Which antibody-directed therapies are being investigated for the treatment of coronavirus disease 2019 (COVID-19)?

Updated: Jun 25, 2021
  • Author: David J Cennimo, MD, FAAP, FACP, FIDSA, AAHIVS; Chief Editor: Michael Stuart Bronze, MD  more...
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Antibodies Granted Emergency Use Authorizationin

Information, including allocation, for COVID-19 therapies granted emergency use authorization is located at the United States Public Health Emergency webpage. 

Owing to the increase in variants of concern (VOC) in the United States, monoclonal antibodies that have gained emergency use authorization have been tested to evaluate activity against VOCs. As of March 24, 2021, distribution has ceased of bamlanivimab alone. Consider use of etesevimab plus bamlanivimab, casirivimab plus imdevimab, or sotrovimab in outpatients who qualify for monoclonal antibodies. 

However, the proportion of SARS-CoV-2 variants of concern (VOCs) with reduced susceptibility to bamlanivimab plus etesevimab (P.1, B.1.351, and B.1.617) sequenced from U.S. residents continues to grow. As of June 11, at least 10 states have ceased using this combination and recommend prescribing casirivimab plus imdevimab or sotrovimab. 

Bamlanivimab plus etesevimab

Bamlanivimab (LY-CoV555; Eli Lilly & Co, AbCellera) is a neutralizing IgG1 monoclonal antibody (mAb) directed against the spike protein of SARS-CoV-2. It is designed to block viral attachment and entry into human cells, thus neutralizing the virus, potentially preventing and treating COVID-19. 

Bamlanivimab is no longer recommended as monotherapy owing to viral variants that are resistant to bamlanivimab. The EUA originally issued in November 2020 for use of bamlanivimab as monotherapy. The manufactuer asked teh FDA to rescind the EUA for monotherapy on April 16, 2021 owing to decreased efficacy to circulating variants in the United States. Instead, use in combination with etesevimab is recommended. 

The FDA issued an EUA for etesevimab (LY-CoV016; Eli Lilly & Co, AbCellera) on February 9, 2021. The EUA permits use in combination with bamlanivimab or treatment of mild-to-moderate COVID19 in adults and adolescents who are at high risk for progressing to severe COVID-19 and/or hospitalization. However, even with this combination, the proportion of SARS-CoV-2 VOCs with reduced susceptibility to bamlanivimab plus etesevimab (P.1, B.1.351, and B.1.617) sequenced from U.S. residents continues to grow. A number of states no longer stock bamlanivimab plus etesevimab.

In this arm of the phase 3 BLAZE-1 trial, the change in log viral load from baseline at day 11 was -3.72 for bamlanivimab 700 mg, -4.08 for bamlanivimab 2800 mg, -3.49 for bamlanivimab 7000 mg, -4.37 for combination treatment, and -3.80 for placebo. Among nonhospitalized patients with mild-to-moderate COVID-19 illness, treatment with bamlanivimab plus etesevimab, compared with placebo, was associated with a statistically significant reduction in SARS-CoV-2 viral load at day 11; however, no significant difference in viral load reduction was observed for bamlanivimab monotherapy. No difference in hospitalization rate was observed between bamlanivimab monotherapy or with the combination. Based on an analysis of available data, the authorized dosage regimen of the combination is bamlanivimab 700 mg plus etesevimab 1400 mg administered together as a single IV infusion. This regimen is expected to have similar clinical effects as the 2800 mg dosages evaluated in the study. [286]

Casirivimab plus imdevimab

An EUA was issued for intravenous coadministration of the monoclonal antibodies casirivimab and imdevimab (REGN-COV; Regeneron) on November 21, 2020 for treatment of mild-to-moderate COVID-19 in adults and pediatric patients aged 12 years and older who weigh at least 40 kg and are at high risk for progressing to severe COVID-19 and/or hospitalization. [287] The mixture is designed to bind to 2 points on the SARS-CoV-2 spike protein. As with bamlanivimab, administration of casirivimab and imdevimab has not shown benefit in hospitalized patients with severe COVID-19. 

