Enzolytics Inc (ENZC)

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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?

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.

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.

https://www.knoxnews.com/story/news/2021/10/04/monoclonal-antibodies-expensive-hard-manufacture-covid-coronavirus/5887418001/