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The development and impact of Nanobodies

Early 1990s. A scorching hot livestock market in Rabat, Morocco. A Belgian scientist named Serge Muyldermans is dealing with a local trader. Although Serge is clearly not in his natural habitat, he looks excited. The camel he just bought for 40,000 Belgian francs – now around 1,000 euros – could be the start of a promising new research avenue for him and the late VUB professor Raymond Hamers. Little do they know that they’re about to write one of the most successful international biotech stories ever.

Fast forward to 2021. More than three decades of research on camel and llama blood has resulted in multiple waves of impact. Over the years, five VIB spin-offs have been founded, dozens of potential medicines have been developed, and the biggest biotech acquisition in Belgian history took place in 2018, when French pharma player Sanofi acquired Ablynx for 3.9 billion euros.

And the research is anything but finished. Since 1996, the VIB-VUB Center for Structural Biology, led by Professor Jan Steyaert, has served as a hotbed for progress in this promising domain. And as we speak, new innovations in the fields of medicine, animal medicine and crop protection are being developed. All of them go back to a seemingly ordinary day in 1989.

Serendipity meets curiosity

Another day at university in 1989. VUB biology students are everything but looking forward to their immunochemistry lab, where they have to detect and sort antibodies – substances that attack invading diseases – from animals such as mice, dogs, rabbits and birds. It’s an experiment with predictable outcomes: all antibodies are more or less similar. That is until Professor Raymond Hamers suggests also testing dromedary blood because he happens to have some leftover blood samples in the freezer from an earlier research project on sleeping sickness.

When the professor reviews his students’ work, some of the results seem to be off. Perhaps the students simply misinterpreted the data. However, Hamers decides to look beyond the obvious explanation. When postdoc student Serge Muyldermans comes to the exact same conclusions, both men are stunned. Dromedary antibodies, and all camelid antibodies, in fact, seem to share a unique and simple structure – one that could offer huge potential for a wide variety of applications.

But in 1989, there was no VIB, no biotech ecosystem, no substantial financing and no professional tech transfer system to protect and further develop the invention. In other words, Hamers and Muyldermans were pretty much on their own.

And that is how, a couple of years later, Serge Muyldermans found himself in a Moroccan market buying a camel to continue researching these particular antibodies, which were soon to be called ‘nanobodies’.

Antibodies 2.0

Science can be a bumpy road, especially when you’re pioneering. The first years came and went with ups and downs. But despite some setbacks in the lab and the mysterious disappearance of the Moroccan camel (probably stolen), the duo was able to further develop their findings. They managed to isolate one part of the camel antibodies, creating ’single-chain antibodies› or «nanobodies».

In the meantime, Raymond Hamers took steps to protect the invention. “The whole patent story was no walk in the park,” he said in previous interviews. “We even paid for it ourselves at an intellectual property office in Paris. Even more, we weren’t careful enough in terms of confidentiality and ownership of our invention. We ran into some issues, but many things changed after our first publication in Nature in 1993. Everybody gradually started to take us seriously.”

Not only pharmaceutical companies reached out, but governments also started to show interest in what was going on in the labs. VIB was founded in 1995, and not a day too soon for this burgeoning new enterprise. Its dedicated Innovation & Business team is concerned exclusively with technology transfer and supports VIB scientists with valorization. Biologist Jan Steyaert came on board to further develop the technology and the business plan. “Finding investors was the trickiest part,” says professor Steyaert. “Investors tended to follow scientific hypes, which mainly featured synthetic antibodies at the time. We were those weird guys that suggested to immunize camels (laughs).”

It would take until 2001 for VIB to bring forth its first nanobody-based spin-off: Ablynx.

In Ablynx’s wake

The launch of Ablynx was only the start of the nanobody success story. The long rocky road from origin to impact also served as a foundation to jumpstart new ventures. Under CEO Mark Vaeck, Ablynx started out with 10 employees and increased to 27 two years later. In 2006, the new CEO Edwin Moses took charge to guide crucial steps in the further evolution of the company. The pipeline was extended to 16 new substances with the potential to serve as foundations for new medicines. Ablynx continued to grow to approximately 500 people and expanded its patent portfolio, pharma collaborations and projects, which had domestic and international press regularly singing its praises as a company that put Flanders on the worldwide biotech map.

In 2018, Ablynx launched the first nanobody-based drug, caplacizumab, which treats aTTP, a rare blood clotting disorder. The successes of Ablynx convinced French pharmaceutical player Sanofi to acquire the company in 2018 for 3.9 billion euros.

Edwin Moses: “Three years after leaving Ablynx, I’m very proud to see that Sanofi continues to invest in the nanobody platform both in Gent and around the world, with the aim to generate more new medicines based on this fantastic technology, and in addition, there are now about 10 former Ablynx employees who have become CEOs. It is fantastic to see this remarkable contribution of Ablynx to the local and international biotech scene.” 

On top of Ablynx’s rise, VIB propelled new developments in nanobody research, resulting in the birth of four more spin-offs. Biotalys (2013, formerly AgroSavfe) is using antibody technology to fight plant disease in agriculture. Confo Therapeutics (2015) is developing a new class of drugs and partnered up with Roche in 2017. ExeVir Bio (2020) is harnessing the technology to treat Covid-19. And for Animab (2020), the focus is to ensure the intestinal health of livestock. On top of this, other VIB start-ups like Orionis and Oncurious make use of nanobody technology.

From nano to mega

Parallel to the creation of new ventures, Jan Steyaert and his team at the VIB-VUB Center for Structural Biology are continuously taking the technology to the next level. In Flanders, the VIB Nanobody Core makes the antibody technology available to academic and industrial partners for a variety of applications.

Today, VIB has contributed to more than 400 nanobody-related peer-reviewed publications in high ranking journals, the establishment of several biotech companies, and of course new breakthroughs. For example, the last couple of years have seen new “Megabodies”, a novel kind of engineered nanobodies, being applied in cryo-electron microscopy to zoom in on the smallest proteins. Or «AcTakines», which combine mutant cytokines with nanobodies, could be used in new treatment approaches for cancer and immune- or inflammation-related disorders.

And the founding fathers? They can be proud of what they achieved. The Nobel Prize in Chemistry Brian Kobilka and Robert Lefkowitz received in 2012 for the discovery of G protein-coupled receptors, based on the groundbreaking structural biology research at VIB, can be seen as the ultimate reward (read the double interview with Brian Kobilka and Jan Steyaert).  

Story by Katrina Wright (VIB)