Why monoclonal antibodies are expensive and hard to make in the fight against COVID-19.

Vincent Gabrielle
Knoxville News Sentinel

Monoclonal antibody treatments have given new hope for those fighting COVID-19, and they've been intensely politicized as well.

Millions in the South, for example, rejected vaccination in favor of monoclonal antibody treatment should they become sick from the devastating delta wave.

But it's not that easy. The treatment is expensive, hard to make and works best when it's used in conjunction with vaccination. 

As hospitals filled and cases skyrocketed in the late summer, demand for monoclonal antibody surged and supplies became more scarce. Through the work of companies to quickly scale up production, the supply appears to be holding. 

More:Despite fears, Tennessee hasn't run low on monoclonal antibodies after all

While monoclonal antibody treatments are effective for some patients there's a lot of confusion about what they are and what they do. 

What is monoclonal antibody therapy?

When a patient undergoes monoclonal antibody therapy, they are infused with high concentrations of antibodies engineered to fight the coronavirus.

Regeneron and Ely Lily are pharmaceutical companies that have been given an FDA emergency use authorization for their cocktail of monoclonal antibodies. A third company, GlaxoSmithKline, has an FDA emergency use authorization for a single antibody infusion.  

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These therapies cost about $2,000 a dose, which includes only about a gram of each antibody. They're expensive, in part, because they aren't traditional chemical drugs. 

Each antibody takes months to identify, isolate and scale and thousands of gallons of nutrients to produce. 

The therapy can be injected with a needle or administered intravenously. 

What are antibodies?

Your body makes its own antibodies in response to infections. The main difference between a monoclonal antibody and your body’s antibodies is diversity.

Each antibody is like a unique key in search of a lock. Keys find their compatible locks, they bind to it, tagging it for the immune system to attack. Antibodies also “neutralize” viruses, preventing them from attaching to cells to infect them.

Dr. David Sullivan, an infectious disease physician at Johns Hopkins Hospital explained that antibody was about the third the size of the spike protein that the coronavirus uses to attach to human cells. "So you just have to have three or four (per spike protein) to prevent it from interacting with a cell. But if you have one antibody on one virus that virus is still going to be able to infect." 

During a COVID-19 infection, your body makes hundreds — if not thousands — of different antibodies each tuned to a different part of the virus. Each is made by a single, unique immune cell. No other immune cell, not even those that are closely related, can produce that exact antibody.

Antibodies are produced by the immune system to fight infection.

Over time, the most successful antibody-making cells edit their antibodies to be better fits while cloning themselves to increase their manufacturing power. This is like your body figuring by trial and error out which key fits a lock. 

Fundamentally, your body always makes more than one version of antibody against the same infectious agent. 

OK, so what are monoclonal antibodies? 

Unlike your body's natural spectrum response, monoclonal antibodies are grown in a lab from a single clone. That’s where the name “mono” comes from. The antibodies are all the same from clones of the same cell. 

The second difference is between monoclonal antibody and your own home-grown antibody is speed. You need several days to mount a natural antibody response, or fewer if you are vaccinated. But administered monoclonal antibodies start working immediately. 

"The first part of the disease is nothing more than the replication of SARS-COV2 in your nose," said Myron Cohen MD, director of the Institute for Global Health and Infectious Diseases at the University of North Carolina-Chapel Hill. "We are trying to check the disease in your nose before severe disease and death, and monoclonal can clearly do that."

How effective are monoclonal antibodies against COVID-19?

When a patient undergoes monoclonal antibody therapy, he or she is effectively getting a very small slice of someone else’s COVID-19 immune response. For that to work on a disease, you need lots more of that one artificial antibody than your body would normally make for itself.

Sullivan likened it to using water to put out a fire. 

"Vaccines are like a little bit of water on the matches beforehand. It doesn't take much to prevent a fire," he explained.

Boxes of Regeneron sit stacked on a table inside one of Tallahassee's monoclonal antibody distribution sites.

Monoclonal antibodies are like using a small amount of water to put out a lit match. Those drops will work on a match, but not on a big fire. 

As the infection gets worse, monoclonal antibodies are less and less effective. 

"If I put a cup of water on an actual fire, it doesn't do as much," he said.

How long do antibodies last? 

And unlike a vaccine, the impact of monoclonal antibodies are fairly short-lived. The body recycles antibodies constantly. Most antibodies have a half-life of roughly 20 days.

Unlike a vaccine, which trains your body to remember, monoclonal treatments do not produce memory. They work best as a rapid response for vulnerable people just after exposure — and in combination with vaccination. 

"Get the antibody to bind to the virus in the nose to reduce replication. Don't let it follow along and keep replicating and you're going to do OK," Cohen explained.

His study is showing results when high-risk people are treated with monoclonal antibodies just after testing positive. "The hospitalization rate is probably tenfold less than it would have been otherwise," he said. 

Why are monoclonal antibodies so hard to produce? 

