Blood from a couple who contracted SARS-CoV-2 in Wuhan, China, early in the outbreak has yielded potent antibodies that have neutralized the virus in the laboratory and protected animals from some effects of the infection. Researchers have also found that combining two of the antibodies may prevent the virus from developing resistance.
In January 2020, the couple traveled to Toronto, Canada, and developed what were among the earliest confirmed cases of COVID-19 in North America.
It can take years to isolate and develop antibodies as treatments, but a team led by scientists at Vanderbilt University Medical Center, in Nashville, TN, drew on recent technological advances to accelerate the process.
Before the pandemic, they developed a way to isolate antibodies and screen them for the ability to neutralize a virus, all within 78 days.
Spurred by the health emergency posed by COVID-19, they streamlined their technique further, until it took them just 35 days to isolate 70 monoclonal antibodies that neutralize SARS-CoV-2 from the couple’s blood samples.
Each monoclonal antibody is produced by a different line of memory B cells — a type of immune cell that “remembers” a particular protein sequence of the virus.
The researchers reported their work earlier this month in the journal Nature Medicine.
After working with 40 of the most effective antibodies, the researchers conducted a second set of studies, described in a paper now accepted for publication in Nature.
In these, they narrowed the field to several antibodies that target a part of the coronavirus’ characteristic spikes that allows it to invade host cells.
Scientists call this area the receptor-binding domain. In SARS-CoV-2, it locks onto a receptor, called ACE2, on the outer membrane of human cells.
An antibody that blocks the receptor-binding domain can, therefore, prevent the virus from entering cells and replicating.
Such an antibody could be produced in large quantities and injected into patients as a treatment. Alternately, a vaccine could provoke the immune system to produce the same antibody for itself, providing protection from future infection.
In their paper, the researchers write:
“Our work illustrates the promise of integrating recent technological advances for antibody discovery and helps to define the [receptor-binding domain of the spike protein] as a major site of vulnerability for vaccine design and therapeutic-antibody development. The most potent neutralizing human [monoclonal antibodies] isolated here also could serve as candidate biologics to prevent or treat SARS-CoV-2 infection.”
Two of the antibodies, which the researchers have labeled COV2-2196 and COV2-2130, recognize two sections of the receptor-binding domain that don’t overlap.
The scientists have shown that the two antibodies were able to bind simultaneously to the spike, neutralizing the virus “synergistically.” In other words, the antibodies were more potent in combination than they were individually.
The two antibodies, together and separately, protected mice from the worst effects of SARS-CoV-2 infection. The researchers observed that compared with untreated animals, these mice showed less weight loss, produced less of the virus, and had less lung inflammation.
Finally, the researchers demonstrated that either COV2-2196 or another neutralizing antibody that they identified, labeled COV2-2381, protected rhesus macaques from SARS-CoV-2 infection.
It is important to note that these antibodies have not yet been tested in humans.
Thanks to their newly streamlined technique for identifying the most potent neutralizing antibodies, however, the scientists were able to share their discovery with manufacturers within weeks.
In June 2020, the pharmaceutical company AstraZeneca signed a deal with Vanderbilt to develop two of the coronavirus-neutralizing antibodies for preventing and treating COVID-19.
A biotech startup company based in Nashville called IDBiologics struck a similar deal with the university to put some of the other antibodies through clinical trials.
Both companies plan to carry out clinical trials this summer.
In their Nature paper, the scientists note that other research groups have found that SARS-CoV-2 is able to evolve “escape mutations” to evade a single monoclonal antibody — but not two antibodies in combination.
They write that this reinforces the need to target different parts of the virus’s spike simultaneously, either through a vaccine or antibody “immunotherapy.”
“Rationally selected therapeutic cocktails like the one described here likely offer greater resistance to SARS-CoV-2 escape. These studies set the stage for preclinical evaluation and development of the identified [monoclonal antibodies] as candidates for use as COVID-19 immunotherapeutics in humans.”
