Could llamas revolutionise human healthcare? Insights from a nanobody lab

“There’s a vast scope of illness that could be treatable using nanobodies,” said Dr Lauren Eyssen, a post-doctoral researcher in the Nanobody Discovery Hub at the Rosalind Franklin Institute, Harwell Science & Innovation Campus.

After Sciad visited the research group in January to learn about their prize-winning work on nanobody-based COVID therapeutics, we were keen to learn more about the exciting potentials of these biomolecules.

“Nanobodies are a version of antibodies found in camelids – camels, llamas, and also sharks,” explained Lauren. “Antibodies are double chain molecules – they have both a heavy and light chain at the end that interacts with their target protein – a COVID spike protein for example. But nanobodies only have a single chain, and they’re ten times smaller than antibodies.” This smaller size offers nanobodies certain advantages which could translate into therapeutic benefits. “Both antibodies and nanobodies bind to a site on the antigen called an epitope, but binding is affected by where this epitope is located. If the epitope is on a smaller, harder to reach region, the smaller nanobody would be able to bind more effectively,” tells Lauren.

And this small size is just one of a suite of benefits of nanobodies. “In the case of therapeutics for respiratory illnesses, nanobodies are very useful because their thermostability means they can be delivered intra-nasally. This is less invasive than an injection and delivers the therapy directly to the lungs,” says Lauren. “Their thermostability also means that nanobody-based therapeutics don’t require the cold chain shipping that we currently require for antibodies.”

For most illnesses, the first step to finding a therapeutic is to find the antigens responsible for disease development or progression. “Once the antigen targets are identified, nanobodies can be produced against these targets, and we can test their therapeutic potential,” says Lauren. “With COVID, the spike protein is the main target for therapies – it’s vital for viral entry, and if you stop viral entry, you stop disease progression.” And beyond COVID, there are many further therapeutic potentials. “Research into nanobody-based cancer therapies is ongoing, but it’s slowed by the complexity of cancer itself – we still need to find the antigen targets. Nevertheless, nanobodies have been used to detect specific cancer markers for their localisation using PET scans, so it’s a positive step forward.”

The task of researchers such as Lauren and her lab group is to find, fine-tune, and produce nanobodies that optimally bind to target antigens. “In order to make nanobody-based therapeutics, the first step is to make a nanobody library that we can ‘fish’ in for nanobodies that bind to our target antigen,” says Lauren, explaining the process. “This is where llamas come in, as making this library requires a small amount of blood from llamas. It’s possible to use naïve libraries from llamas that have never seen our antigen before, but using an immunised library greatly increases the chances of finding a tightly binding nanobody. To make an immunised library, we must immunise the llama with our antigen – think of it like a flu jab we get each year. All procedures are performed in line with the ethical guidelines and under the supervision of trained scientists and veterinarians, with no animal going through the procedure more than once a year.”

After creating the library, the structural biology expertise comes in to play – “once we’ve fished in the library and found tightly binding nanobodies, we determine their DNA sequences and clone them in bacteria or yeast. This means our nanobodies can be recombinantly expressed at scale faster and more cost effectively than monoclonal antibodies.”

The advantages of nanobodies are not limited to therapeutics – they also have potential to advance imaging and visualisation. “Nanobodies can help us visualise antigens inside cells. If we tag nanobodies with a fluorescent moiety or gold nanoparticle, we can visualise their location, thereby revealing the position of a target antigen.” They also have uses in X-ray crystallography where they can help to stabilise proteins to enable higher resolution imaging.

“Nanobodies were first discovered in 1989 and research progressed slowly until the COVID pandemic brought the therapeutic potential of nanobodies to the fore,” said Lauren, looking to the future. “This will hopefully inspire further nanobody-focused research due to their many benefits over conventional antibodies – greater heat stability, improved batch-to-batch consistency, more time & cost-effective production, the list goes on.”

Interested to learn more? Find out about the Rosalind Franklin Institute’s Nanobody Discovery Hub, and read more about the work of Dr Lauren Eyssen.