Scientists are working on developing new laboratory-produced antibodies to fight covid
Some monoclonal antibodies are rendered largely ineffective how the virus mutated; Others are expected to become so this winter if a wave of new omicron subvariants begin to dominate the pandemic landscape. For example, the US Food and Drug Administration recently warned that widely used therapies Bebtelovimab and Evusheld it may no longer work against some versions of the coronavirus.
The development is of particular concern to people with weakened immune systems; vaccines are less effective in these patients and many have turned instead to antibody therapy for protection. As these treatments disappear, 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 Harvard University’s TH Chan School of Public Health.
People with weakened immune systems represent about 3 percent of all Americans and 12 percent of U.S. patients hospitalized with covid-19. Moreover, one of the most effective remaining alternative treatments, Paxlovidit has interactions with other drugs 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 look for new targets among vulnerable parts of the virus.
“I hope some of them will be in clinical trials soon, and then it won’t take long” to see 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.”
One new antibody cocktail developed by biotech company Immune Biosolutions of Sherbrooke, Quebec, is in clinical trials in South Africa and Brazil. Participants receive the treatment in the form of a mist that is sprayed into their mouths for about three minutes while they breathe normally.
“We saw a sharp drop in viral load” during the first phase of safety testing, said Bruno Maranda, the company’s chief medical officer.
For its phase two tests, the company is conducting two different trials to see if the cocktail has the desired effects: one with patients who have mild to moderate covid-19, the other with patients who are hospitalized with severe covid-19.
Two of the three antibodies in the cocktail, known as IBO123, target a known region of the spike protein where the virus binds to a human cell. This area is an obvious place to block the virus, but scientists have discovered a flaw. The target often changes, allowing the virus to evade the obstacles researchers have placed in its path.
“There is a huge immune pressure on the virus,” explained Andrés Finzi, an associate professor at the University of Montréal whose lab helped develop the antibody cocktail. Until now, evolution has favored mutations that allow the spike protein to shake off antibodies that try to stop it from latching onto our cells. These mutations have fueled the rise of variants and sub-variants that are defeated by current laboratory-produced 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 viral and human cell membranes to fuse during the infection process. The new antibody acts like a set of hands that choke the stem helix.
This part of the spike protein is in the crosshairs of scientists because it has stubbornly remained the same even though the virus has released new variants and sub-variants. When a part of a protein resists change, it is a sign that it is important, even necessary, for the protein to work.
If the antibody disrupts this rigid part of the virus, the pathogen is less likely to mutate 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 yet to be tested, Finzi said. Maranda said he expects results from their first phase 2 trial by the end of the year. 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 due to begin in a few weeks.
Two other antibodies that target stable parts of the spike protein were discovered in a laboratory at the Institut Pasteur in Paris and were developed by the French biotech company Spiklmm. They have now entered the first phase of clinical trials.
Hugo Mouquet, head of the Laboratory of Humoral Immunology at the Institut Pasteur, said by email that the two new antibodies were effective in the lab against all common variants of the coronavirus, although they have yet to be tested against the new omicron subvariants BQ .1, BQ.1.1 and XBB.
If approved for use, these antibodies would be given to people with weakened immune systems before they were exposed to the coronavirus. Like the antibody cocktail Evusheld, they would be used to prevent infection. In contrast, Bebtelovimab is given to patients after infection, but within seven days or less of showing symptoms of covid-19.
In addition, a July paper in the journal Science described a pair of new antibodies that target another stable part of the coronavirus spike protein, a fusion peptide. This part of the spike “acts like a grappling hook and inserts itself into the human cell membrane, pulling the membrane closer to the virus membrane,” said Joshua Tan, chief of the Antibody Biology Unit at the National Institute of Allergy and Infectious Diseases.
Although lab-produced antibodies that target the fusion peptide and stem helix are less potent, Tan said, they are effective against a wider range of coronaviruses. In the laboratory, Syrian hamsters treated with one of his team’s antibodies and then infected with the coronavirus suffered less disease and recovered more quickly than infected hamsters that did not receive any treatment.
In a paper published recently in journal Cell Host & Microbe, Tan and 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 weight. Infected hamsters that did not receive either antibody lost about 10 percent of their body weight within six days. The study interpreted weight loss as a measure of disease because sick hamsters tend to eat less.
Tan could not say when the monoclonal antibodies tested in these studies might enter clinical trials.
Bing Chen, a professor of pediatrics at Harvard University who researched the atomic structure of the spike protein, said that so far the antibodies have been directed against the virus binding site remained stronger than those targeting other parts of the protein. He also emphasized that the development of better monoclonal antibodies should not take priority over other medical tools.
“You need much more effective vaccines, for sure,” Chen said. While the vaccines were very effective at first, mutations in the virus allowed more so-called breakthrough infections in people who were fully vaccinated.
And despite early successes with the next-generation cocktail, Immune Biosolutions’ Finzi added a note of caution:
“We should not underestimate the ability of the coronavirus to mutate.”