MER5101, a Novel A beta 1-15:DT Conjugate Vaccine, Generates a Robust Anti-A beta Antibody Response and Attenuates A beta Pathology and Cognitive Deficits in APPswe/PS1 Delta E9 Transgenic Mice

Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115 and Mercia Pharma, New York, New York 10036.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 04/2013; 33(16):7027-37. DOI: 10.1523/JNEUROSCI.5924-12.2013
Source: PubMed


Active amyloid-β (Aβ) immunotherapy is under investigation to prevent or treat early Alzheimer's disease (AD). In 2002, a Phase II clinical trial (AN1792) was halted due to meningoencephalitis in ∼6% of the AD patients, possibly caused by a T-cell-mediated immunological response. Thus, generating a vaccine that safely generates high anti-Aβ antibody levels in the elderly is required. In this study, MER5101, a novel conjugate of Aβ1-15 peptide (a B-cell epitope fragment) conjugated to an immunogenic carrier protein, diphtheria toxoid (DT), and formulated in a nanoparticular emulsion-based adjuvant, was administered to 10-month-old APPswe/PS1ΔE9 transgenic (Tg) and wild-type (Wt) mice. High anti-Aβ antibody levels were observed in both vaccinated APPswe/PS1ΔE9 Tg and Wt mice. Antibody isotypes were mainly IgG1 and IgG2b, suggesting a Th2-biased response. Restimulation of splenocytes with the Aβ1-15:DT conjugate resulted in a strong proliferative response, whereas proliferation was absent after restimulation with Aβ1-15 or Aβ1-40/42 peptides, indicating a cellular immune response against DT while avoiding an Aβ-specific T-cell response. Moreover, significant reductions in cerebral Aβ plaque burden, accompanied by attenuated microglial activation and increased synaptic density, were observed in MER5101-vaccinated APPswe/PS1ΔE9 Tg mice compared with Tg adjuvant controls. Last, MER5101-immunized APPswe/PS1ΔE9 Tg mice showed improvement of cognitive deficits in both contextual fear conditioning and the Morris water maze. Our novel, highly immunogenic Aβ conjugate vaccine, MER5101, shows promise for improving Aβ vaccine safety and efficacy and therefore, may be useful for preventing and/or treating early AD.

