Download Current progress in beta-amyloid immunotherapy

Current progress in beta-amyloid immunotherapy
Dale Schenk1, Michael Hagen2 and Peter Seubert1
As neuroscientists, we are taught that the brain is immune
privileged and thus unlikely to be affected by the peripheral
immune system. Accordingly, initial results demonstrating the
effectiveness of b-amyloid (Ab) immunotherapy in mouse
models of Alzheimer’s disease (AD) were viewed with
considerable surprise and some skepticism. Many groups have
since demonstrated efficacy with Ab immunotherapy in models
of AD, using Ab-based immunogens and anti-Ab antibodies.
Clinical trials involving Ab immunotherapy for AD are in
progress and are providing a wealth of information around the
amyloid hypothesis of AD. Ab immunotherapy is also raising
new opportunities and questions about the general role of the
immune system in neurodegenerative diseases.
Addresses
1
Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco,
California 94080, USA
2
Wyeth Research, 401 N. Middletown Road, Pearl River NY 10965, USA
e-mail: [email protected]
Current Opinion in Immunology 2004, 16:599–606
This review comes from a themed issue on
The immune component of brain disease
Edited by Adriano Aguzzi
Available online 20th August 2004
0952-7915/$ – see front matter
# 2004 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.coi.2004.07.012
Abbreviations
Ab
b-amyloid
AD
Alzheimer’s disease
APP amyloid precursor protein
Introduction
Although Alzheimer’s disease (AD) is characterized histologically by b-amyloid (Ab)-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 Ab as a
possible causative element, and evidence supporting this
‘amyloid hypothesis’ includes the observation that a
chronic reduction in Ab, most notably by Ab 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 [2–12,13]. These encouraging observations
must be balanced with the finding that AN1792, the 42
amino acid form of Ab, resulted in an adverse event
involving meningoencephalitis in a subset of patients
that were treated during clinical trials [14].
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The general target of Ab immunotherapy is clearly some
form or forms of the Ab 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 Ab immunotherapy is warranted. We are continuing to gain additional information from preclinical animal models and
ongoing clinical trials to better understand the potential
of Ab immunotherapy for the treatment of AD.
Beta-amyloid immunotherapy in
animal models
Effects on preclinical pathology
Early work in amyloid precursor protein (APP) transgenic
mice that exhibit widespread amyloid plaque pathology
has demonstrated that immunization with Ab can halt and
perhaps even reverse the development of cerebral amyloid plaques. In very young PDAPP mice, immunization
of Ab1–42 plus adjuvant over the course of one year
resulted in an almost complete absence of Ab plaque
pathology [2]. In a study in older PDAPP mice that had
pre-existing plaques, the same immunization protocol
resulted in levels of plaque pathology lower than normal
baseline levels, and significantly lower than in agematched, untreated controls [2]. In these treated older
mice, clear evidence of active clearance of amyloid by
microglial cells was noted. This first report of an immunotherapeutic approach that could strongly reduce plaque
pathology in APP transgenic mice resulted in a myriad of
questions to better understand the fundamental principles underlying the phenomenon.
The key question of whether a humoral or cellular
response mediates the effectiveness of Ab immunization
was clarified by Bard et al. [3], who demonstrated that
peripheral administration of antibodies to Ab is sufficient
to reduce Ab plaque pathology in PDAPP mice (Table 1).
These authors also demonstrated that anti-Ab antibodies
bind to plaques (Figure 2) and trigger microglial clearance
of amyloid plaques through an Fc receptor-mediated
mechanism in ex vivo brain sections from PDAPP mice
and AD patients. Other investigations into the mechanism of antibody-induced Ab plaque clearance have
yielded slightly different results. DeMattos et al. [10]
showed that a highly specific monoclonal antibody to
Ab, first described by Seubert et al. [15], could apparently
reduce Ab pathology in transgenic mice in the absence of
antibody binding to plaques. It was hypothesized that the
antibody reduced brain plaque density by serving as a
peripheral sink to sequester Ab away from the brain and
prevent deposition of new plaques.
