Pharma & drug development

The strength of sharks

Dutch biotech company Crossbeta Biosciences has been granted an exclusive license to three shark antibodies. They are considered to have huge disease-specific potential for the treatment of Alzheimer’s disease, but how do they work? We find out.

Alzheimer’s disease, the most common form of dementia, is a major area of unmet need. With one in six people over 80 affected, the numbers are steadily growing as the population ages. Today, there are 850,000 sufferers in the UK alone, a figure set to rise to 1 million by 2025 and 2 million by 2051. Worldwide, the numbers are projected to double every 20 years.

Because the condition is so disabling, and the brunt of care is often borne by families, there is a pressing need for new and better treatments. The search is on for a drug that might reverse the disease progression or even stop it from developing in the first place.

For Dutch biotech company Crossbeta Biosciences, Alzheimer’s is a top priority. The company specialises in neurodegenerative diseases associated with misfolded proteins, which, alongside Alzheimer’s, include Parkinson’s, ALS and Huntington’s. Recently, it signed an agreement with another biotech firm, Melbourne-based AdAlta, which will take it a step closer to creating a novel Alzheimer’s therapeutic.

Under the terms of the agreement, Crossbeta will have full licensing and commercialisation rights over three modified shark antibodies, which are thought to hold strong potential for Alzheimer’s disease.

“We will now move forward with developing these novel anti-AßO antibodies as potential treatments of real disease-modification potential and diagnostic use, as early in the disease as possible, for the benefit of Alzheimer’s patients,” said Crossbeta CEO, Guus Scheefhals, on a release.

Why sharks?

So what, exactly, do sharks and their antibodies have to do with dementia? The specifics bear some unpacking. As Samantha Cobb, CEO of AdAlta explains, the shark antibody’s distinct structure makes it an important tool for researchers.

“The molecule has a very long CDR3 binding loop which can bind into novel targets,” she says. “The antibodies are also really stable – we can boil them, put them in acid, they’re protease resistant. We found a number of human proteins that were exactly the same shape and had the same biochemical properties.”

Scientists have been interested in shark antibodies since the 1990s, when their unusual properties first became apparent. In contrast to most antibodies, which have a molecular mass of around 150 kDa, shark antibodies weigh in at just 12-13 kDa. And unlike conventional antibodies, which are more complex in structure, they have a single immunoglobulin variable domain. Their small size, robustness and stability may enable them to penetrate more deeply into tissues.

They also home in on their targets with high affinity and specificity. Thanks to their unusually long binding loop, they are able to recognise a wide range of antigens, including some that are out of reach to current antibody therapies. From a research standpoint, then, shark antibodies hold great promise as a novel class of protein therapeutic.

A diverse library

AdAlta uses a proprietary technology platform to develop i-bodies, a human analogue of shark antibodies with the same desirable properties. It has created a diverse ‘library’ of i-bodies, which can bind to a broad range of targets. Following intensive screening, the company selects suitable candidates for further research. The chosen i-bodies are then refined, using a process known as affinity maturation, to improve their binding capabilities.

“The i-body is essentially the same shape as the shark single domain antibody, and we use the i-body library to identify antibodies for different targets,” says Cobb.

The company’s lead drug candidate, an i-body called AD-114, is being developed for idiopathic pulmonary fibrosis. However, as the collaboration with Crossbeta has reinforced, fibrotic diseases are far from the only potential application.

“We found a shark single domain antibody that only sees the oligomer version of the beta-amyloid (Aβ ) protein – it doesn’t see the monomer version or any other version. This is potentially a new therapeutic strategy for the treatment of Alzheimers,” says Cobb.

The collaboration

When the two companies first joined forced in 2013, it was with an eye to developing oligomer-specific i-bodies. According to the ‘toxic Aβ oligomer’ hypothesis, Alzheimer’s disease occurs when cellular Aβ proteins misfold, clump together in large protein ‘plaques’ and give rise to toxic aggregates called oligomers. These oligomers are small and soluble enough to spread round the brain, killing neurons.

Unfortunately, research in this field has been stymied by the fact that oligomers are so unstable. Because they tend to disintegrate or stick together, it is difficult to develop drugs that bind to them.

Crossbeta’s technology platform produces unusually stable Aβ oligomers, which are not only an invaluable research tool in their own right – they can also be used to screen for new therapeutics.

In this case, AdAlta’s i-body library was screened against Crossbeta’s stable oligomers to identify the best fit. Three candidates emerged, which bind specifically to the Aβ oligomers without affecting the other parts of the protein.

Following the commercialisation agreement, which was signed in November 2016, Crossbeta will manage all future R&D activity. Eventually, the company plans to market the antibodies as a therapeutic agent, with AdAlta receiving royalties.

“They’re planning to commercialise a diagnostic, and they’re also looking to turn the shark single domain antibody into a drug for the treatment of Alzheimer’s disease,” says Cobb.

Both companies are optimistic about the potential for these antibodies, which could one day be used to detoxify the harmful oligomers at an early stage of Alzheimer’s. In doing so, they hope to stop the disease pathogenesis in its tracks.

This article appears in the March 2017 edition of Pharma Technology Focus

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