When President Trump announced an emergency use authorization for convalescent plasma as a “historic” and game-changing treatment for the coronavirus last month, experts were baffled. Although plasma donations from recovered patients have been used to speed recoveries for over a century and may help patients in early stages of Covid-19, there’s not enough research yet on how well this approach works and which antibodies best battle this virus. Now, however, there are preliminary results on a different but related treatment that could help coronavirus patients and solve some of those issues. And the administration hasn’t said much about it. It’s called monoclonal antibodies.
Not all antibodies a body produces in response to this coronavirus are created equal. Some are better at battling SARS-CoV-2 than others. A recovered patient might have a low number of antibodies, but if the antibodies they do have are all really good at neutralizing the virus, then plasma from that patient will be more effective. Another patient could have a high number of antibodies, but none of the antibodies are particularly good against this coronavirus and so they fare worse. Convalescent plasma as a treatment, therefore, is “a little bit of a crude method,” said Rogier Sandiers, a professor of virology at the University of Amsterdam’s Faculty of Medicine. You need large quantities of plasma from recovered patients, and “you have to be lucky with the plasma you get. If there’s no neutralizing antibodies in the plasma at hand, then it’s not going to be very effective.”
But what if the best, most effective antibodies could be designed in a lab and then mass-produced?
To produce what are known as monoclonal antibodies, researchers start from the same convalescent plasma with which patients may now be infused. But then they pull out the antibodies specific to SARS-CoV-2, and from there, they identify the one or two antibodies that rise to the top—the ones that outperform the competition by being the most effective, the stickiest, the most potent.
“And then,” said Sandiers, “you just make it in a manufacturing facility.”
These replicated top-tier antibodies could be used both as a treatment for those in the early stages of Covid-19 and as a “passive vaccine” that high-risk individuals could receive every month. While vaccines and other treatments, like antivirals and convalescent plasma, have taken much of the spotlight, researchers say monoclonal antibodies could be a “major advance” in controlling the pandemic—and could even be used to make sure early vaccines are effective.
Last week, the pharmaceutical company Eli Lilly announced in a press release that a monoclonal antibody its researchers have developed reduced the rate of hospitalization by 72 percent among those with mild Covid-19 in a preliminary study, compared to those who received a placebo. It’s very soon to tell if the drug actually works this well; the phase two trial, conducted among 452 participants, was intended to make sure there were no major side effects before moving to the next phase, which would look at how effective the treatment is in a greater number of people. Even so, Daniel Skovronsky, Lilly’s chief scientific officer, told STAT News that he hoped the U.S. Food and Drug Administration would consider an emergency use authorization to make the treatment available before all of the clinical data is in.
Lilly had hoped its medication would be ready by the end of this month but recently revised the timeline to the end of the year. Clinical trials to test monoclonal antibodies have been plagued by a lack of tests, overstretched hospitals, and hesitant participants. The pharma company Regeneron, which has won $500 million in federal funding commitments to manufacture its two-antibody treatment, was aiming for an ambitious launch of the medication by the end of this summer; instead, now it’s hoping to have initial results this month. In preliminary results of its animal trial, Regeneron’s treatment seemed to help monkeys recover faster with less damage to their lungs. Phase three trials for Regeneron and Lilly both began enrolling participants in August.
Several other drugs have been produced from monoclonal antibodies in the past, including Humira, which is used to treat conditions like arthritis and Crohn’s disease. Monoclonal antibodies can also be used to address conditions ranging from high cholesterol to cancer to eczema. But developing them is expensive, never mind the tight timeline and difficulties scaling up quickly.
In order to explain how monoclonal antibodies work, Meghan May, a professor of microbiology and infectious disease at the University of New England, first wanted to talk about how all antibodies work. And to do that, she wanted me to do the “YMCA.” I raised my arms obediently, feeling a little silly as we spoke over the phone.
