In this feature, we look at the benefits of globally authorized monoclonal antibody treatments, along with some potential safety concerns and challenges in implementation.
As countries continue to roll out vaccines to prevent COVID-19 and achieve herd immunity, scientists continue to work on developing treatments for the disease.
Monoclonal antibodies gained media attention with the news in October 2020 that Donald Trump had received the experimental Regeneron antibody treatment. They have since progressed to allow more widespread use.
This article provides an overview of the current state of monoclonal antibodies for COVID-19 treatment.
Medical News Today also reached out to Dr. Jens Lundgren, an infectious disease specialist at the University of Copenhagen in Denmark, to provide expertise and comments throughout this article. Dr. Lundgren led a trial for the Eli Lilly and Company antibody and is a spokesperson for Regeneron.
The body’s immune system generates antibodies as a defense mechanism against unfamiliar molecules. The scientific term for such unfamiliar molecules is antigens. Molecules from bacteria and viruses can act as antigens, prompting the production of antibodies.
Antibodies bind to antigens. This tells specialized cells of the immune system to kill the invading pathogen.
The bodies of the majority of people who recover from COVID-19 produce antibodies to the SARS-CoV-2 virus. Scientists have found that these antibodies persist for at least 5–7 months after the infection.
However, scientists can also produce these antibodies in a laboratory setting to be infused into the blood.
Monoclonal antibodies are identical copies of an antibody that targets one specific antigen. Scientists can make monoclonal antibodies by exposing white blood cells to a particular antigen.
They can then select a single white blood cell or clone and use this as the basis to produce many identical cells, making many identical copies of the monoclonal antibody.
Each monoclonal antibody is specific to its matching antigen. For COVID-19, there are several authorized monoclonal antibody therapies.
The SARS-CoV-2 virus’s spike glycoprotein, which sits on its surface, functions to facilitate the virus’s entry into the body’s cells. Some SARS-CoV-2 antibodies bind to the spike protein and prevent the virus from entering the cell.
Currently, all the monoclonal antibodies for COVID-19 for which the FDA have issued emergency use authorization target the spike protein.
Bamlanivimab and etesevimab
On February 9, 2021, the FDA authorized the emergency use of combined bamlanivimab and etesevimab for people with mild-to-moderate COVID-19. The EMA are currently reviewing the data behind these antibodies.
“Given the sustained increase in SARS-CoV-2 viral variants in the United States that are resistant to bamlanivimab administered alone, and the availability of other authorized monoclonal antibody therapies that are expected to retain activity to these variants, the U.S. government, in coordination with Eli Lilly and Company, will stop the distribution of bamlanivimab.”
The FDA advise the use of alternative monoclonal treatments in light of the increase in the prevalence of SARS-CoV-2 variants against which bamlanivimab has shown reduced efficacy.
Eli Lilly and Company recently announced their phase 3 clinical trial data in a press release. They said that the combined bamlanivimab and etesevimab therapy reduced the risk of COVID-19 hospitalizations and death by 87% in people with mild-to-moderate symptoms at high risk of severe disease.
However, these beneficial results were in outpatients who were not experiencing severe COVID-19. Dr. Lundgren stated that Eli Lilly and Company are currently investigating the efficacy of these monoclonal antibodies in hospitalized patients through a National Institutes of Health (NIH)-sponsored inpatient clinical trial called ACTIV-3.
Initial results with bamlanivimab have not indicated any particular efficacy for inpatients.
REGN-COV2: Casirivimab and imdevimab
Regeneron developed a “combination antibody cocktail” called REGN-COV2, which contains the antibodies casirivimab and imdevimab.
On November 21, 2020, the FDA authorized the emergency use of REGN-COV2 for mild-to-moderate COVID-19. The EMA have concluded that healthcare professionals can use this treatment for COVID-19 patients at risk of developing severe disease but who do not require oxygen treatment. The agency will continue their rolling review to support national health authorities in European Union countries, who issue authorization for use individually.
