Patients who suffer from Alzheimer’s disease (AD) present typical brain features that can be observed through PET scan brain imaging. Brain images of AD patients show deposits of protein fragments called amyloid β peptides (Aβ).
Source: UCSF Department of Radiology & Biomedical Imaging
Derived from the protein APP, normally found in the membrane of nerve cells, Aβ pieces stick to each other and form aggregates that, with time, grow into plaques. It is thought that both large plaques and smaller clusters of Aβ prevent normal signal transmission between neurons and damage the brain tissue, leading to the loss of memory and to cognitive impairments.
In the search of new treatments for AD, researchers have turned to antibodies against Aβ aggregates, which would bind to the protein fragments and disrupt the disease-causing plaques. Unfortunately, this strategy has proven unsuccessful so far, probably because the antibodies tested were unable to reach and properly bind the Aβ peptides. Now, a new study published in the journal Nature revives hopes on the efficacy of immunotherapy for AD.
Sevigny and colleagues started by testing a collection of human B cells (antibody producing cells) reactive against Aβ aggregates. This screening allowed the researchers to identify the aducanumab antibody, hereafter called ADCmab, which selectively targets Aβ clusters, independently of their size.
Animal testing
The scientists first performed preclinical studies in genetically modified mice affected by a condition similar to AD. These mice in fact produce large amounts of Aβ peptides that build up in their brains, and they develop cognitive deficits.
When the researchers injected a murine analog of ADCmab in the animals, they found that the antibody was able to enter the brain and disrupt the Aβ plaques in several areas, including the cortex and the hippocampus, which direct cognitive processes and memory. These results prompted Sevigny and colleagues to start a human clinical trial, with the goal of defining safety, tolerability and pharmacological properties of ADCmab in people.
Human testing
The researchers selected patients with early or mild AD that presented Aβ aggregates in their brains, and administered them monthly injections of ADCmab for one year. While monitoring the evolution of Aβ brain deposits, the scientists found that after 6 months of treatment there was a significant reduction of Aβ plaques in patients injected with ADCmab, compared to those who received a placebo. Thus, for the first time, an anti-Aβ antibody proved able to properly target and disrupt Aβ deposits in the human brain.
After one year, ADCmab-treated patients also showed slower cognitive decline compared to control patients, suggesting that the neuronal connections that were impaired by the Aβ plaques before ADCmab administration had been recovered from degeneration.
The side-effects
Side effects in ADC-treated patients were generally mild and only some of them suffered from serious adverse effects. The latter consisted in a form of brain edema and in a condition called superficial siderosis, which is characterized by the accumulation of iron on the brain surface following micro-hemorrhages. In several cases though, these serious side effects caused no or mild symptoms and resolved in a few weeks, so that patients could continue the treatment.
This study demonstrates that it is possible to target brain aggregates of Aβ with antibodies and to disrupt them in the brain of AD patients. It also suggests that the reduction of Aβ plaques may slow down brain degeneration and the loss of cognitive functions, giving support to the hypothesis that Aβ deposits are, at least in part, responsible for AD.
If the clinical efficacy of ADCmab is confirmed, this antibody could make a breakthrough in the treatment of AD. A phase 3 clinical trial for ADCmab is already ongoing to formally establish the clinical benefits of ADCmab in AD patients and its ability to slow down AD progression. More antibodies, similar to ADCmab and thus able to reach the brain and successfully disrupt Aβ plaques, could also be developed in the search for the most effective and least toxic therapy.
References:
Sevigny, J., Chiao, P., Bussière, T., Weinreb, P., Williams, L., Maier, M., Dunstan, R., Salloway, S., Chen, T., Ling, Y., O’Gorman, J., Qian, F., Arastu, M., Li, M., Chollate, S., Brennan, M., Quintero-Monzon, O., Scannevin, R., Arnold, H., Engber, T., Rhodes, K., Ferrero, J., Hang, Y., Mikulskis, A., Grimm, J., Hock, C., Nitsch, R., & Sandrock, A. (2016). The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease Nature, 537 (7618), 50-56 DOI: 10.1038/nature19323
Image Credit: University of California, San Francisco- Department of Radiology and Biomedical Imaging
