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Antibody therapeutics will be a key part of the fight against COVID-19, but some do a better job of neutralizing SARS-CoV-2 than others. These antibodies stop infection by preventing the virus from entering cells. Researchers have now used structural biology techniques and binding assays to show four basic ways by which different neutralizing antibodies bind to the spike protein of the novel coronavirus (Nature 2020, DOI: 10.1038 / s41586-020-2852-1) .
These antibodies specifically target the receptor-binding domain of the protein, or RBD. “There was evidence of multiple binding modes, or targets, on the surface of RBD,” explains Christopher O. Barnes, a postdoc in Pamela Bjorkman’s biology lab at the California Institute of Technology. To explore these domains, Barnes used cryoelectron microscopy to visualize neutralizing antibodies bound to spike proteins isolated from people with COVID-19. He was able to see not only where antibodies could bind to an RBD, but also how antibodies could bind to the full peak and how it would be possible for different antibodies to duplicate in one peak. The peak is a complex of three identical proteins, each. of which it has its own RBD. The Caltech team classified four complementary ways in which neutralizing antibodies bind to different sites and orientations of these RBDs.
Many pharmaceutical companies are working to bring SARS-CoV-2 antibodies to the clinic. One promising approach is to use a combination of them. The Regeneron antibody mix that President Donald J. Trump took as part of his treatment for COVID-19 consists of two individual antibodies. These two antibodies correspond to potentially complementary classes, according to the Bjorkman and Barnes system. Michael Hust, who is developing neutralizing antibodies to SARS-CoV-2 at the Technical University of Braunschweig, cautions that there are also differences within classes. “It is not black and white,” says Hust.
Bjorkman is working with a group that uses computational techniques to optimize the binding of antibodies. But Bjorkman says she’s not sure if it will be necessary – the ones that some patients have done naturally are quite effective. While we still have a lot to learn about this virus and our immune response, Bjorkman hopes the work can help researchers predict which antibodies might work best and why, and which cocktails might be most effective in fighting the pandemic.