Current Opinion in Immunology 2004, 16:599–606
600 The immune component of brain disease
Figure 1
Active immunization
Immunotherapeutic
Passive
immunization
Immunization
Aβ1-42
Immune
response
Administration
of monoclonal
anti-Aβ antibodies
Immunoconjugate
Aβ fragment
B-cell
Immunization
Carrier protein
Anti-Aβ antibodies
Antigen-presenting
cell
T-cell
Current Opinion in Immunology
Beta-amyloid (Ab) immunotherapy strategies. Immunotherapy can be achieved through either active immunization with full length Ab or an Ab
immunoconjugate, or passive administration of monoclonal anti-Ab antibodies. After active immunization with Ab1–42, the peptide is processed by
antigen-presenting cells and Ab fragments are presented to T cells. Subsequently, various B-cells that can recognize epitopes on Ab1–42 are
engaged, proliferate and produce polyclonal anti-Ab antibodies. The second type of active immunization approach involves the administration
of small fragments of Ab conjugated to an unrelated carrier protein. The immunological response after immunization of an Ab peptide-carrier
protein conjugate is similar to the first strategy, with the exception that the T cells are stimulated by the carrier protein rather than the Ab
fragment (which lacks T-cell epitopes). The third strategy involves direct administration of monoclonal antibodies directed against Ab and,
as such, does not require any type of immunological response from the host.
Table 1
Overview of preclinical studies investigating the mechanism of immunotherapy-induced b-amyloid plaque clearance.
Authors (year)
Immunization
Mouse model
Key findings
Bard
et al. (2000) [3]
3D6 (anti-Ab1-5)
10D5 (anti-Ab1-16)
PDAPP
Presence of anti-Ab antibodies in CNS after peripheral administration.
Demonstration of anti-Ab antibodies binding to amyloid plaques.
Absence of T-cell proliferative response.
Microglial activation and phagocytosis of Ab deposits after ex vivo
incubation of anti-Ab antibodies with brain sections, mediated
by Fc receptors.
DeMattos
et al. (2001) [10]
m266 (anti-Ab13-28)
PDAPP
Increase in plasma Ab levels after peripheral administration.
Reduction in central Ab deposits.
Absence of anti-Ab antibodies binding to amyloid deposits in the brain.
Bacskai
et al. (2002) [16]
3D6 (anti-Ab1-5)
10D5 (anti-Ab1-16)
PDAPP,
Tg2576
Clearance of diffuse Ab deposits after central administration.
Clearance of diffuse Ab deposits after central administration of
Fab2 fragments of anti-Ab antibodies.
Tg2576
Reduction in Ab load 4–24 hours after central administration,
maintained at three and seven days.
Microglial activation three days after central administration.
Wilcock
et al. (2003) [18]
Abbreviations: Ab, b-amyloid; CNS, central nervous system.
Current Opinion in Immunology 2004, 16:599–606
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Beta-amyloid immunotherapy Schenk, Hagen and Seubert 601
Figure 2
(b)
Bloodstream
Brain
extracellular space
(a)
Aβ monomers
(a)
(a)
Aβ oligomer
Aβ plaque
Current Opinion in Immunology
Beta-amyloid (Ab) dynamics and mechanisms of antibody-induced clearance. Ab exists within the brain in a dynamic equilibrium between
monomer, oligomer and plaque forms. As with other proteins, an equilibrium for Ab exists between the blood and extracellular fluid. (a) Peripheral
anti-Ab antibodies are able to enter the brain at low levels, where they bind to Ab. Investigations into which form of Ab binds to antibodies
to drive immunotherapy-induced improvements in cognitive function in animal models and reductions in neuropathology are underway.