“An antibody molecule is kind of shaped like a Y,” she said. “The stalk part—that’s your legs, touching the floor—is called the constant region. And the hands-in-the-air part is called the antigen-binding region.”
Humans have five different types of antibodies: IgM, IgG, IgE, IgD, and IgA. The first two are most relevant to the SARS-CoV-2 conversation. When you have a recent infection, you have a lot of IgM antibodies, but as the infection fades, they’re replaced with the longer-lasting IgG. The constant region of these antibodies, as you might expect from the name, doesn’t change much from person to person.
But the antigen-binding regions—the arms—can differ dramatically from person to person. “Those are the parts that are really fine-tuned and specific for different viruses, different bacteria, different pollen grains,” May said. When our antibodies first encounter a new virus, they immediately start trying different things, bringing out the whole arsenal of antigens that might work on the new intruder. What seems to work well against SARS-CoV-2 is antigens that bind very tightly to the coronavirus’s spike protein, basically grabbing it in a chokehold to prevent it from attaching to our cells and keep the disease from progressing. In other words, May said, good SARS-CoV-2 antibodies are “sticky.” Some, she said, are more like a preschooler’s glue stick—which is to say, sticky in name only. Others are more like superglue. It’s the superglue level of antigens that work well in lab tests, latching on to the virus and neutralizing it.
Ian Wilson, chair of the Department of Integrative Structural and Computational Biology at the Scripps Research Institute, is one of the researchers evaluating the characteristics and binding sites of effective antibodies. “It’s not just a matter of eliciting an antibody; it’s a matter of eliciting an antibody that can actually prevent an infection,” he told me. “So that means it’s got to bind well, and bind to the right place.”
It’s expensive and time-consuming to isolate and test the antibodies in clinical trials, and it would be difficult to produce enough, Wilson said. “The prices are going down all the time for making antibodies, but at the moment it would probably be challenging to actually get enough to—you couldn’t actually think of doing this to the world population at the moment, I don’t think. Because you’d need to generate them in enough of a quantity and a cheap-enough cost.”
But even if the treatments themselves will be too expensive and limited to have widespread global implications, research on monoclonal antibodies also helps evaluate the effectiveness of potential Covid-19 vaccines. Researchers can look at the antibodies generated by participants in vaccine trials and compare them to the effective antibodies they’ve seen. Sandiers actually started off by researching this very topic: what monoclonal antibodies could mean for a vaccine. But he and his colleagues soon realized that the work they were doing could apply to Covid-19 treatments, as well.
“In the absence of an effective vaccine, such antibodies can be very useful as preventative [treatments],” he told me. “You can passively vaccinate health care workers, or at-risk groups, and they’re temporarily protected. You can also imagine that if we get a vaccine, it won’t be very effective in some at-risk groups; for example, it’s known that elderly people don’t respond to vaccines very well. So these people could be protected with such an antibody treatment.” Monoclonal antibodies have been called a “bridge to a vaccine,” but that bridge could continue protecting vulnerable people even after a vaccine is created.
The research being done on SARS-CoV-2 is advancing the scientific field at a breakneck pace, all of the scientists told me. When it comes to clinical trials for vaccines, for instance, “this is the fastest this has ever moved in human history,” May told me.
“It’s astonishing. I’ve worked on viruses for years. This is the fastest I’ve ever seen anything go,” Wilson said of research on antibodies. “Everybody’s working throughout the world and working well together.”
“The expertise and knowledge that we’re gathering with this epidemic will for sure be relevant for future epidemics, or existing viruses,” Sandiers said. And these rapid advancements are possible because of decades of work on other viruses, the researchers agreed. “Many of the quickest advances that are being made now on SARS-CoV-2 are a consequence of many years of research on, for example, HIV,” Sandiers told me.
That’s why it is important to support scientific research beyond fast-moving pandemics, Wilson said. “Because you never know when you’re going to need to move very, very quickly.”