A Review of the Currently Available Monoclonal Antibodies for COVID-19

ContagionContagion, October 2021 (Vol. 06, No. 5)
Volume 6
Issue 5

Outside of vaccines, these underutilized therapies are the best defense against severe disease.

A Review of the Currently Available Monoclonal Antibodies for COVID-19

Monoclonal antibodies have recently been developed as therapeutic options for the treatment and potential prophylaxis for COVID-19. These specific proteins are made to simulate one of the many defenses of the human immune system. Multiple different monoclonal antibodies have been developed that bind to the spike protein of the SARS-CoV-2 virus, which helps prevent viral attachment and entry into human cells.

In contrast with convalescent plasma, which consists of many antibodies collected from patients who have recovered from infection, monoclonal antibodies are directed toward specific targets. Monoclonal antibodies were developed to help reduce viral load to decrease the risk of developing serious symptoms in patients infected with the SARS-CoV-2 virus.

Currently, 3 monoclonal antibody products have authorized usage for COVID-19.

Bamlanivimab was the first monoclonal antibody given an emergency use authorization (EUA) by the FDA in November 2020 to treat mild-to-moderate COVID-19 in outpatients at high risk of developing severe COVID-19, as further described in Table 1. This is a neutralizing human IgG1κ monoclonal antibody that targets the spike protein of SARS-CoV-2, preventing the attachment of the protein with the human cell-surface ACE2 protein.1 The phase 2 BLAZE-1 trial in patients with mild-to-moderate COVID-19 showed an effect of bamlanivimab on viral loads, but more importantly, the treatment group also had less patients progress to COVID-19–related emergency department visits and hospitalization.2 This effect was particularly pronounced in a high-risk subgroup of patients (body mass index>35 or aged>65 years). However, an increase in circulating COVID-19 viral variants resistant to bamlanivimab alone led to its EUA revocation. In response, Eli Lilly and Company partnered and developed a new monoclonal antibody to be administered with bamlanivimab, etesevimab. Etesevimab is also a neutralizing monoclonal antibody targeting the spike protein of SARS-CoV-2. The combination of bamlanivimab and etesevimab is infused together to combat resistance and different variants of SARS-CoV-2. Both monoclonal antibodies were isolated from convalescent plasma in patients with COVID-19. The FDA granted an EUA for the same indication as monotherapy bamlanivimab in February based on the phase 3 BLAZE-1 trial, which demonstrated a 70% risk reduction of hospitalization or death in patients who received the combination treatment.3 In June, the CDC identified an 11% increase in frequency of the COVID-19 Gamma and Beta variants in the United States, which are not effectively treated by either bamlanivimab or etesevimab. This led the US Department of Health & Human Services to halt distribution of these antibodies that month. However, because bamlanivimab and etesevimab are active against the currently dominant Delta variant, distribution was resumed in September.4

The second authorized therapeutic consists of the 2 monoclonal antibodies casirivimab and imdevimab. As with bamlanivimab and etesevimab, casirivimab and imdevimab are directed against the spike protein of SARS-CoV-2. Distributed together as a cocktail under the brand name REGEN-COV, casirivimab and imdevimab are administered via intravenous infusion or as subcutaneous injections.5 The FDA issued an EUA for the use of casirivimab and imdevimab in the treatment of COVID-19 infection in November 2020. The EUA was more recently revised on July 30 to extend its use for postexposure prophylaxis of COVID-19 as well. Both uses are intended for mild-to-moderate disease in the outpatient setting (Table 1). For use as postexposure prophylaxis, patients with a significant exposure to someone with SARS-CoV-2 infection are eligible if they are either not fully vaccinated or are fully vaccinated but expected to have had an inadequate immune response to vaccination because of an immunocompromising disease or medication use. In a phase 3 treatment study, more than 4000 nonhospitalized patients with mild-to-moderate COVID-19 and at least 1 risk factor for severe disease were randomized to receive either casirivimab-imdevimab or placebo. The casirivimab-imdevimab treatment groups demonstrated a decrease in COVID-19–related hospitalization or all-cause death, as well as a more rapid resolution of COVID-19 symptoms compared to placebo.6 With regard to postexposure prophylaxis, a phase 3 randomized, double-blind clinical trial evaluated 1505 subjects who lived in a household with a patient infected with COVID-19 but were asymptomatic and had a negative SARS-CoV-2 polymerase chain reaction (PCR) test themselves. They were randomized to receive either placebo or casirivimab-imdevimab and followed for serial PCR testing and assessment for development of symptoms. The treatment group demonstrated an 81% risk reduction in the development of PCR-confirmed COVID-19 infection through 29 days.7