Treatment trials

Intravenous casirivimab and imdevimab reduced viral levels and improved symptoms in nearly 800 non-hospitalized patients with COVID-19 disease in a phase 2/3 trial. Results showed treatment with  the 2 antibodies reduced COVID-19 related medical visits by 57% through day 29 (2.8% combined dose groups; 6.5% placebo; p = 0.024). In high risk patients (1 or more risk factor including age older than 50 years; body mass index greater than 30; cardiovascular, metabolic, lung, liver or kidney disease; or immunocompromised status) COVID-19 related medical visits were reduced by 72% (p = 0.0065). [288, 289]  

A phase 3 trial (n = 4,567) in infected outpatients who were at high risk for hospitalization or severe COVID-19 disease found casirivimab plus imdevimab significantly reduced the risk of hospitalization or death. Risk was decreased by 70% with the 1200 mg IV dose (n = 827) and by 71% with 2400 mg IV (n = 1,849) compared with placebo (n = 1,843). [290]  In June 2021, the EUA was updated with a lower IV dose of casirivimab 600 mg and imdevimab 600 mg. The update also allows administration as a SC injection for when an IV infusion is not feasible. 

An ongoing phase 1/2/3 clinical trial of the IV antibody cocktail in hospitalized patients with COVID-19 disease requiring low-flow oxygen found encouraging results. Patients who had not yet mounted their own immune response to SARS-CoV-2 (ie, seronegative for antibodies at baseline) had a lower risk of death or progression to mechanical ventilation after receiving casirivimab and imdevimab (HR: 0.78; 80% CI: 0.51-1.2). Risk of death or mechanical ventilation decreased by approximately 50% after 1 week following treatment with the antibody cocktail. Seronegative patients (n = 217) had much higher viral loads than those who had already developed their own antibodies (seropositive [n = 270]) to SARS-CoV-2 at the time of randomization. In seronegative patients, the antibody cocktail reduced the time-weighted average daily viral load through day 7 by -0.54 log10 copies/mL, and through day 11 by -0.63 log10 copies/mL (nominal p = 0.002 for combined doses). As expected, the clinical and virologic benefit of the antibody cocktail was limited in seropositive patients. [291]   [292] A larger trial will be required to confirm these initial observations. The ongoing UK-based RECOVERY trial continues to enroll hospitalized patients to receive casirivimab and imdevimab. 

Prevention trials

A phase 3 trial showed an 81% reduced risk of symptomatic SARS-CoV-2 infection of household contacts following exposure through day 29. Participants received either a single 1,200-mg SC dose of casirivimab and imdevimab (n = 753) or placebo (n=752) within 4 days following exposure. Risk of symptomatic infection was decreased by 72% in the first week, and 93% in subsequent weeks. Among individuals who developed symptomatic infections, those who received casirivimab and imdevimab cleared the virus faster and had a shorter duration of symptoms compared with placebo. [293]  


Sotrovimab (VIR-7831; VIR Biotechnology; GlaxoSmithKline) is a mAb that binds to conserved epitope of the spiked protein of SARS-CoV-1 and SARS-CoV-2, thereby indicating unlikelihood of mutational escape. This is supported by a preclinical trial showing it retained ability to neutralize SARS-CoV-2 variants (ie, B.1.1.7, B.1.351, P.1). [294]  The FDA granted emergency use authorization May 26, 2021. 

The EUA submission was based on an interim analysis of the COMET-ICE phase 3 trial.  The trial evaluated VIR-7831 as monotherapy for early treatment of COVID-19 in adults at high risk of hospitalization or death. The interim analysis demonstrated an 85% reduction in hospitalization or death in those who received a single IV dose of VIR-7831 (n = 291) compared with placebo (n = 292) (p = 0.002). [295]   

Results from a phase 2 trial (BLAZE-4) of a single IV dose of VIR-7831 coadministered with bamlanivimab in low-risk adults with mild-to-moderate COVID-19 demonstrated a 70% (p < 0.001) relative reduction in persistently high viral load at day 7 compared with placebo. [296]   

Additional trials for VIR-7831 include comparison of IM and IV administration in low-risk adults (COMET-PEAK), IM use in high-risk adults (COMET-TAIL), and IM administration in uninfected adults to prevent symptomatic infection (COMET-STAR). 

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