Science’s COVID-19 reporting is supported by the Pulitzer Center.
The latest recruits in the fight against COVID-19 are munching hay in a South Dakota barn. A biotech company has coaxed genetically modified cows to pump out human antibodies that subdue SARS-CoV-2, the pathogen causing the deadly disease, and it plans to start clinical trials of them this summer.
“This is promising,” says Amesh Adalja, an infectious disease physician at the Johns Hopkins University Center for Health Security. “We want to have as many countermeasures as we can.”
To manufacture antibodies for treating or preventing diseases, companies typically turn to sources such as cultured cells or tobacco plants. But almost 20 years ago, researchers began to develop the approach now pursued by SAb Biotherapeutics of Sioux Falls, South Dakota, to produce antibodies on the hoof. The company genetically alters dairy cows so that certain immune cells carry the DNA that allows people to make antibodies. That upgrade enables the animals to manufacture large quantities of human antibodies against a pathogen protein injected into them, such as the “spike” surface protein of the new coronavirus. “Essentially, the cows are used as a giant bioreactor,” says viral immunologist William Klimstra of the University of Pittsburgh, who has been analyzing the bovinemade antibodies’ potency against SARS-CoV-2.
Cows make good antibody factories, and not just because they have more blood than smaller animals engineered to synthesize human versions of the proteins. Their blood can also contain twice as many antibodies per milliliter as human blood, says Eddie Sullivan, SAb Biotherapeutics’s president and CEO.
The animals may provide another advantage. Most companies trying to produce antibodies to combat COVID-19 have pinned their hopes on mass-producing identical copies of a single version, a so-called monoclonal antibody that homes in on and attaches tightly to a particular section of a virus. Instead of making just one antibody variety, the cows fashion polyclonal antibodies, a range of the molecules that recognize several parts of the virus. “That’s the natural way that our bodies fight disease,” Sullivan says. This diversity may make the cow’s proteins more powerful than monoclonal antibodies, he says, and they may remain effective even if a virus mutates.
When the COVID-19 pandemic erupted, SAb Biotherapeutics had already completed a clinical trial with cow-generated antibodies against Middle East respiratory syndrome, which is caused by a coronavirus related to SARS-CoV-2. Developing that treatment “gave us the initial knowledge to focus on the right target,” Sullivan says. Within 7 weeks the cows were generating antibodies against SARS-CoV-2’s spike.
Before the animals start to release these antibodies into their blood, the cows need a starter immunization—a DNA vaccine based on a portion of the virus’ genome that preps their immune system. Then comes the injection that contains a piece of SARS-CoV-2’s spike protein, which serves as the virus’ passkey to cells. Each month, one cow can yield enough antibodies to treat several hundred patients, Sullivan says.
In test tube studies, Klimstra and colleagues recently pitted the antibodies against so-called convalescent plasma from the blood of COVID-19 survivors. Rich in polyclonal antibodies, the plasma is being tested in clinical trials as a treatment for the virus. The cow antibodies were four times better than convalescent plasma at preventing the virus from entering cells, the company announced last week.
The biotech hopes to begin a clinical trial within the next couple of months, Sullivan says, and wants to test whether infusions of antibodies sifted from the cows’ blood prevent healthy people from getting infected by SARS-CoV-2 and prove beneficial for patients who are already sick.
Not everyone thinks the cows are the best choice for making antibodies, however. Infectious disease physician Manish Sagar of Boston University Medical Center says he will remain skeptical “until I see further proof that production of antibodies in cows is a lot more feasible and economically viable” than other methods. So far, no antibodies generated by the animals have been approved for treating any disease.
But infectious disease specialist Jeffrey Henderson of Washington University School of Medicine in St. Louis describes the cow-produced antibodies as “the logical next step” to the convalescent plasma he has been studying. “The whole approach,” he says, “is based on sound science and on past experience going back more than a century.”