Antibody Treatments May Be Best Hope Against Virus Until Vaccine

April 20, 2020, 9:00 AM

The novel coronavirus is devious, persistent, and, according to some scientists, not even alive. But, as the world has had to learn, this tiny bundle of genetic material is a highly efficient invader. Each particle is armored with roughly 100 protrusions, or spikes, perfectly evolved to latch onto an enzyme on the surfaces of throat and lung cells, then slip into them and replicate millions and millions of times. Older coronaviruses, such as the one that caused severe acute respiratory syndrome, or SARS, operated similarly. The spikes of the new coronavirus, though, clasp human cells much more tightly, which appears to be one reason it spreads more easily. In the three months since scientists in China identified it, the coronavirus has infected more than 2.4 million people around the world and killed at least 165,000.

Neutralizing those spikes may be the best way to prevent the virus from harming its host. And among the most promising approaches to doing that is finding the right antibodies. Multiple companies are doing this, using antibodies from laboratory mice and recovered patients. Unlike existing medicines being tested on the virus—such as hydroxychloroquine, the malaria drug controversially touted by President Trump, and remdesivir, an antiviral compound originally developed by Gilead Sciences Inc. to fight Ebola—antibody drugs are being designed specifically to disable the new virus where it’s most vulnerable. They’re taking advantage of sophisticated technologies developed over the past two decades to create exquisitely targeted medicines. If they work, the therapies could be used in two crucial ways: to treat those already infected and, in the absence of a vaccine, as a short-term prophylactic for those at high risk.

Normally it can take five or more years to develop a drug and move it into human trials. No one wants to wait that long. AstraZeneca, Vir Biotechnology, and Eli Lilly and its biotech partner, AbCellera Biologics, as well as several academic labs, are hoping to start human trials by the end of summer. If all goes well, antibody treatments for those most in need could be available by fall.

Regeneron Pharmaceuticals Inc. expects to move at least as fast. The company is known in the industry for its VelocImmune mice, genetically engineered to develop humanlike antibodies when injected with viral DNA. In this case, Regeneron used genetic material identical to that of the virus in several dozen mice, provoking an immune response. About a month later the scientists removed the mice’s spleens and extracted thousands of antibodies that had developed in response to the viral material. They began sorting through the antibodies, and in mid-April selected a few of the most potent ones to produce at one of Regeneron’s main manufacturing sites for animal trials. News of that milestone produced another bump for the company’s stock, which at press time was the best performer of 2020 on the S&P 500 index. Human trials could begin in June.

It’s possible that none of the antibody treatments Regeneron or any of the other companies develop will be effective. Or they may produce unexpected side effects that limit their use. But many who are watching the research closely think at least one of these treatments will be successful. “The odds are very high this will work, especially when you have multiple programs and multiple manufacturers,” says James Crowe, a veteran immunologist at Vanderbilt University Medical Center who’s working with AstraZeneca Plc and others on Covid-19 treatments. Scott Gottlieb, former head of the U.S. Food and Drug Administration, also sounded optimistic in a recent interview with Bloomberg News, saying, “If I had to place one bet on a drug that could be available by the summer and could have activity and could have a profile that I think could change the contours of the infection, it would be the antibody approaches.”

Enclosures housing VelocImmune mice at Regeneron.
Source: Regeneron

“Our technology lets us go in months where it takes others years,” says George Yancopoulos, Regeneron’s co-founder and chief scientist. Yancopoulos, who won a top award in the Westinghouse Science Talent Search in high school (his company took over the contest from Intel Corp. in 2016), is now 60 and one of the richest scientists in the biotech industry, with a net worth of more than $1 billion. During an interview in March at the company’s headquarters in Tarrytown, N.Y., he wore a Hawaiian shirt, drank a can of soda, and excitedly described how modern antibody technology had evolved over the years from a slow, bespoke process to the industrialized operation that he says Regeneron has perfected.

The company was founded in 1988, went public in 1991, and, as is true of many biotech companies, required many years to get its first drug approved by the FDA. The breakthrough came in 2008, with a compound designed to treat a rare inflammatory disease. Since then, Regeneron has gotten six other drugs on the market. The best known are Eylea, a treatment for macular degeneration, and Dupixent, for severe eczema. A third, a rheumatoid arthritis drug called Kevzara, is being tested on Covid-19 patients; another, the injectable cholesterol-lowering medicine Praluent, cost billions of dollars to develop but hasn’t been a commercial success. Yancopoulos himself takes that one.

Yancopoulos, right, with Christos Kyratsous.
Photographer: Samantha Casolari for Bloomberg Businessweek

Regeneron has been conducting research into infectious diseases for about a decade but doesn’t yet have an approved drug against any. Its first one could be an Ebola treatment. In 2014, after an outbreak in West Africa, Regeneron devised a combination of antibody drugs—an antibody cocktail—that was ready for human trials in only 10 months. Last year, after Ebola reappeared in Congo, the drug combination slashed the death rate in half in a large clinical trial, performing the best of the four treatments tested. It beat ZMapp, a drug that had long been considered the gold-standard treatment for the disease and was featured on the cover of Bloomberg Businessweek in 2014. Regeneron’s Ebola treatment also topped Gilead’s remdesivir, the antiviral drug now being tested in Covid-19 patients. Regeneron has submitted data to the FDA and is waiting for final approval.

The person behind the Ebola success is microbiologist Christos Kyratsous, Regeneron’s 38-year-old vice president for infectious disease research. He and Yancopoulos share the same heritage—Greek Macedonian—and both earned doctorates in microbiology from Columbia. Kyratsous is earnest and soft-spoken, his boss gregarious and fast-talking. Yancopoulos introduces him as “a younger, improved version of me.”

In this crisis, Kyratsous plans to have a drug ready for human trials in just five months. Since January he and his researchers have been working almost all the time on the virus. His grandmother, who lives in Greece, told him she was worried that he was working too much—every time she saw him on television, he was wearing the same sweater. He was working 14 hours a day, but she was seeing the same sweater because every station put up the same corporate photo while he was being interviewed.

Antibody treatment has a long history. In 1901, German doctor Emil von Behring won the first Nobel Prize in medicine by showing that “antitoxins” found in the blood of animals exposed to diphtheria and tetanus bacterium could be used to treat sick animals and transfer immunity against future infection. Scientists didn’t know at the time what these mysterious antitoxins were. They later determined they were blood proteins created by the body to fight infections, and dubbed them antibodies. During World War I, antibody-containing plasma from horses was administered to prevent tetanus in wounded U.S. soldiers. In the midst of the coronavirus pandemic, some hospitals are trying something similar, treating Covid-19 patients with antibody-rich plasma from the blood of those who’ve recovered. This convalescent plasma, as it’s called, may help, but it’s an emergency treatment. It may be hard to scale up, because hospitals have to rely on recovered patients to donate blood. And because the blood contains a mixture of all sorts of antibodies, the more potent ones may be diluted by the others.

Research supplies at the Tarrytown lab.
Photographer: Samantha Casolari for Bloomberg Businessweek

The human body can theoretically make hundreds of millions of different antibodies in a person’s lifetime. When a pathogen is introduced, the immune system responds by producing tens of thousands of new antibodies, each of which can bind to a slightly different part of the pathogen and either directly neutralize it or mark it for destruction by other components of the immune system. After a patient recovers from certain diseases, such as measles, highly specific antibodies can remain in the body for years, remembering the pathogen and rendering the person immune. A person infected with the coronavirus will produce antibodies, some much more effective than others. For researchers the goal is to find the specific ones that work best and concentrate them into a powerful medicine.

Antibody drugs are one of several strategies scientists are pursuing against Covid-19. The long-term goal is a vaccine that would teach the immune system to make antibodies against the virus. But testing a vaccine takes time—likely 12 to 18 months or longer—and it might not work, or, like the flu shot, be only partly protective. That’s why researchers are also hunting for drugs. One possibility is an antiviral drug that could slip into infected cells and interfere with various proteins the virus uses to replicate. These are often administered in pill form, which is ideal. Gilead’s remdesivir, which must be infused, is considered among the most promising of these available options; large-scale human trials should yield results by May. If it or other off-the-shelf drugs don’t work, researchers will have to design custom antivirals from scratch, which also takes time. Antibodies occupy a bit of a middle ground between antivirals and vaccines. They have to be infused or injected, and they’re hard to mass-produce on the same scale as a pill, but the technology allows researchers to move into human trials relatively quickly.

