S1E29 / A Magic Bullet? Monoclonal Antibodies / James Crowe

I'm Dr. Celine Gounder, and this is Epidemic. Today is Tuesday, June 16th.

The Shenley Laboratories, producer of penicillin Shenley and Shenley Pharmaceuticals, presents the Encore Theater.

Back in the 1940s, you could tune into radio dramas about the lives of famous medical scientists: Louis Pasteur, Florence Nightingale, and Paul Ehrlich.

The Encore Theater play tonight: Dr. Ehrlich's Magic Bullet.

Paul Ehrlich was a German scientist in the early 20th century. He worked with Dr. Emil Behring, the Nobel Prize-winning scientist who developed convalescent plasma, the treatment we talked about last Tuesday in our series of episodes on immunology.

Immunity is not a quality of the blood, but something in the blood, specific substances that are formed by the cells, a chemical army which destroys bacteria and poisons. I'm beginning to see what you're getting at.

This chemical army Ehrlich's talking about would end up being antibodies. Remember, convalescent plasma or serum is when you take blood from someone immune to a virus or bacteria and give their antibody-rich blood to another patient to help them fight off the disease. The play based on Ehrlich's life has everything: suspense, a trial would bring everything into the open.

It would be the finish of Ehrlich and his so-called specific science. Do you see them, Emil? Of course I see them. The red rod-like shapes are the tubercle bacilli. Anyone can see them now.

Even romance.

My dear, dear Mrs. Ehrlich, will you marry me?

My darling Dr. Ehrlich, of course I will.

But the reason we're talking about Paul Ehrlich is this other idea he came up with. The magic bullet. See, after Ehrlich helped Behring figure out convalescent plasma, he wanted to go a step further.

I believe it will be possible one day to manufacture immunity to disease in a test tube. Mold little magic bullets to shoot into the bloodstream and destroy invading microbes. And what disease are you specifically going after with this magic bullet? Syphilis.

It took him 10 years, but he finally figured it out. He came up with the first medical treatment for syphilis, and he'd go on to win his own Nobel Prize. Ehrlich had hoped to isolate those antibodies and turn those into magic bullets against syphilis. It didn't quite turn out that way. He used chemicals to cure syphilis, not antibodies. But there's new research going on today that has some saying Ehrlich's antibody magic bullet may be around the corner against COVID.

We have a very long history of being able to use animal or human plasma or serum and just move it from one animal or human to another to confer immunity.

This is James Crow, director of the Vaccine Center at Vanderbilt Medical Center. James and his team are working on a technique to manufacture immunity in a test tube, just like Ehrlich had dreamed of. And that starts by finding just the right antibody for a disease like COVID.

In the way that we're doing it with a single antibody or 2 or 3 antibodies, every molecule we're delivering is doing the job. It's more efficient and it's more reproducible. It's more predictable.

This week on Epidemic, we're discussing the next phase in antibody-based therapies, one that James is spearheading in his work at Vanderbilt. And then we're going to look at the next frontier, how science may soon take us beyond drug treatments. And into a realm where our bodies are programmed to defeat a virus before we've ever encountered it. A true magic bullet. Long before you ever get sick, your body's already full of antibodies.

Well, your body starts with millions of antibodies that have been generated genetically, uh, and You're sort of set up to be ready for almost anything, but the individual antibodies you have are not necessarily perfect or optimized for something that comes along.

They're like a standing army, always ready to attack. And then you get your first infection and—

Your body has an amazing ability to fire off tens of thousands, if not hundreds of thousands, of individual antibodies in response to an infection. The initial antibodies are allowed to mutate and become better.

In other parts of the body, cell mutation is dangerous. It can lead to cancer. But in the immune system, it's a good thing.

Your body allows the antibody genes to mutate, and when they mutate, you can see variants arise, variations on the original antibody that are a little bit better than the original one, and they'll be selected and persist, and then that can go on for multiple stages.

