Researchers at Washington University School of Medicine (WUSM) in St. Louis recently completed a study demonstrating that antibody effector functions represent an important underlying element in the effective treatment of COVID-19 infections. Importantly, of the nine treatments and therapies presently authorized for emergency use in the United States three are derived from monoclonal antibodies, that is those lab-produced antibodies designed to neutralize SARS-CoV-2, the virus behind COVID-19. The treatments are designed to augment or make up for deficiencies in the particular patient’s immune response, producing stronger and more antibodies to resist and overcome COVID-19. But how do these antibodies actually interact with the patient’s immune system during a COVID-19 infection, and even thereafter? Recently, a team from this prestigious St. Louis-based academic medical centers wondered whether these very new investigational products could better understand this question: did these antibodies affect, that is, the triggering of myriad immune cells to support or hurt the body’s effort to wrestle control of the disease? In more scientific terms, what were the monoclonal antibody products’ impact on effector functions? As it turns out, the WUSM St. Louis study team, led by senior author Michael S. Diamond, MD, PhD, found that antibody effector functions actually represent a vital contribution to successfully treating SARS-CoV-2 but as WUSM St. Louis science writer Tamara Bhandari conveys the team found them also to be dispensable when these antibodies are harnessed to inhibit infection.
In a study recently published online in journal Cell, the recent findings here in St. Louis may just provide the intellectual framework to help drug developers not only improve but continuously optimize advanced antibody-based therapies targeting SARS-CoV-2, the virus behind COVID-19. These updates were recently shared in WUSM St. Louis’ News Hub.
What is the Key Finding?
According to lead author Michael S. Diamond, the Herbert S. Gasser Professor of Medicine, this study is of particular importance because due to the pandemic conditions, the makers of these investigational products (e.g. Lilly, Regeneron et al) needed to get effective products in the clinic as soon as possible. Professor Diamond commented that, “Some of the companies removed the effector functions from their antibodies, and other companies are trying to optimize the effector functions.”
But what’s interesting is that the pharmaceutical companies didn’t make these decisions based on substantial data in connection with COVID-19 shared Diamond with Ms. Bhandari. The WUSM investigator summarized that, “Based on our findings, if you have a potentially neutralizing antibody without effector functions and you give it before infection, as a preventive, it will probably work. But if you give it after infection, it won’t work well; you need to optimize effector functions to get maximal benefit.”
What are antibodies in the first place and why are they important?
Also known as immunoglobulin (Ig), the antibody is actually a large, Y-shaped protein harnessed by the immune system to identify and neutralize foreign objects from virus to bacteria in the continuous battle for survival of life. The antibody serves to not only recognize but also act upon molecules associated with a pathogen called an antigen. Each tip of the antibody contains what is known as a paratope which can be thought of as a lock that is designed for one particular epitope (like a key) on the antigen itself. This facilitates the binding of these two entities in a precise way— leading to a sort of tagging of the microbe or what is actually an infected cell for attack by other parts of the person’s immune system. Conversely, the event can lead to the antibody directly neutralizing the pathogen, such as the blocking part of the virus that is key for its successful invasion into other parts of the body.
So once antibodies bind to their specific antigens they apply two main strategies to deal with the antigen. First and foremost, again they serve to block the SARS-CoV-2 pathogen from entering the host cell, which is referred to as “neutralization.”
Now the second strategy involves the recruiting of effector cells and molecules to terminate the pathogen. The main mechanisms associated with this second prong of the antibody strategy include 1) opsonization, 2) complement activation, and 3) ADCC.
How can this process go wrong?
Bhandari with WUSM St. Louis describes that this antibody and antigen interaction can trigger a chain of events that can lead to what unfortunately can become worsening viral infections. Known as “antibody-dependent enhancement,” she shares “interactions between the long arm of antibodies and immune cells can worsen some viral infections, notably infections with the tropical dengue virus. People who have antibodies against one strain of dengue virus are at risk of developing life-threatening dengue fever if they become infected with another strain of the virus” as an example.
How did the monoclonal antibody developers such as Lilly, Regeneron and others deal with this risk?
Interestingly they appeared to have taken opposite approaches when planning in their design and drug development engineering how to avoid the hazards associated with antibody-dependent enhancement. Some drug developers actually modified the sequences in the long arm of the antibodies in an effort to impede interaction with immune cells. While other groups sought to actually bolster antibody effector functions in an outright effort to strengthen force of their monoclonal antibody therapy.
On a quest to better understand the role of antibody effector functions in the context of SARS-CoV-2, the study team established a baseline antibody highly successful at identifying and neutralizing SARS-CoV-2 wrote Bhandari.
They rendered the antibody’s long arm ineffective (not able to stimulate immune cells) so inhibit the antibody’s effector functions.
Then using mice they set up three groups or cohorts including 1) one arm involving the original or 2) the modified SARS-CoV-2 antibodies or 3) a placebo that couldn’t recognize the novel coronavirus. A day before the mice were intentionally infected with the coronavirus the scientists administered the antibodies to the animal subjects.
Interestingly, the monoclonal antibodies administered to the mice a day before protected the animals from infection—it didn’t matter whether antibodies’ effector functions were modified or not. Regardless of monoclonal antibodies, those mice in groups one and two were less impacted by the virus than those mice that were in group 3 (placebo).
The WUSM St. Louis-led team also found that with dissipation of effector function comes changes in not only the type of immune cells triggered to bind to the antigen but also associated behaviors.
Did the WUSM find any indication of antibody-dependent enhancement of disease?
What about post infection? Were there differences?
Yes. As it turns out, the group of mice that received the modified SARS-CoV-2 antibodies (one without effector) were not protected against the coronavirus while the group that received the original unmodified antibody was in fact protected against the virus.
Did the team verify in other experiments?
Yes, WUSM’s Bhandari reports that the team went on to validate these findings, using various antibodies including and precluding effector functions and with different species (hamster). They reproduced the results leading to the conclusion that “Effector functions are an indispensable part of the effective antibody treatment for COVID-19.”
What are the implications for these findings?
The pharmaceutical companies that develop these drugs consider different treatment cases. For example, in cases where they seek to develop pre-exposure prophylaxis (PreP or preventive) such as AstraZeneca’s AZD7442 trial (NCT04625725) based on these WUSM St. Louis findings it may not matter that the effector functions were modified.
However, in cases where that very same investigational therapy is evaluated for use post infection, such as in the clinical trial (NCT04625972) involving post exposure prophylaxis (PEP), the goal is to treat the patient after infection. In these cases, the WUSM St. Louis study findings indicate that according to Professor Diamond as conveyed by Bhandari “…optimizing antibody effector functions could be the key to making a powerful drug.”
What groups funded this study?
∙ National Institutes of Health (NIH)
∙ Defense Advanced Research Project Agency (DARPA)
∙ Fast Grants from the Mercatus Center
∙ George Mason University
∙ The Dolly Parton COVID-19 Research Fund
∙ Future Insight Prize
∙ Helen Hay Whitney Foundation postdoctoral fellowship
∙ University of Georgia
∙ Washington University
About WUSM St. Louis
Washington University School of Medicine’s 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.
Michael S. Diamond, MD, PhD, professor of molecular microbiology, pathology & immunology
James E. Crowe Jr., MD, Vanderbilt University Medical Center
To see the rest of the authors, visit the source.