  • Source
    • "The remainder of the immunohistochemistry was carried out using the Elite ABC Kit (Vector Laboratories) as previously described (Frost et al., 2013). Staining for fibrillar amyloid with 1% Thioflavin S (Sigma-Aldrich) and microhemorrhage with hemosiderin (2% potassium ferrocyanide) was conducted as previously described (Liu et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pyroglutamate-3 amyloid-beta (pGlu-3 Aβ) is an N-terminally truncated Aβ isoform likely playing a decisive role in Alzheimer's disease pathogenesis. Here, we describe a prophylactic passive immunization study in APPswe/PS1ΔE9 mice using a novel pGlu-3 Aβ immunoglobulin G1 (IgG1) monoclonal antibody, 07/1 (150 and 500 μg, intraperitoneal, weekly) and compare its efficacy with a general Aβ IgG1 monoclonal antibody, 3A1 (200 μg, intraperitoneal, weekly) as a positive control. After 28 weeks of treatment, plaque burden was reduced and cognitive performance of 07/1-immunized Tg mice, especially at the higher dose, was normalized to wild-type levels in 2 hippocampal-dependent tests and partially spared compared with phosphate-buffered saline-treated Tg mice. Mice that received 3A1 had reduced plaque burden but showed no cognitive benefit. In contrast with 3A1, treatment with 07/1 did not increase the concentration of Aβ in plasma, suggesting different modes of Aβ plaque clearance. In conclusion, early selective targeting of pGlu-3 Aβ by immunotherapy may be effective in lowering cerebral Aβ plaque burden and preventing cognitive decline in the clinical setting. Targeting this pathologically modified form of Aβ thereby is unlikely to interfere with potential physiologic function(s) of Aβ that have been proposed.
    Full-text · Article · Oct 2015 · Neurobiology of aging
  • Source
    • "Although the protocol demonstrated a potential alternative way to generate high levels of antibody against Aβ plaques, T-cell responses potentially could be autoreactivated if multiple immunizations were required. Liu et al.[29] used a diphtheria toxoid (DT)-conjugated Aβ1–15 vaccine that deleted the T-cell epitope and found that it upregulated CD25+ Tregs. Whether these regulatory T cells were specific for the Aβ peptide and had a major anti-inflammatory impact needs to be further investigated. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction Vaccination against amyloid-β protein (Aβ42) induces high levels of antibody, making it a promising strategy for treating Alzheimer’s disease (AD). One drawback in the past was that clinical trial approval was withheld because of speculation that the Aβ42 vaccine induces CD4+ T cell infiltrations into the central nervous system. To reduce T-cell activation while concomitantly maintaining high anti-Aβ42 titers is a great challenge in immunology. Methods We aimed to demonstrate that coimmunization with Aβ42 protein and expression plasmid can be beneficial in a mouse AD model and can prevent inflammation. We immunized the AD mice with the coimmunization vaccine and assessed behavior change and Aβ42 deposition. Furthermore, to determine the safety of the coimmunization vaccine, we used an induced Aβ42-EAE model to mimic the meningoencephalitis that happened in the AN-1792 vaccine clinical phase II trial and tested whether the coimmunization vaccine could ameliorate T-cell-mediated brain inflammation. Results The coimmunization vaccination reduced Aβ plaques and significantly ameliorated cognitive deficit while inhibiting T-cell-mediated brain inflammation and infiltration. These studies demonstrate that the coimmunization strategy that we describe in this article can ameliorate AD pathology without notable adverse effects in mice. Conclusions A coimmunization strategy leading to the development of a safe immunotherapeutic/preventive protocol against AD in humans is warranted.
    Full-text · Article · May 2014 · Alzheimer's Research and Therapy
  • Source
    • "For example, we recently utilized Mercia Pharmaceutical’s MER vaccine platform, which was shown previously to safely generate titers against self-proteins in two cancer vaccines, to test an Aβ1-15:diptheria toxoid conjugate vaccine called MER5101, which was formulated in an adjuvant, MAS-1, in an AD transgenic mouse model. The vaccine generated high titers and lowered plaques, induced an anti-inflammatory immune response, and improved cognition [38]. And lastly, improving the sensitivity of biomarkers, including imaging of pre-amyloid diffuse plaques, and cognitive/functional tests to detect the earliest changes in AD will allow for better patient selection for clinical trials and more sensitive outcome measures. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia, afflicting more than 30 million people worldwide. Currently, there is no cure or way to prevent this devastating disease. Extracellular plaques, containing various forms of amyloid-beta protein (Abeta), and intracellular neurofibrillary tangles (NFTs), composed of hyper-phosphorylated tau protein, are two major pathological hallmarks of the AD brain. Aggregation, deposition, and N-terminal modification of Abeta protein and tau phosphorylation and aggregation are thought to precede the onset of cognitive decline, which is better correlated with tangle formation and neuron loss. Active and passive vaccines against various forms of Abeta have shown promise in pre-clinical animal models. However, translating these results safely and effectively into humans has been challenging. Recent clinical trials showed little or no cognitive efficacy, possibly due to the fact that the aforementioned neurodegenerative processes most likely pre-existed in the patients well before the start of immunotherapy. Efforts are now underway to treat individuals at risk for AD prior to or in the earliest stages of cognitive decline with the hope of preventing or delaying the onset of the disease. In addition, efforts to immunize against tau and other AD-related targets are underway.
    Full-text · Article · Oct 2013 · Molecular Neurodegeneration
Show more