Companies Race to Develop Drugs That Stay Ahead of Coronavirus Mutations

Drugmakers are racing to develop a new generation of Covid-19 medicines to make them easier to give to patients and to stay ahead of virus mutations that could make some current drugs less effective.

The drugs, known as monoclonal antibodies, are lab-engineered versions of antibodies that simulate the body’s natural immune response to viruses. They are considered among the most promising for preventing infected patients from developing severe or fatal symptoms and keeping them out of the hospital. After catching Covid-19, President

Trump

was treated with one of the drugs and credited it with his speedy recovery. Doctors say the drugs will continue to be important treatments for the foreseeable future as vaccines become more widely available.

When the first generation of drugs were authorized by the U.S. Food and Drug Administration in November to treat patients not yet sick enough to be hospitalized, public health officials worried that there wouldn’t be enough to go around. But those concerns have given way to frustration that the medicines are going unused because of challenges in administering the drugs, which can require about an hour of preparation time before the patient arrives, an hour-long infusion and one hour of monitoring to ensure patients don’t suffer allergic reactions.

Vir Biotechnology, along with partner GlaxoSmithKline, expects results as soon as this month from a Phase 3 study of an antibody drug.



Photo:

Mark Jayson Quines for The Wall Street Journal

To reduce the logistical burden and help get patients treated sooner, researchers are working on new antibody drugs that can be given with quick jabs in the arm, similar to flu shots. They would enable patients to get treated quickly after being diagnosed with Covid-19, said

Michel C. Nussenzweig,

an immunologist and professor at Rockefeller University in New York.

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“That changes everything because you can go get that shot at CVS and go get that shot at your doctor’s office,” said Dr. Nussenzweig, whose lab developed an antibody combination that recently began initial Phase 1 safety studies. “Intravenous administration is a headache. It’s just a cumbersome thing to do.”

AstraZeneca

PLC’s experimental drug, a cocktail of two antibodies, is among the most advanced injection formulations, and the company expects to have data from a Phase 3 treatment study in the second quarter.

AstraZeneca is talking with large pharmacy chains about allowing patients to come in for a rapid Covid-19 test and, if they are positive, to get the antibody shots within the same day or hour.

“We want it to be same day, same location,” said

Mark Esser,

vice president for microbial sciences. “You get them in, you give them a shot, and they are on their way.”

How Monoclonal Antibody Therapy Works

When patients are infected by the new coronavirus, their immune systems should produce antibodies that bind to the virus and prevent it from spreading throughout the body.

Antibodies block a spike protein on the virus’s surface that normally helps the virus latch onto and infect cells.

But some people don’t mount an effective immune response. For them, researchers are developing treatments based on antibodies derived from patients who’ve already recovered from Covid-19. Sick patients receive an infusion of the antibodies in hopes of fighting the infection.

Manufacturing the Antibodies

Donor who had coronavirus

2. In the lab, the B cells are mixed with spike proteins derived from coronavirus

1. From a recovered patient’s blood, researchers isolate B cells, immune cells that make antibodies

Cells implanted

with genes

5. The genes are placed inside cells and grown in bioreactors to produce antibodies in an assembly line fashion

4. Once scientists identify the B cells that most strongly bind to the spike proteins, they isolate the genes inside the cells that produce antibodies

3. B cells latch onto the spike proteins that are most likely to neutralize the virus

6. These highly specific antibodies are concentrated into a liquid solution, poured into vials, and injected into sick Covid-19 patients.

Patient

who has

coronavirus

When patients are infected by the new coronavirus, their immune systems should produce antibodies that bind to the virus and prevent it from spreading throughout the body.

Antibodies block a spike protein on the virus’s surface that normally helps the virus latch onto and infect cells.

But some people don’t mount an effective immune response. For them, researchers are developing treatments based on antibodies derived from patients who’ve already recovered from Covid-19. Sick patients receive an infusion of the antibodies in hopes of fighting the infection.

Manufacturing the Antibodies

Donor who had coronavirus

2. In the lab, the B cells are mixed with spike proteins derived from coronavirus

1. From a recovered patient’s blood, researchers isolate B cells, immune cells that make antibodies

Cells implanted

with genes

5. The genes are placed inside cells and grown in bioreactors to produce antibodies in an assembly line fashion

3. B cells latch onto the spike proteins that are most likely to neutralize the virus

4. Once scientists identify the B cells that most strongly bind to the spike proteins, they isolate the genes inside the cells that produce antibodies

6. These highly specific antibodies are concentrated into a liquid solution, poured into vials, and injected into sick Covid-19 patients.

Patient

who has

coronavirus

When patients are infected by the new coronavirus, their immune systems should produce antibodies that bind to the virus and prevent it from spreading throughout the body.

Antibodies block a spike protein on the virus’s surface that normally helps the virus latch onto and infect cells.

But some people don’t mount an effective immune response. For them, researchers are developing treatments based on antibodies derived from patients who’ve already recovered from Covid-19. Sick patients receive an infusion of the antibodies in hopes of fighting the infection.

