It is estimated that 46.8 million people worldwide are living with dementia, with Alzheimer’s disease the most common form.
Now researchers from the University of Southampton have discovered a possible solution for side effects seen in immunotherapy treatment for Alzheimer’s.
Immunotherapy is a promising strategy for the treatment of Alzheimer’s that uses antibodies to stimulate the immune system to remove pieces of a protein called amyloid beta which accumulates in the brain (in deposits known as plaques) and is thought to be a major factor driving Alzheimer’s neurodegenerative effects.
Antibodies directed against amyloid beta have been able to successfully clear plaques and reverse cognitive deficits in mouse models. However, despite this success, clinical trials using these antibodies caused inflammatory side effects in the brain of Alzheimer’s patients, in particular amyloid-related imaging abnormalities (ARIA), which results in small bleeds and dangerous brain swelling.
The multidisciplinary Southampton team, led by Dr Jessica Teeling, and in collaboration with Lundbeck (a multinational pharmaceutical company based in Denmark), engineered three antibodies to change the way they engage cells in the immune system. They found that small but precise changes in the anti-amyloid antibodies preserved the immunotherapeutic activity without the inflammatory side effects.
Dr Teeling, Associate Professor in Immunology at The Centre for Biological Sciences, said: “New antibodies are entering the clinic for Alzheimer’s disease; therefore, it is important to learn all we can from research into these novel interventions and use antibody engineering technology to optimise their effects.”
While these results underline the potential of antibodies to destroy disease-causing plaques in patients and provide possible future treatments, they also indicate that further work is needed to increase antibody potency, but without increasing inflammatory side effects.
Dr Stavenhagen, Head of Biologics at Lundbeck, said: “These studies provide a roadmap of how to apply the advances in antibody engineering to antibody therapeutics that target neurodegenerative diseases. The next generation of antibody drugs to enter the clinic will contain new technologies and enhancements to improve the properties required to clear plaques, while keeping the rest of the brain safe.”
About this Alzheimer’s disease research
Funding: The study was funded by the Medical Research Council (MRC).
Source: Glenn Harris – University of Southampton Image Credit: The image is credited to the researchers/University of Southampton. Original Research: Full open access research for “Comparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies” by James P. Fuller, Jeffrey B. Stavenhagen, Søren Christensen, Fredrik Kartberg, Martin J. Glennie, and Jessica L. Teeling in Acta Neuropathologica. Published online October 3 doi:10.1007/s00401-015-1484-2
Comparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies
Immunotherapy is a promising strategy for the treatment of Alzheimer’s disease (AD). Antibodies directed against Amyloid Beta (Aβ) are able to successfully clear plaques and reverse cognitive deficits in mouse models. Excitement towards this approach has been tempered by high profile failures in the clinic, one key issue has been the development of inflammatory side effects in the brain (ARIAs). New antibodies are entering the clinic for Alzheimer’s disease; therefore, it is important to learn all we can from the current generation. In this study, we directly compared 3 clinical candidates in the same pre-clinical model, with the same effector function, for their ability to clear plaques and induce inflammation in the brain. We produced murine versions of the antibodies: Bapineuzumab (3D6), Crenezumab (mC2) and Gantenerumab (chGantenerumab) with an IgG2a constant region. 18-month transgenic APP mice (Tg2576) were injected bilaterally into the hippocampus with 2 µg of each antibody or control. After 7 days, the mice tissue was analysed for clearance of plaques and neuroinflammation by histology and biochemical analysis. 3D6 was the best binder to plaques and in vitro, whilst mC2 bound the least strongly. This translated into 3D6 effectively clearing plaques and reducing the levels of insoluble Aβ, whilst chGantenerumab and mC2 did not. 3D6 caused a significant increase in the levels of pro-inflammatory cytokines IL-1β and TNFα, and an associated increase in microglial expression of CD11B and CD68. chGantenerumab increased pro-inflammatory cytokines and microglial activation, but minimal changes in CD68, as an indicator of phagocytosis. Injection of mC2 did not cause any significant inflammatory changes. Our results demonstrate that the ability of an antibody to clear plaques and induce inflammation is dependent on the epitope and affinity of the antibody.
“Comparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies” by James P. Fuller, Jeffrey B. Stavenhagen, Søren Christensen, Fredrik Kartberg, Martin J. Glennie, and Jessica L. Teeling in Acta Neuropathologica. Published online October 3 doi:10.1007/s00401-015-1484-2