Some monoclonal antibodies have become largely ineffective because the virus has mutated; others are expected to be this winter if a wave of new omicron sub-variants come to dominate the pandemic landscape. For example, the US Food and Drug Administration recently warned that the widely used therapies Bebtelovimab and Evusheld might not work against some versions of the coronavirus.
The development is especially 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 it’s a big problem,” said Michael Barnett, an associate professor of health policy and management at the Harvard TH Chan School of Public Health.
People with weakened immune systems make up about 3 percent of all Americans and 12 percent of hospitalized American patients with Covid-19. Additionally, one of the most effective alternative treatments remaining, Paxlovid, has drug interactions that would make it too risky for use by people with compromised immune systems, especially organ transplant patients.
Driven by this urgent need, scientists are exploring new ways to tackle the problem, including antibodies that seek out new targets among vulnerable parts of the virus.
“Hopefully some of these will be in clinical trials soon, and then it won’t take very long” to determine if they work, said William Haseltine, a former Harvard Medical School professor who founded the university’s cancer and HIV/AIDS research. . departments
“Either it protects you from infection, or it doesn’t.”
A new cocktail of antibodies developed by biotech company Immune Biosolutions of Sherbrooke, Quebec, is in clinical trials in South Africa and Brazil. Participants receive the treatment as a mist sprayed into their mouths for about three minutes while breathing normally.
“We saw a sharp decline in viral loads” during Phase 1 safety testing, said Bruno Maranda, the company’s chief medical officer.
For its Phase 2 trials, the company is running two separate trials to see if the cocktail has the desired effects: one with patients who have mild to moderate Covid-19, the other with hospitalized patients with severe Covid-19.
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 snag. The target changes frequently, allowing the virus to escape obstacles that the researchers put in its path.
“There is enormous immunological 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 get rid of the antibodies that try to prevent it from attaching to our cells. These mutations have fueled the emergence of variants and subvariants that are defeating current laboratory-made antibodies.
That’s why the third antibody in the Immune Biosolutions cocktail attacks the opposite end of the protein, called the stem helix. This region is what allows the membranes of viral and human cells 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 remained the same even as the virus has produced new variants and subvariants. When a section of a protein resists change, it’s a sign that it’s 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 get around the attack.
So far, the third antibody has been effective in tests against all variants and subvariants of the coronavirus except for XBB, which has not yet been tested, Finzi said. Maranda said he hopes to see the results of his 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 scheduled to begin in a few weeks.
Two other antibodies that focus on stable portions of the spike protein were discovered in a laboratory at the Pasteur Institute in Paris and developed by the French biotech company Spiklmm. They have now entered phase 1 clinical trials.
Hugo Mouquet, head of the Institut Pasteur’s Laboratory of Humoral Immunology, said by email that the two new antibodies have been effective in a laboratory dish against all common variants of the coronavirus, although they have not yet been tested against the new omicron BQ subvariants. . .1, BQ.1.1 and XBB.
If approved for use, these antibodies would be given to people with weakened immune systems before they have been exposed to the coronavirus. Like the Evusheld antibody cocktail, they would be used to prevent infection. By contrast, Bebtelovimab is given to patients after infection, but within seven days or less of showing symptoms of covid-19.
In addition, a July article in the journal Science described a pair of new antibodies that target another stable section of the coronavirus’s spike protein, the fusion peptide. This part of the spike “acts like a grappling hook and inserts into the human cell membrane, bringing the membrane closer to the virus membrane,” said Joshua Tan, chief of the Antibody Biology Unit at the National Institute of Allergy and Diseases. infectious.
Although lab-made antibodies that hit the fusion peptide and the stem helix are less potent, Tan said, they are effective against a broader 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 disease and recovered faster than infected hamsters that received no treatment.
In a paper published more recently in the Cell Host & Microbe journal, Tan and colleagues identified two more monoclonal antibodies that target the spike protein’s stem helix. In tests with infected hamsters, these antibodies helped the animals maintain weight. Infected hamsters that did not receive either antibody lost about 10 percent of their body weight in six days. The study interpreted weight loss as a measure of illness because sick hamsters tend to eat less.
Tan was unable to say when the monoclonal antibodies examined in these studies might move on to clinical trials.
Bing Chen, a professor of pediatrics at Harvard University who has been investigating the atomic structure of the spike protein, said that until now antibodies directed against the virus binding site has remained more potent than those targeting other sections of the protein. He also stressed that the development of better monoclonal antibodies should not take precedence over other medical tools.
“Much more effective vaccines are needed, for sure,” Chen said. While the vaccines were highly effective from the start, viral mutations have allowed more so-called breakthrough infections in people who are fully vaccinated.
And despite his early successes with his next-generation cocktail, Immune Biosolutions’ Finzi added a note of caution:
“We should not underestimate the mutation capacity of a coronavirus.”