(b) Antibodies might also be able to exert an effect in the periphery by binding to peripheral Ab, thereby disrupting the equilibrium, resulting
in the sequestration of amyloid away from the brain. This hypothesis, however, remains to be definitively demonstrated.
Bacskai et al. [16,17] further elucidated the mechanisms
of Ab immunotherapy-induced plaque clearance through
the use of anti-Ab antibodies applied directly to the
brains of APP transgenic mice, and found that within
two days, the number of plaques was reduced. This study
provided direct evidence that plaques could be physically
cleared by the presence of anti-Ab antibodies. Surprisingly, the same authors also showed that Fab fragments
were sufficient to reverse plaque pathology, raising questions as to whether Fc receptor-mediated phagocytosis
was required for plaque clearance, as originally reported
[3]. This apparent contradiction in findings has recently
been resolved in part by observations from Wilcock et al.
[18], who have demonstrated a two-phase mechanism of
anti-Ab antibody-mediated plaque clearance. The first
phase is fairly rapid and involves clearance of diffuse Ab
without microglial activation; the second is slower, involving clearance of compact Ab through activation of microglial Fc receptors and phagocytosis of pre-existing
plaques. The studies by Wilcock et al. and Bacskai
et al. do have the caveat that antibodies were delivered
directly to the brain, raising the possibility that the effects
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seen were, in part, a result of the relatively high concentrations of antibodies present.
Effects on cognitive performance
The ability of Ab immunotherapy to modify central Ab
deposits is encouraging; however, the obvious next question is whether immunotherapy is able to improve cognitive performance in animal models of AD and, even
more importantly, in patients. To approach this question,
several laboratories have investigated the effect of Ab
immunotherapy on the ability of APP mice to accomplish
several cognitive tasks. Active immunization with Ab1–42
was effective in increasing the performance of APP
transgenic mice to levels similar to nontransgenic littermates in a traditional Morris water maze and in a radialarm water maze [4,5]. These beneficial observations after
interference with anti-Ab antibodies in mice with ADlike pathology appear to support the amyloid hypothesis
of AD.
It is also of interest that certain deficits in animal models
of AD occur in young (preplaque-bearing) animals and
Current Opinion in Immunology 2004, 16:599–606
602 The immune component of brain disease
appear to be related to the overproduction of neuroactive
Ab species. Whether these acute behavioral phenomena
are relevant in AD or are peculiar to the APP transgenic
animal models is an active area of investigation. However,
it should be noted that the antibody m266, which only
binds to soluble forms of Ab, is also effective acutely in
behavioral models of AD [19], suggesting that immunotherapy can act through plaque removal and through
neutralization of neuroactive Ab species. Ongoing and
future clinical studies should reveal whether both plaque
removal and capture of soluble species are required for
optimal efficacy in AD patients.
Immunological considerations
Although Ab immunotherapy has important implications for AD, it also raises several questions regarding
the interaction of the immune system with the brain,
and opens a new avenue of research to explore this
interrelationship.
After immunization with Ab, the peptide is processed by
antigen-presenting cells in the periphery and then presented to T and B cells. Epitope mapping of these events
following Ab immunization in AD patients indicates that
the predominance of T-cell epitopes lies in the central
to carboxy-terminal region of the Ab peptide [20]. This
agrees with the dominant ****Ab T-cell epitope region
identified in nontreated AD and control elderly individuals [21]. By contrast, most of the B-cell or antibodyproducing epitopes detected from immunized patients
reside in the amino-terminal region of the peptide [22].
The latter point is reinforced by the observation that most
anti-Ab mouse monoclonal antibodies that have been
produced are directed to the first 16 amino acids of the
peptide. We know from the passive immunotherapy
studies described above that an antibody response is
sufficient to demonstrate a reduction in amyloid pathology in animal models of AD. Either as a coincidence or a
consequence of plaque reduction, these same antibodies
also improve other aspects of neuropathology in APP
transgenic mice, including neuritic dystrophy and synaptic density [2,23,24]. These findings are difficult to reconcile with the observation that antibodies (such as m266),
which only bind to soluble forms of Ab, are also effective
acutely in behavioral models of AD [19]. The simplest
explanation for these concurrent results is that both
soluble and plaque-related forms of Ab are deleterious
in the brain. This suggests that an antibody that binds
both plaques and soluble forms of Ab would be optimal
for therapeutic administration in AD.
