A-beta Immunotherapy: Lessons From Mice, Monkeys and Men
C.A. Lemere, M. Maier, T.J. Seabrook
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, NRB 636F, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
Alzheimer's disease (AD) is the most common form of dementia.
Currently, there is no effective cure or preventative treatment.
Amyloid-beta protein (A-beta) has become a major therapeutic target in
recent years due to the genetic linkage between AD and mutations in the
amyloid precursor protein (APP) in a small number of families, its
presence in cerebral plaques, and its neurotoxic properties. Many
efforts are underway to either reduce the production of A-beta or
enhance its clearance. In 1999, Schenk and colleagues published the
first report showing that active immunization with full-length,
aggregated A-beta1-42 lowered cerebral A-beta levels in APP transgenic
mice. Since then, we and others have confirmed and extended these
results in various transgenic mouse models using both active and
passive A-beta immunization. In addition to lowering cerebral A-beta,
some, including our group, have reported elevated levels of A-beta in
blood following immunization. Cognitive improvement has also been
reported in association with active and passive A-beta vaccination in
AD mouse models, even in the absence of significant reductions in
cerebral A-beta loads. Last year, we reported that 10 months of active
immunization with full-length A-beta in aged non-human primates,
Caribbean vervets, led to reductions in cerebral A-beta levels and
gliosis while A-beta levels in blood were elevated compared to
age-matched non-immunized animals. Several mechanisms for these
beneficial effects in mice and monkeys have been proposed and include
dissolution or prevention of A-beta aggregates, Fc-receptor mediated
phagocytosis by microglia, neutralization of the effects of A-beta
oligomers at the synapse, and increased efflux of A-beta from the brain
to the periphery. A Phase I trial by ELAN/Wyeth of active A-beta
vaccination was successfully completed in humans in 2001. However, the
ensuing Phase II clinical trial was halted in 2002 due to the
appearance of meningoencephalitis in ~6% of the AD patients enrolled in
the study. Although the exact cause of these adverse events is
unknown, the immunogen, full-length A-beta1-42, may have been
recognized as a self-antigen leading to an autoimmune response in some
patients. Limited cognitive stabilization and apparent plaque
clearance have been reported in subsets of patients while monitoring of
patients continues. A Phase I trial of passive immunization with a
humanized A-beta monoclonal antibody is currently underway. In the
meantime, we are developing novel A-beta peptide immunogens and routes
of immunization for active immunization in mice and monkeys to target
A-beta B cell epitope(s) and avoid A-beta-specific T cell reactions so
as to generate a safe and effective AD vaccine. We remain optimistic
about the potential of such a vaccine for prevention and treatment of
AD.
Key words:
Alzheimer's disease, amyloid-beta protein, immunotherapy, vaccine, B cells
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