In January, 2020, during the earliest days of the novel Coronavirus Disease-2019 (COVID-19) pandemic, a US-based research scientist was exposed to SARS-CoV-2, the virus responsible for the disease, at a family gathering in Beijing1. Recognizing the risk of infection, she quickly sought medical attention upon returning to the United States. By the time her test results came back positive several days later, she had largely recovered from a mild case of COVID-19.
Her scientific training led her to appreciate the potential benefits that could come from her illness. She provided samples of her blood for a research study lead by investigators from Vanderbilt University and AstraZeneca who were working to develop treatments for COVID-19. Within months, samples provided by this anonymous scientist helped to kick-start research in antibody-based treatments for COVID-19 that ultimately lead to an experimental antibody treatment received by US President Donald Trump.
Something Old Is New Again
The novel coronavirus that causes COVID-19 may be new, but the basis for the experimental antibody therapy developed by Regeneron Pharmaceuticals that was used to treat President Trump is far from new.
In 1890, Emil von Behring published research showing that processed blood from animals infected with diphtheria or tetanus could be used to treat other animals, and to prevent or cure the infections. Without fully appreciating the details of his discovery, von Behring laid the foundation for convalescent plasma as a therapy, which has been refined into the antibody treatment that is being used in patients with COVID-19. For his discovery Dr. von Behring was awarded the first Nobel Prize for Physiology or Medicine in 1901.
Filtering the Noise: The Development of Antibody Therapy
While the use of blood products from infected animals or patients as “serum therapy” can be effective treatments, immune-based side effects are common, so a more targeted approach is desired. Since the therapeutic effects of processed blood were first reported by Dr. von Behring, research has been undertaken to identify the elements responsible for the benefits of convalescent plasma. Among the leading candidates identified are antibodies produced by the body to fight off infection.
When the body is infected with a virus it triggers an immune response to target and remove the virus. A critical tool used by the immune system is a group of proteins called “antibodies”. Antibodies are produced by a type of white blood cell that originates in bone marrow, called B-cells2. Each B-cell is unique with specific proteins on its surface to recognize chemicals that are foreign to the body, such as those that are found on a virus.
Once the foreign compound – known as an “antigen” – is bound by the B-cell, the cell grows and divides, producing hundreds of millions of clones of the same cell3. Each B-cell makes and releases 10,000 antibodies into the blood every second. Because the antibodies originate from a single cell that divides and produces identical copies, these antibodies are known as “monoclonal” antibodies.
Symphony of Destruction
The immune response to an infection is a carefully choreographed cascade that ideally leads to the destruction of the foreign invader. In this system antibodies help to coordinate defensive efforts, acting like a symphony conductor.
Antigens on viruses attract antibodies which mark the infectious agent for destruction. The antibody tag may be detected by cells called macrophages and neutrophils which destroy the virus. In some cases, after ingesting the virus, macrophages retain parts of the virus on the surface of the cell and present the antigen to other immune cells to amplify the immune response. This process is called “antigen presentation”.
Neutralizing antibodies are a type of antibody that bind to a molecule on a virus and prevent it from infecting the cell, producing an effect called “sterilizing immunity”. Neutralizing antibodies have emerged as a possible therapy for COVID-19 patients, and are the basis for the Regeneron therapy – called REGN-COV2 – which has been widely publicized after it’s use by President Trump.
The Key to Infection
The antibody cocktail from Regeneron Pharmaceuticals consists of two different monoclonal antibodies that are specifically designed to bind to the spike protein on SARS-CoV2. The spike protein has long been a favourite target for coronavirus therapeutics because it is a key element in the virus infecting cells. In simple terms, the spike protein is the key that inserts into the lock of the cell and opens the door to allow the virus to enter.
Do the Regeneron Antibodies Work?
Lab-based and animal studies have laid the foundation for the Regeneron therapy. In the first study led by Drs. Johanna Hansen and Alina Baum from Regeneron Pharmaceuticals they screened blood samples from mice and humans exposed to SARS-CoV-2 and identified antibodies that bound to the spike protein4. In the follow-up study lead by Dr. Baum, the Regeneron group demonstrated that a combination of two antibodies was effective even as the virus evolved and mutated5.
The antibody cocktail developed by Regeneron is an experimental treatment because of the lack of conclusive data from clinical trials. Two clinical trials (NCT04426695 and NCT04425629) investigating the safety and efficacy of the cocktail are currently underway.
Although the findings are preliminary and have not been peer-reviewed by independent experts, Regeneron released the results from 275 patients enrolled in the clinical trials on September 29, 20206. In their report, Regeneron notes that 8 g of antibody cocktail, the highest dose given, reduced viral levels in patients in early infection whose immune system had not yet started effective production of antibodies. Patients whose immune system had been activated and those who received the lower dose (2.4 g) experienced fewer benefits in terms of reducing viral levels. There were no reported issues with safety in the early stages of these trials.
