IN THE LAB: The Hunt for COVID-19 Antibody Treatments

Faculty and Alumni Research Leads to Some of the Pandemic’s First Drugs
By Christina Hernandez Sherwood | Photographs by Jörg Meyer

In the early 1980s, as scientists were beginning to understand the genetics of human antibodies, a young graduate student in the Columbia biochemistry laboratory of Frederick Alt, PhD, floated a novel idea: Mice genetically modified with genes for human antibodies could be the source of streams of new biologic drugs. Antibodies are attractive as drugs because the natural proteins are long-lasting and, by targeting specific proteins that cause disease, reduce side effects. The idea was described in a 1985 paper the student co-authored with Dr. Alt and Keith Blackwell in the journal Trends in Genetics.

Thirty-six years later, that graduate student, George Yancopoulos, made headlines when his company, the Westchester-based Regeneron Pharmaceuticals, provided a COVID-19 antibody cocktail during President Trump’s coronavirus infection in October 2020. The Regeneron therapy is known as REGEN-COV and mimics the response of a healthy immune system by delivering highly potent antibodies that neutralize the COVID-19 virus. One of the two antibodies that form the treatment was created from the same technology Dr. Yancopoulos first proposed in that Columbia laboratory decades ago.

“We spent probably the first 20 years of the company building that dream that Fred and I proposed in 1985,” says Dr. Yancopoulos, who received his PhD degree in 1986 and his MD in 1987. “It’s the basic technology that has led to our ability to produce more antibody-like biologicals over the last 10 years or so than any other entity or institution.”

George Yancopoulos

Dr. Yancopoulos joined Regeneron as its founding scientist in 1989, a year after Dr. Leonard Schleifer started the company. In 1995, VP&S namesake P. Roy Vagelos’54 began his ongoing tenure as chair of the Regeneron board. For more than a decade, the company honed its technology, which manipulates large segments of mouse DNA to create genetically humanized mice. The Regeneron solution created mice with hybrid antibody genes—half mouse, half human—so the mice can mount a normal immune response to an antigen and produce antibodies appropriate for therapeutic use. Before the desired antibodies are mass produced, more genetic engineering replaces the few remaining mouse parts with human portions to create fully human monoclonal antibodies that can be safely used in humans. This technology, honed from what Dr. Yancopoulos dubbed “the most valuable mouse ever created,” has earned Regeneron billions of dollars in licensing revenue and led to numerous FDA-approved medicines.

Regeneron’s first drug, Arcalyst, which treats the rare hereditary inflammatory disorders known as cryopyrin-associated periodic syndrome, was approved in 2008 by the FDA. Praluent, Regeneron’s first antibody drug, was approved by the FDA in 2015 to treat patients with cardiovascular disease by targeting a molecule called PCSK9 to lower the amount of LDL cholesterol in the blood.

In 2011, Regeneron hired another Columbia graduate, Christos Kyratsous’09 PhD, whose team made two crucial adaptations that would set the stage for the company’s COVID-19 response nearly a decade later. The first was to streamline—and speed up—the company’s drug development process. The second was to enable Regeneron to address infectious diseases which, unlike disorders previously targeted by the company’s therapies, produce an antibody response in the human body. The team modified Regeneron’s existing technology to feed those antibodies, both from the company’s genetically modified VelocImmune mice and from the blood of people recovering from infectious diseases, directly into the Regeneron manufacturing pipeline.

"Given our background in HIV, we recognized that there was plenty we could bring to bear and make a contribution."

Despite these advances, the company’s first infectious disease program was unsuccessful. A promising treatment for respiratory syncytial virus, or RSV, failed in the final stage of clinical development when the single antibody it contained proved ineffective against a virus variant. Dr. Kyratsous would never forget the lesson: Two—or more—antibodies are better than one.

When Regeneron took aim at the deadly Ebola virus, the resulting treatment was a cocktail containing three different antibodies. Because Ebola survivors were so rare and time was of the essence in outbreak conditions, the three antibodies were generated in and harvested from the company’s genetically modified mice. In October 2020, Inmazeb became the first FDA-approved treatment for Ebola—and Regeneron’s eighth FDA-approved drug.

COVID-19 provided another opportunity for Regeneron to use its “rapid response” antibody discovery and development process. Dr. Kyratsous, now the company’s vice president of research in infectious diseases and viral vector technologies, and his team turned to their technology in early 2020 to seek treatment solutions for coronavirus patients expected to fill U.S. hospitals.

David Ho

Meanwhile, just a half-hour’s drive south from Regeneron, another of the world’s leading antibody scientists, David Ho, MD, turned to work on the coronavirus just as he moved his Aaron Diamond AIDS Research Center to Columbia from Rockefeller University. Dr. Ho reached worldwide prominence in the 1990s for his role in developing an HIV drug cocktail that made the virus a survivable condition. 

In 2003, he had halted his ongoing HIV work to help scientists in China combat the SARS coronavirus. He decided to again pause his laboratory’s HIV research—most recently focused on developing drugs that could be administered less frequently than the daily cocktail and engineering antibodies to cure the disease—to target this new and dangerous coronavirus. “By the second week of January, we recognized that this was a SARS-like coronavirus,” says Dr. Ho, the Clyde’56 and Helen Wu Professor of Medicine at VP&S. “Given our background in HIV, we recognized that there was plenty we could bring to bear and make a contribution.”

