M. Alejandra Tortorici works as a virologist at the Institut Pasteur, Paris, France. She is also visiting scientist at the Biochemistry Department, University of Washington, Seattle, USA. Dr Tortorici holds a Bachelor in Biological Sciences from the University of Buenos Aires, and a PhD from the University of La Plata. She carried out postdoctoral studies at the Institute of Allergy and Infectious Diseases at the National Institutes of Health, USA and at the Molecular and Structural Virology Laboratory CNRS-INRA, Gif-sur-Yvette, France. During her research career, she focused on human and animal virus pathogens, with the goal of better understanding their mechanism of entry into cells and replication in order to develop new and better treatments.
What are neutralising monoclonal antibodies and how are they produced?
Alejandra Tortorici: Neutralising antibodies are antibodies elicited upon natural infection that are capable of blocking the biological effect of a pathogen, for example a virus, and are therefore capable of reducing or stopping the disease caused by that pathogen. The human natural antibody response is polyclonal, which means it will generate antibodies that react against multiple targets present in the pathogen. Some of those antibodies are neutralising.
The spike (S) of SARS-CoV-2 is the main target of neutralising antibodies upon infection. In the laboratory, it is possible to isolate individual neutralising antibodies, each of them reactive against one specific region (or epitope) in S and each of them are characterised by a potency (or neutralisation capability). These antibodies can be recombinantly produced in the lab and they are called neutralising monoclonal antibodies (mAbs).
What evidence do we currently have of their efficacy against SARS CoV-2?
Alejandra Tortorici: Several papers, including our recent article in Science, have shown the efficacy of recombinant neutralising mAbs isolated from convalescent patients in vitro using pseudovirus assays or in vivo, using animal models. However, the best evidence of the efficacy of neutralising antibodies is that the majority of people infected with SARS-CoV-2 recover. This is in great part due to the action of the natural immune response which includes neutralising antibodies elicited during infection.
What studies are needed to fill gaps in our knowledge of SARS-CoV-2 neutralising mAbs responses? Studies of the onset and duration of virus shedding in affected patients are needed, but what else?
Alejandra Tortorici: We need to know how long the protection elicited by natural infection or by available vaccines will last. In addition, we need to understand the basis of different pathogenesis of COVID-19 in individuals of the same family (i.e. people with similar genetic backgrounds).
Could the antibody development programmes and the use of cocktails of neutralising mAbs reduce the emergence of viral mutations?
Alejandra Tortorici: Definitely. Cocktails of ultra-potent mAbs against different epitopes will be more effective at reducing the emergence of viral mutations than single antibody therapy.
Neutralising mAbs can be used both as a treatment and as a prevention. What are the likely optimal scenarios for therapeutic and prophylactic intervention using neutralising monoclonal antibodies against SARS CoV-2?
Alejandra Tortorici: Because of the high production and manufacturing costs, I would imagine that neutralising mAbs would be better used therapeutically, but this is not my area of expertise.
There are neutralising mAbs that are more effective and others that are less so. Recently, we have seen ‘ultra-potent human antibodies’ against SARS-CoV-2 being described. Can you give a bit more information about these?
Alejandra Tortorici: The lower the amount of a mAbs needed to reach the IC50, which is the amount of mAbs necessary to neutralise 50% of the virus, the better. Ultra-potent antibodies can neutralise SARS-CoV-2 at a significantly lower dose (one digit number of IC50) compared with other mAbs. Lower doses reduce costs of production and manufacturing.
Monoclonal antibodies are now an effective class of drugs in the pharmacopoeia, and can be used to treat a wide-range of indications such as arthritis and other inflammatory diseases, cancer and infectious diseases. Why have there been so few programmes for the production of antiviral mAbs so far, compared to other therapeutic areas? Is it linked to the fact that, at least until now, many viral infections do not have large markets?
Alejandra Tortorici: I think that could be a reason, since the cost of production of mAbs is high. However, I do not have specific information about this topic since this is not the area of my expertise. Recently (in October 2020), the US Food and Drug Administration (FDA) approved Inmazeb (atoltivimab, maftivimab, and odesivimab-ebgn), a mixture of three monoclonal antibodies, as the first FDA-approved treatment for Zaire ebolavirus (Ebola virus) infection in adult and paediatric patients. I am sure this will pave the way for further approvals of this kind of treatment.
Do you have any other closing thoughts to mention?
Alejandra Tortorici: Prophylactic and therapeutic use of neutralising mAbs could help during a pandemic before safe and efficient vaccines become available worldwide. In addition, they are a useful alternative for people who respond poorly to vaccination.