Antibodies are specialized proteins produced as part of the body's immune response. Neutralizing antibodies bind to pathogens, such as SARS-CoV-2, stopping it from infecting host cells. Neutralizing antibodies have shown immense promise as COVID-19 treatments. These Y-shaped proteins block the coronavirus from slipping into human cells, obstructing interactions between the virus' spike protein and ACE2 cell-surface receptors.
Several clinical trials have shown that these antibodies when administered early after a diagnosis, may prevent hospitalization in patients at high risk for severe complications from the disease.
The immune system produces such a vast universe of neutralizing antibodies against a single viral target, each with distinct properties. Some might bind more strongly to the spike protein, for instance. However, until now, questions have lingered on how to rank the potency of discovered SARS-CoV-2 antibodies based on their characteristics. Would neutralizing antibodies that latch on more strongly to the spike protein have more therapeutic value for COVID-19 patients?
No, says a study published in the high-impact journal Cell, providing evidence that neutralizing antibodies are far more complex than initially thought. In the investigation, scientists analyzed a panel of six antibodies known to target the SARS-CoV-2 spike protein specifically. As predicted, these antibodies all had a specific affinity for the spike protein.
Unexpectedly, however, a subset of these neutralizing antibodies bound to sites on the spike protein actually enhanced binding to ACE2. Here, antibody binding locked the spike protein in a molecular conformation typically seen in its "pre-binding" state.
Interestingly, while theoretically classed as neutralizers, these antibodies triggered the formation of cell fusions called syncytia—a phenomenon associated with extensive lung damage in patients with severe COVID-19 symptoms. "We show that stabilization of different Spike conformations leads to modulation of Spike-mediated membrane fusion with profound implications for COVID-19 pathology and immunity," wrote the authors.
Together, these and other findings as part of the study provide new guidelines for drug developers with therapeutic neutralizing antibodies in their pipelines, highlighting the importance of studying antibody binding on a structural level to predict their dynamics in vivo.