Last updated: November 12, 2020
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Monoclonal antibodies are a type of therapeutic agent under investigation for the treatment of COVID-19. These agents are often created by identifying pathogen-specific B cells of patients who have recently recovered from an infection or by utilizing mice genetically modified to have an immune system (Marovich, June 2020). Once the B cells are identified, the genes of immune globulin heavy and light chains are recovered. These genes are then expressed to produce monoclonal antibodies. Monoclonal antibodies have singular activity against a predetermined target; they therefore differ from convalescent plasma, which consists of polyclonal antibodies in serum derived from patients who are convalescing from an infection (Marston, April 2018). Monoclonal antibodies have been developed for the treatment and prophylaxis of other viral infections, such as HIV, influenza, RSV, MERS-CoV, Ebola and Zika virus (Walker, January 2018). Of these, only monoclonal antibodies targeting RSV and Ebola have been shown to be effective in human trials (with the former having FDA approval) (Marovich, June 2020). Several products targeting the other aforementioned viruses are currently being studied in clinical trials.
The majority of monoclonal antibody products under development for SARS-CoV-2 target the spike protein, which the virus utilizes to enter host cells (Marovich, June 2020).
The products farthest along in clinical trials have been created by Eli Lilly and Regeneron. Eli Lilly’s monoclonal antibody regimen, LY-CoV555, consists of two antibodies directed against the SARS-CoV-2 spike protein and its receptor binding domain; Regeneron’s product, REGN-COV2, consists of two antibodies that bind to different regions of the SARS-CoV-2 spike protein receptor binding domain.
In November 2020, the FDA granted emergency use authorization for bamlanivimab, also known as LY-CoV555, in outpatients based on an interim analysis of an outpatient phase 2 randomized controlled trial.
Outpatient trials in progress
To date, the only published data on the use of monoclonal antibodies to treat COVID-19 is an interim analysis of BLAZE-1, a phase 2 clinical trial examining the use of bamlanivimab in outpatients (Chen, October 2020). The interim analysis was of 452 patients deemed to be at high risk for progressing to severe COVID-19 and/or hospitalization. Patients were randomized to receive either a single infusion of one of three doses of LY-CoV555, or placebo. The analysis found that five out of 309 patients who received LY-CoV555 required a visit to the emergency department or hospitalization (1.6%), compared to nine out of 143 of the placebo population (6.3%). A statistical analysis of these results was not reported, likely due to the small numbers of patients who experienced these events.
Notably, the primary endpoint of the study was a change from baseline in the viral load at day 11; this endpoint was not met in the trial. However, the trial was designed before there was a general understanding of the viral dynamics of SARS-CoV-2 infection; we now know that by day 11 the viral load in most patients will be low (see RT-PCR Testing). No serious adverse events occurred in the treatment arm.
Other outpatient trials examining the use of LY-CoV555 are ongoing.
Inpatient trials in progress
ACTIV-3 is an NIH-sponsored inpatient phase 3 clinical trial comparing bamlanivimab and remdesivir against placebo and remdesivir. In October 2020, the trial's independent data safety monitoring board recommended pausing the study after noting the group of patients who received five days of LY-CoV555 had a different clinical status than the group who had received placebo and subsequently halted enrollment after determining a lack of efficacy. Other LY-CoV555 trials continue, and further data is forthcoming.
REGN-COV2, developed by Regeneron, consists of two antibodies that bind to different regions of the SARS-CoV-2 spike protein receptor binding domain. In October 2020, an independent data monitoring committee recommended halting a study examining the use of REGN-CoV in hospitalized patients requiring high-flow oxygen or mechanical ventilation, due to a potential safety signal and an unfavorable risk/benefit profile. Other cohorts continue to enroll. Regeneron also has ongoing trials examining the use of its product in outpatients with COVID-19; current data is only available via press release.
A review of the literature on this topic will be developed once relevant clinical data in humans are made fully available to the public.