The antibodies get better and better with each wave.

And when I say better, it binds to the virus better, it binds tighter, it doesn't fall off. If it's doing that at the right place, that means it inhibits the virus better and becomes a better and better part of your response. And if we pull it out of the body, it becomes a better and better drug, essentially.

Scientists have long known that some antibodies are more important than others, but now we have the technology to figure out which, in all those millions of antibodies, are the most important for a given disease. It all starts with a blood sample. In this case, a sample from a recovered patient whose blood contains antibodies against the virus James is studying.

We may take a typical blood tube that you would give at your doctor or provider's office. We'll take a tube of blood like that and isolate the white blood cells.

Our bodies have white blood cells and red blood cells. White blood cells carry out the immune response.

There'll be 10 million of those cells in that tube, and that's a lot of cells to deal with.

And that's because, as we discussed in previous weeks, there are several aspects of the immune response, and there are soldiers ready to go at every stage.

And so within the white blood cells, there are many types of immune cells. You have cells that eat organisms or debris called macrophages. And you have cells that go around and kill cancer cells, and those are called natural killer cells. So they're roaming around looking for cancer cells to kill. And then you have what is called the adaptive immune system cells, which are the B cells and the T cells. And these are cells that respond to an infection, remember them, and then come back later in the memory response. And so T cells respond to antigens or parts of microorganisms that are being displayed on your cells, whereas the other type of adaptive immune cell called B cells are the ones that make antibodies.

Among the 10 million cells in a collected sample, these B cells are the ones that James's team is searching for.

Of the white blood cells, only about 5% of them are B cells. The ones that make antibodies.

And even within those, they need to continue narrowing the results.

And if we only take B cells, typically something like 1 in 10,000 or 1 in 100,000 of those B cells is specific for the virus that we're interested in.

Think about it like 10 million people singing at the same time. There's something in all that noise that has the answer you're looking for, but you can't hear it with all the other songs playing at the same time. But what if there was a way to cut through all that noise and find the signal you're looking for? So once you can finally hear that song, you can memorize it, and then you can sing it whenever you want. As many times as you want. Monoclonal antibodies are like that song—copies of that original antibody.

And more recently, we've been able to pull those out of the body, thousands at a time, and to use them individually as single antibodies, or what are known as monoclonal antibodies. And we can test them and figure out how well they inhibit the virus. Some don't work at all. Basically binding the virus but not inhibiting.

And others work incredibly well.

All the way to an antibody that will completely inhibit the infection at doses that are almost so low we can't measure them.

And this is where the new technology is speeding the process.

So using recently engineered devices, you can take a pool of cells, thousands or millions, run them into these devices, and the devices will segregate them out or deposit one cell into each compartment.

These devices are called microfluidic chambers.

And they're like little cups that hold one cell. And at that point, we have a single cell that makes a single antibody, and that's very powerful because that's what we're ultimately trying to do, is to find one or two antibodies that are the winners, that have the best activity. And that's been a major innovation that's allowed us to drill down and, and find the needle in the haystack.

Once James is able to isolate the individual cells to see what antibodies they produce, his team needs to study exactly what happens when these antibodies meet a virus. For that, they create a simulation. Viruses needle into cells in our body. Then they take over those cells and turn them into mini factories to make more and more virus.

So in your body, your body's composed of cells, and the virus enter those cells, make more of themselves, assemble, and come back out and start the cycle all over again. We can mimic that process in the lab by taking cells from a person that will grow in the lab forever in plastic or glass dishes. We can just use it over and over and over again and keep it going for years or decades.

To do this, they often use cancer cells. This is because cancer cells have the rare ability to replicate over and over again, sometimes forever. In the body, this infinite replication can kill someone.. But in the lab, this deadly trait can be harnessed to make lots of viruses and then test which antibodies are most effective against them.

