The COVID-19 virus has mutated to outperform leading antibody therapies.Better Things Coming | Chemistry

In 2020, with the novel coronavirus disease (COVID-19) pandemic raging and no other effective drugs found, monoclonal antibodies (mAbs) have emerged as a life-saving treatment. But now, three years later, the SARS-CoV-2 virus has mutated and the US has withdrawn all approvals for antibodies to fight the novel coronavirus, as drugs that target parts of the original virus have become ineffective. rice field.

Researchers around the world are now trying to revive antibody therapy by redesigning it to target less mutable targets. “There’s a new approach that poses a much harder challenge to avoiding the virus,” says virologist Paul Bienius of the Rockefeller University. For example, just this week, researchers in Canada reported that they had created an antibody-like compound that could simultaneously capture dozens of sites on viral proteins. It acts as a kind of molecular Velcro that suppresses the virus even if some sites are damaged. Mutated to avoid drug candidates. Other researchers have taken less radical approaches to generate mutation-resistant antibodies.

But everyone worries that the study will take time to reach clinics. With the pandemic emergency declared over in the United States and elsewhere, governments and industry may be less motivated to develop promising new COVID-19 treatments. “There is no longer a business model for this,” said Michael Osterholm, a public health expert at the University of Minnesota.

All of the initial life-saving antibodies glowed at the tips of spikes, the protein SARS-CoV-2 uses to bind to its human cell-surface receptor angiotensin-converting enzyme 2 (ACE2). During his first two years of the pandemic, spike changes were sufficient to keep her mAb working. However, as people with antibodies from previous infections or vaccinations encountered the virus, new variants emerged with extensive mutations in the ACE2-binding region known as the receptor-binding domain (RBD). Mutants evaded treatment and drug companies were thrown into chaos. “By the time you separate the good, [mAb] The virus has moved on,” said Laura Walker, who heads the infectious disease biotherapeutic discovery and engineering division at Moderna.

Researchers are now looking for antibodies that target the portion of the spike that the virus cannot mutate without losing its ability to infect cells. “People are after the hidden gem, targeting something too conserved for viruses to mutate,” says Jean-Philippe Julien, an immunologist at the University of Toronto.

For example, in March, an international team led by researchers from the University of Italy and Switzerland We isolated several human antibodies that targeted conserved targets on spikes, does not change across multiple virus variants. One binds to a site known as a fusion peptide and prevents the virus from fusing with human cells. In cell-based assays, the antibodies bound to four different coronavirus families, including SARS-CoV-2. Another antibody that targets the spike site, known as the stem helix, blocked all SARS-CoV-2 variants from fusing with human cell membranes. The group reports in its March 10 issue. scientific immunologyA ‘bispecific’ antibody that binds both the RBD and another region called subdomain 1 (SD1) that is involved in cell fusion has also been used to transform mice into ancestral and omicron SARS-CoV-2 mutants. It has also been found to protect against

Other groups are pursuing the same strategy. Researchers at Fred Hutchinson Cancer Center (FHCC) reported in a bioRxiv preprint in March that they were as well. Isolation of an SD1-targeting antibody that protects mice from all recent concerns. And in January, a group led by antibody biologist Joshua Tang at the National Institute of Allergy and Infectious Diseases Cell hosts and microorganisms or Other fusion peptide- and helix-binding antibodies can neutralize a wide range of SARS-CoV-2 variants in animals. “We’re seeing more and more broad-spectrum antibodies because they’re targeting spikes in different regions,” says FHCC virologist Julie Overbaugh, who led the SD1 study.

Another approach targets the human protein ACE2 to which SARS-CoV-2 and its analogues bind on the cell surface. Last week, Bieniaz and his colleagues reported: encouraging results of natural microbiology. They injected mice with a soluble copy of the human ACE2 receptor. Thirty-five days later, they screened the animal sera for antibodies that target ACE2 and block SARS-CoV-2 binding. They chose the most potent one and injected it into mice infected with SARS-CoV-2 variants or various other sarvecoviruses (a group of human and animal viruses that includes SARS-CoV-2). . The antibody “was equally effective against all of them,” says Bieniasch.

“This looks pretty promising,” Oberbaugh says. But she and others are concerned that targeting human proteins could cause side effects. They worry that ACE2’s normal function might be interfered with because it helps regulate blood pressure, among other roles. Recent reports have further raised concerns by suggesting that people infected with Long Covid may: produce antibodies against its own proteins, including ACE2. Bieniasz agrees that more animal and human trials are needed for this strategy, but early cell culture studies show that his group’s antibodies do not interfere with the proper working of ACE2. It seems that

A third strategy aims to alter the structure of the antibody itself in hopes of making it more potent. Antibodies are usually Y-shaped and have two arms that can bind to two separate targets. Julien and his colleagues designed a spherical ‘multibody’ family with his 24 binding sites each. A new study published this week found that scientific translational medicineToronto Team I designed two different multibodiesOne targeted all 24 binding sites to the same site on the spike protein of SARS-CoV-2, and the other targeted three different sites. When they injected multibodies into infected mice, they found that both designs neutralized the virus at doses well below those required for conventional antibodies. The three targeted multibodies neutralized all recent submutants as well as a broad range of viruses more distantly related to SARS-CoV-2.

Impressed by these results, Walker warns that because multibody strategies are new, they have a long way to go to the clinic. Researchers need to validate that multibodies circulate for days, if not months after injection, and developers have to show that the drug can be produced reliably and cheaply. “It’s not enough [mAbs] It works fine, but [it’s also] It’s about availability,” says Osterholm.

But the momentum needed to turn new antibodies into approved drugs may be waning. President Joe Biden’s administration launched Project Next Generation in March to help commercialize vaccines, monoclonal antibodies and other therapeutics. But the $5 billion in the effort could quickly evaporate, likely falling victim to ongoing negotiations between the administration and Congress over the U.S. debt ceiling. With little government support, drug companies may be reluctant to pour hundreds of millions of dollars into commercializing new treatments. “It will require long-term investments,” says Osterholm. “That’s what we’re missing.”

At the same time, Mr. Tan said, “There are at least a few companies who continue to be interested.” At least he has one big market left. It’s the immunocompromised people who make up about 3% of the U.S. population. Still, promoting new treatments is “obviously more difficult than it was a year or two ago,” he says.