Here’s where Regeneron and other biotech companies come in. In 1975 scientists devised technology to mass-produce what’s called a monoclonal antibody—a single, highly potent antibody that targets exactly one site on one virus. It took decades to perfect the technique, but today many of the world’s bestselling drugs—particularly those for cancer and autoimmune diseases such as rheumatoid arthritis—are monoclonal antibodies. Regeneron’s Dupixent is among them.

Monoclonal antibodies are rarely used, however, for infectious disease. They’re expensive, often costing $30,000 a year or more, and antibiotics and vaccines have to be cheap to be widely used. And the development process was slow relative to the urgent demands of a pandemic. That has changed. A few years ago, Vancouver-based AbCellera invented a credit card-size “lab on a chip” device that uses machine vision to test hundreds of thousands of antibody-producing cells at once. The company showed that in only 55 days it could isolate influenza-neutralizing antibodies from human blood that were effective enough to protect mice against an otherwise lethal dose of the virus.

In the current crisis, AbCellera started with blood from a patient who’d recovered from Covid-19. It received the sample on Feb. 25, began screening antibody-producing cells four days later, and by March 3 had sorted through 5 million of them, finding 500 antibodies that bound to the virus’s spike protein. Then, because AbCellera focuses on discovering drugs, not developing and manufacturing them, its chief executive officer, Carl Hansen, got in touch with a company that does, Eli Lilly. They’d already been talking about working together on other antibody drugs. By April, Lilly, with help from the U.S. National Institutes of Health, had narrowed AbCellera’s original 500 antibodies to 20 that lock onto particular sites on the spikes. After more testing, Lilly expects to select three or four for human trials that could begin as early as July. “We always hope there’s just one antibody that’s really, really great, and we can devote our full manufacturing resources to that,” says Dan Skovronsky, Lilly’s chief scientific officer. But the company is preparing to make more than one.

When pandemic fears were becoming a reality in late January, among the first calls Rick Bright made was to Regeneron CEO Leonard Schleifer. Bright is the director of the Biomedical Advanced Research and Development Authority, or Barda, a division of the U.S. Department of Health and Human Services. Barda has given Regeneron about $300 million over the past five years to work on Ebola, influenza, and other diseases. “They liked us because we said we could go extremely fast,” Kyratsous says. Bright urged Regeneron to make Covid-19 its top priority. Schleifer immediately agreed.

Kyratsous was already at work. When Chinese researchers shared the gene sequence of the coronavirus in mid-January, his team ordered synthetic DNA for the spike protein for a couple of hundred dollars per sample. They injected the synthetic DNA into genetically engineered mice. No need to collect blood from recovered patients; the mice generate human antibodies in about a month.

Machinery at Tarrytown used to grow antibodies.
Photographer: Samantha Casolari for Bloomberg Businessweek

By the beginning of March, Regeneron’s mice had produced thousands of antibodies that bound to the spike protein on the virus, and by the end of the month, Kyratsous and his team had carefully sorted through them and selected the 40 or so that were most effective. Then Regeneron had to test the antibodies against the actual virus. For that it turned to Matthew Frieman, a coronavirus expert at the University of Maryland School of Medicine in Baltimore and longtime collaborator.

Frieman, who helped Regeneron work on Middle East respiratory syndrome, or MERS, was one of the first researchers in the U.S. to gain access to samples of the live virus when it became available in early February. He has a secure lab and a staff used to handling deadly pathogens, making him a very popular man. He’s been logging 18-hour days, performing his own drug research and assisting more than a dozen drug and biotech companies as they test possible Covid-19 drugs and vaccines. He spends all day in the lab, heads home to have dinner with his family, and continues to work afterward.