Manufacturing the Antibodies

Donor who had coronavirus

2. In the lab, the B cells are mixed with spike proteins derived from coronavirus

1. From a recovered patient’s blood, researchers isolate B cells, immune cells that make antibodies

Cells implanted

with genes

5. The genes are placed inside cells and grown in bioreactors to produce antibodies in an assembly line fashion

3. B cells latch onto the spike proteins that are most likely to neutralize the virus

4. Once scientists identify the B cells that most strongly bind to the spike proteins, they isolate the genes inside the cells that produce antibodies

6. These highly specific antibodies are concentrated into a liquid solution, poured into vials, and injected into sick Covid-19 patients.

Patient

who has

coronavirus

When patients are infected by the new coronavirus, their immune systems should produce antibodies that bind to the virus and prevent it from spreading through the body.

Antibodies block a spike protein on the virus’s surface that normally helps the virus latch onto and infect cells.

But some people don’t mount an effective immune response. For them, researchers are developing treatments based on antibodies derived from patients who’ve already recovered from Covid-19. Sick patients receive an infusion of the antibodies in hopes of fighting the infection.

Manufacturing the Antibodies

Donor

who had coronavirus

1. From a recovered patient’s blood, researchers isolate B cells, immune cells that make antibodies

2. In the lab, the B cells are mixed with spike proteins derived from coronavirus

3. B cells latch onto the spike proteins that are most likely to

neutralize

the virus

4. Once scientists identify the B cells that most strongly bind to the spike proteins, they isolate the genes inside the cells that produce antibodies

Cells implanted

with genes

5. The genes are placed inside cells and grown in bioreactors to produce antibodies in an assembly line

fashion

6. These highly specific antibodies are concentrated into a liquid solution, poured into vials, and injected into sick Covid-19 patients.

Patient

who has

coronavirus

Another challenge is the emergence of coronavirus variants thought to be driving a surge of infections in the U.K. and South Africa, though they are not yet believed to be widespread in the U.S. It is well known that the more people are infected by a virus, the more likely it is to mutate. Some scientists said it appears that the U.K. and South African variants developed as a way for the virus to evade the immune response, which raises the potential for antibody drugs to be less effective.

“You really don’t want to give a virus a chance to reproduce in so many people—it’s asking for trouble,” said

Dennis Burton,

a professor of immunology and microbiology at Scripps Research Institute.

The South African variant appears to be resistant to a drug made by

Eli Lilly

& Co., the first to be authorized in the U.S. by the FDA, making it less effective in patients infected by that variant, a company spokeswoman said. The second drug cleared by the FDA, from

Regeneron Pharmaceuticals Inc.,

should still be effective, because it is a cocktail of two distinct antibodies and only one of them is affected by the South African variant, said

Jesse Bloom,

a biologist and associate professor at Fred Hutchinson Cancer Research Center.

“We’ve pursued the cocktail strategy from the beginning so that if a variant ever arises you’re still going to have a functional drug,” said

Christos Kyratsous,

Regeneron vice president of research for infectious diseases and viral vector technologies.

Lilly’s drug, bamlanivimab, is fully effective against the U.K. variant in lab tests conducted by the company, the spokeswoman said. Independent scientists said they haven’t been able to verify the drug’s effectiveness because Lilly hasn’t published the antibody’s genetic sequence.

Regeneron’s drug appears to be effective against the U.K. variant, according to the company and Dr. Bloom. The company is also working on additional cocktail combinations to address any future mutations that do become resistant to its cocktail.

Anticipating the risk of resistant virus mutations, researchers are working on “broadly neutralizing” antibodies that could be effective against many different coronavirus variants.

Virus-fighting antibody drugs are typically modeled on antibodies derived from the immune cells of recovered patients, but Covid-19 patient samples were in short supply early last year. As an alternative, Adimab LLC, a privately held antibody developer, received from the National Institute of Allergy and Infectious Diseases a patient sample from an earlier coronavirus that caused the 2003 SARS outbreak.

The viruses are genetically similar, and there are certain structural elements common to both viruses. A team led by

Laura Walker,

Adimab’s deputy director of antibody sciences, found an antibody from the sample that it thinks will be effective against new variants of the current coronavirus and any future SARS-like coronaviruses.

“We haven’t identified any resistant strains to our antibody yet,” Dr. Walker said.

Adimab spun out the drug into a new company, Adagio Therapeutics Inc., and raised $130 million in venture capital from investors including Polaris Partners and

Alphabet Inc.’s

GV, formerly Google Ventures. Adagio plans to start clinical trials this month and could seek authorization as soon the third quarter.

Partners

Vir Biotechnology Inc.

and

GlaxoSmithKline

PLC took a similar approach and are testing an antibody drug modeled on a 2003 SARS survivor that is designed to remain effective even as new virus variants emerge. The companies expect results from a Phase 3 study as soon as this month that, if positive, could be used to seek regulatory authorization.

Vir’s antibody can recruit other immune cells to attack the virus after it has infected cells, while most antibody drugs only block the virus from entering new cells, said Vir Chief Executive

George Scangos.

Vir’s treatment trials are testing an IV infusion formulation, but the company is working on making the drug available as a shot, he said.

As new coronavirus variants sweep across the world, scientists are racing to understand how dangerous they could be. WSJ explains. Illustration: Alex Kuzoian/WSJ

Write to Joseph Walker at [email protected]

Corrections & Amplifications
B cells are recovered from patients’ blood. An earlier version of a graphic in this article incorrectly said B cells are recovered from patients’ plasma. (Corrected on Jan. 19, 2021)

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