Removal of Aβ from the brain has been advanced as a potential treatment of AD. Studies in transgenic mice expressing mutant human amyloid precursor protein genes (APP-Tg mice) suggest that Aβ-binding antibodies clear brain Aβ deposits and correct the behavioral deficits evident in this animal model. The favorable effects were observed following peripheral administration of Aβ-binding monoclonal antibodies10,11
(passive immunotherapy) and after active immunization with Aβ itself (active immunotherapy), which induces the synthesis of Aβ-binding antibodies.12–14
The effects were evident when the antibodies were administered both prior to11
the appearance of Aβ plaques in the murine brain. These findings lead to clinical trials of active Aβ immunotherapy as a treatment for AD. Two important points emerged from the human trials.15
First, only about 20% of the recipients developed Aβ-binding antibodies, reflecting the limited immunogenicity of the Aβ vaccine formulation. Second, the trials were suspended because ≈5% of the immunized patients developed sterile meningoencephalitis, suggesting an inflammatory reaction. Patients who produced Aβ-binding antibodies displayed reduced decline of certain cognitive functions,16
but the therapeutic benefit has been subject to debate.17
Antibodies with Aβ-binding activity can cause undesirable side effects,18
and there is also the potential of harmful cell-mediated immunity after immunization with Aβ. The latter concern is eliminated if preformed Aβ-binding antibodies are employed for passive immunotherapy. A Phase II trial of Bapineuzumab, a humanized reversibly binding monoclonal Aβ-binding immunoglobulin G (IgG), administered intravenously to mild-to-moderate AD patients has been conducted.19
There was no indication of unacceptable inflammatory reactions, but a dose-limiting incidence of vasogenic edema was evident. This effect may be due to microbleeds caused by deposition of immune complexes in cerebral blood vessels (). AD patients homozygous for the apolipoprotein E4 allele are predisposed to increased Aβ accumulation and early development of AD.20
Administration of the Aβ-binding antibody to patients who were not homozygous for the apolipoprotein E4 allele resulted in significantly reduced cognitive decline and a lesser tendency toward vasogenic edema. The favorable effect on cognition did not reach statistical significance in the intent-to-treat population. From these results, there is cautious support for passive AD immunotherapy using Aβ-binding antibodies, but the safety and efficacy of the procedure leave room for improvement.
FIG. 1. Passive immunotherapy of Alzheimer disease (AD) with amyloid β peptide (Aβ)-binding immunoglobulin G (IgG). Reversibly binding IgG injected into peripheral blood can enter the brain in small amounts and help clear Aβ by mechanisms (more ...)
Eli Lilly has advanced its own humanized monoclonal IgG into Phase III trials. This IgG binds an epitope located in the middle region of Aβ, whereas Bapineuzumab binds the Aβ amino terminus.21
Detailed information about the beneficial and side effects of the Lilly monoclonal IgG has not been released, but the company has indicated that antibody administration induces an increase of Aβ levels in cerebrospinal fluid and peripheral blood.22
To the extent that the observed increase of peripheral Aβ is due to release from the brain peptide stores, the antibody may exert a favorable effect.
Interestingly, healthy humans and AD patients produce Aβ-binding autoantibodies spontaneously.23
Pooled human IgG marketed as intravenously administered immunoglobulins (IVIG) formulations contains small amounts of Aβ-binding autoantibodies. Early-stage clinical trials entailing intravenous administration of very large IVIG doses to AD patients (e.g., 1.2
grams/kg over 3 days) were encouraging, but no definitive evidence for efficacy is available yet.24
No side effects have been reported.
Aβ-binding IgGs are proposed to reduce Aβ deposition in the brain by the following mechanisms ()25,26
: (1) Small amounts of peripherally administered IgGs may cross the blood-brain barrier (BBB; ≈0.1% of injected IgG dose) and bind Aβ in the brain. Microglial cells then ingest the immune complexes via an Fcγ-receptor mediated process that results in Aβ clearance; (2) the IgGs can also bind the neonatal Fc receptor (FcRn) located on the abluminal (brain) side of the endothelial cells constituting the BBB, thereby facilitating Aβ efflux into the periphery; (3) Aβ binding to IgG may constrain the peptide into a nonaggregable conformation; and (4) according to the “peripheral sink” hypothesis,21
Aβ is cleared from the brain without IgG entry into the brain. In this hypothesis, Aβ binding by antibodies in peripheral blood perturbs the equilibrium between the peptide pools in the brain and periphery, thereby inducing Aβ release from the brain. In principle, these mechanisms are not mutually exclusive and may be triggered by the same antibody.