A Presidential Experiment: What are Monoclonal Antibodies?

When President Donald Trump was hospitalized with coronavirus disease 2019 (COVID-19), he received an experimental treatment that is still in clinical trials, including at UNC Medical Center in Chapel Hill.

Monoclonal antibody treatment uses antibodies manufactured in a laboratory that are designed to attached to the coronavirus to prevent it from entering into cells.

“This looks like a promising treatment approach,” says David A. Wohl, MD, who is one of the leads of COVID-19 treatment studies at UNC Medical Center. “But we need to complete our trials before we know how effective and safe monoclonal antibodies for COVID-19 might be, particularly for people who are sick but not yet hospitalized.”

Pharmaceutical company Eli Lilly reported this month that in an early phase trial its monoclonal antibody tended to reduce levels of SARS-CoV-2 (the coronavirus) in individuals with COVID-19. In addition, of the few participants in the study who needed medical attention at an emergency room or hospital, a greater proportion had received placebo, rather than the active drug. But these data are from a small study of 112 patients. Now, researchers are conducting a larger phase 2 and 3 clinical trial of this monoclonal in outpatients at UNC and other academic medical centers across the country. Dr. Wohl helps lead this federally funded trial. A separate trial of the same drug but in hospitalized patients has been paused while an independent monitoring board reviews the safety data.

Another company pursuing this approach is Regeneron, which created a cocktail containing two monoclonal antibodies. Like Eli Lilly, it has reported positive findings in an early study of its treatment, with reductions in the level of virus in the noses of those treated with the active drug compared to placebo.  This treatment is the one doctors at Walter Reed National Military Medical Center gave President Trump, along with several other medications.

But what are monoclonal antibodies exactly? And why might they be our best hope for a safe and effective treatment against SARS-CoV-2, if and when they become available to the general public?

How Antibodies Fight COVID-19

When we get an infection, various parts of our immune system fight against the invading pathogen. In the case of COVID-19, one part of the immune response is a neutralizing antibody, a protein the body makes that latches onto a piece of the notorious spike protein of this particular coronavirus. Once the antibody neutralizes the virus, other parts of the immune system swoop in to dispatch the virus. This general process is how people recover from COVID-19.

In the absence of a strong neutralizing antibody, the virus enters the body’s cells and replicates. The more this replication process is allowed to happen unhindered, the sicker an individual can get.

Convalescent plasma—the blood product taken from recovered COVID-19 patients—ideally also contains neutralizing antibodies against SARS-CoV-2. But this plasma can be somewhat of a ‘mixed bag’ as some people may make lots of antibodies that are very good at attaching to the virus while others may make few such antibodies. At present, there has not been a well conducted, large trial demonstrating a benefit of convalescent plasma for COVID-19.

The UNC Medical Center is studying whether plasma with a lot of neutralizing antibodies is a safe and more effective treatment than plasma with a lesser amount of antibodies. Still, it won’t be entirely clear that it was the antibodies in the plasma that made the treatment effective.

A More Targeted Antibody Treatment

“Monoclonal antibodies jump to the next step,” Dr. Wohl says. “Monoclonals can take the guess work out of whether this bag of plasma has the right antibodies or not.”

To design monoclonal antibodies for treatment for COVID-19, researchers can look at the antibodies made by survivors to see which seem particularly good at neutralizing the virus. Those that bind to SARS-CoV-2 spike protein on the surface of the virus can prevent the virus from entering and harming cells. Laboratories can make copies of the antibodies that work best. Each one of these antibodies—one, as in “mono”—is cloned many times in a lab. Thus, “monoclonal” antibodies are made with the idea that they could do in a person what they do in the lab, latch onto the coronavirus spike so that the spike cannot latch onto human cells.

More than a dozen pharmaceutical companies are pursing this approach, and the UNC Medical Center is one of many sites across the country enrolling participants in a clinical trial to determine the effectiveness of monoclonal antibodies and other therapies for people who are diagnosed with COVID-19 but are not hospitalized. The ACTIV-2 Trial is sponsored by the National Institutes of Health and Operation Warp Speed to coordinate COVID-19 research and speed development of the most promising treatments to reduce the time to recovery and prevent people from progressing to needing to be hospitalized. The ACTIV-2 Trial is leveraging the NIH’s AIDS Clinical Trials Group, which is experienced in the evaluation of treatments for patients.

The trial has launched an extensive outreach campaign to reach the many different people including Black, Indigenous, Hispanic, and other vulnerable populations disproportionately acquiring COVID-19. More information can be found at www.riseabovecovid.org .

“So far, from what we’ve seen, monoclonals do seem to have anti-viral effect in early phase studies,” Wohl says. “But we really have to study these in larger clinical trials. At UNC we’re studying monoclonal antibodies in early treatment of COVID-19, especially in outpatients because that’s when you really want to use a therapeutic, before someone is severely ill. By the time someone is hospitalized, you are rescuing them. And that will likely demand other, more aggressive approaches.”

Wohl says, that monoclonals are not just for treatment but also may be useful for prevention. He is a regional lead for a national study of the use of the monoclonal made by Eli Lilly in nursing homes where COVID-19 is breaking out. In this trial, residents and staff are recruited to see if administration of the monoclonal can prevent infection and spread of the virus. Other researchers at UNC are enrolling household members of those with COVID-19 for a similar study of the Regeneron cocktail.

UNC researchers also are conducting clinical trials for a COVID-19 vaccine.

Visit the COVID-19 Prevention Network to learn more about participating in a COVID-19 clinical trial. If you’ve tested positive for COVID-19 in the last five days, visit Rise Above COVID to learn about treatment studies.