Antibody cocktails Eli Lilly and Regeneron Pharmaceuticals have now received emergency use approval from the U.S. Food and Drug Administration (FDA) for the treatment of Covid-19. Such antibodies attach to the virus protein and prevent it from entering the cells. However, with spike mutations in the new variants, there are concerns that some of these treatments will become ineffective.
Eli Lilly treatment consists of two antibodies that are injected intravenously into patients. The European Medicines Agency (EMA) is reviewing this cocktail. The FDA only approved one of those antibodies, bamlanivimab, in November. In January, Eli Lilly reported reducing the risk of developing symptomatic Covid-19 by up to 80% when given to residents of nursing homes in the United States.
The FDA has approved the Lilly combination for mild to moderate patients with Covid-19 who are at risk of severe disease. He also approved two Regeneron antibodies for mild to moderate Covid-19 back in November (casirivimab and imdevimab). Former US President Donald Trump claims that Regeneron cured him with a combination of Covid-19 late last year.
Monoclonal antibodies are synthetic proteins created in mammalian cell culture. They mimic our natural antibodies. A number of them are a successful anti-inflammatory method, and two that block the proinflammatory cytokine interleukin-6 reduce mortality in severely ill patients with Covid-19.
In 2019, seven of the 10 best-selling drugs were monoclonal antibodies. Some of the newer monoclones target viruses. In fact, the FDA approved a cocktail of three monoclonal antibodies from Regeneron against the Ebola virus in 2020. They release a viral glycoprotein that binds to a cellular receptor. The FDA has approved another antibody (Ebanga) that interferes with binding.
For Sars-CoV-2, most monoclonal antibodies were created to target the portion of the protein classes that bind to the human Ace2 receptor. “You can basically make unlimited amounts of that antibody in a bioreactor as a biological drug,” says James Crowe, an immunologist at Vanderbilt University Medical Center in the United States.
This approach differs from the use of convalescent plasma taken from recovered patients with Covid-19. Convalescent plasma can be injected into sick patients, but it contains thousands of antibodies against many different antigens. “Only a small percentage of those antibodies would be for coronavirus,” Crowe says. ‘While monoclonal antibodies are 100% for coronavirus, so it’s more like a drug.’ Convalescent plasma is a far more variable product because it comes from individual patients.
To develop new monoclonal antibodies against Sars-CoV-2, scientists first choose from thousands of potential candidates, and then mix several with the virus in the laboratory to identify the most powerful ones. ‘It’s like looking for a needle in a haystack [initially], ‘says Crowe. ‘The next step is usually testing on small animals to determine if they are protective, and then on larger animals, such as macaque monkeys.’
All of this takes time, which is why Crowe was so impressed with Eli Lilly’s progress. ‘They were in the clinic until June 2020, which is a miracle. The fastest ever, ‘says Crowe. It is bamlanivimab, discovered in a blood sample taken from one of the first patients in the United States to recover from Covid-19.
Unfortunately, antibodies are generally disappointed in the treatment of severely ill patients with Covid-19. “The results of very sick patients were a bit dubious,” says Aashish Manglik, a biochemist at the University of California, San Francisco in the United States. “They have to give large doses of the vaccine, almost eight grams per patient.” Crowe explains that “the longer you wait, the harder it is to treat” with antibodies.
Another issue is that existing antibody therapies require an intravenous infusion. This means that mild or moderately ill patients must go to a health facility when they are probably most contagious. “The logistics of introducing many people to such an institution pose a challenge to the widespread application of the antibody approach,” says Manglik. Crowe describes the intravenous infusion as a “moderate barrier to frequent use.”
The ability of a virus to escape with a single antibody is quite high
James Crowe, Vanderbilt University Medical Center
AstraZeneca is undergoing five phase 3 clinical trials in combination with two antibodies (designated AZD7442), developed at Crowe’s laboratory in Vanderbilt. This cocktail can be given as an injection, and one test with 5,000 participants will test it as a preventative injection. “It’s an intramuscular injection, so it’s going to be a lot easier to use than an intravenous infusion,” Crowe says.
Cocktails look more favorable than solitary antibodies. Antibodies developed by Vir Biotechnology and GSK are combined with Eli Lilly antibody (bamlanivimab) to treat patients as part of a new study. The two bind to different parts of the protein classes.
“The ability of a virus to escape with a single antibody is pretty high,” Crowe says. “But his ability to avoid two antibodies, against different parts of the virus, is very small.” Combinations are insurance against virus escape.
This issue is all the more critical because some variants have mutated class proteins and avoid some antibodies. One of Eli Lilly’s antibodies is unlikely to work against some new variants, Crowe says, while Regeneron’s antibodies have a moderate effect on mutants.1 “When new variants spread around the world,” Crowe says, some of these monoclonal antibodies may not be optimal against some strains of the virus.
The best solution for rescuing patients infected with coronavirus is to combine approved antibodies from different companies, says immunologist Hans-Martin Jäck of the University of Erlangen-Nuremberg in Germany, who has developed two monoclonal antibodies against Sars-CoV-2 spikes. The test site could collect approved antibodies and test them against the new mutant in a few weeks, he says. ‘If you combine the most effective in one cocktail, then one will almost certainly succeed against any new variant.’ However, this concept would require some rethinking of drug regulators.
Researchers are also studying alternative approaches. Manglik has developed fully synthetic anti-protein nanotels from a library of two billion compounds. “We’re doing animal testing and hope to get into clinical trials in the next few months.” The nanobod could be given directly into the nose or airways, he added.
Nanoparticles are small proteins originally identified in camel species such as llamas and alpacas, which make up these mini-versions of antibodies. The first such miniature antibody was approved by the European Clinical Agency for Clinical Use in 2018: the Nanobody Sanofi (Cablivi) for a rare blood clotting disorder.
Another strategy is to develop ‘broadly neutralizing antibodies’ that will target a range of related viruses. Laura Walker, American biotechnology company Adagio Therapeutics, and colleagues have created an antibody that neutralizes Sars-CoV-2,2 but also related coronaviruses, including Sars-CoV. It does so by targeting a conserved region of the receptor binding domain, which they call the “Achilles’ heel” and a possible target for future pan-sars vaccines. An extended version of the half-life antibody (ADG20) entered a clinical trial a few weeks ago and will be given as an injection.
Monoclonal antibodies can be used as prophylaxis, immediately after someone has been exposed to Sars-CoV-2, unlike a vaccine. For now, however, existing monoclonal antibodies must be infused and thus remain a logistically challenging option in many environments.
Unlike anti-inflammatory conditions, Jäck says “antibodies won’t be a hit for the coronavirus because they’ll only need those who can’t be vaccinated,” like immunologically vulnerable people. However, he adds that antibody therapies will certainly save lives.