Monoclonal antibodies (mAbs) were the first treatments authorized by the Food and Drug Administration (FDA) for people with COVID-19 who were not hospitalized. These antibodies attach to the virus surface spike protein and allow it to be cleared. This is how monoclonal antibodies mimic those natural antibodies made by people who are able to fend off the virus. However, when the SARS-CoV -2 virus began to mutate or change its spike protein, variants emerged that were resistant to these mAbs, rendering them all ineffective and leaving less than a handful of antivirals as treatment options for COVID-19.
SAB-185 is a novel mAb studied through the ACTIV-2 initiative by the ACTG. This mAb is uniquely created in cows rather than in cells grown in a laboratory, as most mAbs are made. To get cows to make SAR-CoV-2 antibodies, they are first injected with a vaccine that delivers DNA designed to code for the SARS-CoV-2 spike protein. Then they are repeatedly administered immunizations with spike protein to trigger a broad antibody response against it. Unlike most mAbs that target a specific portion of the spike protein, these antibodies can be made to different parts of the spike, and therefore, may be better able to remain effective against viral variants. In addition, cows make a lot of plasma, so these antibodies can be “harvested” from the animals in large quantities to be purified for administration intravenously to people.
This blinded phase 2 trial was conducted in the United States between April and August 2021, when the Delta variant was dominant, and enrolled 446 people 18 years of age and older within 10 days of testing positive for COVID-19. Participants were randomized to one of two doses of a single intravenous infusion of SAB-185 (low and high) or placebo. Their median age was 38 years and 86 percent were white, half were Hispanic/Latino, and almost 60 percent were female. Most did not have risk factors for progression to severe COVID-19 and about a third were vaccinated against COVID-19.
SAB-185 was found to be safe and well-tolerated with no significant difference in adverse events seen with either dose compared to placebo. People who were randomized to SAB-185 were more likely to have undetectable SARS-CoV-2 RNA in deep nasal swabs compared to people who received placebo at days 3 and 7 but not at day 14 after treatment. However, these early differences between treatment and placebo did not achieve statistical significance except for the high dose group at day 7. There were also trends for lower levels of SARS-COV-2 RNA in the nasal swabs from those treated with SAB-185; however, there was no measured impact of the mAb on symptoms. There were very few hospitalizations among the relatively young cohort of participants, few of whom had risks for serious COVID-19, and no differences between the study groups. None died.
Based on the encouraging virologic response, especially of high dose AB-185, and safety profile, SAB-185 graduated to phase 3 study. The results of that trial were reported in April 2023 and will soon be published. SAB-185 did not received FDA authorization for use in the United States and the continued emergence of SAR-CoV-2 variants presents a challenge the development of mAbs that can remain effective as the virus changes.
While this study did not result in bringing new therapeutic option to the market, we learned a lot about the response of the virus to mAbs and the limitations of this technology when viruses mutate. We also learned more about how antibodies help to control the replication (reproduction) of virus. And it confirmed the ACTG’s ability to successfully conduct platform studies in the face of a pandemic. Science is a process that is iterative. We must try many approaches before we find the best answer.
Reference:
Taiwo BO, Chew KW, Moser C, Wohl DA, Daar ES, Li JZ, Greninger AL, Bausch C, Luke T, Hoover K, Neytman G, Giganti MJ, Olefsky M, Javan AC, Fletcher CV, Eron JJ, Currier JS, Hughes MD, Smith DM; ACTIV-2/A5401 Study Team. Phase 2 Safety and Antiviral Activity of SAB-185, a Novel Polyclonal Antibody Therapy for Nonhospitalized Adults With COVID-19. J Infect Dis. 2023 Jul 14;228(2):133-142. doi: 10.1093/infdis/jiad013. PMID: 36661240; PMCID: PMC10345463.