Antibodies are expensive to produce because of the difficult process of isolating and quality testing thousands and thousands of candidates. This process can take up to a year and requires a lot of technical expertise. 

"You've got to go through validation: Does it block the disease?" said John Kenney, president and co-founder of Antibody Solutions, a contract research company specializing in monoclonal antibody development. "You might come up with many potential candidates." 

This process can involve checking donated human immune cells to see if they make good antibodies. It can also involve infecting mice that have been genetically modified to have a human immune system.

Regeneron confirmed to Knox News that they used both a humanized mouse process and patient samples to rapidly identify candidates. 

"One of the antibodies came from human survivor blood," wrote Regeneron spokesperson Tammy Allen an email to Knox News. "The other came from one of our special mice." 

Each candidate cell and antibody is stress-tested until the field is narrowed down. The cells need to produce a lot of antibody. The antibodies need to attach to the target of interest. 

"It takes about 3 to 6 months to discover the cell that's making a high number of the antibody you really want," Sullivan said. "Once you have it, you have to put it into a large bioreactor to feed the cells to have it make the protein (antibody)."

As the coronavirus mutates new antibodies need to be identified and scaled up. Larger companies maintain pools of candidates in the event this occurs. Regeneron confirmed to Knox News that they maintained a bank of candidates in case their current cocktail loses efficacy.

Why monoclonal antibodies so expensive? 

Sunni Williams, a registered nurse, fills syringes with Regeneron in Tallahassee last month.

Scaling up production is not simple. Antibody production is typically measured by  grams, not tons.

On average, it costs between $95 and $200 to manufacture a single gram of antibody. That cost does not include research, development or the cost of infusion into a patient.

The manufacturing cost is high because antibodies need to be built inside of mammalian cells to be kept alive. This means the cells need a body-temperature home, fluids, nutrients and cell-signaling molecules that say, “Yes, keep making antibodies.”

Each cell only makes so much each day. A single gram of antibody requires about a liter or more of expensive, nutrient-laced culture to produce. Although some processes can generate higher yields.

Monoclonal antibody drugs are seen at the Antibody Infusion Clinic at Vanderbilt University Medical Center on Friday, January 29, 2021 in Nashville, Tenn.

On the small scale, laboratories can spend thousands of dollars on grams of custom-built antibodies.

At the start of the pandemic, Regeneron had about 40,000 liters of bioreactor capacity per year. After a partnership with Roche, the company gained about 100,000 liters of new capacity. Unlike a smaller manufacturer, their process is able to deliver higher yields per liter.

Regeneron said that they had delivered nearly 2.65 million doses to the federal government this year meaning that this is enough to make roughly 9,700 doses a day, each containing slightly more than a gram of antibody. 

Scaling that up means building tank-sized reactors that are capable of circulating thousands of gallons of nutrient-balanced fluids to billions of cell clones every day. The tanks aren’t empty, either. The interiors are often multi-chambered and full of fibrous surfaces on which cells can grow. 

"You are talking about an apparatus the size of a tanker truck," Sullivan said. "And it's not just an empty bag. It has a lot of complex engineering." 

Kenney told Knox News that bioreactors are difficult to clean and are often designed to be used once and discarded. That means a part of the cost is constantly replacing bioreactors.

And don't forget antibodies must be purified and quality tested to ensure they're safe to give to patients.

More antibodies mean more lab space

Manufacturing and development restrictions are exacerbated each time new variant emerges. Manufacturers are forced to find new antibodies, or cocktails of multiple antibodies, that are effective. This is the reason why Regeneron and Ely Lilly use two antibody cocktails instead of one antibody.

"We purposefully employ a multi-antibody cocktail approach," Allen, the Regeneron spokesperson, said. "The risk of the combination losing efficacy is diminished since the virus would need to mutate in multiple, distinct locations to evade both antibodies."

Each antibody in the cocktail needs its own manufacturing and purification lines.

Not many laboratories have that capacity. Across the industry, there is simply more demand for antibodies for research, cancer treatment and niche disease treatment.

"The ecosystem right now is that you have a lot of smaller companies," Kenney said. "When it comes to producing a batch to treat everyone in the world that capacity is just not there."

Vaccines and monoclonal antibodies work best together

Experts say that, fundamentally, monoclonal antibody therapy and vaccines should be viewed as complementary approaches to the same problem. Vaccines are the first line of defense because they prevent infections from occurring.

Monoclonal antibodies are a therapy for vulnerable people who get sick after vaccination or cannot be vaccinated in the first place. They are intended as the second line of defense against COVID-19.

"They are trying to get ahead of an infection to give you a head start," Cohen said. 

Experts anticipate that, in the future, monoclonal antibody treatments will expand to encompass additional diseases. And demand stemming from the fight against COVID-19 will, over time, expand manufacturing over the long term. 

"We're in the beginning of a new era of infection," Cohen said. Progress is there, but vaccines are still best. "Monoclonal antibodies are not really going to compete at all with vaccines."

A previous version of this story included a misstatement about the size of antibodies. The size has been corrected.