Current progress in beta-amyloid immunotherapy
Introduction
Although Alzheimer’s disease (AD) is characterized histologically by β-amyloid (Aβ)-containing plaque lesions and tau-containing neurofibrillary tangles in the brain [1], the primary cause of the disease is currently not well understood. Genetic evidence has implicated Aβ as a possible causative element, and evidence supporting this ‘amyloid hypothesis’ includes the observation that a chronic reduction in Aβ, most notably by Aβ immunotherapy (Figure 1), leads to a reduction in AD pathology and improvements in cognitive performance in animal models of the disease and, potentially, in AD patients 2., 3., 4., 5., 6., 7., 8., 9., 10., 11., 12., 13.••. These encouraging observations must be balanced with the finding that AN1792, the 42 amino acid form of Aβ, resulted in an adverse event involving meningoencephalitis in a subset of patients that were treated during clinical trials [14••].
The general target of Aβ immunotherapy is clearly some form or forms of the Aβ peptide; however, the precise mechanisms involved are still under investigation and several theories currently exist. Accordingly, thorough consideration of the immune system, its components, and the positive or negative role they play in Aβ immunotherapy is warranted. We are continuing to gain additional information from preclinical animal models and ongoing clinical trials to better understand the potential of Aβ immunotherapy for the treatment of AD.
Section snippets
Effects on preclinical pathology
Early work in amyloid precursor protein (APP) transgenic mice that exhibit widespread amyloid plaque pathology has demonstrated that immunization with Aβ can halt and perhaps even reverse the development of cerebral amyloid plaques. In very young PDAPP mice, immunization of Aβ1–42 plus adjuvant over the course of one year resulted in an almost complete absence of Aβ plaque pathology [2]. In a study in older PDAPP mice that had pre-existing plaques, the same immunization protocol resulted in
Clinical observations with AN1792
Improvements in pathology and cognition in mouse models of AD after treatment with AN1792 (Aβ1–42), together with the observed safety characteristics in a broad range of animal species, led to the initiation of Phase 1 clinical studies in AD patients. Extensive animal work, plus previous experience, suggested that AN1792 combined with the saponin QS-21 as an adjuvant would be optimal for clinical studies. In two Phase 1 studies involving administration of single or multiple doses of
Future directions with β-amyloid immunotherapy
Although the success of Aβ immunotherapy as a treatment for AD remains speculative, the early clinical data are encouraging. The most near-term approaches involve three different strategies (Figure 1), with the greatest amount of information available for the forerunner, AN1792(QS-21). Development of this compound has been terminated at Phase 2 for safety reasons, although efficacy signals, including evidence of plaque reduction in treated patients and improvement in some preliminary efficacy
Implications for other neurodegenerative disorders
The idea of using antibodies to reduce or eliminate neuropathology in vivo is very exciting and has been actively discussed by several individuals since the initial publication in 1999, reporting attenuation of AD-like pathology by Aβ immunotherapy [2]. Antibodies have subsequently been shown to be highly effective in mouse models of prion disease 37., 38.. Recent studies have shown, for example, that conversion of the nonpathogenic form of prion protein to the toxic scrapie form can be blocked
Conclusions and future directions
Considering that the first publication describing the efficacy of Aβ immunotherapy in an AD animal model occurred only 5 years ago, it is astonishing to consider that Phase 2 data are already becoming available. Unsurprisingly, it is still too early to know its ultimate potential in AD specifically, and neurodegeneration generally. Perhaps the most intriguing aspect of the approach is the finding that it can reduce pathology in both animal models and in patients, supporting the utility of these
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The authors thank the patients, families and carers of those who participated in clinical studies of AN1792, and acknowledge those who gave consent for the postmortem examination of a family member. R. Black, M. Grundman, C. Gombar and J. Callaway provided careful review of the draft and D. Clemett assisted in the development of the manuscript.
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