Utrecht University: Human antibodies each bind in their own unique way to the SARS-CoV-2 spike

After a corona infection, our bodies produce a variety of different antibodies to neutralize the corona virus. Within that broad variety, each antibody appears to bind to the virus in a unique way. This was discovered by a research team led by biochemist Albert Heck at Utrecht University, together with colleagues at Amsterdam UMC and the Scripps Research Institute. The group published their results in ACS Central Science, which selected the paper as its cover article.

Coronaviruses are characterised by so-called spike proteins, located at the exterior of the virus. These proteins allow the virus to attach to cells, enabling it to spread further. Our immune system recognises spike proteins. It produces antibodies that bind to the spike proteins, preventing the virus from attacking us.

Trinity of spike proteins
Coronavirus spike proteins arrange themselves in groups of three proteins, called trimers. “Based on that knowledge, you would expect that each group of spike proteins would also bind three antibodies,” says Heck.

Albert Heck
Prof. Albert Heck
But much to the surprise of Heck and colleagues, this does not always seem to be the case. Heck’s team discovered that spike protein groups can also bind to two or even just one antibody. The strength of the binding also appeared to vary. All human antibodies they examined, showed a different binding pattern.

Heck and colleagues propose various explanations for these differences in binding. One possibility is that antibodies sometimes get in each other’s way, reducing the number of spike proteins they can bind to. In addition, the strength of the binding between antibodies and spike protein can vary, a phenomenon called avidity. Also, antibodies can simultaneously bind to two binding sites on a single spike protein, or even bind to two different trimers at the same time.

Cherry picking
All these differences may imply that some antibodies are more suited to combat corona infections than others. According to Heck, this offers opportunities to develop new medicines against coronavirus infections. He envisages it should be possible to select the ‘best’ antibody from a pool of antibodies obtained from the blood of corona patients. That antibody would then be used as a template for new medicines.

Measuring individual molecules
Heck and colleagues tracked down the unique binding properties of antibodies using extremely sensitive measurements. They utilised two variants of a technique called mass spectrometry, which separates substances based on their molecular composition. The specific novel variants used by Heck’s team, called single-molecule mass spectrometry, can distinguish individual molecules.

This approach has not been used before, said researcher Victor Yin, who is part of Heck’s research group at Utrecht University. “Our approaches provide new highly sensitive avenues to understand how antibodies interact with their viral targets.”

The technologies could also rapidly be applied when new spike variants of concern emerge, like omicron

Albert Heck
Prof. Albert Heck
Utrecht Institute for Pharmaceutical Sciences (UIPS)
For this project, Heck collaborated with colleagues at Amsterdam UMC and the American Scripps Research Institute. “Working together in this project was not always easy, due to coronavirus restrictions in our countries,” says Heck. “But still, we were able to develop unique tools that can measure how patient derived antibodies can bind and neutralize the SARS-CoV-2 virus, aiding in the selection of the best candidate for therapeutic development. The technologies could also rapidly be applied when new spike variants of concern emerge, like omicron.”

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