Through the spring of 2020, Dr. Ho and his team used blood samples from five of the sickest COVID-19 patients treated at Columbia to isolate antibodies that could block the virus from attacking healthy cells and prevent the disease from progressing. By the year’s end, Dr. Ho’s laboratory had not only found some of the most potent antibodies against COVID-19, but also re-engineered some of those antibodies to be bi-specific, meaning they could bind two different parts of the virus instead of just one. These bi-specific antibodies could, he says, be used to develop even more powerful drugs that cost less and are easier to administer than their counterparts. (Columbia Technology Ventures handles the licensing that transforms discoveries into potential clinical products.)

Back at Regeneron, the company again took a combination approach to its COVID-19 antibody development. The resulting cocktail of REGEN-COV consists of two antibodies: casirivimab from a genetically modified mouse and imdevimab from a human who recovered from the virus. The antibodies bind simultaneously to different parts of the virus’ spike protein, so the virus would need to mutate in two distinct locations to evade both antibodies. “We could have gone much more rapidly with individual antibodies,” Dr. Yancopoulos says. “But we felt it was critical to utilize a cocktail of antibodies to protect against mutant viral escape.”

"The president’s response was highly consistent with exactly how similar patients responded in the clinical trial. It’s not too much of a stretch to think that he was the perfect patient."

Just days after Regeneron released preliminary data on its COVID-19 cocktail, showing that it reduced viral levels of people in early stages of infection, President Trump’s medical team contacted the company to request compassionate use of the cocktail. “The president was very early in his disease course, had seemingly not yet mounted his own antibody response, and had high viral titers,” says Dr. Yancopoulos. “Those are the patients who potentially have the most to gain from our treatment.”

After the president received Regeneron’s cocktail, as well as other drugs including the steroid dexamethasone and the antiviral remdesivir, Trump’s doctors reported his viral levels dropped. “The president’s response was highly consistent with exactly how similar patients responded in the clinical trial,” Dr. Yancopoulos says. “It’s not too much of a stretch to think that he was the perfect patient.”

Research Updates

Just as the COVID-19 pandemic has changed, antibody treatments are an ever-changing research focus. Some developments from the past few months:

  • In January, after news broke of United Kingdom and South Africa variants, separate studies by Dr. Ho’s lab and Regeneron scientists found that Regeneron’s antibody cocktail remained effective against these variants, although the potency of one of the two antibodies in the cocktail was reduced against the South African variant. Similar in vitro studies have confirmed REGEN-COV’s retained potency against variants first identified in Brazil, New York, and California.
  • In March, Regeneron announced the results of the largest trial to date assessing COVID-19 treatments for high-risk, non-hospitalized patients. The company’s antibody cocktail, REGEN-COV, was found to reduce the risk of hospitalization or death by about 70%.
  • Phase 3 clinical trial data announced in April showed that a single dose, administered via subcutaneous injections, of REGEN-COV taken within four days of a household member’s COVID-19 diagnosis could prevent the spread of the disease among family members. (Columbia participated in the study.) Regeneron will share the data with the FDA and request expansion of its emergency use authorization to use a 1,200 mg subcutaneous dose for COVID-19 prevention in appropriate populations.
  • The rapid, at-home COVID-19 test that Dr. Ho’s laboratory is developing, known as CoV-SCAN, won funding from the New York City Economic Development Corporation. Using the same technology as a home pregnancy test, CoV-SCAN uses a nasal swab sample to determine within 15 minutes whether a person carries high levels of the virus and is capable of infecting others.

About seven weeks after President Trump received Regeneron’s COVID-19 antibody cocktail, the FDA granted the drug emergency use authorization for early stage, non-hospitalized COVID-19 patients. 

By the middle of December, two COVID-19 vaccines received FDA emergency use authorization, and the country’s vaccine rollout began.

Both Dr. Yancopoulos and Dr. Ho plan to continue their antibody research, and Columbia and Regeneron are discussing a potential collaboration on COVID-19 antibodies. Despite the vaccines, people will still get sick with COVID-19 and need antibody treatments, says Dr. Ho. And others, for instance those with suppressed immune systems, might not respond effectively to the vaccine. “Our work is just as urgent now as it was last spring,” Dr. Ho says, noting that some senior members of his team continue to live in Columbia medical student housing to enable round-the-clock work. “It certainly hasn’t slowed down, just like the pandemic.” While Dr. Ho continues his COVID-19 work, which includes developing a simple, rapid, and inexpensive COVID-19 test, he has begun to think about restarting the HIV projects his team left behind.

As Regeneron works toward full FDA approval of its COVID-19 antibody cocktail, the company is also studying the drug’s effectiveness in later-stage patients, as well as its potential to prevent infection.

The full story of COVID-19 has yet to be written as vaccines and variants make headlines even into 2021, but Dr. Yancopoulos says he hopes science’s successes against the virus will mobilize the country—and the world—to re-engage in science to solve current threats to human health, including Alzheimer’s disease, diabetes, and obesity. “If we don’t address these, it’s going to dwarf the societal and economic impacts, and the human devastation, that we saw from this pandemic,” he says. “This was almost, I hate to say it, a trial run for the bigger challenges facing mankind.”