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 blocking the virus from entering cells. Researchers have now used structural biology techniques and binding assays to show four basic modes by which different neutralizing antibodies bind to the novel coronavirus’s spike protein (Nature 2020, DOI: 10.1038/s41586-020-2852-1).
These antibodies specifically target the protein’s receptor-binding domain, or RBD. “There was evidence of multiple binding modes, or targets, on the RBD surface,” explains Christopher O. Barnes, a postdoc in Pamela Bjorkman’s biology lab at the California Institute of Technology. To explore these domains, Barnes used cryo-electron microscopy to visualize spike-protein-bound neutralizing antibodies isolated from people with COVID-19. He could see not just where antibodies might bind to one RBD but also how the antibodies might bind to the full spike and how it might be possible for different antibodies to double up on one spike.The spike is a complex of three identical proteins, each of which has its own RBD. The Caltech team classified four complementary ways in which the neutralizing antibodies bind to different sites and orientations of these RBDs.
Many pharma firms are working on getting antibodies for SARS-CoV-2 into the clinic. A 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. Those two antibodies correspond to potentially complementary classes, according to Bjorkman and Barnes’s system.Michael Hust, who is developing SARS-CoV-2 neutralizing antibodies at the Technical University of Braunschweig, cautions that there are also differences within the classes. “It is not black and white,” Hust says.
Bjorkman is working with a group using computational techniques to optimize the binding of the antibodies. But Bjorkman says she’s not sure if that will be needed—the ones some patients have made naturally are quite effective. While we still have much to learn about this virus and our immune response to it, Bjorkman hopes the work can help researchers predict what antibodies might perform better and why, and which cocktails might prove most effective at fighting the pandemic.