16th September 2020
New drug highly effective against SARS-CoV-2
Scientists at the University of Pittsburgh School of Medicine have isolated the smallest biological molecule to date that completely and specifically neutralises SARS-CoV-2, the virus that causes COVID-19.
This antibody component, which is 10 times smaller than a full-sized antibody, has been used to construct a drug – known as Ab8 – for potential use as a therapy against SARS-CoV-2.
Ab8 is highly effective at preventing and treating SARS-CoV-2 infection in mice and hamsters, according to a new study published in the journal Cell. Its tiny size not only increases its potential for diffusion in tissues to better neutralise the virus, but also makes it possible to administer the drug by alternative routes, including inhalation. Importantly, it does not bind to human cells – a good sign that it won’t have negative side effects in people.
“Ab8 not only has potential as therapy for COVID-19, but it also could be used to keep people from getting SARS-CoV-2 infections,” said co-author John Mellors, Distinguished Professor of Medicine at Pitt. “Antibodies of larger size have worked against other infectious diseases and have been well tolerated, giving us hope that it could be an effective treatment for patients with COVID-19 and for protection of those who have never had the infection and are not immune.”
The tiny antibody component is the variable, heavy chain (VH) domain of an immunoglobulin, which is a type of antibody found in the blood. It was found by “fishing” in a pool of more than 100 billion potential candidates using phages and the SARS-CoV-2 spike protein as “bait”. Ab8 is created when the VH domain is fused to part of the immunoglobulin tail region, adding the immune functions of a full-size antibody without the bulk.
Dimiter Dimitrov, Ph.D., senior author of the Cell publication and director of Pitt’s Center for Antibody Therapeutics, was one of the first to discover neutralising antibodies for the original SARS coronavirus in 2003. In the ensuing years, his team discovered potent antibodies against many other infectious diseases, including those caused by MERS-CoV, dengue, Hendra and Nipah viruses.
Clinical trials are testing convalescent plasma – which contains antibodies from people who already had COVID-19 – as a treatment for those battling the virus, but there isn’t enough plasma for those who might need it, and it isn’t proven to work.
In response to this challenge, Dimitrov and his team set out to isolate the gene for one or more antibodies that block the SARS-CoV-2 virus, which would allow for mass production. In February, they began sifting through large libraries of antibody components made using human blood samples and found multiple therapeutic antibody candidates, including Ab8, in record time.
Wei Li, Ph.D., sifted through antibody components and found multiple therapeutic candidates in record time.
Next, a team at the University of Texas Medical Branch (UTMB) in Galveston, Texas, tested Ab8 using SARS-CoV-2 on cells. At very low concentrations, Ab8 was found to completely block the virus from entering cells. They then tested it on live mice. Even at the lowest dose, Ab8 decreased by 10-fold the amount of infectious virus in those mice compared to their untreated counterparts. The same effect was seen in hamsters, during separate tests conducted by scientists at the University of Saskatchewan, Canada. Finally, a team at the University of British Columbia, also in Canada, uncovered the unique way Ab8 neutralises the virus so effectively by using sophisticated electron microscopic techniques, described in their journal paper.
“The COVID-19 pandemic is a global challenge facing humanity, but biomedical science and human ingenuity are likely to overcome it,” said Mellors. “We hope that the antibodies we have discovered will contribute to that triumph.”
Abound Bio – a newly formed company backed by the University of Pittsburgh Medical Center – has licensed Ab8 for worldwide development.
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