A company’s quest for antibody drugs to fight COVID-19

When COVID-19 struck New York City on Saturday afternoon, March, twelve scientists were anxiously swarming around computers in a suburban pharmaceutical company’s lab. Over the course of weeks, they desperately took blood from early survivors and mice with a human-like immune system around the world to test thousands of potential treatments.

It was time for the results.

The screen flashed a total of hundreds or thousands of glowing green dots for most samples. Then they saw some 10, some 2, and finally zero.

The researchers cheered and the boss sent out for champagne.

The absence of dots means that there are no infected cells. Scientists have discovered an antibody that blocks the coronavirus.

This was the beginning of a drug that would eventually bring the US President and others to fight COVID-19.

Antibodies are substances that help the immune system bind to the virus and eliminate it, but it takes several weeks after infection or vaccination to form the most effective antibody. Drugs such as those developed by these scientists at Regeneron Pharmaceuticals Inc. aim to be immediately helpful with a concentrated dose of one or two of the most effective antibodies.

Drugs administered by IV have been tested to prevent infection in people at high risk of not being vaccinated yet, such as those living with COVID-19 patients. It is also being tried as a treatment immediately after infection to avoid serious illness.

They are some of the most complex drugs that exist, are made in a tedious and high-tech process, and are at risk of ruin at every stage. Antibodies are derived from living cells, unlike chemicals that are simply mixed in the laboratory. Companies use zoo-wide cells such as monkeys, hamsters, mice, horses, cows, and llamas.

Each drug begins with one coronavirus survivor.

For example, Eli Lilly collaborated with Ab Cellera, a Canadian company that obtained strong antibodies from early Canadian cases. GlaxoSmithKline and VirBiotechnology found one in the blood frozen for years at a Swiss laboratory in survivors of SARS, another coronavirus that caused a fatal outbreak in 2003.

Regeneron’s two-antibody drug is unique. One is from Singapore’s COVID-19 survivors and the other is from the company’s genetically modified mice.

People make hundreds or thousands of antibodies after infection, but “most of them aren’t very good at blocking coronaviruses,” said Christos Kyratsous, a microbiologist who led Regeneron’s research. .. “You are looking for a needle in a haystack,” he said.

The quest began in January when Chinese scientists identified a new virus. Dr. Sumati Shivaparasingham, a Regeneron scientist who worked at the US Centers for Disease Control and Prevention, began looking for blood samples from people infected early, long before they could make good antibodies.

“We were essentially calling people all over the world” — China, Thailand, the United Kingdom, Europe — unlucky, she said.

Suddenly, they received a call from Dr. David Lai of the National Center for Infectious Diseases, Singapore. He knew that Regeneron had antibodies to a similar coronavirus disease, Middle East Respiratory Syndrome or MERS. According to Lai, the number of cases of COVID-19 is starting to increase, and “I was thinking about what else to do” because no effective treatment has yet been shown.

Scientists immediately ruled out the use of MERS antibodies, but agreed to look for new viruses. Rye asked three of his patients, two men and a woman who had recovered from COVID-19 pneumonia, to give blood.

It was dangerous. Blood cells survive for about two days and fly to New York in 18 hours. The sample must then pass through customs and be sent to Regeneron’s lab in Tarrytown, NY.

“It was exciting,” Lai said was horrifying. “I was worried that flight delays and mistakes along the way could make the sample useless.”

According to Shiva Parasingham, when the courier rushed to Singapore Airport, “blood is warm in the tube.”

COVID-19 arrived on March 13, the day the United States declared a national emergency. Sivapalasingam worked late at home when he received an email from a colleague in the lab.

“They were jumping up for joy because the cells were fresh, viable and perfect,” she said.

Others, meanwhile, have worked with animals raised to have a human-like immune system, which Regeneron’s CEO calls “magic mice.” When vaccinated with some of the viruses, they don’t get sick, but they make “almost the same antibodies that humans make,” Kyratsous said. Of these mice, it takes only 20-30 to develop the drug.

B cells are contained in the blood of mice and patients, and each makes a specific antibody that is carried to its surface. The goal is to find antibodies that attach to the virus and prevent it from infecting cells.

