In the race to develop a safe, effective treatment for COVID-19, biotech companies like Regeneron and Vir Biotechnology, led by Cornell alumni, have turned to antibodies — which are naturally created by the human immune system — as a form of therapeutic treatment.
But what are antibodies, and how can they be repurposed into drugs to help people recover from COVID-19?
Prof. Avery August, immunology, researches how the immune system responds to infection, and broke down each company’s approach to antibody treatments and why they might work as a treatment for the coronavirus.
Antibodies are proteins made by specific cells in the immune system. The immune system produces antibodies when it comes into contact with something foreign to the body and then tries to identify that molecule or pathogen for the future, August said. These antibodies are used to target and stop any infections.
“The antibodies are produced and then circulate in the blood, and act to protect you if you get exposed to that [foreign] thing again,” August said. Antibodies are also what an individual’s immune system produces in response to vaccines, which are dead or altered forms of a pathogen.
August noted that antibodies are especially useful because they can be collected from blood and used for antibody treatments.
Since antibodies are so large, they are difficult to chemically synthesize in a lab. So, antibodies produced for drug therapies are usually made by either bacteria or cell lines — both have been genetically engineered to produce antibodies, according to August. Often, these antibodies are integrated into a mixture, usually referred to as antibody cocktails, that can be used as a treatment for viral infections.
“They’re made in these huge vats where the cells are grown and…secrete the antibodies,” August said. “The [secreted] fluid is collected, and the antibodies are then purified from that fluid and packaged as drugs.”
August explained that since mice have an immune system similar to humans, scientists can utilize this similarity by exposing mice to a specific target, allowing the mice to develop an immune response, and then collecting the mice’s B cells.
B cells, or antibody-producing immune cells can then be grown in a culture, and antibodies specific to the desired target can be purified from the cells and used as a therapeutic.
However, this method of antibody production has one caveat.
“The problem with using antibodies from mice is that a mouse antibody is slightly different from a human antibody,” Avery said. “You can use [them] as a drug, but eventually, humans start to make an immune response against the mouse antibody. So it stops working.”
To overcome this hurdle, Regeneron and a few other biotech companies have genetically engineered mice to have a human immune system, so mice can directly produce human antibodies in response to a target.
According to Regeneron’s website, this is accomplished by replacing the genetic coding for a specific part of mouse antibodies with counterpart genes that are expressed in humans, allowing for the rapid and robust production of fully human antibodies.
Although this process of identifying, testing and producing antibodies as therapeutics can sometimes take years, Regeneron’s approach of using mice with human immune systems significantly accelerates the process because any identified antibodies can then be quickly converted into drugs for humans, August added.
“In the past…when we didn’t have these mice that have human immune systems, we had to generate the antibodies in mice, and then genetically engineer those antibodies so they look like human antibodies, which can take some time, and then make them into drugs,” August explained.
In developing treatments for COVID-19, Regeneron is currently selecting antibody candidates to test a mixture of two antibody treatments for human clinical studies. The studies are slated to begin by early summer. Regeneron is also currently conducting clinical trials to evaluate the use of its drug Kevzara in the potential treatment of critical COVID-19 patients based on clinical data from China.
Vir Biotechnology has a different approach to developing antibody treatments. Instead of combining two antibodies in a mixture, Vir is selecting one antibody candidate and modifying it to allow for the antibodies to last longer in the body and produce white blood cells, which can lead to long-term immunity. In the search for antibody candidates, Vir’s goal is to find “pan-coronavirus antibodies” that could work in most future coronavirus outbreaks.
Regeneron and Vir also adopted the approach of isolating antibodies from the blood of humans who have already recovered from COVID-19.
According to August, there are two reasons for collecting blood from recovered coronavirus patients. One reason is that antibodies can be purified from the blood of those individuals and then be used to treat other humans.
However, using antibodies from recovered coronavirus patients has its limits. This treatment method is extremely expensive and it takes approximately two to four donors to treat one person, August said.
The second reason is that since the blood from recovered COVID-19 patients contain the B cells producing antibodies against the virus, those B cells can be identified and purified from the blood. Antibodies can then be genetically engineered in the lab to produce a drug people can use.
Although costly, antibody treatments are still a key player in the search for a drug that can treat COVID-19.
Small-molecule drugs are cheaper to make and easier to administer in the form of pills, but run the risk of losing their effectiveness if the virus mutates, August said. Antibodies are more likely to provide effective, longer-term protection since they specifically target the non-mutating regions of the virus, but need to be administered through injections.
While the course of this pandemic is uncertain, there is promise in antibody treatments. Mixtures of antibodies, usually referred to as antibody cocktails, have been instrumental in combating viral infections and have been the focus of Ebola treatment research.