We take an antibody that may inhibit the virus, we mix it with virus in a test tube and let it sit for an hour, and then we can sit there and watch them with video cameras or with other measurements and see what the individual cells are doing and the antibodies they're producing, and we can measure the antibody at a single-cell level in very, very small volumes. And if the antibody attaches and inactivates the virus, then when we put that mix onto a cell, like a cancer cell on a plastic dish, no more virus will come out. We just won't see anything happen. The virus will not replicate. And so that's called neutralization, where we're inhibiting the virus.

Basically, no new viruses means the antibodies are working. These are what we call neutralizing antibodies. They neutralize the threat.

But if we, we add an antibody and virus, wait an hour, and then put it on cells, and then the virus kills all the cells, then we know the antibody didn't work or did not neutralize. So that's the test we use to measure the activity, and it's sort of a simulation of a virus infecting your body. So we're treating cells instead of treating your body.

So now that James's team knows which antibodies work the best, they need to manufacture them. A lot of them.

We could try to take the cells out of your body and keep them alive in the laboratory and grow them and make more of them, but that's very challenging.

For this, his team relies on another recent technology called high-throughput next-generation sequencing. The name doesn't exactly roll off the tongue, but it's incredible technology. It was first developed as part of the Human Genome Project, and it makes it possible to rapidly sequence or decode millions or even billions of antibody genes.

When we do the sequencing, we get back a computer file that designates the letters either G, A, T, C, and these go on for hundreds or thousands of letters in a row. It's a code.

It's almost like computer code. Those letters A, C, T, G, they're the bytes that make up our DNA. Everything in our body is coded with those 4 letters. They're like the ones and zeros of computer code. Genes are chunks of DNA that are like recipes, telling the body how to make different proteins.

So in our case, the protein made by the gene is an antibody. So if we take a cell, a B cell making an antibody, and we get the antibody gene out, now we have the recipe. We can go to a manufacturing situation like a factory.

Once James's team has the genetic recipe for the antibody, They can send that recipe to a company that can manufacture as much of the gene sequences as they want. It's like a computer printer, only for DNA. This step is called synthetic genomics.

So you put the code in and out comes physical DNA, you know, the chemical DNA, and that DNA is essentially printed out with the code for that particular antibody. And so synthesizing the DNA is a very critical step, and that's only a a recent innovation that we could do that at scale. It used to be you could make 1 or 2 or 10 pretty slowly, but now there's techniques for making thousands of these at a time, and it speeds things up for us.

Kind of like a book printer making copies of a cookbook, these manufacturing facilities print out thousands of gene copies and ship them back to James's lab.

And we can put that gene into another cell that will grow forever This is where they use cancer cells, for example. And we can convert our producer cell in our lab into a cell that continually makes the one antibody that used to be in your body. And we get the antibody protein in the test tube that you used to make in your body.

Traditionally, the next step is to produce these monoclonal antibodies at scale.

Take the DNA we've synthesized that encodes an antibody and put it into a manufacturing cell in a factory and we grow those in a bioreactor. It looks like a big beer vat. These can be 10,000-liter reservoirs that are growing cells to produce this antibody. But that's a slow process, and developing those processes typically would take 2 years just for one antibody.

Sometimes we can't wait 2 years, like right now, for example. So what if we didn't need all these steps?

The fastest way would be to skip the whole manufacturing And what if we went right from the gene that we synthesize and put it directly in your body? You know how to manufacture a protein, that's what your body does all the time, and let your body be the bioreactor. Let your body take the gene and make the protein inside.

Your body does this with DNA and another part of the genetic code called RNA. So this tremendous scientific advance is really a way of kick-starting the body's natural process. It's sort of like James and his team are cheating the system, giving the body the answer key to a multiple-choice test. But in this case, that answer key is synthetic genetic code. The body doesn't have to figure out what antibodies will work. That synthetic genetic code tells it what to make.

That's one of the new frontiers. And in fact, we've already done a prototype experiment of this.

