Posted March 28, 2023

Gordon Freeman, Ph.D., Dana-Farber Cancer Institute

SARS-CoV-2, the coronavirus responsible for COVID-19, infects a healthy cell by using projections called spike proteins to snag a protein called ACE2 on the outer membrane of a healthy cell. Once the spike protein latches onto the ACE2 receptor, it pulls the healthy cell close and drives the spike through the outer membrane, allowing the virus to release its RNA into the hijacked host. Many coronaviruses use this method to infect healthy cells. Although antibodies can target spike proteins, antibodies typically only work against a single coronavirus strain and can be rendered ineffective by mutations. As a result of these mutations, antibodies authorized by the U.S. Food and Drug Administration (FDA) to treat COVID-19 may eventually become ineffective.

In fiscal year 2020 (FY20), the Peer Reviewed Medical Research Program (PRMRP) released program announcements specifically addressing emerging viral diseases and respiratory health to counter the COVID-19 pandemic. Dr. Freeman and his team at the Dana-Farber Cancer Institute used their FY20 PRMRP Technology/Therapeutic Development Award to develop a new therapeutic, DF-COV-01, that targets spike proteins in a novel way. DF-COV-01 works by tricking the virus’ spike proteins into binding to “decoy” receptors that mimic ACE2. When the SARS-CoV-2 virus binds to DF-COV-01, this triggers a structural change in the virus that neutralizes it – essentially “popping” the top of the spike protein off the virus and blunting its ability to infect a healthy cell. DF-COV-01 may maintain this activity against future SARS-CoV-2 variants because they need to use ACE2 to infect a cell. Similarly, it may work against other coronaviruses that could enter the human population and cause future pandemics because many coronaviruses in nature also use ACE2 to infect cells.

Dr. Freeman and his team began by evaluating the biological and physical characteristics of four DF-COV compounds (DF-COV-01 through DF-COV-04) to assess their ability to neutralize SARS-CoV-2 – first using infected human lung cells, and then in animal models. During their research, they discovered that changes in two structural elements in DF-COV-01 allow it to attach more tightly to the virus and extend its serum half-life; further, this optimized DF-COV-01 reduced the severity of the SARS-CoV-2 infection in the animal model.

They successfully developed a stable, high-productivity cell bank to produce DF-COV-01 and developed manufacturing and control processes in accordance with industry standards to support large-scale production of DF-COV-01. They established a small biotechnology company with the Dana-Farber Cancer Institute to manage anticipated clinical trials of DF-COV-01 and also submitted a patent application for DF-COV-01. Dr. Freeman and his team are currently working with the FDA to submit an Investigational New Drug application for DF-COV-01, which would make it eligible for use in clinical trials. If successful, DF-COV-01 could prevent new infections of ACE2-dependent novel coronaviruses as well as slow down existing infections and speed patient recovery.

References:

Torchia JA, Tavares AH, Carstensen LS, et al. 2022. Optimized ACE2 decoys neutralize antibody-resistant SARS-CoV-2 variants through functional receptor mimicry and treat infection in vivo. Science Advances 8(49):eabq6527. https://www.science.org/doi/10.1126/sciadv.abq6527.

Links:

Public and Technical Abstracts: Development of DF-COV for the Treatment and Prevention of COVID-19 and Associated Immunopathologic Respiratory Complications

Top of Page