Combination therapies appear to prevent emergence of drug resistance – sciencedaily


Antibody-based COVID-19 therapies are often given to patients who are at high risk of serious illness and hospitalization. However, there have been nagging questions about whether these antibody therapies retain their effectiveness as disturbing new viral variants emerge.

New research at the Washington University School of Medicine in St. Louis suggests that many, but not all, therapies made from combinations of two antibodies are effective against a wide range of variants of the virus. In addition, combination therapies appear to prevent the emergence of drug resistance.

The study, in mice and hamsters, tested all single and combination antibody therapies approved for emergency use by the Food and Drug Administration (FDA), or that are under evaluation in advanced stage clinical trials, against a panel of international and emerging experts. American variants of SARS-CoV-2, the virus that causes COVID-19.

The results, published on June 21 in the journal Nature, suggest that COVID-19 drugs made up of two antibodies often retain their effectiveness as variant therapy even when in vitro studies – experiments conducted in a box – indicate that one of the two antibodies has lost part or all of its ability to neutralize the variant.

“We knew how these antibodies behaved in vitro, but we don’t give people drugs based solely on cell culture data,” said lead author Michael S. Diamond, MD, PhD, Herbert S professor of medicine. Gasser. “When we looked at animals, there were surprises. Some of the combinations gave better results than we thought, based on in vitro data. And there was no drug resistance for the combinations, in all of the different variations. We are going to need to continue monitoring the effectiveness of antibody therapy as more variants emerge, but combination therapy is likely needed to treat infections with this virus as new variants emerge. “

So-called monoclonal antibodies mimic those generated by the body to fight the virus that causes COVID-19. Administering antibody therapies bypasses the body’s slower and sometimes less efficient process of making its own antibodies. At the time this study began, there were two dual antibody combination therapies and one single antibody therapy approved by the FDA for emergency use. The FDA withdrew the authorization for the single antibody therapy, bamlanivimab, in April on the grounds that it was not effective against the variants circulating at the time. In May, the FDA cleared single antibody sotrovimab as a treatment for COVID-19.

In total, the researchers evaluated antibodies matching those approved by the FDA manufactured by Eli Lilly and Co., Regeneron and Vir Biotechnology / GlaxoSmithKline, as well as the antibodies currently in development by AbbVie, Vir and AstraZeneca which are in trials. clinics.

The researchers – led by co-first authors Rita E. Chen, MD / PhD student, Emma S. Winkler, MD / PhD student, and Brett Case, PhD, postdoctoral researcher – tested the antibodies against a panel of variants virals containing key mutations in their spike genes. The SARS-CoV-2 virus uses a spike protein to invade cells. All COVID-19 monoclonal antibody therapies work by interfering with the interaction between the spike protein and cells.

The panel included mutations found in three of the four variants that were designated “variants of concern” by the World Health Organization – Alpha (first identified in the UK), Beta (South Africa) and Gamma ( Brazil) – as well as an emerging variant from India similar to the Delta variant of concern. They also tested variants from New York and California. The researchers used a mixture of virus samples originally obtained from people with COVID-19 and laboratory strains genetically engineered to contain key mutations.

The researchers evaluated the antibodies in hamsters and two strains of mice. The researchers first gave the animals antibodies – either alone or in the same combinations in which they are given to treat patients – a day before infecting them with one of the variants of the virus. The researchers monitored the animals’ weight for six days, then measured the amount of the virus in their noses, lungs and other parts of the body.

Although some individual antibodies showed reduced or no ability to neutralize viral variants in a dish, low doses of most combinations of antibodies protected against disease caused by many variants. The researchers sequenced viral samples from the animals and found no evidence of drug resistance in viruses from any of the animals that had been treated with combination therapies.

“Dual therapy appeared to prevent the emergence of resistant viruses,” said co-author Jacco Boon, PhD, associate professor of medicine, molecular microbiology, and pathology and immunology. “Resistance has developed with some of the monotherapies, but never with a combination therapy. “

Since COVID-19 antibody-based therapies are primarily used to treat people already infected, the researchers also evaluated the performance of the combinations of antibodies when given after infection with the beta variant. The beta variant was chosen because it was found to be the most likely to escape neutralization in laboratory experiments and has the greatest resistance to COVID-19 vaccines. The antibody cocktails corresponding to those of AstraZeneca, Regeneron and Vir were all effective in reducing disease caused by the Gamma variant; AbbVie’s was only partially protective and Lilly’s didn’t show any efficacy.

“It will be useful in the future to understand how these monoclonal antibodies will behave as variants continue to emerge,” said Diamond, who is also a professor of molecular microbiology and pathology and immunology. “We need to think through and generate combinations of antibodies to preserve our ability to treat this disease. And we will need to watch for resistance – although, in my opinion, using specific combinations will make this less of a problem.”


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