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A study, published in Nature Communications, reports on a human monoclonal antibody that neutralizes SARS-CoV-2 (and SARS-CoV) in cell culture.
Professor Tony Carr, Professor Molecular Genetics in the Genome Damage and Stability Centre (GDSC) at the University of Sussex, said:
“This is an interesting scientifically robust report of an antibody that can reduce the infectivity of SARS-CoVID-2.
“The block to infectivity is entirely based on cell culture work, but the previous literature supports the proposal that this reagent should be explored further as a potential treatment.
“One interesting observation is that the antibody binding does not interfere directly with the binding of the virus to the ACE2 receptor, opening the possibility that it can be used in combination with other antibodies. While there is a long way to go before we know if this antibody could be therapeutically useful as a treatment, this is an important step forward.”
Dr Jane Osbourn OBE, Chief Scientific Officer at Therapeutics and BIA board member, said:
“The development of vaccines for COVID-19 is rightly getting focussed attention and this is a key route to providing protection to the population from SARS-COV2. However, not all people will be capable of mounting an effective active immune response to a vaccine and it is important to develop passive immune approaches, as additional options, to reduce the risk of infection in the elderly or immune compromised.
“To enable this the profiling of panels of SARS-CoV and SARS-CoV2 antibodies to be used as passive immune therapies, to complement vaccine approaches is building pace and providing important insights in to the mechanisms of viral neutralisation. The successful development of neutralising antibodies as treatments and prophylactics will depend on careful triage and selection of combinations of antibodies, which have the potential to synergise to enable easy dosing of patients and ensure that viral replication is blocked through different mechanisms to avoid resistance.
“The group here provide a clear and well characterisation example of such an antibody, 47D11, which binds to the SARS-COV2 in the conserved core of the receptor binding domain and has the potential to be used in combination with other antibodies recognising different parts of the virus, for example which block the viral spike protein binding to host cells. As such this antibody could be a valuable part of the future arsenal of options for development.”
Dr James Gill, Honorary Clinical Lecturer, Warwick Medical School, and Locum GP, said:
“Nature Communications this morning have declared a potential game changing discovery with regard to COVID19.
“The problem with viral infections is that we are exceptionally limited when it comes to treatments. People are aware of anti-viral medications, but the issue with medications such as these is they need to be started as soon as a patient develops an infection.
“If an antiviral is only started when the patient requires hospital admission then it’s a little bit like turning off the water mains after the house has already been flooded for a week. Yes you may have stopped the source of the flood, but the house has already been accruing damage for the past week. The fact that the ceiling is now caving, or in the case of the patient the lungs failing, is the most dangerous issue, rather than the water / virus itself.
“Thus antivirals often provide only a slight benefit, both due to their lateness of application, but also as they are not 100% effective in stopping further virus production in the body
“The Nature Communications team have found something which has the potential to be much more effective. An antibody to the virus which caused the 2003 SARS outbreak, which, due to the similarity with the related COVID-19 virus, is also able to neutralise the COVID-19 virus
“This is NOT a new treatment, but has the potential to allow the development of a new treatment protocol. Simply because we have found an antibody which neutralises a virus in a group of cells in a lab Petri dish doesn’t mean that we can expect the same response in patients, nor expect to see a positive change in a patient’s clinical condition – BUT this is certainly a very promising discovery, coming from a robust scientific approach, and should be viewed as a reason for optimism.”
Dr Simon Clarke, Associate Professor in Cellular Microbiology, University of Reading, said:
“The spike protein on the surface of coronavirus allows it to fuse with its human target cells. The researchers in this study have developed an antibody that binds to the spike and blocks virus entry into cells. Antibodies like this can be made in the lab instead of purified from people’s blood and could conceivably be used as a treatment for disease, but this has not yet been demonstrated. While it’s an interesting development, injecting people with antibodies is not without risk and it would need to undergo proper clinical trials.”
Dr Penny Ward, Visiting Professor in Pharmaceutical Medicine at Kings College London and Chair of the Education and Standards Committee of the Faculty of Pharmaceutical Medicine, said:
“In general yes, although no antibody developed using the Harbour mouse technology has yet to be approved in any indication.”
“In general yes; the study documents protection against infection of VERO6 cells by SARS CoV and SARS CoV2 virus in the presence of the antibody. It would have been significantly improved by documenting in vivo protection/therapeutic effect in an animal model.”
“We know that SARS CoV and SARS CoV2 share sequence homology in many viral proteins so it is not surprising that an antibody produced to a conserved region of the binding protein might be active against both coronaviruses. What is more surprising is that the antibody does not appear to reduce binding to the cell surface receptor, but rather to prevent direct cell to cell spread via syncytial formation. The authors have suggested that this may enable combination antibody therapy with an antibody directed against the receptor binding domain in future.”
“They have detected a novel antibody sequence which inhibits growth of SARS and COVID-19 coronaviruses in an in vitro assay. The antibody is a fully human antibody format IgG1 antibody developed using the transgenic Harbour Mouse system.”
“This was a standard assay set up in a laboratory which has significant experience with the methods used. They have reported results of either duplicate or triplicate assays and the narrow SD reported graphically suggests comparable results in each experiment. There was no variation in the design to explore incubation periods or to investigate application of antibody after transfection. Given the reported mechanism is by inhibition of direct transcellular spread, I would have liked to have seen a post infection application as part of the experimental design.”
“The work was done in cells. There are several animal models of COVID-19 infection and without having results from any in vivo studies, it is not possible to conclude that the product will be effective in vivo in humans. This potential would be greatly enhanced if antiviral effect was observed in an animal model. In addition, the binding data provided and the range of EC90s in the graphical displays suggest that high concentrations of the antibody may be required to be effective in vivo.”
