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Designing an Antibody to Identify Pathogens of Alzheimer’s Disease

Combined team from the University of Cambridge, University College London and Lund University, developed a way to design an antibody to identify toxic particles that destroy healthy brain cells.

In a paper published in PNAS, the researchers presented their method that is able to recognise amyloid-beta oligomers, the hallmark of Alzheimer’s disease, providing hope to the possibility of new diagnostic methods for Alzheimer’s and other forms of dementia.

“There is an urgent unmet need for quantitative methods to recognise oligomers – which play a major role in Alzheimer’s disease, but are too elusive for standard antibody discovery strategies,” said Professor Michele Vendruscolo from Cambridge’s Centre for Misfolding Diseases, who led the research. “Through our innovative design strategy, we have now discovered antibodies to recognise these toxic particles.”

As one of the leading causes of death in UK, dementia results in a healthcare burden of £26 billion each year and is expected to more than double in the next 25 years. Alzheimer’s disease is the most common form of dementia, and have been over 400 clinical trials. At present there are no drugs approved for treatment of the disease.

“While the amyloid hypothesis is a prevalent view, it has not been fully validated in part because amyloid-beta oligomers are so difficult to detect, so there are differing opinions on what causes Alzheimer’s disease,” said Vendruscolo. “The discovery of an antibody to accurately target oligomers is, therefore, an important step to monitor the progression of the disease, identify its cause, and eventually keep it under control.”

The lack of methods to detect oligomers has been a major obstacle in the progress of Alzheimer’s research. Thus, hampering the development of effective diagnostic and therapeutic interventions and led to many uncertainties about the amyloid hypothesis.

“Oligomers are difficult to detect, isolate, and study,” said Dr Francesco Aprile, the study’s first author. “Our method allows the generation of antibody molecules able to target oligomers despite their heterogeneity, and we hope it could be a significant step towards new diagnostic approaches.”

The method is based on an approach for antibody discovery developed over the last ten years at the Centre for Misfolding Diseases. Based on the computational assembly of antibody-antigen assemblies, the method enables the design of antibodies for antigens that are highly challenging, such as those that live only for a very short time.

The researchers designed an antibody with at least three orders of magnitude greater affinity for the oligomers over other forms of amyloid-beta. This difference is the key feature that enables the antibody to specifically quantify oligomers in both in vitro and in vivo samples.

The team hopes that this tool will enable the discovery of better drug candidates and the design of better clinical trials for people affected by the debilitating disease. They also co-founded Wren Therapeutics, a spin-out biotechnology company based at the Chemistry of Health Incubator, in the recently opened Chemistry of Health building, whose mission it is to take the ideas developed at the University of Cambridge and translate them into finding new drugs to treat Alzheimer’s disease and other protein misfolding disorders.

The antibody has been patented by Cambridge Enterprise, the University’s commercialisation arm. [APBN]