Although it is widely agreed that antibodies are eliciting
positive effects in AD models of the disease, two negative
immunological consequences of the response against Ab
have been demonstrated. In a model of hemorrhagic
stroke involving very high overexpression of Ab and
severe congophilic angiopathy, passive administration
Current Opinion in Immunology 2004, 16:599–606
of an antibody to Ab resulted in an approximately twofold
increase in the frequency and severity of strokes [25].
However, clinical experience with AN1792 (Ab1–42) in
AD patients did not result in an increased stroke incidence, nor were strokes a clinical feature of those patients
(described below) that developed meningoencephalitis
[14]. A further report has shown that immunization with
Ab1–42 combined with multiple injections of pertussis
toxin can result in cellular infiltrates in immunologically
sensitive C57/BL6 mice but this rarely occurs when either
agent is injected alone [26]. Again, the relevance of these
findings for patients receiving AN1792 is not clear, and
additional studies are underway to better understand the
immunological implications underlying the observation.
These two reports do, however, identify areas for further
study regarding Ab immunotherapy, particularly from the
perspective of potential safety concerns. As Ab immunotherapy is at the crossroads of immunology and the
nervous system, a deeper understanding of the mechanisms involved will have important consequences, not only
for the treatment of AD but also for a better basic
scientific understanding of the interplay between these
two systems.
Several reports have investigated the question of whether
a pre-existing immune response to Ab occurs in patients
or elderly individuals in the absence of any immunization
[27–29]. Overall, these studies have supported the view
that low levels of antibodies to Ab do sometimes exist in
elderly individuals without AD but do not result in any
measurable toxicity, and antibody levels tend to be
reduced in patients with the disease. Although these
findings make it tempting to speculate that naturally
occurring antibodies to Ab are protective against AD,
the levels of antibody are low and inconsistent, making
the conclusion difficult to substantiate. Nevertheless, it is
possible that a very low anti-Ab titer present for many
years might be sufficient to protect against AD, although
only lengthy studies, in many individuals, will be able to
confirm or eliminate this possibility.
Clinical observations with AN1792
Improvements in pathology and cognition in mouse models of AD after treatment with AN1792 (Ab1–42), 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 AN1792(QS-21) to
approximately 80 patients, the treatment appeared to be
well tolerated with no clear drug-related safety concerns
[30]. Based on these findings, a larger Phase 2 study
involving 372 patients was initiated. However, this study
was halted because of the development of symptoms
consistent with meningoencephalitis in some patients
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Beta-amyloid immunotherapy Schenk, Hagen and Seubert 603
who received AN1792(QS-21) [14]. The study remained blinded to patients and physicians for one year
to allow for investigation of potential efficacy as a result
of, on average, two injections of AN1792(QS-21). Analysis
of the Phase 1 multiple dose study shows an advantage on
measures of disability in patients treated with AN1792
compared with placebo [30]; analysis of the Phase 2
study is in progress. Hock et al. analyzed the data from
a single center (30 patients) participating in the Phase 2
study and reported positive results for some efficacy
measures in AN1792 antibody responders compared with
nonresponders [13]. Confirmation of these results will
await analysis and publication of the full, unblinded
study. The wealth of information being accumulated
from AN1792 studies is highly informative at two levels:
firstly, it is relevant to the potential utility of Ab immunotherapy in AD; and secondly, to the testing of the
amyloid hypothesis.
