Abstracts & Commentary
Sources: Hock C, et al. Nature Medicine. 2002;8(11):1270-1275; McLaurin J, et al. Nature Medicine. 2002; 8(11):1263-1269; Pfeifer M, et al. Science. 2002;298:1379.
When trials of Elan’s AN1792 vaccine for Alzheimer’s disease (AD) were halted this past year owing to the development of an inflammatory encephalitis in 15 study participants, the future of this novel therapeutic approach came into doubt. Although no further injections of AN1792 are being performed on patients, follow-up studies of surviving subjects are in progress, as well as animal studies designed to further characterize the effects of amyloid immunization. The results of 3 recent investigations suggest that immunotherapy still has the potential to become a treatment for AD but that the road to its successful development is likely to be a long one.
Hock and colleagues in Zurich, Switzerland, reported limited results from the Elan beta-amyloid (A-beta) vaccination trial in humans, including examinations of sera from 24 of the participants. They documented the presence of antibodies in sera obtained an average of 55 days after the second injection of AN1792. These antibodies were found to react against diffuse and neuritic amyloid plaques as well as vascular amyloid. The antibodies appeared specific for A-beta and did not cross-react with amyloid precursor protein (APP) or soluble amyloid monomers and oligomers. Approximately 20% of those tested had high antibody titers (greater than 1:10000) after only 2 injections. They conclude that vaccinating humans with A-beta can produce antibodies with a high degree of selectivity for the type of amyloid found in neuritic plaques.
McLaurin and colleagues sought to further define the effects of immunization by identifying the range of peptides within A-beta to which antibodies most avidly bind. In studies using a transgenic mouse model of AD, they used multiple independent methods to demonstrate that high-affinity binding involves the 4-10 peptide region of A-beta. Moreover, antibodies targeting this region were shown to inhibit amyloid fibrillogenesis and amyloid cytotoxicity in mouse brains without eliciting an inflammatory response of the type seen in the human immunization trials. This suggests that vaccines engineered to react with smaller regions of the A-beta molecule might exert therapeutic benefits without the inflammatory side effects associated with AN1792.
Pfeifer and colleagues encountered a problem using amyloid immunotherapy in transgenic mice that had not been previously reported.. They passively immunized 21-month-old APP23 mice (a transgenic line that develops human amyloid AD-like neuropathology) by weekly intraperitoneal injections of a monoclonal antibody against a 4-amino-acid portion of the human A-beta. After 5 months there was a 23% reduction in neocortical amyloid load, with the majority of the clearance affecting the 42-peptide form of A-beta in diffuse plaques. Amyloid deposits in blood vessels in the form of congophilic angiopathy (CAA) were not significantly reduced by vaccination, yet more than twice the number of hemorrhages occurred in immunized animals than placebo-treated controls. The severity of hemorrhage in immunized animals was also increased in comparison to controls. The distribution of hemorrhages suggests that passive immunization increases the risk of cerebral hemorrhage by weakening the walls of amyloid-laden blood vessels associated with CAA, a common condition in the brains of AD patients.
These studies highlight several interesting issues relating to amyloid immunotherapy for AD. The Hock et al study establishes that high titers of antibodies against A-beta can be produced by humans after active immunization with the 42-peptide form of A-beta. The McLaurin et al study suggests that immunization targeting a smaller component of the A-beta molecule may reduce inflammatory side effects. A striking difference, however, between the antibodies produced in humans and those found in mice is that the human antibodies did not react against soluble forms of A-beta. Soluble oligomeric forms of A-beta are thought to be important to the pathogenesis of AD, and the lack of reactivity of the human antibody against soluble A-beta could compromise the therapeutic effect of this approach. More work needs to be carried out to address this issue.
The occurrence of cerebral hemorrhage in older animals passively immunized against A-beta is another potentially serious blow to the immunization approach. CAA is virtually ubiquitous in the brains of AD patients, and potential therapies that target A-beta in plaques are likely to have some effect on amyloid in blood vessels. It is unclear whether the occurrence of cerebral hemorrhage is related to the use of passive, rather than active, immunization or a consequence of treating older animals with a significant vascular amyloid burden. Future approaches may need to incorporate strategies that minimize effects on vascular amyloid or stabilize blood vessel walls after amyloid inclusions have been removed. Clearly, there is a considerable amount of additional research that needs to be carried out before the immunization approach can be safely retried in humans. Nevertheless, the problems identified to date do not appear to be insurmountable, and the basic approach is still quite viable.
— Norman R. Relkin, MD, PhD, Associate Professor of Clinical Neurology and Neuroscience, New York Presbyterian Hospital-Cornell Campus, Assistant Editor, Neurology Alert.