Endocrine research spurs synthetic antibody development for COVID-19
A team of researchers at the Icahn School of Medicine at Mount Sinai, in collaboration with GenScript, are developing a synthetic antibody to SARS-CoV-2, the virus that causes COVID-19. This antibody is intended to block the virus from entering human lung cells, and, if successful in trials, could be a potential treatment option for patients infected with the novel coronavirus.
As Healio previously reported, endocrinologists are focusing on the mechanism of entry of the virus into cells — angiotensin-converting enzyme 2, or ACE2, which has been established as the COVID-19 receptor; however, data are conflicting regarding its translational relevance. Healio spoke with Mone Zaidi, MD, PhD, MACP, professor of endocrinology, diabetes and bone disease at the Icahn School of Medicine at Mount Sinai and director of the Mount Sinai Bone Program, about how a synthetic antibody could block a key COVID-19 protein from interacting with the ACE2 receptor, the timeline for human trials, and the important endocrine research in bone disease and obesity that led to this latest development.
How has your past research on a follicle-stimulating hormone antibody for bone loss and obesity led you and your colleagues to develop a potential artificial antibody treatment for COVID-19?
Zaidi: We are endocrinologists, but we also cross disciplines. One of the questions some years ago that we tackled was what are the mechanisms behind bone loss during the menopause transition? Through the SWAN study, it became clear to us that women were losing bone well before estrogen levels declined, during late perimenopause. This struck a chord with us — perhaps, follicle-stimulating hormone (FSH) levels, which are elevated during this time, were contributing to this bone loss. We have raised a number of antibodies which block FSH action and found that not only could we prevent bone loss by blocking FSH action in animal models, but that we also could increase bone formation.
More recently, we learned we could reduce body fat and increase thermogenesis. We also have evidence that blocking FSH lowers cholesterol. So, we could use one FSH blocking antibody to cure diseases that affect millions of people, men and women.
The antibody that we had developed was based on computational modeling using the crystal structure of the FSH receptor complex. We identified a binding site, modeled in mice. The idea was, if you could “cap” that binding site, FSH would not be able to access the receptor. Today we have a humanized monoclonal antibody that blocks FSH that we believe could be taken to people in about 18 months.
Over the years, we have become very interested in highly targeted blocking antibodies. When COVID-19 came to the forefront, I looked at some of the literature. I am not an infectious disease expert, but it is quite clear that convalescent plasma therapy, or the use of natural antibodies harvested from people who have survived COVID-19, indeed, has shown promise in treating this virus. Our goal was to develop a similar, but targeted, artificial antibody, which we hope will have the ability to disengage and block COVID-19 from entering our cells.
How would an artificial antibody for COVID-19 work?
Zaidi: Convalescent serum is antibodies that are made against the COVID protein, which then get transferred into other individuals to block the virus from infecting cells. The concept here, like the FSH antibody, is to somehow “cap” the major spike protein, or S1 protein, on the COVID-19 virus. The S1 protein attaches the virus to the ACE2 receptors, which are present on a variety of cells, including lung and gut cells. The idea is to prevent that very initial interaction between the S1 protein and the ACE2 receptor.
With the expertise we have in creating antibodies, I said, “Why are we not doing it?” Vaccines are preventive, but let’s look at the use of convalescent serum and what we would generally call passive immunization, that is, when a person is given someone else’s antibodies who was already sick with the virus. This type of work dates back to 1896, when there were similar discoveries for the diphtheria toxin. This concept of passively immunizing people using premade antibodies is more than 100 years old. That is exactly what we are doing. It has worked in treating Ebola virus as well.
The difference between us and others is that others are using whole COVID protein. We are going to be directing, in a highly targeted manner, that region of the COVID protein that binds to the ACE2 receptor so we can “cap” it, as we have done with FSH.
You and your colleagues are collaborating with GenScript to generate this synthetic human antibody. What are the first steps?
Zaidi: The initial step — modeling the crystal structure of COVID-19 — is already available, so, we don’t have to do that. We have a collaborator at University College London who has been working with us to define the binding regions. The selection of that binding region is important, because a protein is not a linear sequence. It is a three-dimensional structure. It is important to target the regions that are accessible. If there are amino acids that are buried within the protein, but are a part of the sequence, the antibody is never going to reach them. Those kinds of considerations have led to us clearly defining an antibody sequence — or perhaps more than one sequence — to raise the antibody against and then check whether that antibody binds to the intact protein.
Once we can do that, the first step is to create a custom version of the S1 spike protein peptide sequence, which will be used to generate the antibody. In a week or so, we should have the peptide sequence, through our collaboration with GenScript. They made our FSH antibody, and they are absolutely first class in this field. Once we give them the final sequence, they would start making their antibody, which should take about 8 weeks. Once we have the human antibody in our hands, which would be research grade, then the next step will be testing it.
How soon can we expect to see results from a human trial?
Zaidi: Our aim is to have a targeted antibody for the first human trials within the next 12 months, but it could be sooner if everything goes as planned. We are not virology experts, but there is a huge virology program here at Mount Sinai, headed by Peter Palese, PhD, professor and chair of microbiology, who is a member of the National Academy of Sciences. He has done flu and Ebola virus work. He has agreed to test this antibody. This effort really is interdisciplinary. We have used structural biology, antibody production facilities, our own ideas on testing, and then the viral testing in Dr. Palese’s lab. If we can do this in 6 months and start getting positive results, we would then move into large-scale production. That is when we would need people like National Institute of Allergy and Infectious Diseases Director Anthony S. Fauci, MD, to facilitate production. Then this could proceed to human trials.
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