmful autoreactive Th cells in mice, rabbits, and monkeys. 40,[65][66][67][68] Importantly, immunizations of mouse models of AD with EV induced therapeutically potent antiAb antibodies that inhibited accumulation of AD-like plaque pathology in the brains of older mice, reduced glial activation, and prevented the development of behavioral deficits in aged animals without increasing the incidence of microhemorrhages. 40,42,43 In this study, we decided to compare the efficacy of our EV strategy in preventive and therapeutic settings in parallel.…”

“…40,[65][66][67][68] Importantly, immunizations of mouse models of AD with EV induced therapeutically potent antiAb antibodies that inhibited accumulation of AD-like plaque pathology in the brains of older mice, reduced glial activation, and prevented the development of behavioral deficits in aged animals without increasing the incidence of microhemorrhages. 40,42,43 In this study, we decided to compare the efficacy of our EV strategy in preventive and therapeutic settings in parallel. Results from these combined www.moleculartherapy.org studies demonstrated that the preventive, but not therapeutic, vaccination strategy was effective in reduction of AD-like pathology in the brains of aged Tg2576 mice (Figures 2, 3A, and 3B) without increasing the incidence of microhemorrhages and CAA ( Figures 3C and 3D).…”

“…5,[44][45][46][47] We analyzed the levels of soluble Ab 40/42 peptides in the homogenates of brains of vaccinated and age-matched control Tg2576 mice. Data presented in Figure 2C revealed a significant reduction of both Ab 42 and Ab 40 soluble molecules in homogenates isolated from the brains of EV-immunized Tg2576 mice compared to that isolated from the brains of control animals injected with adjuvant alone.…”

“…40,42,43 In this study, we decided to compare the efficacy of EV targeting the N terminus of Ab in preventive and therapeutic settings in parallel. More specifically, we started immunizations of Tg2576 mice at a time when they possessed low (at 6-6.5 months old) and high (at 16-19 months old) levels of AD-like pathology, respectively ( Figures 1A and 1B).…”

“…30,35,36 In fact, we recently pointed out that active Ab-vaccines tested in clinical trials so far have produced ambivalent results due to their inadequate immunogenicity. 31 To support our position and suggest an effective future clinical trials protocol, we decided for the first time to test the efficacy of our proteinbased epitope vaccine (EV) composed of three copies of immunogenic N-terminal epitope of Ab [37][38][39][40][41] and two Th epitopes from tetanus toxoid (TT) in preventive and therapeutic settings in parallel. More specifically, to simulate disease stages in humans (i.e., prodromal, mild to moderate, and severe AD), we studied the immunogenicity and efficacy of EV (reduction of Ab pathology and cognitive impairments) in Tg2576 mice that, at the start of vaccination, possess low, moderate, and high AD-like pathology.…”