Amyloid-based immunotherapy for Alzheimer's disease in the time of prevention trials: the way forward

Abstract

Both active and passive anti-β-amyloid (Aβ) immunotherapies for the treatment of Alzheimer's disease (AD) have demonstrated clearance of brain Aβ deposits. Among passive immunotherapeutics, two Phase III clinical trials in mild-to-moderate AD patients with bapineuzumab, a humanized monoclonal antibody directed at the N-terminal sequence of Aβ, were disappointing. Also solanezumab, directed at the mid-region of Aβ, failed in two Phase III trials in mild-to-moderate AD. Another Phase III trial with solanezumab is ongoing in mildly affected AD patients based on encouraging results in this subgroup. Second-generation active Aβ vaccines (CAD106, ACC-001, and Affitope AD02) and new passive anti-Aβ immunotherapies (gantenerumab and crenezumab) have been developed and are under clinical testing. These new anti-Aβ immunotherapies are being tested in prodromal AD, in presymptomatic subjects with AD-related mutations, or in asymptomatic subjects at risk of developing AD. These primary and secondary prevention trials will definitely test the Aβ cascade hypothesis of AD.

Keywords:

• active immunotherapy
• Alzheimer's disease
• cognitive disorders
• dementia
• gantenerumab
• monoclonal antibody
• passive immunotherapy
• solanezumab

Financial & competing interests disclosure

This research was supported by Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale (PRIN) 2009 Grant 2009E4RM4Z. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Senile plaques, mainly composed by the accumulation of β-amyloid (Aβ) peptide, and neurofibrillary tangles, a product of the tau protein hyperphosphorylation, are the principal neuropathological lesions of Alzheimer's disease (AD). These neuropathological hallmarks are surrounded by dystrophic neurites and microglial cells.

• Few therapeutic approaches based on active and passive immunization against tau protein are currently available, almost all in preclinical phase.

• Both active and passive anti-Aβ immunotherapies demonstrated to clear Aβ deposits from the brain of AD patients in neuroimaging and neuropathological studies.

• AN1792, an active anti-Aβ vaccine preparation, showed some signs of clinical efficacy in AD patients, but it has been discontinued because it caused autoimmune meningoencephalitis in a minority of subjects.

• Second-generation amyloid-based active vaccines and passive anti-Aβ immunotherapies are under extensive clinical investigation, with several monoclonal antibodies against Aβ in Phase III clinical trials.

• Bapineuzumab, a humanized monoclonal antibody recognizing N-terminus of Aβ, showed in Phase III clinical trials on AD patients no treatment benefits in cognitive and functional measures, with a high incidence of amyloid-related imaging abnormalities.

• Solanezumab, a monoclonal antibody directed at the mid-region of Aβ, has shown some beneficial cognitive effects in mildly affected AD patients. A Phase III study in mild AD patients is ongoing to confirm these potential benefits.

• Some secondary prevention trials on the anti-Aβ monoclonal antibodies solanezumab, gantenerumab and crenezumab will investigate when exactly AD treatment has to be started, focusing on therapy in asymptomatic subjects at risk of AD or presymptomatic AD subjects.