“Based on the data that has been made available about the therapy it appears the therapeutic has greatest benefit in those with the highest viral loads,” notes Dr. Krutika Kuppalli, an Assistant Professor in the Division of Infectious Diseases at the Medical University of South Carolina and an Emerging Leader in Biosecurity Fellow at the Johns Hopkins Center for Health Security.
According to Dr. Kuppalli the effectiveness of the treatment may be limited by the relatively narrow window that it may work in.
“The strength of the therapy is for those early on in their disease course. It is important to remember that many times patients don’t present to the hospital until they are quite ill and at that point the benefit of the therapeutic may not be that great since the inflammatory response has kicked in.”
Dr. Lynora Saxinger, the co-Chair of the COVID-19 Scientific Advisory Group to Alberta Health Services/Emergency Coordination Centre and an infectious disease specialist from the University of Alberta, is cautious about the limited results from the clinical trials.
“Promising results in early trials give a green light to study promising treatments, but to be honest, only 1 in 5 drugs in development make it through to licensure because they don’t work as well as they need to, or side effects or problems are found,” Dr. Saxinger says. “We can’t assume the usefulness of these based on current information.”
Confirmation of Concept
Prior to the announcement of the preliminary findings by Regeneron, Eli Lilly and Company reported preliminary data from the BLAZE-1 clinical trial using their own SARS-CoV2 neutralizing antibody that was developed in collaboration with the Canadian biotechnology company AbCellera7. Like Regeneron, the early findings from Eli Lilly were generally positive, with a reduction in viral load at the mid-range dose of 2.8 g. Interestingly both the low (0.7 g) and high (7 g) dose did not lower viral load in the BLAZE-1 trial. The reason for this unusual finding is not known.
Jury Is Out
The positive results from Regeneron and Eli Lilly both support the concept that monoclonal antibody therapies may benefit COVID-19 patients. While these findings may appear novel, antibody therapy has already enjoyed some success for the treatment of cancer8 and other infectious diseases like Ebola9.
Could therapies that have immune mechanisms work better than antiviral therapies? Dr. Kuppalli, who worked as a medical director of an Ebola Treatment Unit in Sierra Leone during the West African Ebola outbreak, points to the PALM randomized clinical trial that was performed during the 2018 Ebola outbreak in the Democratic Republic of Congo. The study looked at four different therapeutics, including the antibody therapies ZMapp, REGN-EB3, and mAb114, and the antiviral drug remdesivir. In the end the antibody cocktail developed by Regeneron Pharmaceuticals – REGN-EB3 – and the monoclonal antibody mAb114 created by the Vaccine Research Center proved most effective10, although the Ebola virus is a very different virus than SARS-CoV-2.
These studies support the concept of antibody therapy for COVID-19, but safety of these products, and their effectiveness in preventing or reducing severity of illness, remains unclear.
What Lies Ahead
Treatments that manipulate or mimic the immune response run the risk of triggering adverse reactions, ranging from a mild fever or rash, to trouble breathing and cardiac complications. Some therapeutic monoclonal antibodies have been reported to damage blood vessels which is of particular concern for conditions like COVID-19, which itself causes injury to the circulatory system.
Although the early results of COVID-19 monoclonal antibody clinical trials have not shown significant safety issues, a broader patient base with a range of disease severity is needed before these novel treatments can be declared safe. Finally, monoclonal antibody therapies are very expensive and difficult to make in large quantities so their possible impact will be limited by availability and cost.
“Prevention remains the cornerstone of protection from COVID-19,” points out Dr. Saxinger.
The treatment of President Trump has garnered significant attention for antibody therapies, but science is not determined by public relations or press releases. The fact remains that despite his standing as a global leader, President Trump is just a single patient.
It is also important to note that in addition to the Regeneron antibody therapy, President Trump’s medical team has acknowledged using a number of therapies including dexamethasone and remdesivir, both of which remain experimental treatments for COVID-19 patients.
“We need a randomized control trial,” says Dr. Kuppalli. “We need to look at the Regeneron therapy in comparison to remdesivir, dexamethasone, and any other therapeutics which may be considered for COVID-19. We also need to look at how combinations perform in comparison to monotherapy.”
The success or failure of antibody therapy for the treatment of COVID-19 patients will remain undetermined until science provides the definitive answer. And no amount of political spin can change that.
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- 6. Regeneron Pharmaceuticals Inc. Regeneron’s REGN-CoV2 Antibody Cocktail Reduced Viral Levels and Improved Symptoms in Non-Hospitalized COVID-19 Patients. September 29, 2020. Link here
- 7. Eli Lilly and Company. Lilly announces proof of concept data for neutralizing antibody LY-CoV555 in the COVID-19 outpatient setting. September 16, 2020. Link here
- 8. National Cancer Institute. Monoclonal Antibodies: How do monoclonal antibodies work against cancer? September 24, 2019. Link here
- 9. National Institutes of Health. Two drugs reduce risk of death from Ebola. December 10, 2019. Link here
- 10. Schindell B, Kindrachuk J, Kuppalli K. What the 2018 DRC Ebola Epidemic Taught Us About Outbreak Response and Experimental Countermeasures. Contagion Live: Infectious Diseases Today. April 14, 2020. Link here