Encephalitis associated with AN1792
Although Ab1–42 immunization was thoroughly tested in
various animal species, under numerous conditions, and
no safety concerns arose during Phase 1 clinical trials to
preclude initiation of larger studies, 18 patients (6%)
receiving AN1792(QS-21) developed meningoencephalitis in the Phase 2 study [14]. A subsequent postmortem
diagnosis of encephalitis was made in one patient treated
with AN1792(QS-21) in a Phase 1 trial who died approximately one year after her last injection from a cause not
directly attributable to study treatment [31]. The symptoms and signs of encephalitis included headache, confusion, and changes on magnetic resonance imaging
scans; of the 18 patients in the Phase 2 study, 12 have
returned to their baseline status and six have experienced
some type of prolonged neurological deficit [14]. Extensive immunological analysis of humoral and cellular
responses was performed in these patients. The majority
of patients had IgG responses to Ab, and all patients
mounted at least a small IgM response. There was no
correlation of the severity of encephalitis with either the
level or epitope specificity of the antibody response,
suggesting that the encephalitis was caused by something
other than anti-Ab antibodies. Moreover, the vast majority of individuals who mounted an antibody response to
Ab did not develop encephalitis.
Effects on pathology
In mouse models of AD, both passive administration
of anti-Ab antibodies and active immunization with Ab
resulted in clearance of Ab-containing plaques [3,10,
15,16,18] and lessening of cognitive impairment [4,5,
9,32,33]. The fundamental question of whether similar
findings might be seen in AD patients receiving Ab
immunotherapy is beginning to be addressed through
postmortem reports (consent was given by family members prior to post-mortem examinations) of patients who
received AN1792(QS-21) in clinical studies (Table 2). In
the three cases (two with encephalitis) reported to date,
the brain tissue clearly had neuropathological findings
consistent with AD, but there were also brain regions that
were uncharacteristically devoid of plaques [31,34] (E
Masliah, personal communication), concurrent with a
high level of microglial staining for Ab. It was concluded
that immunization with AN1792(QS-21), rather than a
chance occurrence, resulted in the plaque clearance
observed in these cases [31,34].
In contrast to the case without encephalitis, marked Tcell infiltrates were apparent in the two encephalitis cases
(Table 2). This suggests that the encephalitis observed
in some individuals treated with AN1792(QS-21) might
result from a T-cell response against Ab1–42. Preliminary
immunological analyses of patients who received
AN1792(QS-21) have shown that the predominant T-cell
Table 2
Overview of neuropathological findings in Alzheimer disease patients who received AN1792(QS-21).
Authors (year)
Immunizations
Encephalitis
Key findings
Nicoll
et al. (2003) [31]
AN1792 50 mg +
QS-21 100 mg 5 injections
Yes
Extensive areas of neocortex with few plaques.
Persistence of neurofibrillary tangles, neuropil threads
and cerebral amyloid angiopathy.
Ab immunoreactivity associated with microglia.
Macrophage infiltration of cerebral white matter.
T lymphocyte (CD4+) meningeal infiltrate.
Ferrer
et al. (2004) [34]
AN1792 225 mg +
QS-21 100 mg 2 injections
Yes
Focal depletion of diffuse and neuritic plaques.
Persistence of cerebral amyloid angiopathy.
Collapsed plaques surrounded by activated microglia.
T lymphocyte (CD4+, CD8+, CD3+, CD5+, CD7+) meningeal infiltrate.
E Masliah, personal
communication
AN1792 225 mg +
QS-21 100 mg 3 injections
No
Focal depletion of diffuse and neuritic plaques.
Persistence of neurofibrillary tangles, neuropil threads.
Ab immunoreactivity associated with microglia/macrophages.
Absence of white matter changes and minimal lymphocytic
meningeal infiltrate.
