At least since last year, since the beginning of Coronapandemie, is the word “antibody“It has almost become a part of our everyday language. These little watchdogs are an important part of our immune system to fight off infection by clinging to surface structures of a bacterium or bacteria Virus to pin. In this way they prevent the virus or bacterium from multiplying and humans – for example, from COVID-19 – got sick. Producing such antibodies in large quantities and injecting them into the sick would be one way of successfully fighting diseases. US President Donald Trump stresses that he is at his Coronainfektion was treated in this way and therefore recovered so quickly.
However, the antibodies with which it was treated are very complex in structure. They do not get very deep into the tissue and can possibly cause unwanted complications. In addition, antibodies are very difficult and time consuming to produce, making them unsuitable for widespread use.
“Nanobodies” as a solution
“In contrast, we rely on a different group of molecules, the nanobodies,” explains Dr. Florian Schmidt, who works at the Institute for Innate Immunity University of Bonn leads an Emmy Noether group on this promising new area of research. “These are antibody fragments that are so simply structured that they can be produced by bacteria or yeast, which is associated with lower costs.” These nanobodies are much smaller than classic antibodies. They therefore penetrate the tissue better and can also be produced more easily in larger quantities.
However, a difficulty remains here too. Since the immune system produces an almost infinite number of different antibodies that all recognize different target structures, only very few can do that, for example SARS-Coronavirus-2 incapacitate. Finding these antibodies is like looking for a single grain of sand on Germany’s Baltic coast, Schmidt admits. “To do this, we first injected a surface protein from the coronavirus into an alpaca and a llama,” explains the scientist. “Your immune system then mainly produces antibodies that are directed against this virus. Llamas and alpacas also offer the advantage that, in addition to complex normal antibodies, they also produce a simpler variant that can serve as the basis for nanobodies. “
Using blood samples that they took from the animals a few weeks later, the scientists obtained the genetic information of all the antibodies they were currently producing. After this “library” still contained millions of different blueprints, they used an elaborate process to sort out those that were on the surface of the Coronavirus recognize the spike protein. “In total, we received dozens of nanobodies, which we then examined further,” explains Dr. Paul-Albert König, head of the Core Facility Nanobodies at the Medical Faculty of the University of Bonn and first author of the study.
Four out of several million
In the end, four molecules were actually effective against the pathogen in cell cultures. “Using X-ray structure and electron microscopy analyzes, we were also able to show how they interact with the virus’ s spike protein,” explains König.
When infected with the SARS-CoV-2 virus, the spike protein acts like a kind of Velcro strip with which the virus attaches to the cell. Once this process is complete, the Velcro strips off the component that is important for attachment and the envelope of the virus fuses with the cell. “The nanobodies also seem to trigger this structural change before the virus hits its target cell – an unexpected and novel mechanism of action,” says König. “The change is presumably irreversible; the virus can no longer bind to its target cells and infect them. “
Another great advantage of Nanobodies over antibodies is that, due to their simple structure, they can be easily combined into molecules that can be hundreds of times more effective. “We fused two nanobodies that are directed against different parts of the spike protein,” explains König. “This variant was highly effective in cell cultures. We were also able to demonstrate that this drastically reduces the likelihood that the virus will become resistant to the active ingredient through a mutation. ”In the medium term, König and his colleagues are convinced that the molecules could develop into a new, promising therapeutic option. The company Dioscure Therapeutics, a spin-off from the University of Bonn, is now to test the nanobodies in clinical studies.
Institutions from Germany, Sweden and the USA were involved in the study, which was supported by the Federal Ministry of Education and Research, among others. Further sponsors are the Medical Faculty of the University of Bonn, the German Research Foundation, the Klaus Tschira Boost Fund, the Baden-Württemberg Foundation and the MWK Baden-Württemberg. In the USA, the Bill and Melinda Gates Foundation, the US Department of Energy, the National Institutes of Health (NIH), the National Institute of General Medical Sciences (NIGMS) and the National Cancer Institute (NCI) supported the project, in Sweden the Swedish Research Council and the Knut and Alice Wallenberg Foundation.
The researchers published the results of their study in the specialist publication Science released.
cover photo: Cell culture vessels with stained cells, in which virus replications can be quantified through the holes in the cell lawn (plaques) caused by the virus. © Volker Lannert / University of Bonn