They did this experiment not long before the COVID outbreak when they were investigating a different virus with a company called Moderna. And the funding for that research came from an interesting place: the Pentagon's Defense Advanced Research Program, DARPA. DARPA is the government agency behind the development of stealth technology, GPS, and the precursor to the internet.

DARPA said, well, one of the problems is if an epidemic occurs, it takes 2 to 10 years to get a solution. That's too slow. And so DARPA put out a call, a grant call, and said, we want a solution from blood sample in a person who survived to injecting people to treat or prevent them 60 days later. That was, that was the goal. And you could say, that's crazy. That has never been done in history. And no one could do that. That's impossible. It's silly. They put out this challenge and we're one of the few sites that they chose as performer sites to work on moving very fast. So we've been pushing, pushing, pushing to get the technologies and pipelines strung together in a way where we can do antibody discovery within weeks. And I'm really proud of our group in that during the SARS-CoV-2 epidemic, we got finally a sample from a survivor who had a good number of B cells making antibodies to the virus. And we used our pipeline technologies, and 24 days later, we handed sequences to a manufacturing partner to make those antibodies. And they're being made for clinical trials this summer.

James's team compressed the discovery timeline down to days when it would normally have taken years.

So we made an antibody that was for a virus called chikungunya, which is an arthritis-causing virus. And we, we gave them that sequence. They made the RNA and they put that RNA into people. They injected it in their arm and the recipients made the antibody in their own bodies. And so It's sort of a temporary gene transfer, temporary gene therapy.

The gene doesn't last long. A week or two later, it's gone. But in those two weeks, your body has produced the necessary antibody.

That can theoretically be done very, very quickly. Could be done cheaply if the technologies evolve. And I think we're going to see more of that in the future. But the first-in-man experiment was with the chicken gunya antibody last year, and we were Really excited to be part of that and to show that it could work.

You might recognize the name of the pharmaceutical company that James worked with in this experiment. Moderna is currently working on an RNA-based vaccine for COVID. We talked a bit about the Moderna vaccine and others 2 weeks ago in episode 25. Moderna's vaccine was the first to be put into human trials, and in those trials, they're using very similar technology to what James is doing.

Exactly, it's the same idea. In that case, the RNA is encoding for the virus protein, and they put the RNA in your body, and your body makes the viral protein, and you essentially vaccinate yourself. So the virus protein is being made in you, and then you respond to it.

That's a vaccine use of RNA. What James is currently doing is a bit different. It would come in before vaccines are finalized.

In our case, we're trying to transfer an antibody from one person to another And it's actually a simpler idea because the recipient of an antibody RNA does not have to really respond to it. They just make it and they have instant immunity.

A vaccine can take weeks and sometimes months to generate an optimal immune response. Giving the body the code, the recipe, to make monoclonal antibodies before encountering a virus would speed that process.

But if we give the antibody gene, you know, theoretically 2 days later you have the immunity that you need. So it's a, it's a very exciting technology that I'd like to pursue more.

There are several ways monoclonal antibodies could be used.

One would be preventing completely before you're even exposed. So you could identify high-risk individuals like people who work in emergency rooms or that sort of scenario and give everyone the protection they need before they're exposed.

That could potentially be given to everyone in the country at the start of a second or third wave of transmission to keep it under control. The scientific term for this is prophylaxis, when a therapy is given to prevent an illness.

The next scenario might be what's called post-exposure prophylaxis. That's a scene where you go to an event and, um, you were not infected, but it turns out somebody at the event event with whom you stood and talked was infected at the time, but people did not know. Now you've been exposed. You may or may not be infected. If you are infected, you don't have symptoms yet. You have a very low-level infection.

In this case, you'd be treating the virus early, before it's had a chance to replicate in the body.