The NIH, on the other hand, have stated that there is not enough evidence to support its use and that there is a need to review phase 3 trial data, which were released on March 23, 2021.
According to Regneron’s phase 3 clinical trial data, the combined casirivimab and imdevimab antibodies reduced the risk of COVID-19 hospitalizations and death by 70% in people with mild-to-moderate symptoms.
Like Eli Lilly and Company, Regeneron are conducting trials to test the efficacy of these antibodies in inpatients — particularly those who need oxygen or a mechanical ventilator as a result of COVID-19.
However, in October 2020, Regeneron received advice to halt enrollment for people on high flow oxygen or mechanical ventilators until further data had been collected. This was due to a possible safety risk. They are continuing enrollment for people receiving no or low flow oxygen.
There are concerns that the immune system may overreact in response to COVID-19 and lead to a cytokine storm, in which excessive amounts of inflammatory proteins called cytokines can cause life threatening levels of inflammation.
Interleukin 6 (IL-6) is a type of inflammatory cytokine. Antibodies that block this cytokine from binding to other cells may alleviate the danger of COVID-19-related inflammation.
The Russian biotechnology company BIOCAD developed the antibody levilimab (Ilsira) to prevent cytokine storm-related complications caused by COVID-19. The Russian Federation’s Ministry of Health approved its use for COVID-19 treatment on June 5, 2020.
According to Dmitry Morozov, BIOCAD’s general director, “The results of clinical trials of the drug, initiated on April 24, demonstrate that levilimab therapy can significantly reduce mortality among [people] with COVID-19 and the burden on the health system.”
However, the data supporting the use of levilimab have not been published.
This antibody has current approval from the FDA to treat rheumatologic disorders. Tocilizumab does not yet have authorization from the FDA to treat COVID-19.
The NIH, however, recommend these antibodies for hospitalized COVID-19 patients on the condition that healthcare professionals use them in conjunction with other treatments, such as dexamethasone.
These antibodies also work to prevent cytokine storms, but instead of targeting cytokines, they target specific molecules on the cell surface, or cluster of differentiation (CD) antigens, that are involved in regulating the immune response.
Indian biopharmaceutical company Biocon tested their anti-CD6 monoclonal therapy itolizumab as a treatment for COVID-19. The Drugs Controller General of India authorized the antibody for use in India in June 2020.
In contrast to the FDA-authorized antibodies for treating mild-to-moderate COVID-19, this antibody is intended for people with moderate-to-severe COVID-19.
Some physicians have raised concerns about Biocon’s small trial size of 30 participants, stating that it does not provide enough data to support the treatment’s efficacy. Regardless, the regulatory agency have deemed it safe and plan to continue studies to evaluate the evidence.
Healthcare professionals currently administer monoclonal antibodies via intravenous infusions in specialized medical facilities. As noted in the clinical trials, most of the treatments work most effectively for non-hospitalized patients in the early stages of COVID-19.
Currently, the FDA have authorized treatments for mild-to-moderate COVID-19 in patients at “high risk [of] progression to severe disease.” The FDA define this as meeting at least one of the following criteria:
- having a body mass index (BMI) equal to or greater than 35
- having chronic kidney disease, diabetes, or an immunosuppressive condition
- being older than 65 years
- being older than 55 years and having cardiovascular disease, hypertension, chronic obstructive pulmonary disease, or another chronic respiratory disease
- being aged 12–17 years and having a BMI equal to or greater than the 85th percentile for one’s age and sex (according to Centers for Disease Control and Prevention [CDC] clinical growth charts), sickle cell disease, heart disease, a neurodevelopmental disorder, medical-related technological dependence, asthma, or another chronic respiratory disease requiring daily medication
Both Eli Lilly and Company and Regeneron state that their combined antibody therapies may cause hypersensitivity reactions, with the most common side effects including infusion-related reactions and allergic reactions.
Infusion-related reactions include:
- chest pain
- difficulty breathing
- an irregular heartbeat
- low or high blood pressure
- throat pain
Allergic reactions include anaphylaxis.
