Two human neutralizing antibodies have been isolated that bind to the glycoprotein spike of the SARS-CoV-2 virus and thereby prevent the virus from entering host cells. Although the antibodies appear capable of working alone—each binds a different epitope on the spike’s receptor binding domain (RBD)—they may work better as a team, that is, if they are administered together in an antibody “cocktail.”

The new findings come from scientists in China affiliated with the Chinese Academy of Sciences (such as the Beijing Institutes of Life Science and the Tianjin Institute of Industrial Biotechnology) and other institutions in the nation. These scientists report that the antibodies—which are called B38 and H4—were isolated from a patient who recovered from COVID-19. The scientists also present results indicating that the antibodies block the SARS-CoV-2 spike from binding to the human ACE2 receptor.

Details appeared May 13 in the journal Science, in an article entitled, “A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2.”

“A competition assay indicates their different epitopes on the RBD, making them a potential virus-targeting mAb-pair to avoid immune escape in future clinical applications,” the article’s authors wrote. “Moreover, a therapeutic study in a mouse model validated that these antibodies can reduce virus titers in infected lungs.”

The results obtained with the mouse model suggest that the antibodies may offer therapeutic benefits. To understand how these benefits are achieved, the scientists carried out a structural analysis and generated images of RBD-B38 complex. This complex, the scientists determined, reveals that “most residues on the epitope overlap with the RBD-ACE2 binding interface, explaining the blocking effect and neutralizing capacity.” In other words, B38 binds to a subset of the amino acids bound by ACE2 in the RBD. This finding suggests why B38 confers such strong neutralizing effects.

To determine whether B38 and H4 target the same epitope, the scientists performed an epitope competition assay by bio-layer interferometry: “The Ni-NTA sensor labeled with the RBD was saturated with B38 IgG and H4 IgG was flowed through, or the sensor was first saturated with H4 IgG and B38 IgG was flowed through. Although RBD was saturated with the first antibody, the second antibody could still bind to RBD, but with some inhibition. This suggests that B38 and H4 recognize different epitopes on RBD with partial overlap.”

Consequently, the scientists suspect that B38 and H4 can each bind simultaneously to different epitopes on RBD such that both antibodies together may confer a stronger neutralizing effect than either antibody on its own—a prediction supported by in vitro experiments. This feature also means that, should one of the viral epitopes mutate in a way that prevents the binding of one of the two antibodies (a phenomenon known as immune escape), the other antibody may yet retain its neutralizing activity.

The authors of the current study propose that a “cocktail” containing both antibodies could provide prophylactic and direct therapeutic benefits for COVID-19 patients. They also assert that the new information regarding the viral spike epitopes could aid the development of small molecule antivirals and vaccine candidates to fight the SARS-CoV-2 virus.

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