And then the third scenario would be we know someone's infected. They have symptoms and their PCR or antigen test is positive. So we know they have it. And we give it to stop them from progressing. So the goal is not really to cure the infection so much as to keep them where they are. So if they're mild disease, keep them mild, not even going to the hospital. If they're in the hospital, keep them out on the regular floor and not have to go to the ICU. And if they're in the ICU, keep them on oxygen and not have to go on a ventilator to support their breathing. Breathing. So you're just trying to stop the progression of disease. So those are all places where you could imagine using antibodies, and they're very interesting because they're so flexible. You can use them for treatment like you would a small molecule antiviral drug, but you could also use them for prevention like you would use a vaccine. So their poly-functionality is one of their most interesting attributes. You know, you have one substance that can many things.

But some researchers have doubts. They're concerned that if the body is dependent on these monoclonal antibodies, then it could blunt the natural immune response and leave people more vulnerable to future infection.

Theoretically, if you had an antibody that was so effective that you did not get any virus replication or just a wisp of infection in your body, you may not have enough exposure during that event to become immune yourself long-term.

But James isn't all that worried that antibodies would significantly blunt our natural immune response.

The reality is it's pretty difficult to completely blunt immune responses with any kind of treatment, an antiviral, including antibodies. So usually you have an immune response even though The antibody is reducing the amount of virus. It does not reduce it to zero. It reduces the amount of the virus, but not completely. The goal is to reduce symptoms, but not necessarily to try to get to zero virus. So I doubt that we'll see blunting, and if we did, it's a solvable problem. And he's especially not concerned about blunting in terms of COVID That would be an exceptionally good problem to have, in my opinion. If we had an antibody that worked so well you could not even become infected, we'll deal with the lack of long-term immunity from that exposure later because really later we're going to have vaccines and we'll induce long-term immunity with vaccines.

We've also heard researchers expressing concerns over something called antibody-dependent enhancement. This is when antibodies can actually make an infection worse.

Yes, so there are specialized cells in the white blood cells that I talked about earlier that have a receptor on their surface that grab antibodies and then pull those antibodies inside them. And the reason they're there is antibodies will tag a virus protein or a bacterial protein, and these other immune cells will grab the antibody. When they grab the antibody, they know they're also pulling in the virus or the bacterial antigen, and they sort of process it and then present it to other immune cells. So this is a good feature. That antibodies tag proteins and pull those materials in.

The problem is when this goes awry.

The problem is if the antibody tags, say, a virus but does not inhibit the virus, the virus is still able to replicate, then you're actually pulling more virus into those cells than if you just had no antibody at all. So theoretically, that would be a risk.

It doesn't happen often. Most of the evidence for antibody-dependent enhancement is with dengue fever, a mosquito-borne virus.

And for sure, we can see in dengue that you can get enhancement of growth in the lab. If you put the virus on cells, certain cells, you can make it grow better. Whether or not that happens in people's bodies is less clear.

Do you get antibody-dependent enhancement with COVID It's still being investigated.

If you take that type of thinking to coronavirus, there are some experiments that show in certain situations with animal coronaviruses in particular, you can get an antibody to make the virus grow better in vitro or even sometimes in animal models.

Animal models often inform our understanding of how a virus behaves in humans, but they can't tell us everything.

I think most experts don't think that's going to happen with coronavirus because the virus doesn't grow efficiently in these immune cells. And so if it gets dragged in, it's probably a dead end. I'm not certain about that. I think that's a very important area of research, and many people are looking at that right now, but it's probably not a critical issue, but it's one that needs to be addressed head-on.

We've surveyed a lot of different technologies and approaches to COVID these last few weeks, and like we've said before, there's likely going to be lots of solutions to this pandemic, not just one. Monoclonal antibodies might sound like a moonshot idea, but who knows? If it works, maybe there'll be a podcast drama about James and his team and their magic bullet.

For the rest of my life, I'm going to be thanking you, and so will all doctors and all people, not only in our time, but in all the times to come. You're an honor to your profession, your country, and your sense Epidemic is brought to you by Just Human Productions.

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