Some monoclonal antibodies have been rendered largely ineffective because the virus has mutated; others are expected to become so this winter if a wave of new omicron subvariants were to dominate the pandemic landscape. For example, the US Food and Drug Administration recently warned that widely used therapies Bebtelovimab and Evusheld may no longer work against certain versions of the coronavirus.
The development is particularly worrisome for people with weakened immune systems; vaccines are less effective in these patients, and many have instead turned to antibody therapy for protection. As these treatments decline, millions of people are at increased risk of contracting covid-19.
“I would say that’s a big deal,” said Michael Barnett, associate professor of health policy and management at Harvard University’s TH Chan School of Public Health.
People with weakened immune systems make up about 3% of all Americans and 12% of American patients hospitalized with covid-19. Additionally, one of the most effective remaining alternative treatments, Paxlovid, has interactions with other drugs that would make it too risky for use by people with weakened immune systems, especially transplant patients. of organ.
Driven by this urgent need, scientists are exploring new ways to tackle the problem, including antibodies that seek new targets among vulnerable parts of the virus.
“Hopefully some of them will go into clinical trials soon, and then it won’t take long” to find out if they work, said William Haseltine, a former Harvard Medical School professor who founded academic research on cancer and HIV/AIDS. departments.
“Either it protects you from infection or it doesn’t.”
A new cocktail of antibodies developed by the Sherbrooke biotechnology company Immune Biosolutions is undergoing clinical trials in South Africa and Brazil. Participants receive the treatment as a mist sprayed in their mouths for about three minutes while breathing normally.
“We saw a big drop in viral load” during phase 1 safety testing, said Bruno Maranda, the company’s chief medical officer.
For its phase 2 tests, the company is conducting two separate trials to see if the cocktail has the intended effects: one with patients with mild to moderate covid-19, the other with patients hospitalized with covid-19. strict.
Two of the three antibodies in the cocktail, known as IBO123, target a familiar region of the spike protein where the virus attaches to a human cell. This region is an obvious place to block the virus, but scientists have discovered a downside. The target changes frequently, allowing the virus to move away from obstacles researchers put in its path.
“There is enormous immune pressure on the virus,” explained Andrés Finzi, an associate professor at the University of Montreal whose lab helped develop the antibody cocktail. So far, evolution has favored mutations that allow the spike protein to rid itself of antibodies that try to prevent it from latching onto our cells. These mutations have fueled the rise of variants and subvariants that beat current lab-made antibodies.
That’s why the third antibody in Immune Biosolutions’ cocktail attacks the opposite end of the protein, called the stem helix. This region is what allows viral and human cell membranes to fuse together during the infection process. The new antibody acts like a pair of hands strangling the stem helix.
This section of the spike protein is in the crosshairs of scientists because it has stubbornly stayed the same even as the virus has produced new variants and subvariants. When a section of a protein resists change, it is a sign that it is important, even essential, for the protein to work.
If an antibody disrupts this rigid part of the virus, the pathogen is less likely to mutate to circumvent the attack.
So far, the third antibody has been effective in testing against all variants and subvariants of the coronavirus except XBB, on which it has not yet been tested, Finzi said. Maranda said he expects to see results from their first phase 2 trial by the end of the year. The organizers of the second trial are still recruiting patients with severe covid-19. A third trial testing the cocktail’s ability to prevent infection is expected to begin in a few weeks.
Two other antibodies that focus on stable parts of the spike protein were discovered in a lab at the Institut Pasteur in Paris and developed by French biotech company Spiklmm. They have now entered phase 1 clinical trials.
Hugo Mouquet, head of the humoral immunology laboratory at the Institut Pasteur, said by email that the two new antibodies were effective in a laboratory dish against all common variants of the coronavirus, although they did not have not yet been tested against the new omicron BQ.1, BQ.1.1 and XBB subvariants.
If approved for use, these antibodies would be given to people with weakened immune systems before they were exposed to the coronavirus. Like the Evusheld antibody cocktail, they would be used to prevent infection. In contrast, bebtelovimab is given to patients after infection, but within seven days or less of the onset of covid-19 symptoms.
Additionally, a July article in the journal Science described a pair of novel antibodies that target another stable section of the coronavirus spike protein, the fusion peptide. This part of the tip “acts like a grappling hook and inserts itself into the human cell membrane, bringing the membrane closer to the viral membrane,” said Joshua Tan, head of the antibody biology unit at the National Institute of Allergy. and infectious diseases.
Although lab-made antibodies that hit the fusion peptide and stem helix are less potent, Tan said, they are effective against a wider range of coronaviruses. In the lab, Syrian hamsters treated with one of his team’s antibodies and then infected with the coronavirus suffered less severe illness and recovered faster than infected hamsters who received no treatment.
In a paper published more recently in the journal Cell Host & Microbe, Tan and his colleagues identified two other monoclonal antibodies that both attack the stem helix of the spike protein. In tests on infected hamsters, these antibodies helped the animals maintain their weight. Infected hamsters that received none of the antibodies lost around 10% of their body weight in six days. The study interpreted weight loss as a measure of disease, because sick hamsters tended to eat less.
Tan could not say when the monoclonal antibodies examined in these studies might enter clinical trials.
Bing Chen, a professor of pediatrics at Harvard University who has studied the atomic structure of the spike protein, said that so far antibodies to the virus binding site remained more potent than those targeting other sections of the protein. He also stressed that developing better monoclonal antibodies should not take priority over other medical tools.
“You need much more effective vaccines, that’s for sure,” Chen said. While vaccines were very effective at first, viral mutations allowed more so-called breakthrough infections in fully vaccinated people.
And despite their early success with their next-gen cocktail, Immune Biosolutions’ Finzi added a note of caution:
“The ability of a coronavirus to mutate should not be underestimated.”
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