The SARS-CoV-2 virus that causes COVID-19 has killed 6 million people worldwide since 2019.
Researchers have now discovered a monoclonal antibody that potentially acts as a powerful universal coronavirus therapy once morest the COVID-19 virus and all its variants of concern, including delta and omicron. It also shows efficacy once morest the deadly coronaviruses SARS, the severe acute respiratory syndrome that emerged in China in 2002, and MERS, the Middle East respiratory syndrome that emerged in Saudi Arabia in 2012. It even shows efficacy once morest several cold coronaviruses. .
This universal activity results from the monoclonal antibody targeting a region of the viral spike protein that is highly conserved among beta-coronaviruses, but is also essential for the virus to attach and enter cells, leading to infection.
In animal experiments, the monoclonal antibody protected once morest infections when given as an intraperitoneal injection or nasal dose. The report is published on the non-peer-reviewed site BioRxiv by co-lead authors James J. Kobie, Ph.D., and Mark R. Walter, Ph.D., of the University of Alabama at Birmingham , and Luis Martinez-Sobrido, Ph.D., of the Texas Biomedical Research Institute, San Antonio, Texas.
The monoclonal antibody, and another monoclonal antibody discovered earlier by the researchers, are being developed as a therapeutic cocktail for COVID-19 under license from Aridis Pharmaceuticals, a California biopharmaceutical company.
The overall goal of researchers at UAB, Texas Biomedical and Aridis is to find antibodies that do not allow immune evasion by mutated variants of SARS-CoV-2, the virus that causes COVID-19. This includes Omicron and all future variants of concern. It is hoped that identifying and studying these antibodies can lead to the development of vaccines that protect once morest all coronaviruses.
“SARS-CoV-2 marks the third time in the past two decades that a beta-coronavirus has caused significant human mortality,” Kobie said. “SARS-CoV-2 has caused the most infections and deaths worldwide. New variants pose the risk of evading the immune system – even in vaccinated and previously infected people – and there remains the possibility that other genetically distinct coronaviruses will emerge as new pandemic strains in the future. »
Vaccines and other monoclonal antibodies once morest SARS-CoV-2 have largely focused on the receptor binding domain, or RBD, located at the head of the spikes that project from the surface of the SARS-CoV-2 virus. Each virus has 24 to 40 spikes. The RBD is very good at eliciting an immune response, but this part of the spike allows for many mutations that can let the virus evade antibodies.
One of the keys to the current research was to find an antibody target on a part of the tip called S2 or the stalk region. This region is highly conserved and only rarely mutates as this would disrupt its essential function. After the spike-head RBD attaches the coronavirus to a receptor molecule on the surface of a target cell, the S2 stalk acts to bring the virus inside the target cell. There, the virus replicates, killing the cell and releasing a horde of new infectious virions.
The search for useful antibodies began with the screening of blood samples from recovering adult patients at UAB Hospital through the UAB COVID Enterprise Biodepot led by Paul Goepfert, MD, and Nathaniel Erdmann, MD, Ph.D., UAB Division of Infectious Diseases. Memory B cells in the blood that bound to custom S2 protein baits developed by Walter and engineered to mimic the natural state of the spike’s S2 domain were used to create a panel of unique cells capable of producing monoclonal antibodies humans, or hmAbs, which then might be tested for effectiveness once morest the virus. Memory cells targeting S2 are rare because the RBD is immunodominant; its various antigenic sites represent 90% of the neutralizing activity of convalescent plasma.
Seventeen hmAbs showed binding to the S2 protein. Only four of them were able to neutralize a SARS-CoV-2 pseudovirus and live SARS-CoV-2, including the beta and omicron variants.
The top performer, 1249A8 hmAb, had the broadest and most potent neutralizing activity, once morest strains that included the original Wuhan, China, SARS-CoV-2, omicron variant, SARS and MERS, and two cold viruses.
hmAb protected mice once morest SARS-CoV-2 disease, as measured by body weight maintenance and virus clearance from mouse lungs four days post-infection. Additionally, 1249A8 hmAb showed synergy when used in combination with 1213H7, another hmAb discovered by the researchers. 1213H7 is active once morest spike RBD.
The 1249A8, 1213H7 cocktail – when administered nasally, 12 hours following infections with SARS-CoV-2 Delta or the first SARS virus isolated in 2002 – had broad therapeutic activity in hamsters.
“Many SARS-CoV-2 RBD-specific hmAbs have been approved for clinical use,” Kobie said. “But unfortunately, several have become useless with their inability to neutralize worrying variants, including Omicron, highlighting the perilous future of RBD-only mAb therapies once morest coronaviruses. »
“The ability of 1249A8, given as a single dose, to attenuate SARS-CoV-2 pathology and viral load once morest all variants of concern tested when used prophylactically or therapeutically, as well as the added benefit of combine with a broad and potent RBD-specific hmAb, substantiate its clinical potential. »
Aridis uses both hmAbs in its AR-701 cocktail designed for administration by inhalation. AR-701 is designed for long-acting efficacy, lasting a year or more when used in humans.
