Scientists Discover Fastest Way to Identify Potent, Neutralizing Human Monoclonal Antibodies Against SARS-CoV-2

With samples from a few hundred people, the Pitt team of scientists has built multiple libraries containing a total of one trillion human antibodies over the last several years. With such a large number, odds are that these libraries contain an effective antibody against any pathogen and the challenge in identifying the right antibodies in the libraries has been mastered by the team. In contrast, the major method used this year to identify antibodies that neutralize SARS-CoV-2 was to find patients who have recovered from COVID-19, isolate their cells that produce antibodies against the virus and extract the antibodies from those cells. Large numbers of antibodies then must be screened to find those that bind most tightly to the virus, which adds more time to the discovery process. So while the Pitt team had identified Ab1 back in February, major companies did not have their monoclonal antibodies until the end of March or early April.

When Chinese scientists published the genetic sequence for SARS-CoV-2 in January of this year, the Pitt team rapidly generated the virus’s receptor binding domain - part of the spike protein that attaches to human cells - and used it as “bait” to pan their multiple libraries of monoclonal antibodies. The scientists decided to focus only on the receptor binding domain as a bait because their team was the first to identify it during the original SARS outbreak in 2003 and show that it is the most important part of the spike protein to attract potent neutralizing antibodies. The Pitt team panned their libraries against the spike protein receptor binding domain in February, quickly washing away useless antibodies and homing in on the most promising candidates, which block the virus from binding to the ACE2 receptor. The team struck “gold” in just six days.

Ab1 is a fully human monoclonal antibody that neutralizes SARS-CoV-2 by tightly binding to the virus, preventing it from infecting human cells. In tests on hamsters, regular mice and mice genetically engineered to express the human ACE2 receptor - the entry point of SARS-CoV-2 into cells - Ab1 was highly effective at preventing and treating COVID-19 or its animal analogue. Ab1 currently is in production and could be added to Operation Warp Speed or other human clinical trials as early as January 2021.

“The main differences between our rapid ‘panning’ method and the ‘screening’ process used by most companies this year to discover antibodies against SARS-CoV-2 is that panning is much quicker than screening, and we don’t have to wait for infected patients to recover and make antibodies,” said senior author Dimiter Dimitrov, Ph.D., director of Pitt’s Center for Antibody Therapeutics (CAT). “We found our monoclonal antibody in under a week in February, which validated how well our panning methods work. This will save precious time in getting antibody therapy into people the next time a deadly virus emerges.”

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University of Pittsburgh School of Medicine