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TWINCORE researchers show how viruses escape the immune defence system
Monoclonal antibodies against SARS-CoV-2 were considered a promising approach for the prevention and therapy of corona virus infections. However, the ongoing evolution of the virus regularly produces new variants that are no longer neutralised by the antibodies. Researchers from TWINCORE, together with partners from Hanover and Bern, have now been able to clarify the underlying mechanism in more detail. Instead of using a single antibody, they propose the combination of several antibodies for treatment. They have published their findings in the scientific journal eBioMedicine.
One of the fundamental mechanisms in immune defence is the formation of antibodies that can recognise pathogens and render them harmless. In nature, antibodies occur as a diverse mixture produced by many different cells of one type, making them polyclonal. In contrast, monoclonal antibodies which are all identical are laboratory-engineered to recognize a single specific target and are generally used as medication to treat or prevent infections. Several monoclonal antibodies were developed and approved for the treatment of coronavirus infections during the pandemic. "However, monoclonal antibodies have a significant weakness," says Dr. Matthias Bruhn, postdoctoral researcher at the Institute for Experimental Infection Research at TWINCORE and lead author of the present study. "A single mutation in the virus can be enough for an antibody to lose its effectiveness."
Bruhn and his cooperation partners have observed this Achilles' heel in the antibodies they developed themselves, the effectiveness of which they wanted to demonstrate in an animal model. "Our colleagues at the University of Veterinary Medicine Hannover Foundation (TiHo) tested our antibodies in a preclinical hamster model," says Bruhn. "We saw the expected protective effect in most of the animals. But three of the animals fell ill anyway." The researchers then characterised the coronaviruses from the diseased animals in more detail and discovered a single change in the viral genome. Such changes commonly known as viral escape mutations were also found in other antibody studies.
As a replacement for animal experiments they successfully reproduced the observation in cell cultures. "The location of the mutation in the viral genome is directly influenced by the specific antibody used," says Maureen Obara, a PhD student at the Institute for Experimental Infection Research. "These mutations consistently occur at the binding site of the respective antibody."
The team then developed a strategy to prevent the appearance of viral escape mutations during monoclonal antibody treatment. "We copied the recipe for this strategy directly from nature, from the immune system," says Bruhn. "On one hand, the weak point can be virtually mutated away by a targeted counter-mutation of the antibody. And on the other hand, two or even three monoclonal antibodies can be used simultaneously to bind the virus at the same time." Using this approach, they were able to mimic the naturally occurring mixture of different antibodies.
In addition to the researchers from TWINCORE and the TiHo, co-operation partners from the Hanover Medical School and the Swiss Institute of Virology and Immunology (IVI) in Bern were also involved in this research project. "The collaboration with national and international colleagues has once again made a decisive contribution to the success of this study," says Prof. Ulrich Kalinke, Director of the Institute for Experimental Infection Research and Executive Director of TWINCORE. "This networking is made possible by alliances such as the RESIST Cluster of Excellence and DZIF, the German Centre for Infection Research."
Prof. Ulrich Kalinke ulrich.kalinke@twincore.de
Dr. Matthias Bruhn matthias.bruhn@twincore.de
https://doi.org/10.1016/j.ebiom.2025.105770
https://twincore.de/news/antibodies-with-an-achilles-heel This press release on twincore.de
Maureen Obara and Matthias Bruhn
© TWINCORE/Grabowski
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