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Current Opinion in Immunology 2004, 16:599–606
604 The immune component of brain disease
epitopes are in the carboxyl terminus of Ab [20]. Of
particular interest, patients from the Phase 1 multidose
trial generated primarily a Th-2 immunological response,
whereas those in the Phase 2 study generally exhibited a
Th-1 response [20]. These two studies differed only by
the introduction of a detergent (polysorbate-80) to aid
the manufacturing and stability of the peptide. Further
investigation will be required to determine whether this
formulation change affected the immunological profile to
Ab1–42. These findings of the neuropathological and the
cellular response to AN1792(QS-21) are important in
designing improved approaches for both passive and
actively administered Ab immunotherapy.
Future directions with b-amyloid
immunotherapy
Although the success of Ab 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 endpoints, have been observed [13,30,31,
34]. The observation that Ab immunotherapy can
reduce Ab plaque burden in AD patients means that,
at the very least, immunotherapy will provide a fundamental clinical test of the amyloid hypothesis.
Overall, the findings with AN1792(QS-21) strongly support further development of Ab immunotherapy towards
the obvious goals of eliminating or reducing safety issues
and in optimizing the efficacy signals. For example, in an
attempt to avoid safety concerns, approaches that avoid a
T-cell response to Ab, such as passive immunotherapy
with a humanized monoclonal antibody or active immunization with immunoconjugates, are now in development.
Immunoconjugates of b-amyloid peptides
Ab immunoconjugates are being pursued by several academic institutions and pharmaceutical companies as
potential treatments for AD. These immunoconjugates
are typically composed of a fragment of the Ab peptide,
usually derived from either the amino-terminal or the
central region, linked to a carrier protein that provides
T-cell help (Figure 1). By design, the immunogeninduced T-cell response from such an immunogen cannot
be directed to Ab and hence a classical T-cell-mediated
autoimmune response is not possible. This approach also
offers the possibility of generating a more consistent and
heightened antibody response to Ab compared with that
generated by injection of the entire Ab peptide. Studies
in APP transgenic mice and other species have confirmed
these assumptions [6,24,35,36]. At least one such immunoconjugate is in late-stage preclinical development for
Current Opinion in Immunology 2004, 16:599–606
the treatment of AD (data on file, Elan Pharmaceuticals/
Wyeth Pharmaceuticals).
Monoclonal antibodies
Passive immunotherapy using a humanized monoclonal
anti-Ab antibody will entirely eliminate a cellular
response to Ab. Moreover, should any adverse event
occur after administration, dosing can be stopped and
thus the therapeutic entity is eliminated from the body,
limiting prolonged exposure. This approach will also
ensure that essentially every individual treated will
receive the same dose of antibody — a factor difficult
to control with a traditional immunization. Thus, passive
immunotherapy has advantages over active immunization
from both efficacy and safety perspectives. At the time of
writing, one such monoclonal antibody, AAB-001, is in
Phase 1 clinical trials in the USA, although it will be some
time before we understand its potential for efficacy in AD
or obtain meaningful information on its safety profile.
Although an argument can be made that a passive antibody approach might adequately cover the overall field of
Ab immunotherapy, depending upon the required dose
and duration of treatment, immunization might also be a
preferred approach. This is particularly true if prophylactic immunization against AD emerges as a viable
strategy for prevention.
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 Ab 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 by the presence of some, but not all, antibodies to
the prion protein [39,40]. It is anticipated that, with time,
additional efforts in other neurodegenerative disorders
such as Huntington’s disease and Parkinson’s disease will
be attempted, and it will be interesting to discover
whether similar efficacy occurs.
Conclusions and future directions
Considering that the first publication describing the efficacy of Ab 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
models to guide future treatments. Clinical results will
hopefully soon also confirm the relationship between
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Beta-amyloid immunotherapy Schenk, Hagen and Seubert 605
cognitive improvements seen in the animal models to
those in the human disease state. Several crucial outstanding questions remain regarding Ab immunotherapy,
but it is anticipated that at least some investigational
findings will have a profound effect on our understanding
of the interplay between the immune and neurological
systems and on the potential for using immunotherapy in
the clinical treatment of AD and other neurodegenerative
disorders.
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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