“It is too early to say: it could be used both to prevent and treat infection however without studying this in an animal model, it is not clear which of these approaches might be most efficient.”
Professor Polly Roy OBE, FMedSci, Professor of Virology, London School of Hygiene & Tropical Medicine, said:
“Yes, it is a very good scientific paper with data that one can expect.”
“The data is very good and their conclusion is appropriate. This group is well known for their research in Coronaviruses.”
“Yes, very well, although it is a novel finding. “
“They detected a cross neutralizing antibody shared by both SARS-Cov and SARS-CoV 2 in the cell receptor binding portion of the spike but independent of receptor binding inhibition site. In other words, this site could be targeted for drug design in addition to the drugs that inhibit virus binding to the cell.”
“Nothing that I am aware of.”
“In the culture cells.”
“Possibly, but it is too early to say.”
Prof Gary McLean, Professor in Molecular Immunology, London Metropolitan University, said:
“These are synthetic antibodies from mice that contain human antibody genes that they had immunised previously with the SARS virus. First they identified one particular antibody that cross reacted with the SARS-CoV-2 and categorised this one further and showed it also neutralises SARS and SARS-CoV-2 pseudoviruses – not the native viruses, ones that have pieces of SARS in another virus backbone.
“Because it is not done in people and the antibody is not even found in people as far as we know there are limitations. However it is a nicely done study that could provide a potential biotherapeutic that could be used to treat Covid-19. The research also uncovers an important target site of both SARS and SARS-CoV-2 that antibodies can target and could potentially be used to help the vaccine approach.”
Prof Babak Javid, Principal Investigator, Tsinghua University School of Medicine, Beijing, and Consultant in Infectious Diseases at Cambridge University Hospitals, said:
“This is a very interesting study. One of the most widely touted experimental (though not yet proven) treatments for Covid is the use of convalescent plasma — i.e. blood products from patients that have recovered from Covid, to treat new patients. The scientific rationale is that convalescent plasma contains a mixture of antibodies that can neutralize the novel coronavirus SARS-CoV2, the cause of Covid. However, use of convalescent plasma is difficult to scale and make widely available as a treatment and has some potential safety concerns since it is a blood product. Therefore there has been intense scientific interest in identifying individual antibodies that can also neutralize SARS-CoV2. This is because we are able to manufacture large quantities of individual antibodies (known as monoclonal antibodies or mAbs) at scale as a pharmaceutical treatment for Covid. Monoclonal antibodies also don’t have the safety concerns of administering blood products. In fact, the current recommended treatment for Ebola is a ‘cocktail’ of several mAbs that neutralize the virus.
“Many academic labs and several pharmaceutical and biotech companies have already started the process of identifying mAbs that target SARS-CoV2 from patients recovered from Covid, and results from a few of these efforts have already been shared widely. The researchers in this study have taken a slightly different approach. They used a “humanized mouse” that made human-like antibodies, and injected these with a variety of purified “spike proteins” (which the virus uses to infect human cells) of various human coronaviruses including those that cause SARS and MERS as well as the common cold, but NOT SARS-CoV2, the cause of Covid [presumably because this part of the experiment was performed before Covid, but that is NOT explicitly stated in the paper, so it is only my conjecture]. This ‘immunisation’ resulted in production of neutralizing antibodies that target the spike protein, and the researchers purified 51 of these. They then proceed to test all 51 to see if they could neutralize SARS-CoV2, and 4/51 could. One of these 4 could prevent infection of cells with SARS-CoV2, as well as SARS-CoV (the cause of SARS).
“For all neutralizing mAbs that work for SARS-CoV2 currently under investigation, they all work in the same way: they prevent the virus binding to the receptor for the virus on human cells, ACE-2. However, importantly and intriguingly, when the researchers tested their mAb (which they called 47D11) to see if it worked in the same way, their data suggested that it did not, although they were unable to fully figure out the way it did neutralize the virus. The reason this is important is that if we are to use mAbs as a potential new therapy for Covid, we will probably need to make a ‘cocktail’ of 2 or 3 mAbs that neutralize the virus. It is likely that if the mAbs work in slightly different ways, that will be potentially a more potent and more effective treatment than if they all target and work via exactly the same mechanism.
“Although this research is in an early stage, it would be useful to see if adding 47D11 to other mAbs neutralizing SARS-CoV2 (that work via the other currently understood mechanism, i.e. prevention of binding to ACE-2) increases the potency of activity, especially in animal models. If so, this would suggest a path forward for making novel mAb cocktails as a potential treatment for Covid.”
https://www.nature.com/articles/s41467-020-16256-y
All our previous output on this subject can be seen at this weblink: www.sciencemediacentre.org/covid-19/
Declared interests
Dr Jane Osbourn: “Is leading a BIA antibody taskforce – looking at a potential therapeutic for COVID-19, still in very early stages at this point.”
Dr Penny Ward: “I am semi-retired, but I am owner/Director of PWG Consulting (Biopharma) Ltd a consulting firm advising companies on drug and device development. Until July 2019 I was Chief Medical Officer of Virion Biotherapeutics, which was a company developing broad spectrum RNA therapy for the treatment/prevention of respiratory virus infections.”
Prof Babak Javid: “I have colleagues at Tsinghua that have identified some of the other mAbs, but I am not personally involved in that work in any way.”
Prof Gary McLean: “No conflicts”
Dr Simon Clarke: “No conflicts”
Dr James Gill: “No conflicts”
Professor Polly Roy: “No conflicts”
Professor Tony Carr: “No conflicts”