The Hunt for Therapeutic Antibodies for COVID-19
With a vaccine still many months away, scientists are racing to engineer effective antibody treatments to quell the virus. Our Q&A with Charles River's Katherine Vousden.
With COVID-19 ravaging millions worldwide, doctors have tried giving their patients plasma from recovered people, which contains antibodies to the virus. While this is showing promise as a treatment, some researchers are exploring other ways of developing antibody treatments that are more potent, safer and sustainable than using fresh plasma.
One way is by isolating the antibody producing cells from the plasma of convalescent patients to find the handful that are producing antibodies that actually neutralize the virus. Such antibodies are valuable because they can inactivate the infectivity of SARS-CoV-2 by binding to the spike protein that enables it to enter human cells. Once found, these antibodies can be mass produced and used to treat or even prevent COVID-19.
Another strategy goes virtual. Researchers are employing computer software to mutate antibodies induced by the SARS virus—which is similar to SARS-Cov-2—into millions of variants. Scientists can then sort through this vast mutational space to find the best candidates against the COVID-19 virus.
Here is a Q&A that will hopefully help understand more how these engineered antibodies work and what their chances are of helping patients infected with SARS-CoV-2.
Q. Let’s start with the basics. What is a neutralizing antibody?
A. A neutralizing antibody is an antibody that not only binds to the target but also prevents it from performing its normal function. In the case of COVID-19, neutralizing antibodies are typically ones that bind to a protein on the viral outer coat (often referred to as the ‘spike protein’) in such a way as to prevent the virus from attaching to, and infecting, human cells.
Q: What are some of the ways neutralizing antibodies might be used in preventing COVID-19?
A. Antibodies can be used as an alternative to vaccines to prevent infection in high-risk groups. Vaccination works by injecting a non-infective version of the virus, or specific virus protein, so an individual is able to produce their own antibodies without actually getting sick. This means that antibodies are already available to neutralize the virus when a real infection occurs. For vaccination to work well however, the individual needs to have a healthy immune system— which often isn’t the case in some vulnerable groups. This is where administering antibodies instead of a vaccine can come in really useful—you’re no longer relying on your own immune system to mount an immune response to the virus as you’ve already been supplied with some ready-made ‘magic bullets’ to prevent infection. Antibodies can also be used prophylactically to give immediate, short-term immunity to those most at risk from catching it in the first place—such as health care workers.
Q. Are these neutralizing antibodies also useful in treating people infected with COVID-19?
A. Absolutely – in fact this is the main focus of most antibody research at the moment. Critically ill patients with COVID-19 require a medicine that can rapidly clear the virus and prevent any further damage being done. Antibodies not only neutralize the virus but also aid in its destruction and removal from the blood stream, making them ideal critical care medicines.
Q. What are some of the strategies companies are using to identify and isolate these therapeutic antibodies?
A. There are already a large number of anti-SARS-CoV-2 neutralizing antibodies at various stages of development across the world, and a variety of approaches to identify these antibodies have been successfully used. Antibodies have been extensively characterized from specific antibody expressing cells (B-cells) isolated from recovered patients, generated through immunizing mice with the key COVID-19 coat protein, or identified through other antibody isolation methods such as phage and yeast display. Another novel approach used by CRL’s antibody discovery partners, Distributed Bio, has been to take existing antibodies shown to neutralize SARS and MARS viruses from previous epidemics, and rationally bioengineer them using computational methods coupled with rapid in vitro display and screening techniques. These antibodies are currently being developed by Centivax, the therapeutic spin-out of Distributed Bio.
Q. So are these synthetic antibodies or naturally occurring antibodies?
A. The term ‘natural’ antibody is most often applied to those isolated directly from either human B-cells or through immunization strategies, with ‘synthetic’ applying to those antibodies that have come through an in vitro display route. However this distinction becomes a little blurred, as most antibodies that are intended for therapeutic application are generated recombinantly and have been engineered in some way, regardless of how they were initially isolated. Even antibodies that come from a ‘natural’ source may subsequently be altered to improve how well they neutralize, make them behave better during manufacture, change how long they stay around in the bloodstream for and even the type and strength of interaction they have with the immune system. The important thing is that any antibody isolation, engineering and manufacturing strategy keeps the antibody appearing as human/ natural as possible to avoid being identified as a threat by the immune system and triggering an immune response against itself.
Q. How effective are these engineered antibodies in combating COVID-19?
A. It’s too early to say if engineered antibodies will fulfil the hope of offering a way to combat, or protect against, COVID-19 infection, but data on those molecules that are progressing towards to the clinic is certainly promising. For example, in recent studies using Centivax’s lead antibodies in separate independent laboratories, hamsters could be successfully treated for COVID-19 infection -with an impressive 97 % reduction of virus detectable in the lungs of these animals. The antibodies were also able to prevent infection when given to both healthy and immune compromised hamsters before exposure to virus – so modelling the type of successful prophylactic administration required in those for whom a vaccine may be less effective.
Q. When might these engineered antibodies be reading for human trials?
A. The great news is that clinical trials have already started. At the time of writing there are four antibody-based anti-SARS-CoV2 studies initiated: Eli Lilly/ Junshi Biosciences (JS016), Eli Lilly/Abcellera (LY-CoV555), Tychan Pte Ltd (TY027) and Regeneron (REGN-COV2), with many others—including those being developed by Centivax—not far behind. As this is a rapidly evolving story, the Antibody Society’s coronavirus website is a great way to keep up to date: https://www.antibodysociety.org/coronavirus/
You can hear more about Distributed Bio’s antibody discovery and optimization technologies and the identification of Centivax’s lead anti-SARS-Cov2 molecules at an upcoming Webinar on 23rd July, 11 am ET.