Monoclonal antibodies were once the star of outpatient COVID-19 treatments. Since they first became available in 2020 – even before the first vaccines – more than 3.5 million infusions factory-grown proteins have been given to patients in the United States to help reduce the risk of hospitalization.
But one by one, different monoclonal treatments lost their effectiveness against new variants of the coronavirus. The rise of antiviral pills Paxlovid earlier this year has further shaken their appeal.
Now a new wave of omicron subvariants who are the better yet to dodge current immune system defenses have taken over in the United States. They are expected to phase out bebtelovimab, the latest monoclonal antibody treatment for the coronavirus. Soon it will join bamlanivimab, casirivimab, sotrovimab and others in the graveyard of monoclonals that once targeted past COVID strains until they were overwhelmed by variants that escaped their protection.
“The monoclonals have had their day, like the Model T or the biplane,” says Carl Dieffenbachdirector of the Division of AIDS at the National Institutes of Health and head of the NIH’s Pandemic Antiviral Program“Now it’s time to move on.”
Not everyone entirely agrees. Monoclonals are still useful, some doctors say, for treating a vulnerable population.
“There are severely immunocompromised patients who are not likely to mount an immune response to the virus, even if you treat them with antiviral drugs,” says Dr. Raymond Reasonable, an infectious disease specialist in the transplant division at the Mayo Clinic. “This is the group that is going to be most affected by the lack of antibody therapies.”
Additionally, new research is underway to develop new types of monoclonal antibodies that may even be resistant to new variants.
How monoclonals work – and what they face
Monoclonal antibody treatments have always had one major weakness – they are easily thwarted by new strains of COVID. It is a defect that is rooted in their operation.
Monoclonal antibodies are lab-grown proteins that supplement your body’s immune system – which in most people naturally produces antibodies to ward off possible threats at any time.
“You and I and every human being who has a functioning immune system is walking around with probably billions of totally different antibody molecules just circulating in our bloodstream,” says Derek Lowe, chemist and blogger for the journal. Science“Each of us has a totally different sequel. There are more of them than there are stars in the sky.”
The tiny Y-shaped proteins lurk in the blood at low concentrations, “waiting and waiting until they bump into something they stick to very well, and find their soul mate, basically. “, explains Lowe. This “soul mate” is an antigen – a foreign substance that has entered the bloodstream, such as a bacterial protein or a virus or a grain of pollen.
Once a monoclonal antibody has found its kindred spirit — in the case of COVID, a specific part at the tip of the SARS-CoV-2 virus — it binds to the surface of the antigen. Then it sends signals to the immune system, “like hey, I have a live one,” Lowe says.
The strongest antibodies can stop the virus in its tracks simply by binding to it. For example, “if you have an antibody that sticks to the tip of the spike protein at the commercial end of the virus – just because it’s stuck firmly to that means the virus can’t infect a cell”, explains Lowe.
The spike protein has been the target of all monoclonal antibody treatments that attack the virus so far. But it was a fickle soulmate, changing with new variants, leaving the monoclonal antibodies adrift in the bloodstream with nowhere to bind.
Companies have stopped marketing these monoclonals. The feds have stopped promising to buy them in quantity, making it a riskier bet for businesses.
“There are antibodies, but no one has the $200 million to develop them,” Dieffenbach said, citing costs that include producing the antibodies, conducting trials and getting them cleared by the Food and Drug Administration. Some companies thought it wasn’t worth it, for a product that could become obsolete within months, he says.
To be clear, these are antibody treatments for outpatient treatment. There is another type of monoclonal antibody treatment for hospitalized patients that remains viable. Actemra, as it is called, is not susceptible to viral mutation because it targets the body’s immune response to the virus, rather than the virus itself.
New research directions and potential return
There might still be hope for monoclonals. Drugmakers and government agency researchers are now revamping the strategy, looking for monoclonal antibodies that could last.
“At the start, the goal was to find the most potent antibodies,” says Joshua Tan, Head of Antibody Biology Unit at the NIH. “Now there is a realization that we need to find antibodies that might work not only against the [current version of the] coronavirus, but no matter what.”
In his laboratory in Rockville, Maryland, Tan and the researchers working with him are looking for antibodies that target parts of the virus that have remained the same on several different viruses within the large coronavirus family. “We’re looking at other parts of the spike protein that may be more consistent and harder to mutate,” Tan says.
To achieve this, researchers in Tan’s lab take immune cells from the blood of patients who have recovered from COVID and bombard them with tiny plastic pellets coated with advanced proteins from different older coronaviruses to see which cells respond. “Not the [COVID] variants, but SARS-CoV-1, SARS-CoV-2, MERS [etc.]”, specifies post-doctoral researcher Cherrelle Dacon. “These are seven different coronaviruses, which infect all humans.
Immune cells that react to several different coronaviruses make antibodies that bind to part of the spike protein that stays the same across them.
It’s a laborious process: isolating individual immune cells, find those that make antibodies in response to various spike proteins — then use them to make more antibodies that they can grow, analyze, and test, to figure out what they actually bind to on the virus. The process takes about three to four months each cycle, Tan says.
Tan says the good news is that they found antibodies that stick to several different coronaviruses. They published some of the results earlier this summer in Science.
But the problem the researchers ran into is that the monoclonal antibodies they found aren’t that potent. Tan says there seems to be a trade-off – between how a monoclonal antibody against COVID-19 works and how long it lasts before the virus abandons the antibody’s target.
An analogy: If the coronavirus had human body parts (which it doesn’t), the old, highly efficient monoclonals knock the spike protein of the virus squarely on the nose. In contrast, the new monoclonals Tan finds attempt to grab him by the armpit. “One of the problems seems to be that it’s harder to get to those parts,” Tan says, “what is the larger, less powerful [antibodies] the need is for the spike protein to change shape” so they can grab it.
Tan works to find ways around this compromise. He says you can potentially modify the antibody, changing parts of it to increase its potency – a process that is largely theoretical at the moment and will take some time to unfold.
So while Tan and other researchers work on the next generation of monoclonal antibodies — those that work well against all kinds of coronaviruses, possibly even future pandemic viruses — the nation is entering a long lull without antibody treatments. monoclonals that work against the dominant strains of SARS-CoV-2.
“The disappointment is there because you’re losing a really good drug,” Razonable says. “But you focus on the next options. The virus is adapting, and we are also adapting based on what we have.”
Fortunately, while Tan and others continue the long game with antibodies, there are other treatments, like Paxlovid pills and remdesivir infusions, that still work against COVID.
And the rapid research and development of antibody treatments has opened up possibilities beyond COVID. “It has improved the production of monoclonals for cancer, for immunological diseases,” says Dieffenbach, “it will be easier to produce monoclonals in the future thanks to the lessons learned from SARS-CoV-2. Nothing has been wasted here.”