Researchers at Utrecht University, Erasmus Medical Center and Harbour BioMed (HBM) have identified a fully human monoclonal antibody that prevents SARS-CoV-2 from infecting cultured cells. Discovery of the antibody, which also neutralizes the related SARS-CoV coronavirus, represents an initial step towards developing a fully human antibody to treat or prevent COVID-19, and also potentially future diseases caused by viruses from the same coronavirus subgroup.
“This discovery provides a strong foundation for additional research to characterize this antibody and begin development as a potential COVID-19 treatment,” said Frank Grosveld, PhD. co-lead author on the study, Academy Professor of Cell Biology, Erasmus Medical Center, Rotterdam and Founding CSO at Harbour BioMed. “The antibody used in this work is ‘fully human,’ allowing development to proceed more rapidly and reducing the potential for immune-related side effects.”
Grosveld and colleagues report on the antibody in Nature Communications, in a paper titled, “A human monoclonal antibody blocking SARS-CoV-2 infection.”
Both SARS-CoV-2 and the SARS-CoV virus that emerged in 2002, belong to the Sarbecovirus subgenus of the Betacoronavirus family of coronaviruses. The two viruses crossed species barriers from an animal reservoir, and can cause life-threatening respiratory illness in humans. By May 4th 2020 there were more than 3.4 million confirmed cases of SARS-CoV-2 worldwide, and in excess of 230,000 deaths. The SARS-CoV strain caused ~8000 infections, with a lethality of 10%. There are currently no approved targeted therapeutics are available for COVID-19, the disease caused by SARS-CoV-2.
Monoclonal antibodies targeting “vulnerable sites” on viral surface proteins are increasingly recognized as a promising class of drugs against infectious diseases, and have shown therapeutic efficacy for a number of viruses, the authors wrote. Coronavirus-neutralizing antibodies primarily target the trimeric spike (S) glycoproteins on the coronavirus surface that mediate entry into host cells. The S protein has two functional subunits. The S1 subunit, which is composed of four core domains, S1A through to S1D, mediates attachment to the host cell. The S2 domain mediates fusion of the viral and cell membranes.
The spike proteins of SARS-CoV-2 and SARS-CoV share 77.5% identical amino acid sequence, and are structurally very similar, the investigators continued. They commonly bind the human angiotensin converting enzyme 2 (ACE2) protein as the host receptor. “Potent neutralizing antibodies often target the receptor interaction site in S1, disabling receptor interactions,” the authors continued.
For their reported antibody discovery effort, Grosveld and colleagues built on work that the groups had carried out on antibodies targeting SARS-CoV, explained co-lead author Berend-Jan Bosch, Associate Professor, Research leader at Utrecht University. “Using this collection of SARS-CoV antibodies, we identified an antibody that also neutralizes infection of SARS-CoV-2 in cultured cells.” The human antibody identified, 47D11, was generated using Harbour BioMed’s H2L2 transgenic mouse technology.
47D11 was shown to bind to cells expressing the full-length spike proteins of both SARS-CoV and SARS-CoV-2, and potently inhibited viral infection of cultured cells. Tests showed that the antibody targeted the S1B receptor-binding domain (RBD) of the spike proteins of both viruses. The fact that the antibody is cross-reactive indicates that it likely targets the conserved core structure of the S1B RBD, the investigators suggested. “Such a neutralizing antibody has potential to alter the course of infection in the infected host, support virus clearance or protect an uninfected individual that is exposed to the virus,” Bosch stated.
Interestingly, the team’s results suggested that 47D11 neutralizes SARS-CoV and SARS-CoV-2 through “a yet unknown mechanism” that is different from receptor-binding interference. “Alternative mechanisms of coronavirus neutralization by RBD-targeting antibodies have been reported including spike inactivation through antibody-induced destabilization of its prefusion structure, which may also apply for 47D11,” the team noted.
“In conclusion, this is the first report of a (human) monoclonal antibody that neutralizes SARS-CoV-2,” the concluded. “This antibody will be useful for development of antigen detection tests and serological assays targeting SARS-CoV-2 … this antibody—either alone or in combination—offers the potential to prevent and/or treat COVID-19, and possibly also other future emerging diseases in humans caused by viruses from the Sarbecovirus subgenus.”
“This is groundbreaking research,” said Jingsong Wang, PhD, founder, Chairman & Chief Executive Officer of HBM. “Much more work is needed to assess whether this antibody can protect or reduce the severity of disease in humans. We expect to advance development of the antibody with partners. We believe our technology can contribute to addressing this most urgent public health need and we are pursuing several other research avenues.”