Immunotherapy for Alzheimer's Disease: Rational Basis in Ongoing Clinical Trials

Abstract

Amyloid-β (Aβ) immunotherapy has recently begun to gain considerable attention as a potentially promising therapeutic approach to reducing the levels of Aβ in the Central Nervous System (CNS) of patients with Alzheimer's Disease (AD). Despite extensive preclinical evidence showing that immunization with Aβ(1-42) peptide can prevent or reverse the development of the neuropathological hallmarks of AD, in 2002, the clinical trial of AN-1792, the first trial involving an AD vaccine, was discontinued at Phase II when a subset of patients immunized with Aβ(1-42) developed meningoencephalitis, thereby making it necessary to take a more refined and strategic approach towards developing novel Aβ immunotherapy strategies by first constructing a safe and effective vaccine. This review describes the rational basis in modern clinical trials that have been designed to overcome the many challenges and known hurdles inherent to the search for effective AD immunotherapies. The precise delimitation of the most appropriate targets for AD vaccination remains a major point of discussion and emphasizes the need to target antigens in proteins involved in the early steps of the amyloid cascade. Other obstacles that have been clearly defined include the need to avoid unwanted anti-Aβ/APP Th1 immune responses, the need to achieve adequate responses to vaccination in the elderly and the need for precise monitoring. Novel strategies have been implemented to overcome these problems including the use of N-terminal peptides as antigens, the development of DNA based epitope vaccines and vaccines based on passive immunotherapy, recruitment of patients at earlier stages with support of novel biomarkers, the use of new adjuvants, the use of foreign T cell epitopes and viral-like particles and adopting new efficacy endpoints. These strategies are currently being tested in over 10,000 patients enrolled in one of the more than 40 ongoing clinical trials, most of which are expected to report final results within two years.

Targeting of Monomer/Misfolded SOD1 as a Therapeutic Strategy for Amyotrophic Lateral Sclerosis

“…Importantly, immunization with SEDI peptide directed a Th2-biased immune response, which promotes antibody production and suppresses the Th1-type proinflammatory response. Of note, it was a Th1 immune response that led to meningoencephalitis in a subset of patients receiving immunizations of A␤ peptide in the AN1792 clinical trial for Alzheimer's disease (for review, see -González et al, 2011). Interestingly, Urushitani and colleagues (Takeuchi et al, 2010) have shown that immunization with WT-apo SOD1 induces a higher Th2/Th1 milieu than G93A-apo SOD1 vaccination, indicating the importance of antigen selection in obtaining the desired outcomes.…”

Apoptosis in Alzheimer’s Disease: An Understanding of the Physiology, Pathology and Therapeutic Avenues

“…Although adequate preclinical data accentuated that immunization with Ab(1-42) peptide ameliorates disease symptoms by curtailing the development of the neuropathological hallmarks of AD in 2002 yet the first clinical trial of AN-1792 AD vaccine was terminated at Phase II due to the development of meningoencephalitis in patients [20]. Further, anti-Ab monoclonal antibodies Bapineuzumab, Solanezumab also failed to show neuroprotective effect in phase III clinical trials of AD in turn inducing side effects such as meningoencephalitis, vasogenic edema in patients [118].…”

“…Despite the significant improvement in research related to apoptotic mechanisms there is no substantial therapeutic strategy to stop or slow this process. Additionally, there exists a considerable ambiguity between several preclinical and clinical studies with respect to disease mechanism and therapeutic strategies [19,20]. Therefore, this review throws light on various apoptotic mechanisms and the possible therapeutic avenues for AD.…”

Amyloid-β Immunotherapy Reduces Amyloid Plaques and Astroglial Reaction in Aged Domestic Dogs

“…Due to the initially severe adverse effects observed in humans [33,34], further studies focused on the design of effective and safe immunotherapy [35,36]. One of these immunotherapies, based on a mixture of fibrillar Aβ components, has been developed in our laboratory with great effectiveness and complete safety in domestic dogs with CDS [37].…”