Experimental drug works differently than antibodies that lose effectiveness against SARS-CoV-2 virus

The investigational drug, described in a report published today in Scientists progress, is not an antibody, but a related molecule known as the ACE2 receptor decoy. Unlike antibodies, the ACE2 decoy is much harder for the SARS-CoV-2 virus to escape, because mutations in the virus that would allow it to avoid the drug would also reduce the virus’s ability to infect cells. Dana-Farber scientists have found a way to make this type of coronavirus-neutralizing drug more potent in animals infected with COVID-19 and to make it safe to administer to patients.

This report comes at a time when antibodies used to treat COVID-19 have lost their effectiveness because the viral spike protein has mutated to evade the antibody target.

The researchers, led by first author James Torchia, MD, PhD, and senior author Gordon Freeman, PhD, identified the characteristics that make ACE2 lures particularly potent and long-lasting. For example, they found that when they included a piece of the ACE2 protein called the collectrin-like domain, it made the drug stick more tightly to the virus and last longer in the body. Their experiments showed that ACE2 decoys have potent activity against the COVID-19 virus because they trigger an irreversible change in the structure of the virus – they “pop off” the top of the viral spike protein so that it cannot bind to the cell-surface ACE2 receptor and infect cells.

The SARS-CoV-2 virus is covered in projections called spike proteins that allow the virus to infect cells. The spike protein binds to the ACE2 receptor on the cell surface and then folds up, driving the spike into the cell, allowing the virus to enter. ACE2 decoys attract the virus to bind to the decoy instead of the cell, “popping” the spike and inactivating the virus before it can enter the cells. This explains the surprising potency of the drug: not only does it work as a competitive inhibitor, but it permanently inactivates the virus. Since binding to ACE2 is necessary for infection, the variants can change but they must continue to bind to ACE2, making the drug persistently active against all variants.

The researchers say that in addition to treating antibody-resistant variants of SARS-CoV-2, the drug described in this study could be useful in treating new coronaviruses that may emerge in the future to infect humans. Indeed, many coronaviruses in nature about to enter the human population also use ACE2 to infect cells.

Although the drug, called DF-COV-01, has yet to be tested in humans, manufacturing development is nearing completion and preclinical studies needed for regulatory approval are underway, with the goal of advance the drug to clinical trials.

This work was supported by a Technology/Therapeutic Development Award from the Department of Defense CDMRP Peer-Reviewed Medical Research Program. Additional support was provided by a National Institutes of Health grant, an Evergrande MassCPR award, and a COVID-19 FastGrants grant.

The work was performed by a collaborative team including scientists from the Dana-Farber Cancer Institute, Massachusetts General Hospital Vaccine and Immunotherapy Center, Boston University Aram V. Chobanian & Edward Avedisian School of Medicine, National Emerging Infectious Disease Boston University Laboratory, Colorado State University and Boston Children’s Hospital.