Current Active Anti-β-amyloid Immunotherapy for Alzheimer's Disease
The administration of Aβ antigens (active vaccination) or anti-Aβ antibodies (passive vaccination) stimulates Aβ clearance from the Alzheimer's disease brain and represents the most innovative approach of anti-Alzheimer's disease therapy. Among active immunotherapeutic procedures, based on the inspiring results of preclinical studies with preaggregated Aβ1–42 administered with the immune Freund's adjuvant, the first anti-Aβ vaccine (AN1792) tested in Alzheimer's disease patients included full length Aβ1–42 peptide with an adjuvant (QS21) that preferentially promoted T-cell-mediated immune responses.
The results from the first Phase I trial demonstrated good tolerability of AN1792. In the following trial using multiple-dose AN1792, there was no significant difference of adverse effects between AN1792 and a placebo group, but one patient developed meningoencephalitis. Unfortunately, in a Phase IIa trial on 372 mild-to-moderate Alzheimer's disease patients, AN1792 caused meningoencephalitis in approximately 6% of the treated individuals and the trial was suspended. At autopsy, an excessive Th1-mediated response was suggested by cytotoxic T-cell reactions surrounding some cerebral vessels, although the exact cause of toxicity in these patients is unknown. The initial finding that AN1792 vaccination may cause increased losses in Alzheimer's disease brain because of Aβ removal was later integrated with the long-term observation that patients with significant antibody responses showed similar brain volumes to placebo-treated patients. Post-mortem histopathological examinations of a few patients showed clearance of parenchymal senile plaques. Approximately, only 25% of Alzheimer's disease patients treated with AN1792 had an anti-Aβ antibody response. It has been shown that antibody responders had statistically significant improvement on composite scores of memory function compared with the nonresponders or placebo-treated patients, and a slower rate of cognitive and functional decline compared with patients who did not form antibodies. AN1792 treatment could be more effective if started before the development of clinically significant Alzheimer's disease-related pathology. Therefore, if immunization begins at earlier stages of the disease, the Aβ-lowering effects could have increased cognitive benefits. This hypothesis has been confirmed by the presence of tau-related pathology in cortical areas cleared of Aβ, while in transgenic mouse models of Alzheimer's disease early vaccination was shown to prevent the formation of both Aβ deposits and hyperphosphorylated tau aggregations, therefore preventing the formation of new tangles without affecting those already formed. Another study on long-term clinical outcomes of AN1792 in 80 patients of the multiple-dose Phase I trial showed that the burden of Aβ correlated inversely with antibody titer after vaccination, but with no effect on survival or progression of dementia. Based on the clinically significant adverse events and questionable clinical efficacy, the vaccine was abandoned.
Notwithstanding the failure of AN1792 vaccination, at present, a plethora of preclinical studies of anti-Aβ active immunization approaches are underway. These vaccines were designed to reduce the potential for a Th1-mediated cellular immune response and, with appropriate modifications of the antigenic presenting Aβ-peptide, to favor a humoral response. In fact, an ideal anti-Aβ vaccine should elicit a robust anti-Aβ antibody, stimulating a Th2 (T-helper) immune response. A series of preclinical studies on transgenic mouse models of Alzheimer's disease showed examples of second-generation active anti-Aβ vaccines by testing alternate immunogens and adjuvants to overcome an inappropriate T-cell response, including nontoxic/nonfibrillar, soluble Aβ-derivative immunogens, adenovirus vector vaccines encoding Aβ1–15 and Aβ3–10, phage display of epitope EFRH (Aβ3–6), DNA vaccines targeting Aβ, Aβ 'retroparticles', and Aβ species (YM3711), short amino-terminal Aβ fragments that target the B-cell epitope avoiding T-cell activation, herpes simplex virus amplicons coding for Aβ, active vaccination against ankyrin G, and with an epitope vaccine (Lu AF20513) in which the T-helper cell epitopes of Aβ1–42 were replaced by two foreign Th epitopes from tetanus toxoid, P2, and P30, and the immunodominant B-cell epitope of Aβ1–12. Moreover, various adjuvants and routes of administration (oral, intranasal, and transcutaneous) are under investigation to improve the safety, efficacy, and ease of use of anti-Aβ vaccines.
Ten years after the failure of AN1792, CAD106 was developed as the second generation of active Aβ immunotherapy, reaching clinical development. CAD106 comprised only a small Aβ fragment (Aβ1–6) which is a B-cell epitope coupled to an adjuvant carrier formed by 180 copies of the coat protein of bacteriophage Qβ, providing T-cell help for the anticipated immune response. Immunization with CAD106 prevented brain senile plaque accumulation in two transgenic Alzheimer's disease mouse models, with reductions of up to 80% in the senile plaque area compared with controls. Recently, a Phase I clinical trial assessed the safety and tolerability of CAD106, showing that 67% of patients receiving 50 μg CAD106 and 82% receiving 150 μg CAD106 developed Aβ antibody response meeting the prespecified responder threshold. This trial reported adverse effects of nasopharyngitis and injection site reactions but no cases of meningoencephalitis. However, the study was not powered to show any clinical differences between CAD106-treated and control patients. These studies encourage larger, longer studies for B-cell targeted immunotherapy, and five Phase II clinical trials on CAD106 were completed recently and the data analyses are pending. CAD106 is one of the new peptide vaccines too short (six amino acids long) to activate T-cells and with only the parts needed for the generation of Aβ-specific antibodies remaining. Another two of these B-cell targeted peptide vaccines for active immunizations, ACC-001 (vanutide cridificar) and Affitope AD02, are currently in Phase II clinical trials. Although ACC-001 is a conjugated N-terminus peptide attached to an immunostimulatory carrier protein using the surface-active saponin adjuvant QS-21, Affitope AD02 comprises the smaller Aβ immunogens (Aβ1–6) and aluminum hydroxide as adjuvant. Early clinical data from Phase I trials confirmed for these peptide vaccines positive antibody responses with no signs of adverse autoimmune inflammation, but further Phase II trials are needed for these active immunization therapies.