If a person experiences any of these side effects, the companies recommend that the healthcare professional administering the treatment consider slowing or stopping the infusion and providing appropriate care.
There have been concerns that the use of monoclonal antibodies may cause antibody-dependent enhancement (ADE).
This occurs when the bound antibody further promotes, rather than prevents, the virus’s entry into cells. As a result, the virus can replicate more effectively within the cell.
So far, there is no evidence to suggest that COVID-19 monoclonal antibodies can cause this phenomenon.
This is also the case with similar risks. The bamlanivimab and etesevimab fact sheet notes that the antibodies could potentially weaken the body’s immune system against future infection, but no studies have examined this yet.
Newly emerging variants of SARS-CoV-2 — such as the ones that scientists first identified in the United Kingdom, South Africa, and Brazil — may be resistant to some of the currently available antibodies.
When a mutation changes the virus’s proteins, particularly the spike protein, it can result in a significant change in the viral antigen, making it harder for the antibody to bind.
The FDA are continuing to update their fact sheets to reflect the impact on the authorized antibodies, and they state that Regeneron’s combined antibodies continue to demonstrate efficacy against the most prominent variants.
“This demonstrates the power of combination antibody treatments, an approach we took from initial development, since we knew the virus was likely to evolve,” a spokesperson from Regeneron commented.
“This way, if one antibody loses potency, there is still an ‘insurance policy’ of the second antibody that binds in a different location to still block the virus from infecting healthy cells.”
Lack of global access
The high cost of mass-producing monoclonal antibodies, along with the complexities of implementation, make the treatment inaccessible to many low- and middle-income countries.
According to a report by the International AIDS Vaccine Initiative and Wellcome, a global charity that funds biomedical research, around 80% of all monoclonal antibody therapies — including those for cancer — are sold only in the U.S., Canada, and Europe. This leaves just 20% for the rest of the world’s population.
Monoclonal COVID-19 therapies are available mostly for free in the U.S. However, there are likely barriers to access in other countries.
Another key aspect of this treatment is that healthcare professionals must administer it at specialized medical facilities, such as hospitals or treatment centers, over multiple sessions in order to show benefit.
The pandemic and increased COVID-19 cases have heavily limited these resources, making it more difficult to distribute this treatment.
In the U.S., Regeneron state that they have “established best practices for setting up these separate spaces and training staff, while infusion time for REGEN-COV [REGN-COV2] has also been reduced to as low as 20 minutes.”
“Subcutaneous administration and lower doses are also being tested, which could further enhance convenience of administration in the future.”
The next few sections look at some alternative COVID-19 treatment options.
A clinical trial showed that treatment with remdesivir (Veklury) sped up recovery time in adults receiving hospital treatment for COVID-19 who showed signs of infection in their lower lungs. The drug reduced the time of hospitalization from an average of 15 to 10 days.
Most people who have recovered from COVID-19 have naturally produced antibodies in their plasma that can fight the SARS-CoV-2 virus. Scientists are continuing to assess whether or not this plasma can protect others from developing severe COVID-19.
These treatments have shown benefit in the treatment of COVID-19 in people who need to be in the hospital. However, they do not address the need for early intervention to prevent COVID-19 from progressing to severe disease.
Dr. Lundgren stated:
“The possible clinical benefits from monoclonal antibodies are exclusively observed in [people] prior to admission to the hospital and have been shown to reduce the risk of disease progression. Conversely, remdesivir and dexamethasone are established treatment[s] for hospitalized patients, but not for the […] group mentioned above.”
The most effective way to prevent COVID-19 is to get vaccinated and continue to adhere to non-pharmaceutical interventions, such as mask wearing and physical distancing. For those who develop COVID-19, more treatment options are gradually becoming available.
Monoclonal antibody treatments are most effective within a few days of receiving a COVID-19 diagnosis. If a person is experiencing COVID-19 symptoms and is part of a high risk group, they should speak with a healthcare professional about the available treatment options and whether one is appropriate for them.