Researchers at the University of Pittsburgh School of Medicine have discovered the fastest way to identify strong, inactivated human monoclonal antibodies against SARS-CoV-2, the virus that causes COVID-19.
The method – as well as a trio of successful animal studies on an antibody known as “Ab1” – is described today in Proceedings of the National Academy of Sciences. Ab1 is on track to start clinical trials in humans early next year.
At any given time, the human body contains up to 10 billion different types of antibodies. With samples from several hundred people, senior author Dimiter Dimitrov, Ph.D., Director of the Center for Antibody Treatment (CAT) of Pitt, and his team over the past few years have built many libraries containing a total of 1. trillion human antibodies. In such large numbers, the odds are that these libraries contain an effective antibody against any pathogen – the challenge is to correctly identify the antibodies in the libraries, which the Pitt team has mastered. .
“Creating a diverse antibody library is an art,” says co-author John Mellors, MD, head of infectious diseases at Pitt and UPMC. “Not everyone can do it. Dr. Dimitrov and his team not only identified potential therapies in record time, before most Americans knew that a pandemic was breaking out, but it was not in the past. By announcing their methods, they better prepare the world for the future of emerging diseases. “
In contrast, the main method used this year to identify antibodies that neutralize SARS-CoV-2 is to find patients who have recovered after COVID-19, isolating their cells to produce antibodies. fights viruses and extracts antibodies from those cells. A large number of antibodies must then be screened for antibodies that most closely bind to the virus, increasing the time for discovery. So while the Pitt team identified Ab1 in February, the large companies still haven’t had their monoclonal antibodies until late March or early April.
When Chinese scientists announced the genetic sequence of SARS-CoV-2 in January this year, Dimitrov’s team quickly created the viral receptor binding region – a part of the mutant protein attached to the cell. human cells – and use it as “primers” to migrate multiple libraries of monoclonal antibodies. Dimitrov decided to focus only on the receptor-binding region as a bait because his team were the first to identify it during the initial SARS outbreak in 2003 and showed that it was the most important part of the mutant protein. variable to attract strong neutralizing antibodies.
Like prospects trying to find gold in alluvial rivers during the Gold Rush in California, Dimitrov’s team tuned their libraries against the spike in protein receptor binding regions in February, quickly wash off useless antibodies and look for the most promising candidates, stop the virus. binds to the ACE2 receptor. The team achieved “gold” in just six days.
Ab1 is a fully human monoclonal antibody that neutralizes SARS-CoV-2 by binding tightly with the virus, preventing the virus from infecting human cells. In tests on hamsters, normal mice and mice genetically engineered to express the human ACE2 receptor – the entry point of SARS-CoV-2 into cells – Ab1 is highly effective in prevention and treatment. COVID-19 or analogue in animals. The Ab1 is currently in production and could be added to Operation Warp Speed or other human clinical trials as early as January 2021.
“The main difference between our quick ‘scan’ and the ‘screening’ procedure used by most companies this year to detect antibodies against SARS-CoV-2 is the scanning method. It is much faster than screening and we don’t have to wait for infected patients to recover and make antibodies, ”says Dimitrov.“ We found our monoclonal antibodies in less than a week on February, this confirmed the performance level of panning methods. This will save valuable time in giving antibody therapy the next time a deadly virus emerges. “
Last month, Mellors and Dimitrov announced the discovery of Ab8, a smaller but very powerful antibody isolated from their antibody library by Dr. Wei Li, assistant director of the Center for Resistance Therapy. Who also discovered Ab1. Ab8 is not grown as far as Ab1, but as a smaller molecule it can be injected subcutaneously or even via inhalation, which could make it more practical for widespread use.
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Wei Li et al. Rapid determination of a human antibody with high therapeutic and prophylactic efficacy in three animal models infected with SARS-CoV-2, Proceedings of the National Academy of Sciences (Year 2020). DOI: 10.1073 / pnas.2010197117
Provided by University of Pittsburgh
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