How monoclonal antibodies lost the battle with new COVID variants

Monoclonal antibodies have been the star of outpatient treatments for COVID-19. Since it first became available in 2020 — even before the first vaccines — more than 3.5 million injections of the factory-grown protein have been given to patients in the United States to help reduce the risk of hospitalization.

But the various monoclonal treatments have lost, one after another, their effectiveness against the new variants of the Corona virus. The emergence of the antiviral pill Paxlovid earlier this year has dampened its appeal.

Now, a new wave of Omicron sub-variants that are best yet at evading the current defenses of the US immune system have taken over and are expected to wipe out bebtelovimab, the last monoclonal antibody treatment standing against the coronavirus. And soon it will join bamlanivimab, casirivimab, sotrovimab and others in the graveyard of monoclonal organisms that once targeted earlier COVID strains until they were hemmed in by variants that evaded protection.

“Animals were monoclonal then, like the Model T or biplanes,” says Carl Dieffenbach, MD, director of the division of AIDS at the National Institutes of Health and lead of the NIH’s Antiviral Epidemiology Program, “and now is the time to move on.”

Not everyone totally agrees. Some doctors say that monoclonal compounds are still useful in treating high-risk populations.

“There are severely immunosuppressed patients who are not likely to develop an immune response to the virus, even if you treat them with antiviral medication,” says Dr. Raymond Razonable, an infectious disease specialist in the Mayo Clinic’s division of transplantation. “This is the group that will be most affected by the absence of antibody-based therapies.”

There is more new research underway to develop new types of monoclonal antibodies that can counteract the new variants.

How monoclonals work – and what’s up against them

Monoclonal antibody therapies have always had a major weakness — new COVID strains easily overcome them. It is a flaw discovered in the way it works.

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

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

The little Y-shaped proteins lurk in the blood in low concentrations, “waiting and waiting until they hit something to stick to really well, and find their soulmate,” Lowe explains. A “soul mate” is an antigen – a foreign substance that has entered the bloodstream, such as a bacterial protein, virus, or pollen.

Once the monoclonal antibody finds its intimate companion — in the case of COVID, a specific fragment 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 most powerful antibodies can stop the virus in its tracks by simply binding to it. For example, “If you have an antibody that sticks to the tip of a protein spike at the working end of the virus — just the fact that it’s stuck so tightly means that the virus can’t infect a cell,” Lowe says.

The spike protein has been the target of almost all monoclonal antibody therapies hunting the virus to date. But it was a fickle soulmate, changing with new variables, letting monoclonal antibodies escape into the bloodstream with nowhere to stick.

Companies have stopped bringing these monoclonal organisms to market. The federal government has stopped promising to buy them in large quantities, making them an even riskier bet for companies.

“There are antibodies, but no one has $200 million to develop them,” Dieffenbach says, noting the costs that include producing antibodies, running trials and getting FDA clearance. 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 therapies for outpatient treatment. A different type of monoclonal antibody therapy for hospitalized patients remains viable. Actemra, as it is called, is not susceptible to viral mutation because it targets the body’s immune response to the virus, not the virus itself.

New directions in search and potential comebacks

There may still be hope for monoclonal animals. Drug makers and researchers at government agencies are now retooling the strategy, searching for monoclonal antibodies that could stick.

“In the beginning, the focus was ‘let’s just find the most effective antibodies,'” says Joshua Tan, chief of the Antibody Biology Unit at the National Institutes of Health. Not only [current version of the] Corona virus, but whatever may come.”

In his lab in Rockville, Maryland, Tan and the researchers working with him are searching for antibodies that target parts of the virus that have remained intact in several different viruses within the larger coronavirus family. “We’re looking at other parts of the spike protein that might be more consistent and might be more difficult to mutate,” says Tan.

To achieve this, researchers in Tan’s lab are taking immune cells from the blood of patients who have recovered from COVID, and showering them with small plastic pellets covered in spike proteins from different, older coronaviruses to see which cells respond. “Not [COVID] variants, but SARS-CoV-1, SARS-CoV-2, and MERS [etc.],” explains postdoctoral researcher Cherrelle Dacon.” These are seven different coronaviruses, all of which infect humans. ”

Immune cells that react to many different coronaviruses make antibodies that bind to a portion of the spike protein that remains intact across them.

It’s a tedious process: Isolate individual immune cells, find the ones that make antibodies in response to the different spike proteins — and then use those antibodies to produce more antibodies that they can scale up, analyze and test, to see what they are on to the virus. Re-binding indeed. Tan says the process takes about three to four months per cycle.

The good news, Tan says, is that they’ve found some antibodies that stick to many different coronaviruses. They published some of the findings earlier this summer in Science.

The problem the researchers ran into, however, is that the monoclonal antibodies they discovered aren’t very potent. There appears to be a trade-off, Tan says — between how well a monoclonal antibody works against COVID-19, and how long it lasts before the virus gives up the antibody’s target.

An analogy: If the coronavirus had human body parts (which it doesn’t), ancient, highly effective monoclonal organisms would hit the virus spike protein directly on the nose. In contrast, the new monoclonal Tan animals try to grab them by the armpits. “One of the problems seems to be that it’s hard to get to those parts,” says Tan. [antibodies] The need for the spike’s protein to change shape so they can grab it.

Tan is working on ways around this trade-off. He says you can tweak the antibody, altering parts of it to increase its effectiveness—a process that’s largely theoretical at the moment, and one that will take some time to work out.

So while Tan and other researchers work on the next generation of monoclonal antibodies — ones that work well against all types of coronaviruses, and possibly even future pandemics — the nation enters a long lull without monoclonal therapies that work against the dominant strains of SARS-CoV. -2.

“The disappointment is there because you’re missing out on 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 available.”

Fortunately, while Tan and others are pursuing the long game with antibodies, there are other treatments, such as baxlovid pills and remdesivir injections, that still work against the coronavirus.

The research and rapid development of antibody therapies has opened up possibilities beyond COVID. “It has improved the production of monoclonals for cancer and immune diseases,” Dieffenbach says. “It will be easier to produce monoclonals in the future because of the lessons learned from SARS-CoV-2. Nothing was wasted here.” [Copyright 2022 NPR]

Leave a Reply

%d bloggers like this: