Nanobodies, miniscule antibodies with unique properties, are a major biotech innovation

Someday soon, patients with rare diseases or cancers may be treated with new therapies developed from an unusual source: llamas.

Llamas and related animals have a unique form of antibodies, the protein that the immune system produces to attack infections or rogue cells in the body. Compared to antibodies from humans or other animals, these antibodies have a more simple architecture and can be transformed in the lab into substances called Nanobodies, which are just a tenth the size of conventional monoclonal antibodies. This gives them the potential to reach disease targets in the human body that are inaccessible to conventional antibodies and allows scientists to create proteins able to reach multiple targets at the same time.

Over the last 20 years the scientific community has been working with conventional antibodies, which can address only one or, more recently, two treatment targets, and because of their size and rigidity can only access certain target sites,” Buyse said. “With Nanobodies, you can connect them like beads on a string, which provides much more flexibility. We’ve discovered something that can address multiple sites on the same target or multiple targets on the same or different pathways.”

Nanobodies were discovered by accident when a professor at a Belgian university was teaching a university class on antibodies and gave students a supply of dromedary camel blood from another project for their lab work. When the students finally isolated and analyzed what they found, it was a type of antibody that had never been seen before. From that discovery, almost a dozen years of research followed, to learn more about how Nanobodies work and how to bring them from the lab to manufacturing and into the clinic.

Nanobodies are now produced by extracting the genetic information for these special antibodies from a small amount of blood drawn from llamas, which are closely related to the camel. Those are then transformed into Nanobodies, which are in turn mass produced with the help of microorganisms, a simple and efficient manufacturing process.

The ability of these Nanobodies to go after many targets at once presents advantages for researchers trying to develop treatments for many different conditions.
For example, researchers working in the pre-clinical space on more effective cancer treatments are focusing on checkpoint inhibitors, antibodies that prevent cancer cells from “hiding” themselves from the body’s immune system. Cancer cells are clever, though, and can develop the ability to use a different pathway to evade the immune system. Nanobodies could be used to deliver several checkpoint inhibitors at once, greatly diminishing the chances for cancer cells to evade destruction.

Similarly, Nanobodies offer the potential to create more effective anti-viral treatments. Many viruses consist of several strains with small but crucial differences in their appearance to the immune system, which makes it difficult to develop effective vaccines. With Nanobodies, due to their access to conserved target sites that cannot be addressed with conventional antibodies broader strain recognition and better neutralization is achievable.

Nanobodies are also more stable than conventional antibodies. “You can expose a Nanobody to harsh conditions and it will still function, so you can formulate them differently from conventional antibodies,” Buyse said. “We’ve tested it in pre-clinical studies for pulmonary delivery, for absorption through the lungs, creating very small droplets, a process that conventional antibodies couldn’t withstand. They also have very low viscosity, so even when you concentrate them highly, you can still inject them with very small syringes. These are very practical attributes that could make a big difference in developing treatments”.

Buyse points out that after 12 years of research, Nanobodies have gone from being experimental to “a validated platform” thanks in part to the more than 2,000 patients and volunteers who have been given Nanobodies in various trials. In addition, it has proved possible to generate Nanobodies against every target that researchers have worked on so far, she said, including very difficult targets such as G-protein coupled receptors (GPCRs) or ion channels. This makes the technology “simple and tried in the clinic” Buyse says.

As for the llamas – they and their camel cousins haven’t yet revealed the secret behind why they make Nanobodies that only very few other creatures are known to do. “Nobody really knows what the evolutionary advantage was,” Buyse said. “Finding these Nanobodies was just remarkable.”