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Combination therapies appear to prevent drug resistance from developing
Matt Miller
MD / PhD student Rita Chen (left) and Brett Case, PhD, a postdoctoral fellow, prepare to work with SARS-CoV-2, the virus that causes COVID-19, under strict biosecurity conditions. Chen, Case, and MD / PhD student Emma Winkler co-led a study with virologist and immunologist Michael S. Diamond, MD, PhD at the Washington University School of Medicine in St. Louis to assess how well antibody-based were Drugs for COVID-19 work against a number of virus variants.
COVID-19 therapies made from antibodies are often given to patients who are at high risk of serious illness and hospitalization. However, there have been nagging questions as to whether such antibody therapies will remain effective when worrying new virus variants emerge.
New research at the Washington University School of Medicine in St. Louis suggests that many, but not all, therapies that consist of combinations of two antibodies are effective against a variety of variants of the virus. In addition, combination therapies appear to prevent drug resistance from developing.
The mouse and hamster study tested all single and combination antibody-based therapies approved by the Food and Drug Administration (FDA) for emergency or evaluated in late-stage clinical trials against a panel of emerging international and US variants of SARS-CoV-2, the virus that causes COVID-19.
The results, published June 21 in the journal Nature, suggest that COVID-19 drugs, which consist of two antibodies, often retain their effectiveness as a therapy against variants, even after in vitro studies – experiments, which were done in a bowl – indicate that one of the two antibodies has lost some or all of the 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 senior author Michael S. Diamond, MD, PhD, Herbert S. Gasser Professor of Medicine. “When we looked at animals, there were some surprises. Some of the combinations performed better than we thought based on in vitro data. And there was no combination resistance whatsoever across all variants. We will need to continue to monitor the effectiveness of antibody therapy if more variants appear, but combination therapy to treat infections with this virus will likely be needed if more variants appear. “
So-called monoclonal antibodies mimic those the body makes to fight off the virus that causes COVID-19. Administering antibody therapies bypasses the body’s slower and sometimes less effective process of making its own antibodies. When this study began, there were two dual antibody combination therapies and a single antibody therapy approved by the FDA for emergency use. The FDA withdrew the approval of 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 approved the single antibody sotrovimab for the treatment of COVID-19.
Overall, the researchers evaluated antibodies that match the FDA-cleared antibodies from Eli Lilly and Co., Regeneron and Vir Biotechnology / GlaxoSmithKline, and the antibodies currently being developed in clinical trials by AbbVie, Vir and AstraZeneca.
The researchers – led by co-first authors Rita E. Chen, an MD / PhD student, Emma S. Winkler, an MD / PhD student, and Brett Case, PhD, a postdoctoral fellow – tested the antibodies against a number of virus variants Contained key mutations in their spike genes. The SARS-CoV-2 virus uses spike protein to enter cells. All COVID-19 therapies based on monoclonal antibodies work by disrupting the interaction between spike protein and cells.
The panel included mutations found in three of the four variants identified by the World Health Organization as “Variants of Concern” – Alpha (first identified in the UK), Beta (South Africa) and Gamma (Brazil) – and one emerging variant India, which resembles the Delta variant of concern. They also tested variants from New York and California. The researchers used a mixture of virus samples originally taken from people with COVID-19 and laboratory strains that had been 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 – individually or in the same combinations in which they were administered to treat patients – one day before they infected them with one of the virus variants. The researchers monitored the animals’ weight for six days and then measured the amount of virus in the nose, lungs, and other parts of the body.
Although some individual antibodies showed reduced or no ability to neutralize virus variants in a dish, low doses of most antibody combinations protected against diseases caused by many of the variants. The researchers sequenced virus samples from the animals and found no evidence of drug resistance in viruses from animals treated with combination therapies.
“The dual therapy seemed to prevent the emergence of resistant viruses,” says co-author Jacco Boon, PhD, Associate Professor of Medicine, Molecular Microbiology, and Pathology and Immunology. “With some monotherapies resistance occurred, with combination therapies never.”
Since antibody-based COVID-19 therapies are mainly used to treat people who are already infected, the researchers also evaluated how well the antibody combinations perform after infection with the beta variant. The beta variant was chosen because laboratory experiments have shown that it is most likely to escape neutralization and has the highest resistance to COVID-19 vaccines. The antibody cocktails similar to those of AstraZeneca, Regeneron, and Vir were all effective in reducing diseases caused by the gamma variant; AbbVie’s was only partially protective and Lilly’s showed no effectiveness at all.
“It will be useful in the future to understand how these monoclonal antibodies will behave as more variants emerge,” said Diamond, who is also a professor of molecular microbiology and pathology and immunology. “We need to think about and generate antibody combinations in order to maintain our ability to treat this disease. And we have to watch out for resistance – although in my opinion using certain combinations makes this less of a problem. “
Chen RE, Winkler ES, Case JB, Aziati ID, Bricker TL, Joshi A, Darling T, Ying B, Errico JM, Shrihari S, VanBlargan LA, Xie X, Gilchuk P, Zost SJ, Droit L, Liu Z, Stumpf S. , Wang D, Handley SA, Stine WB, Shi PY, Davis-Gardner ME, Suthar MS, Knight MG, Andino R, Chiu CY, Ellebedy AH, Fremont DH, Whelan SPJ, Crowe JE, Purcell L, Corti D, Boon ACM , Diamond MS. In vivo efficacy of monoclonal antibodies against SARS-CoV-2 variant strains. Nature. June 21, 2021. DOI: 10.1038 / s41586-021-03720-y
This study was supported by the National Institutes of Health (NIH) Grant and Contract Numbers R01 AI157155, U01 AI151810, U01 AI141990, R01 AI118938, 75N93019C00051, HHSN272201400006C, HHSN272201400008C, and HHSN75N93019C00074; the Children’s Discovery Institute, grant number PDII2018702; the Defense Advanced Research Project Agency, Grant No. HR0011-18-2-0001; the Dolly Parton COVID-19 Research Fund at Vanderbilt University; Quick grants; the Mercatus Center at George Mason University; and the Future Insight Prize from Merck KGaA.
The 1,500 faculty physicians at Washington University School of Medicine are also the medical staff for the Barnes-Jewish and St. Louis Children’s Hospitals. The School of Medicine is a leader in medical research, teaching, and patient care and consistently ranks among the top medical schools in the country according to the US News & World Report. The School of Medicine is affiliated with BJC HealthCare through its affiliation with Barnes-Jewish and St. Louis Children’s Hospital.
