Generality?
In 1999 it was discovered that a vaccine was able to lead to a reduction of β-amyloid accumulation in transgenic mice that developed an excess of the precursor of this protein, APP, which was discussed in the previous chapters.
To date, identifying a variant of antibodies that is able to eliminate the accumulations of amyloid that characterize Alzheimer's disease, but with few side effects, remains the goal to pursue.
Regarding the therapeutic aspect, a distinction is made between active and passive immunotherapy.
- Active immunotherapy involves stimulating the immune system to obtain an antibody response directed against the Aβ protein. In other words, it is a vaccine for Alzheimer's disease.
- Passive immunotherapy, as mentioned above, consists of the introduction of already constituted anti-amyloid antibodies, which aim to prevent the formation of Aβ plaques or increase their elimination.
Active immunotherapy in animal models
Treatment of transgenic animal models overexpressing a mutated form of the human APP protein by using an Aβ vaccine was shown to lead to the blockage of amyloid accumulation in the brains of these animals. Following these data, the scientific community began to treat mice overexpressing APP at a greater age, when the first amyloid deposits began to be present.
The efficacy of the vaccine was revealed not only in animal models of transgenic mice, used by different research groups, but also in other animal species. In fact, many mammals develop a memory loss as they age. Furthermore, this memory loss has been observed not to be associated with amyloid protein deposits. Thus the development of a strategy for a new vaccine in Alzheimer's disease represents a vast and continuously evolving area in the field of research. However, the approach pursued in most cases continues to target B-cell activation (through active immunization) and then production of specific antibodies (using passive immunization).
Given the positive response of animal experiments, the testing of vaccines in patients suffering from Alzheimer's disease has also begun. The vaccine, known as AN1792, was used in a sample of 60 patients, treated with one or more doses of the vaccine. The first observation was the finding of a variable antibody response, in which some of these patients did not develop appreciable results against the antigen. For this reason, in the middle of the clinical trial, the addition of an adjuvant, QS-21, occurred in order to increase the response to the vaccine. It is important to remember that in the I-phase of clinical development, no adverse effects were found. Unfortunately, during the phase-II clinical trial, following the development of aseptic meningoencephalopathy (an inflammatory reaction of the central nervous system to the vaccine) in a group of patients, the trial was stopped.
Despite the interruption of the trial for cases of encephalitis during phase II of the clinical trial, the researchers continued to monitor the patients, measuring their antibody response. They then carried out tests to assess cognitive functions and showed that in the year following the development of the antibody response to the vaccine, patients showed lower cognitive decline than patients in whom no detectable amount of antibodies were present. Moreover, some of these patients, following the initial treatment that was then suspended, showed a certain stability in the following years, this to indicate that the immunotherapeutic approach can be found however beneficial, despite the adverse reactions highlighted.
Passive immunotherapy
The importance of passive immunotherapy is given by the fact that the passive administration of preformed antibodies can obviate the response of the T lymphocytes to active vaccination (responsible for the adverse effects of the vaccine), while maintaining the important biological activities associated with the efficacy on the deposits of amyloid.
Due to the low vaccine response observed in the various clinical trials undertaken, and due to the onset of several T-cell-dependent side effects, many scientists have begun to evaluate passive immunotherapy treatments with monoclonal anti-amyloid antibodies.
The first studies conducted on animal models for Alzheimer's disease, by the pharmaceutical company Elan, showed that following intracranial administration of anti-amyloid antibodies, changes could be observed in amyloid accumulations and in the activation of microglia (cells that, together with neurons, make up the nervous system), quickly enough. It has been observed, for example, that in a week, when antibodies were administered, there were brain regions that were "cleaned" of amyloid accumulations and free antibodies.
Subsequently, the efficacy of passive immunotherapy in animals with amyloid deposits was verified, in which systemic administration of antibodies was performed. These animals were systemically administered at an age of 18-22 months, which corresponds to an age of 65-75 years in humans. A reduction of compact plaques was observed by 90% compared to control animals, to which control antibodies were administered.
A first report on this experiment, however, has brought to light that passive immunotherapy can cause micro-memory in animals with amyloid deposits in later life. However, even the animals that showed this adverse effect, however, later showed some benefits with regards to memory recovery.
To obviate the adverse effect of micro-memory, the antibodies have been modified with appropriate techniques of enzymatic deglycosylation. Currently a humanized version of these antibodies is in phase II of clinical development (ponezumab).
Obviously the problems associated with active immunization have prompted several pharmaceutical companies to orient their clinical studies using monoclonal antibodies against the β-amyloid protein. Among these antibodies, to date, the most advanced is the bapineuzimab.
