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Abeta DNA Vaccination for Alzheimers Disease: Focus on Disease Prevention

Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, 92697-4540, USA.
CNS & neurological disorders drug targets (Impact Factor: 2.7). 03/2010; 9(2):207-16. DOI: 10.2174/187152710791012080
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ABSTRACT Pre-clinical and clinical data suggest that the development of a safe and effective anti-amyloid-beta (Abeta) immunotherapy for Alzheimer's disease (AD) will require therapeutic levels of anti-Abeta antibodies, while avoiding proinflammatory adjuvants and autoreactive T cells which may increase the incidence of adverse events in the elderly population targeted to receive immunotherapy. The first active immunization clinical trial with AN1792 in AD patients was halted when a subset of patients developed meningoencephalitis. The first passive immunotherapy trial with bapineuzumab, a humanized monoclonal antibody against the end terminus of Abeta, also encountered some dose dependent adverse events during the Phase II portion of the study, vasogenic edema in 12 cases, which were significantly over represented in ApoE4 carriers. The proposed remedy is to treat future patients with lower doses, particularly in the ApoE4 carriers. Currently there are at least five ongoing anti-Abeta immunotherapy clinical trials. Three of the clinical trials use humanized monoclonal antibodies, which are expensive and require repeated dosing to maintain therapeutic levels of the antibodies in the patient. However in the event of an adverse response to the passive therapy antibody delivery can simply be halted, which may provide a resolution to the problem. Because at this point we cannot readily identify individuals in the preclinical or prodromal stages of AD pathogenesis, passive immunotherapy is reserved for those that already have clinical symptoms. Unfortunately those individuals have by that point accumulated substantial neuropathology in affected regions of the brain. Moreover, if Abeta pathology drives tau pathology as reported in several transgenic animal models, and once established if tau pathology can become self propagating, then early intervention with anti-Abeta immunotherapy may be critical for favorable clinical outcomes. On the other hand, active immunization has several significant advantages, including lower cost and the typical immunization protocol should be much less intrusive to the patient relative to passive therapy, in the advent of Abeta-antibody immune complex-induced adverse events the patients will have to receive immuno-supperssive therapy for an extended period until the anti Abeta antibody levels drop naturally as the effects of the vaccine decays over time. Obviously, improvements in vaccine design are needed to improve both the safety, as well as the efficacy of anti-Abeta immunotherapy. The focus of this review is on the advantages of DNA vaccination for anti-Abeta immunotherapy, and the major hurdles, such as immunosenescence, selection of appropriate molecular adjuvants, universal T cell epitopes, and possibly a polyepitope design based on utilizing existing memory T cells in the general population that were generated in response to childhood or seasonal vaccines, as well as various infections. Ultimately, we believe that the further refinement of our AD DNA epitope vaccines, possibly combined with a prime boost regime will facilitate translation to human clinical trials in either very early AD, or preferably in preclinical stage individuals identified by validated AD biomarkers.

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Available from: David H Cribbs, Aug 24, 2015
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    • "The first vaccine for Alzheimer's disease, known as AN1792, was composed of immunogenic fibrillar Aβ42 extracted from amyloid plaques and an adjuvant (SQ21). The vaccine induced the synthesis of antibodies against Aβ component in the brain of AD patients and the reduction of Aβ deposits if administered before the cerebral deposition of amyloid plaques [144]. Since the adjuvant may act as a powerful activator of Th1 lymphocytes, about 6% of immunized patients developed autoimmune meningoencephalitis that led to death in some cases [145]. "
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    • "However, a large Phase III clinical use humanized monoclonal antibodies (bapineuzumab) are expensive and require repeated dosing to maintain antibodies therapeutic levels in the patient. In the event of an adverse response to the passive therapy, antibody delivery can be simply halted (Panza et al., 2009; Cribbs, 2010). Compared to an adverse response of the passive therapy with antibody delivery, active immunization has several significant advantages including lower cost and the typical immunization protocol which could be much less intrusive to the patient. "
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    • "In this review article, we focused on the status of clinical trials on active and passive immunotherapeutics targeting A in AD, with particular emphasis on preclinical and clinical findings on bapineuzumab. IMMUNOTHERAPY FOR ALZHEIMER'S DISEASE Anti-A immunotherapy represents the most powerful strategy for reducing brain A load in AD patients [21] [22]. The idea of eliciting an immune response to exogenous administered A peptide in humans was originally described in 1990 in a US patent application by a physician and an experimental immunologist [23]. "
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