LA JOLLA, Calif. — Last year, scientists from Scripps Research and Toscana Life Sciences studied the blood of 14 COVID-19 survivors to find the strongest antibodies against the SARS-CoV-2 virus. One of the key molecules that emerged – now in stage II/III trials in Italy – was an antibody called J08, which appeared to be able to both prevent and treat COVID-19.
Now the same group – a collaboration between scientists from Scripps Research and in Italy and France – has visualized exactly how J08 binds to different variants of SARS-CoV-2 in different conformations, explaining what makes the monoclonal antibody so powerful. The research, published in Proceedings of the National Academy of Sciences, suggests that the J08 antibody, due to its flexibility, is likely to remain effective against future variants of COVID-19.
“While we can’t predict which variants of COVID-19 will emerge next, understanding the details of J08 reveals what works against the virus, and perhaps how we can engineer antibodies to be even more potent,” says lead author Andrew Ward, PhD, professor of integrative structural and computational biology at Scripps Research.
When a person is exposed to a virus like SARS-CoV-2, their body generates a variety of antibodies that bind to different sections of the virus to eliminate it from the body. Scientists designing vaccines and treatments for COVID-19 are interested in what makes some of these naturally produced antibodies, like J08, more effective than others. In the months since Ward and his collaborators first identified J08, it became clear that the antibody, unlike many others, was potent against a variety of COVID-19 variants.
In the new work, the researchers determined the three-dimensional structure of J08 as it binds to the SARS-CoV-2 spike protein. They confirmed that J08 successfully attached to the Alpha, Beta, Gamma, and Delta variants and neutralized the viruses, preventing them from replicating. However, J08 attached to the Omicron variant about 7 times slower and then quickly detached. About 4,000 times more D08 were needed to completely neutralize Omicron SARS-CoV-2 compared to other variants.
“With variants other than Omicron, this antibody binds quickly and does not detach for hours and hours,” says co-first author Gabriel Ozorowski, principal investigator in Scripps Research’s Ward Laboratory. “With Omicron, we were initially happy to see that it still binds, but it falls off very quickly. We have identified the two structural changes that are causing this.
The team showed that, for all variants, J08 binds to a very small section of the virus, a section that generally remains the same even when the virus mutates. Additionally, J08 could attach in two completely different orientations, like a key that manages to unlock a door whether it’s right side up or upside down.
“This small, flexible footprint is part of why J08 is able to resist so many mutations – they don’t impact antibody binding unless they’re in this very small part of the virus,” says co-first author Jonathan Torres, Head of Scripps Research’s Ward Laboratory.
The Omicron variant of SARS-CoV-2, however, had two mutations (called E484A and Q493H) that changed the small area of the virus that interfaces directly with J08, anchoring it in place. Ward and his collaborators found that if only one of these mutations is present, J08 still manages to bind and strongly neutralize the virus, but mutations in both are what make it less effective against the Omicron variant.
The researchers say the new results support continued clinical trials of the J08-based monoclonal antibody.
“I think we’re pretty confident that future variants won’t necessarily have these two critical mutations at the same time like Omicron,” Ozorowski says, “which gives us hope that J08 will continue to be very effective.”
In addition to Torres, Ozorowski, and Ward, authors of the study, “Structural insights into a highly potent pan-neutralizing SARS-CoV-2 human monoclonal antibody,” include Hejun Liu, Jeffrey Copps, and Ian Wilson of Scripps Research; Emanuele Andreano, Noemi Manganaro, Elisa Pantano, Ida Paciello, Piero Pileri, Claudia Sala and Rino Rappuoli from Fondazione Toscana Life Sciences; Giulia Piccini and Emanuele Montomoli from VisMederi; Lorena Donnici, Matteo Conti and Raffaele De Francesco from the Istituto Nazionale Genetica Molecolare (INGM); and Cyril Planchais, Delphine Planas, Timothée Bruel, Hugo Mouquet and Olivier Schwartz from the Institut Pasteur.
This work was supported by funding from Toscana Life Sciences, through European Research Council (ERC) Advanced Grant Agreement Number 787552 (vAMRes), the Horizon 2020 Research and Innovation Program of the European Union (653316), Italian Ministry of Health (COVID-2020 -12371817), Institut Pasteur, Institut Pasteur COVID-19 Emergency Funding Campaign, ANRS, Vaccine Research Institute (ANR-10- LABX-77), Labex IBEID (ANR-10-LABX-62-IBEID), ANR/FRM Flash Covid PROTEO-SARS-CoV-2, IDISCOVR and the Bill & Melinda Gates Foundation (OPP1170236/INV-004923).
About Scripps Research
Scripps Research is an independent, nonprofit biomedical institute ranked the world’s most influential for impact on innovation by the Nature Index. We advance human health through profound discoveries that address pressing medical concerns around the world. Our drug discovery and development division, Calibr, works hand-in-hand with scientists from all disciplines to bring new drugs to patients as quickly and efficiently as possible, while teams at the Scripps Research Translational Institute harness genomics , digital medicine and advanced computing to understand individual health and make healthcare more efficient. Scripps Research also trains the next generation of top scientists at our Skaggs Graduate School, consistently named one of America’s Top 10 Chemistry and Biological Sciences programs. Learn more at www.scripps.edu.