University of Pittsburgh School of Medicine scientists have discovered the fastest way to identify strong, neutralizing human antibodies against SARS-CoV-2caused by a virus COVID-19.
The method – as well as a trio of successful animal studies on an antibody called “Ab1” – is described today (November 2, 2020) 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. With such a large number, the odds are that these libraries contain an effective antibody against any pathogen – the challenge is to correctly identify the antibody 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. Not only did Dr. Dimitrov and his team identify potential therapies in record time, before most Americans knew that a pandemic was breaking out, but by announcing their methods, even better prepared for the world for future 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 bind most closely to the virus, increasing the time for discovery. So while the Pitt group 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 a “primer” to migrate multiple libraries of monoclonal antibodies. Dimitrov decided to focus only on the receptor-binding region as bait because his team was 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, stopping the virus. binds to the ACE2 receptor. The team achieved “gold” in just six days.
Ab1 is a completely human monoclonal antibody that disables SARS-CoV-2 by binding closely 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 pan “method and the” screening “process 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 the infected patient to recover and produce antibodies, ”says Dimitrov. “We found our monoclonal antibody in less than a week in February, which has confirmed the activity level of the panning method. 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 Treatment Center. Antibodies, humans have also discovered Ab1. Ab8 does not go as far in development as Ab1, but as a smaller molecule it has the potential to be injected subcutaneously or even via inhalation, which could make it more practical for wide use. cobble.
Reference: “Rapid determination of a human antibody with high therapeutic and prophylactic efficacy in three animal models infected with SARS-CoV-2” by Wei Li, Chuan Chen, Aleksandra Drelich, David R. Martinez, Lisa E. Gralinski, Zehua Sun, Alexandra Schäfer, Swarali S. Kulkarni, Xerseyi Liu, Sarah R. Leist, Doncho V. Zhelev, Liyong Zhang, Ye-Jin Kim, Eric C. Peterson, Alex Conard, John W. Mellors, Chien -Te K. Tseng, Darryl Falzarano, Ralph S. Baric and Dimiter S. Dimitrov, November 2, 2020, Proceedings of the National Academy of Sciences.
DOI: 10.1073 / pnas.2010197117
Ab1 was assessed through a collaboration with Dr. Chien-Te Kent Tseng, at the University of Texas Medical Center (UTMB) for the Center for Biology and Emerging Diseases; Ralph Baric, Ph.D., at the University of North Carolina at Chapel Hill (UNC); and Darryl Falzarano, Ph.D., at the University of Saskatchewan.
Abound Bio, a start-up UPMC-backed company – co-founded by Mellors and Dimitrov – licensed Ab1 and Ab8 to develop worldwide.
Additional authors for this study are Chuan Chen, Ph.D., Zehua Sun, Ph.D., Xianglei Liu, MD, Ph.D., Doncho V. Zhelev, Ph.D., Liyong Zhang, Ph .D., And Dr. Ye-Jin Kim, all of Pitt; Aleksandra Drelich, Ph.D., of UTMB; David R. Martinez, Ph.D., Lisa E. Gralinski, Ph.D., Alexandra Schäfer, Ph.D., and Sarah R. Leist, Ph.D., all UNCs; Swarali S. Kulkarni, M.Sc., University of Saskatchewan; Eric C. Peterson, MS and Alex Conrad, MS, MBA, both of Abound Bio.