He and his colleagues mix various doses of antibodies with the virus. Then they add African green monkey kidney cells to the mix—a standard type of cell that most viruses can infect—and wait to see if the cells survive. The goal is to find the antibody that binds the tightest to the right place. It’s easy to tell when it works: Living cells are stained purple, and when they die the color disappears. Several of the Regeneron antibodies appear promising in preliminary tests, Frieman said in a short interview in early April while he was driving home: “Everything is moving just the way it has been supposed to.”

At the same time, scientists around the world have found more than 3,000 gene sequences of the virus, from Asia, Europe, and North America, Kyratsous says, and they’re not all identical. The virus is evolving. Some parts of the protein spikes so central to finding a treatment are mutating, meaning they could potentially evade an attack. Regeneron is looking specifically for antibodies that latch onto the spots that aren’t evolving. “We want antibodies that bind tightly, neutralizing the virus, and are binding to sites that are not changing very frequently or not at all. That’s how we’re screening,” Kyratsous says.

Regeneron hopes it will be able to produce 200,000 prophylactic doses a month by August.
Photographer: Samantha Casolari for Bloomberg Businessweek

In mid-April, Regeneron chose its final antibodies to test—more than four and fewer than 10, the company says—on monkeys. Then a select few will be tested on humans. Concurrently, without waiting for those results, the company is also getting ready for large-scale production. By the end of May “we will know if there is anything horribly wrong,” Kyratsous says. Because the drugs are targeted so specifically to the virus, he doesn’t expect to see any signs of toxicity in the monkeys. If there are none, human trials could get under way by the end of June.

Getting antibodies into trials is one problem. Manufacturing them at an enormous scale is another. Antibodies are far more difficult to produce than traditional medicines, requiring plants that cost hundreds of millions of dollars to build and maintain. These drugs are not simple chemicals like the ones in Tylenol or Prozac or Viagra. They’re complex proteins made inside living cells and purified in sterile vials or injectors.

Because most monoclonal antibody drugs are so-called specialty drugs for advanced lung cancer, multiple sclerosis, and other diseases, there is limited capacity globally to make them. “Antibody drugs are fast to develop and reasonably likely to work but inefficient in terms of manufacturing,” says Skovronsky at Lilly. He says companies, nonprofits, and the government are discussing how to share manufacturing plants. “If it turns out our antibody doesn’t work and someone else’s does, probably we would offer capacity for them. And the opposite would be true,” he says. “No one is looking at this as a moneymaking commercial business. It’s just how quickly can we help.”

Regeneron says it’s designed its plants for speed and flexibility. Some biotech companies have customized plants for each of their major drugs. “If they have 10 products, they have 10 plants,” Yancopoulos says. “We have one process for all of our drugs. We’ve McDonaldized the manufacturing process.” Regeneron is already retooling one of its major manufacturing plants, in Rensselaer, N.Y., to make Covid-19 antibodies. It may shift much of its other production to Ireland to further increase its capacity for Covid-19 antibody production in New York.

At high doses the drugs might prevent the disease from progressing in hospitalized patients. At lower doses, the same antibodies could work as a prophylactic, conferring immediate but short-term immunity to doctors and other first-line responders. The company says it hopes by August it will be able to produce 200,000 prophylactic doses a month. Already infected patients might require a dose 10 times as strong; the company could make about 20,000 of those a month.

Kyratsous says the long-term goal is to make drugs with what he calls cross-reactive antibodies, which would be effective not just against this coronavirus but against others that have already emerged—and still more that are likely to.

Antibody treatments won’t eliminate the need for a vaccine. They might not work on critically ill patients. And as a prophylactic, the drug would likely have to be given every couple of months. It wouldn’t be practical to treat all high-risk people with regular antibody infusions. But the treatments might help communities return to a seminormal state until a vaccine is finally available. —With Anna Edney

Read more: There’s a Big Problem With Coronavirus Immunity Certificates

To contact the authors of this story:
Robert Langreth in New York at rlangreth@bloomberg.net

Susan Berfield in New York at sberfield@bloomberg.net

To contact the editor responsible for this story:
Daniel Ferrara at dferrara5@bloomberg.net

Jeremy Keehn

© 2020 Bloomberg L.P. All rights reserved. Used with permission.

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