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Regeneron’s Antibody Cocktail Wants to Join the Immunotherapy Revolution

The innovative technology that allowed scientists to harness the power of antibodies in the struggle against disease is being tried against COVID-19 but it’s too early to claim victory

The name “Regeneron” has been in the news lately because their antibody cocktail was administered to Donald Trump when he was diagnosed with COVID-19, and there is hope that this experimental therapeutic (not yet approved by the Food and Drug Administration or FDA) might help treat hospitalized patients.

The use of lab-grown antibodies to treat diseases is not new; in fact, it’s part of a fantastic revolution that has taken place over the past twenty years as scientists have mobilized cutting-edge technology to turn a natural process into a precise medical intervention. And the best way to understand this revolution is to put you, dear reader, in the driver’s seat.

A crash course in antibody wrangling

Imagine you are a doctor and you have a patient in front of you infected with the coronavirus. They are not doing well. Normally, some of their white blood cells would be producing antibodies, these Y-shaped proteins that are tailor-made using a variety of genetic building blocks to recognize very specific parts of very specific microbes and thus attack these invaders. But maybe it’s too early for your patient to make these antibodies. Maybe their antibodies aren’t very good at recognizing parts of the coronavirus. Maybe they’ll never make these antibodies. So what if you could give them antibodies already configured to recognize and fight off the coronavirus?

To achieve this, you would traditionally have infected a laboratory animal with the coronavirus, waited for that animal’s white blood cells to produce antibodies, collected the blood, and extracted and purified the antibodies. You would know, of course, that not all of these antibodies are the same. Different white blood cells from the animal would have made slightly different antibodies against the coronavirus, and these antibodies will bind to slightly different bits of the virus. A lineage of identical white blood cells will produce antibody A against the coronavirus, while a different lineage of white blood cells will produce antibody B. Because the cells within a single lineage are identical, they are clones of each other. The antibodies made by these different clones are known as “polyclonal antibodies” (meaning “from many clones”). In their early days, therapies that relied on polyclonal antibodies would often trigger some undesirable immune responses in patients, so you look for a potentially safer alternative.

Ideally, you would want monoclonal antibodies: these are identical antibodies made from a single lineage of white blood cells. But you run into the problem of making enough of them. You can’t keep inoculating animals with the coronavirus and extracting the small amount of antibodies they have made. To scale up production, you need to take the cells that make these antibodies and grow them in the lab. The problem is that at a certain point, these precious cells stop dividing and die. You’re going to need to perform a bit of magic and figure out a way for them to escape death.

So you use a technique pioneered by George Köhler and César Milstein in 1975 (which earned them the Nobel Prize in Physiology or Medicine a decade later): you fuse the white blood cell that is making these antibodies with a cancer cell that has achieved immortality. The resulting product is called a hybridoma and it has the best of both worlds. It makes the antibodies you need and it doesn’t die. Fear not: the fact that a cancer cell is used in the process will not turn the antibodies into cancer-causing agents. That’s not how cancer works.

But now you run into another problem! A lot of the early experiments in harnessing therapeutic antibodies were done in mice because they are a common laboratory animal. So the white blood cell you are using comes from a mouse and the antibodies it makes are mouse antibodies. Superficially, an antibody is an antibody, but there are parts of a mouse antibody that the human immune system can recognize as foreign, and that would lead your patient to potentially develop systemic inflammation and a sort of allergic reaction against the mouse antibodies. To avoid that, you knock down your mouse’s immune system and you introduce in your mouse human cells that will essentially build a human immune system inside the animal. This allows the mouse to make so-called “humanized antibodies.” This is actually one half of the technology that Regeneron uses for its antibody cocktail against the coronavirus.

The other half is an antibody that comes from a human patient who survived COVID-19 and whose white blood cells were collected. The Regeneron cocktail thus consists of a humanized antibody from a mouse and a fully human antibody from a human patient, infused via an intravenous drip. The reason why the company chose this combination of two antibodies (instead of a single one) is that if one of the parts of the virus mutates and is no longer recognized by antibody A, another part of the virus will still be able to be recognized by antibody B (and there is basic laboratory research by Regeneron that provides evidence for this). It’s not unlike how HIV combination therapy is successful because it contains multiple drugs that attack the virus in different ways, thus reducing the risk of resistance. As to why a humanized mouse antibody was used when they had access to full human antibodies, it’s simply that they collected as many antibodies against the coronavirus as they could using both methods and proceeded to test them to find the best combination.

We do trials because we do not know the answer in advance

The technology described above to purify monoclonal antibodies and use them as a therapeutic is now widely used to treat diseases like cancer and autoimmune diseases. The first such therapy was approved in 2002 by the FDA, initially for use against rheumatoid arthritis. These therapeutic antibodies have to be infused in the body over the course of several hours or injected using a syringe or autoinjector, as the antibodies would otherwise be digested before reaching their target. Once inside the body, they bind to the molecule they were made to recognize and thus help stop a specific disease process, like an inflammation cascade that leads to psoriasis, for example.

Regeneron is not the only one working on a lab-grown antibody solution for patients hospitalized because of COVID: dozens of pharmaceutical companies, including Eli Lilly, have jumped on the bandwagon. And even though these types of therapeutics have been around for 20 years, we should not jump to the conclusion that they will work against the coronavirus. At the time of writing, Regeneron had not released its data on the clinical trials it has conducted on its antibody cocktail; all we have are press releases and basic research studies. Making antibodies for immunotherapy takes time and is expensive, and the price tag on these therapeutics is often several tens of thousands of dollars a year. It has also been reported that, especially when used against cancer, their benefits vary largely from one patient to the next. There might be biological markers that could predict if one patient would benefit more than another, but often these markers remain unknown.

Just because these antibodies are being tested in phase III clinical trials (the last phase before requesting approval to commercialize the product), it does not follow that these antibodies will succeed in these trials. In fact, over 21 monoclonal antibody therapies have failed in the past few years to clear the bar set by a phase III trial. A recent trial by Eli Lilly for its own anti-COVID antibody was paused due to a potential safety concern that needs to be investigated. These trials are not mere administrative hurdles; we do them because we do not know what the results will be in advance. And with Trump declaring the Regeneron cocktail he received (among many other interventions) a “cure,” he might have unwittingly made things harder for the company he owns stocks in. Phase III trials compare an experimental therapeutic against a placebo (or standard of care). When participants learn they might be receiving a placebo instead of Trump’s “cure,” they might think twice before signing on the dotted line. That’s the problem with blind enthusiasm. It can impede scientific research.

Take-home message:
- The modern clinical use of specific antibodies as treatments for diseases dates back 20 years
- White blood cells that produce the needed antibodies die at some point in the lab and are thus typically fused to a cancer cell that has achieved immortality so that they can be grown indefinitely
- Many pharmaceutical companies, including Regeneron, are testing specific antibodies and cocktails of antibodies to help treat patients hospitalized with COVID-19 but no data in humans has been released yet


@CrackedScience

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