Scientists first screen B cells by mixing some of the pointed proteins that cover the virus with B cells and screening the cells with the antibody that connects them. Researchers then decipher the genetic recipe for each antibody. The gene grows very rapidly and mass-produces selected antibodies, such as mini-biofactory, so it is placed in a type of hamster cell that is widely used in the pharmaceutical industry.

Next, there is a big challenge. Each antibody is tested by mixing uninfected cells with a “pseudovirus” (a domesticated virus that carries a spiky protein and is modified to glow green when it enters the cell).

Each antibody enters the wells of a grid of plastic containers, such as a giant ice tray. A computer connected to the microscope counts the number of cells in each well to see how well each antibody blocked the virus.

These are the results of Kristen Pascal’s visit to the lab on Saturday, March 14th.

She brought in pizza and pies for Pi Day, a day celebrated by scientists, as 3, 1, and 4 are the first three digits of Pi Day, an important number in mathematics. I remembered that.

Dr. George Yancopoulos, Kyratsous, another manager, and co-founder of the company, floated behind the chair while the computer was counting the glowing spots.

“There are probably 1 to 2,000 green spots in each well,” with 10 hits and 2 hits. When they saw some zeros, Jancopros ordered champagne.

“We really had really good antibodies,” she said. “We knew we were in good shape. We thought we could actually make a difference.”

Those antibodies were from mice. Two weeks later, this process was repeated on human samples from Singapore.

In total, Regeneron has tested over 3,300 antibodies, competing with each other like gladiators in the lab, and choosing two that bind to spike proteins at different locations to make it more difficult for the virus to escape. did.

“I was very relieved because I chose the best antibody … but it was very, very stressful because I couldn’t go back,” said Kyratsous. “These are going into production.”

Dan Van Plou’s job is to take what’s called a “recipe” from Tarrytown’s lab, put it through his “test kitchen” at a Regeneron production facility near Albany, New York, and mass-produce it as a medicine. Is to find a way to do it. It’s like making some artisan cupcakes for tasting and then getting a big wedding order. “So now I need to understand how to make a 1000 for a VFW hole,” he said.

First, the fast-growing hamster cells containing the genetic recipe for the selected antibody are placed in a container called a bioreactor. “You are trying to imitate your body,” he explained. It keeps cells warm, whisks in the air to oxygenate, remove carbon dioxide, and provide nutrients at the right pace for cells to grow.

They gradually move to larger and larger bioreactors until the cells become very dense and switch from replication to antibody production — “it looks like a really big craft beer brewery,” Van Plew said.

Pollution is always a risk.

“At any given time, whether you’re touching a product or running a bioreactor, there will be 1,500 people touching the process,” says every car you drive, shoes you wear, and anything you touch is a potential danger. is. Said.

When the final bioreactor work is complete, the contents are purified to remove some of the cells, leaving only the antibody and filling the vial.

Production took 45 days — “speed of light compared to standard process”, typically 3-5 months.

Human research began in early June. In October, President Donald Trump got the drug under the provision of “compassionate use,” but it gave him because most patients recovered spontaneously and received other treatments. There is no way to know if you have done anything good. The Food and Drug Administration permits the use of Regeneron and Eli Lilly antibody drugs in emergencies for patients with mild and moderate illness who do not require hospitalization during the course of the study. Testing in more severe inpatients was suspended due to concerns that the drug might not help in that situation.

Regeneron sells other antibody medications for heart disease, cancer and other symptoms. The 2012 MERS outbreak was the first time we tried to create it quickly because of an infectious disease. “We were very fortunate as a society,” said Kyratsous, who did not expand production, as MERS turned out not to spread easily from person to person.

When Ebola broke out in 2014, Regeneron developed the antibody and made its first production in the outbreak situation. However, it took nine months, and by then the number of cases had decreased. There was another outbreak in 2018 to prove the value of the drug.

Many of the same scientists were waiting when the new coronavirus emerged.

“We knew exactly what to do … we had done this before,” Kyratsous said. “I feel like Regeneron was waiting for a moment like this.”

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Marilynn Marchione can be followed on Twitter at http://twitter.com/MMarchioneAP.

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The Associated Press’s Department of Health Sciences is supported by the Department of Science Education at the Howard Hughes Medical Institute. AP is solely responsible for all content.