How monoclonal antibodies lost the battle against new COVID variants

Monoclonal antibodies were once the star of outpatient treatments for COVID-19. Since they first became available in 2020 – before the first vaccines – patients in the US have been given more than 3.5 million infusions of the factory-grown proteins to reduce the risk of hospitalization.

But little by little, various monoclonal treatments have lost their effectiveness against new variants of the coronavirus. The rise of the Paxlovid antiviral pills earlier this year has further diminished its appeal.

Now, a new wave of omicron subvariants has taken over in the United States, which are the best at evading current immune system defenses to date. They are supposed to switch off bebtelovimab, the last treatment with monoclonal antibodies against the coronavirus. It will soon join bamlanivimab, casirivimab, sotrovimab and others in the graveyard of monoclonal antibodies that once targeted earlier COVID strains until they were overtaken by variants that eluded their protection.

“Monoclonal animals had their time, like the Model T or the biplane,” says Carl Dieffenbach, director of the Division of AIDS at the National Institutes of Health and director of the NIH’s Antiviral Program for Pandemics, “Now is the time to move on . ”

Not everyone fully agrees. Monoclonal drugs are still useful, some doctors say, for treating a vulnerable population.

“There are severely immunocompromised patients who are unlikely to mount an immune response to the virus, even when treated with antiviral drugs,” says Dr. Raymund Razonable, an infectious disease specialist in the Mayo Clinic’s transplant unit. “This is the group that will be most affected by the lack of antibody-based therapies.”

In addition, new research is being conducted to develop new types of monoclonal antibodies that could even exist against new variants.

How monoclonals work – and what they are dealing with

Monoclonal antibody treatments have always had a major weakness – they are easily outmaneuvered by new COVID strains. It’s a flaw burned into their way of working.

Monoclonal antibodies are lab-grown proteins that complement your body’s immune system – which in most people naturally produces antibodies all the time to look for potential threats.

“You and I and any human being that has a functioning immune system are walking around with probably trillions of completely different antibody molecules just circulating in our blood,” says Derek Lowe, chemist and blogger for the journal Science“Each of us has a very different set of them. There are more of them than there are stars in the sky.”

The tiny, Y-shaped proteins lurk in low concentrations in the blood, “waiting and waiting until they happen to stumble upon something they’re really attached to, and they basically find their soulmate,” explains Lowe. This “soul mate” is an antigen – a foreign substance that has entered the bloodstream, like a bacterial protein or a virus or a pollen grain.

Once a monoclonal antibody has found its soulmate — in the case of COVID, a specific part at the tip of the SARS-CoV-2 virus — it binds to the antigen’s surface. It then sends signals to the immune system, “like hey, I’ve got a live one,” says Lowe.

The strongest antibodies can stop the virus simply by attaching itself to it. For example, “If you have an antibody that’s stuck to the tip of the spike protein on the business end of the virus — just the fact that it’s firmly stuck to it means the virus can’t infect a cell,” says Lowe.

The spike protein has been the target of all monoclonal antibody treatments that track the virus. But it was a fickle soulmate, mutating with new variants and letting the monoclonal antibodies float in the bloodstream without being able to bind.

Companies have stopped marketing these monoclonal drugs. The federal government stopped promising to buy them in bulk, making it a riskier bet for companies.

“There are antibodies out there, but nobody has the $200 million to develop them,” Dieffenbach says, citing the costs, which include making the antibodies, conducting studies and getting them approved by the Food and Drug Administration. Some companies didn’t think it was worth it for a product that would likely be obsolete within months, he says.

To be clear, these are antibody treatments for outpatient use. There is another way of treating hospitalized patients with monoclonal antibodies that remains viable. Actemra, as it is called, is not prone to viral mutations because it targets the body’s immune response to the virus rather than the virus itself.

New directions in research and a possible comeback

There may still be hope for monoclonal drugs. Drug makers and researchers at government agencies are now retooling strategy and looking for monoclonal antibodies that might last.

“Initially, the focus was, ‘let’s just find the strongest antibodies,'” says Joshua Tan, director of the Antibody Biology Division at the NIH. “Now there’s an awareness that we need to find antibodies that probably don’t just work against it [current version of the] Coronavirus, but whatever may come.”

Joshua Tan, head of the Antibody Biology Division at the NIH.

/Pien Huang/NPR

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Pien Huang/NPR

Joshua Tan, head of the Antibody Biology Division at the NIH.

At his lab in Rockville, Md., Tan and the researchers he works with are looking for antibodies that target parts of the virus that have remained the same across several different viruses within the larger coronavirus family. “We’re looking at other parts of the spike protein that may be more consistent and difficult to mutate,” says Tan.

To do this, researchers in Tan’s lab are taking immune cells from the blood of patients who have recovered from COVID and throwing tiny plastic beads covered with spike proteins from different, older coronaviruses at them to see which ones cells respond to it. “Not the [COVID] Variants, but SARS-CoV-1, SARS-CoV-2, MERS [etc.]’ clarifies postdoc Cherrelle Dacon. “These are seven different coronaviruses that infect everyone.”

The immune cells that respond to several different coronaviruses make antibodies that bind to a part of the spike protein that stays the same across them.

It’s a laborious process: isolating individual immune cells, finding the ones that make antibodies in response to various spike proteins — and then using those to make more antibodies that they can scale up, analyze, and test, to find out what they’re actually doing to the virus binding. The process takes about three to four months per cycle, Tan says.

Tan says the good news is that they’ve found some antibodies that stick to several different coronaviruses. They released some of the results earlier this summer in Science.

Right: Tan holds a chip that is loaded with immune cells that are sorted and tested against different viruses.  Left: The screen of the Beacon, a machine that isolates individual immune cells so researchers can test which respond strongly to more than one coronavirus.

/Pien Huang/NPR

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Pien Huang/NPR

Right: Tan holds a chip that is loaded with immune cells that are sorted and tested against different viruses. Left: The screen of the Beacon, a machine that isolates individual immune cells so researchers can test which respond strongly to more than one coronavirus.

But the problem the researchers have encountered is that the monoclonal antibodies they found are not that strong. According to Tan, there seems to be a trade-off – between the effectiveness of a monoclonal antibody against COVID-19 and the time it takes for the virus to leave the antibody’s target.

An analogy: If the coronavirus had human body parts (which it doesn’t), the ancient, highly potent monoclonals hit the virus’s spike protein square on the nose. In contrast, the new monoclonal tan try to grab it by the armpit. “One of the problems seems to be that it’s harder to reach those parts,” says Tan, “the wider, the less effective.” [antibodies] The spike protein has to “change its shape” in order for them to grab it.

Tan is working to find ways around this trade-off. He says they could potentially modify the antibody, swapping out parts of it to increase its effectiveness – a process that’s largely theoretical at the moment and will take some time to work out.

So, as Tan and other researchers work on the next generation of monoclonal antibodies—ones that work well against all types of coronaviruses, perhaps even against future pandemics—the nation enters a long hiatus of no monoclonal antibody treatments, which act against dominant SARS strains -CoV-2.

“The disappointment is there because you lose a really good drug,” says Razonable. “But you are focused on the next options. The virus is adapting, and so are we, based on what we have available.”

Luckily, with Tan and others following the long antibody game, there are other treatments like Paxlovid pills and Remdesivir infusions that still work against COVID.

And the discovery and rapid development of antibody treatments has opened up possibilities beyond COVID. “It has improved the production of monoclonal drugs for cancer, for immunological diseases,” says Dieffenbach, “Based on the lessons learned from SARS-CoV-2, it will be easier to produce monoclonal drugs in the future. Nothing was wasted here.”

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