A COVID treatment looms large: New variants outperform most monoclonal antibodies: Shots

Antonio Rapuano receives an infusion of a monoclonal antibody to treat his COVID in Albano, Italy in 2021. Such infections have been an effective treatment for COVID during the pandemic, but doctors are now finding that most monoclonal antibodies no longer work against the new variant of SARS—CoV-2.

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Yara Nardi/Reuters

Antonio Rapuano receives an infusion of a monoclonal antibody to treat his COVID in Albano, Italy in 2021. Such infections have been an effective treatment for COVID during the pandemic, but doctors are now finding that most monoclonal antibodies no longer work against the new variant of SARS—CoV-2.

Yara Nardi/Reuters

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

But one after the other, different monoclonal treatments have lost their effectiveness against the new forms of coronavirus. The rise of Paxlovid antiviral pills earlier this year further reduced their appeal.

Now, a new wave of Omicron subvariants that have so far bested the immune system’s existing defenses have taken over the US, hoping to knock out bebetovimab, the last monoclonal antibody treatment standing against the coronavirus. . Soon, it will join the graveyard of bamlanivimab, casirivimab, sotrovimab and other monoclonals that once targeted previous COVID strains until they were driven out by variants that evaded their protection.

“Monoclonals have had their day, like the Model T or the biplane,” says Carl Dieffenbach, director of the AIDS department at the National Institutes of Health and head of the NIH’s antiviral program for epidemiology, “now it’s time to move on.” ,

Not everyone completely agrees. Some doctors say that monoclonals are still useful for treating vulnerable populations.

An infectious disease specialist in the Transplant Division at Mayo Clinic, Dr. “There are severely immunosuppressed patients who are unlikely to mount an immune response to the virus, even if you treat them with antiviral drugs,” says Raymund Reasonable. “This is the group that is going to be most affected by the absence of antibody-based therapies.”

Is there further research going on to develop new types of monoclonal antibodies that can also be against the new variants.

How do monoclonals work – and what are they up against

Monoclonal antibody treatments have always had one major weakness – they are easily outclassed by new COVID strains. It’s a flaw that’s baked into the way they work.

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

“You and I and every human being who has a functioning immune system is probably walking around with trillions of completely different antibody molecules circulating in our blood,” says Derek Lowe, a chemist and blogger for the journal. science“Each one of us has a completely different suit of them. There are more of them than there are stars in the sky.”

The tiny, Y-shaped proteins lurk in the blood in low concentrations, “waiting and waiting until they bump into something they stick to really well, and they’re basically the soul of their own.” find,” Lowe explains. That “soulmate” is an antigen—a foreign substance that enters the bloodstream, such as a bacterial protein or virus or pollen grain.

Once a monoclonal antibody finds its life partner – in the case of COVID, a specific part on the tip of the SARS-CoV-2 virus – it binds to the surface of the antigen. Then, it sends a signal to the immune system that’s like, “hey, I’ve got a live one,” says Lowe.

The most powerful antibodies can stop the virus just by binding to it. For example, “If you have an antibody that sticks to the tip of the spike protein at the business end of the virus – the mere fact that it’s stuck on tightly means the virus can’t infect the cell.” says Lowe.

The spike protein has so far been the target of all monoclonal antibody therapies that go after the virus. But it has been a fickle soul mate, changing with new variants, leaving monoclonal antibodies in the bloodstream with nowhere to bind.

Companies have stopped marketing these monoclonals. The federal government stopped short of promising to buy them in quantity, making it a riskier bet for the companies.

“There are antibodies out there, but nobody has $200 million to develop it,” Dieffenbach says, citing the costs involved in producing the antibodies, running the tests, and getting them authorized by the Food and Drug Administration. Some companies thought it wasn’t worth it, for a product that was likely to become obsolete in a matter of months, he says.

To be clear, these are antibody treatments for outpatient treatment. There is a different type of monoclonal antibody treatment for hospitalized patients that remains viable. Actemra, as it’s called, isn’t as susceptible to virus mutations because it targets the body’s immune response rather than the virus itself.

New directions in research, and a possible comeback

There may still be hope for monoclonals. Researchers at drugmakers and government agencies are now reshaping the strategy in search of monoclonal antibodies that can last.

“In the beginning, the focus was, ‘Let’s find the most potent antibodies,'” says Joshua Tan, head of the Antibody Biology Unit at NIH. “Now, there’s an awareness that we need to find antibodies that are likely to work not only against [current version of the] Coronavirus, but whatever may come.”

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

Pien Huang / NPR

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Pien Huang / NPR

In his lab in Rockville, MD, Tan and the researchers he works with are looking for antibodies that target parts of the virus that remain the same on many different viruses within the larger coronavirus family. “We are 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 are taking immune cells from the blood of patients who have recovered from COVID, and treating them with tiny plastic pellets covered with spike proteins from different, older coronaviruses to see if For which cells react. “Not there [COVID] variants, but SARS-CoV-1, SARS-CoV-2, MERS [etc.],” explains post-doctoral researcher Cheryl Deacon. “These are seven different coronaviruses, all of which infect humans.”

Immune cells that react to many different coronaviruses are making antibodies that bind to a part of the spike protein that remains the same among them.

It’s a painstaking process: isolating individual immune cells, finding those that make antibodies in response to different spike proteins – and then using them to make more antibodies to find out what they’re doing to the virus. Can analyze and test for. really binding. This process takes about three to four months in each cycle, says Tan.

The good news, Tan says, is that they have found some antibodies that stick to many different coronaviruses. They published some results earlier this summer science,

Right: Tan holds a chip ready to be loaded with immune cells that will be sorted and tested against different viruses. Left: Screen of Beacon, a machine that separates individual immune cells so researchers can test which respond strongly to more than one coronavirus.

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Pien Huang / NPR

But the problem the researchers have put forward is that the monoclonal antibodies they have found are not that potent. Tan says there seems to be a tradeoff — how well a monoclonal antibody works against COVID-19, and how long the virus lives before the antibody hits its target.

An analogy: If the coronavirus had human body parts (which it doesn’t) the spike protein of an old, highly effective monoclonal virus would hit the nose straight. In contrast, the new monoclonal TAN is trying to grab it from the sidelines. “One of the issues seems to be that those parts are harder to reach,” says Tan. “What the wider, the less powerful [antibodies] The spike protein needs to change shape” so that they can hold it.

Tan is working to find ways around this tradeoff. He says you could 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 work out.

So while Tan and other researchers are working on the next generation of monoclonal antibodies — ones that work well against all types of coronaviruses, perhaps even future pandemics — the nation may be entering a long lull without any monoclonal antibody treatments. that works against the major strains of SARS. -Cov-2.

“The frustration is because you’re missing out on a really good drug,” says Reasonable. “But you focus on the next options. The virus adapts, and we adapt too, based on what’s available to us.”

Fortunately, as Tan and others chase the long game with antibodies, there are other treatments, such as Paxlovid tablets and remdesivir infusions, that still work against Covid.

And the research and rapid development of antibody treatments has opened up possibilities beyond COVID. “This has improved the production of monoclonals for cancer, for immunologic diseases,” says Dieffenbach, “because of the lessons learned from SARS-CoV-2, it will be easier to produce monoclonals in the future.” Nothing is wasted here.

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