A Review of the Currently Available Monoclonal Antibodies for COVID-19

Sotrovimab is the third monoclonal antibody currently available for the treatment of COVID-19 since its EUA was announced May 26. A product of GlaxoSmithKline, sotrovimab was created from an antibody identified in 2003 in a survivor of severe acute respiratory syndrome (SARS).8 It is administered as a single intravenous infusion given over 30 minutes.9 As with the above-mentioned therapies, sotrovimab is indicated for mild-to-moderate infection in those who are at risk for progression to severe disease. Its use is currently limited to the outpatient setting in patients meeting the criteria in Table 1. The ongoing, randomized, controlled phase 3 COMET-ICE trial is investigating the use of sotrovimab in nonhospitalized patients with symptomatic COVID-19 infection and risk factors for disease progression. The primary end point being investigated is hospitalization for more than 24 hours or death within 29 days. An interim analysis of 583 patients showed that risk of progression was reduced by 85% in those treated with sotrovimab compared to placebo.10

Though similar in their current indications, the available antibody therapies have several differences. Casirivimab-imdevimab is currently the only monoclonal antibody formulation with an EUA for use as postexposure prophylaxis. It is also the only therapeutic currently available as a subcutaneous injection. Route of administration is important to consider because the need for infusion may limit the access to and feasibility of obtaining treatment in a timely fashion, and it can limit capacity at infusion centers compared to a more quickly administered formulation. Sotrovimab for intramuscular injection is currently under investigation in a phase 3 clinical trial (NCT04913675) and could further improve the logistics of administering monoclonal antibody therapy.

Additionally, when choosing a monoclonal antibody therapy for treatment, it is important to take into consideration the predominant circulating strains of the local area. Table 211 highlights the activity of each available monoclonal antibody products against different COVID-19 variant strains. Although these monoclonal antibody products are currently indicated only for patients not hospitalized for COVID-19, their use in the inpatient setting has been evaluated with mixed results. A clinical trial yet to be peer reviewed suggests the use of casirivimab-imdevimab in seronegative patients hospitalized with COVID-19 may reduce 28-day mortality, and bamlanivimab failed in an earlier study of hospitalized patients.12,13

A Review of the Currently Available Monoclonal Antibodies for COVID-19

Health care providers in the emergency department, urgent care, primary care, and testing sites are encouraged to support the administration of these monoclonal antibodies in appropriate patients to help reduce the progression of COVID-19 infection. At present, no other therapies exist that can prevent progression to severe disease that requires hospitalization. Clinician vigilance to refer eligible patients for monoclonal antibody therapy is key to improve outcomes and hospital capacity.


  1. Fact sheet for health care providers emergency use authorization (EUA) of bamlanivimab and etesevimab. FDA. Accessed Aug 31, 2021. https://www.fda.gov/media/145802/download
  2. Chen P, Nirula A, Heller B, et al; BLAZE-1 Investigators. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with COVID-19. N Engl J Med. 2021;384(3):229-237. doi:10.1056/nejmoa2029849
  3. Gottlieb RL, Nirula A, Chen P, et al. Effect of bamlanivimab as monotherapy or in combination with etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial. JAMA. 2021;325(7):632-644. doi:10.1001/jama.2021.0202
  4. Planas D, Veyer D, Baidaliuk A, et al. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature. 2021;596(7871):276-280. doi:10.1038/s41586-021-03777-9
  5. Fact sheet for health care providers emergency use authorization (EUA) of casirivimab and imdevimab. FDA. Accessed August 31, 2021. https://www.fda.gov/media/145611/download
  6. Fact sheet for health care providers emergency use authorization (EUA) of sotrovimab. FDA. Accessed August 31, 2021. https://www.fda.gov/media/149534/download
  7. Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-COV antibody cocktail clinical outcomes study in COVID-19 outpatients. MedRxiv. Preprint posted online June 6, 2021. doi:10.1101/2021.05.19.21257469
  8. O'Brien MP, Forleo-Neto E, Musser BJ, et al; Covid-19 Phase 3 Prevention Trial Team. Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19. N Engl J Med. Published online Aug 4, 2021. doi:10.1056/NEJMoa2109682
  9. Gupta A, Gonzalez-Rojas Y, Juarez E, et al. Early Covid-19 Treatment With SARS-CoV-2 Neutralizing Antibody Sotrovimab. MedRxiv. Preprint posted online May 28, 2021. doi:10.1101/2021.05.27.21257096
  10. SARS-CoV-2 variant classifications and definitions. CDC. Updated September 17, 2021. Accessed September 21, 2021. https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html
  11. Cathcart AL, Havenar-Daughton C, Lempp FA, et al. The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2. bioRxiv. Preprint posted online August 6, 2021. doi:10.1101/2021.03.09.434607
  12. RECOVERY Collaborative Group; Horby P, Mafham M, Peto L, et al. Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. MedRxiv.Preprint posted online June 16, 2021. doi:10.1101/2021.06.15.21258542
  13. ACTIV-3/TICO LY-CoV555 Study Group; Lundgren JD, Grund B, Barkauskas CE, et al. A neutralizing monoclonal antibody for hospitalized patients with Covid-19. N Engl J Med2021;384(10):905-914. doi:10.1056/NEJMoa2033130
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