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Anti-SARS-CoV-2 Monoclonal Antibodies

Last Updated: April 21, 2021

Background

The SARS-CoV-2 genome encodes four major structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N), as well as nonstructural and accessory proteins. The S protein is further divided into two subunits, S1 and S2, that mediate host cell attachment and invasion. Through its receptor-binding domain (RBD), S1 attaches to angiotensin-converting enzyme 2 (ACE2) on the host cell; this initiates a conformational change in S2 resulting in virus-host cell membrane fusion and viral entry.1

Many individuals with COVID-19 produce neutralizing antibodies to SARS-CoV-2 about 10 days after disease onset, with higher antibody levels observed in those with severe disease.2 The neutralizing activity of COVID-19 patients’ plasma was correlated with the magnitude of antibody responses to SARS-CoV-2 S and N proteins. Monoclonal antibodies targeting the S protein have the potential to prevent SARS-CoV-2 infection and to alleviate symptoms and limit progression to severe disease in patients with mild to moderate COVID-19, particularly in those who have not yet developed an endogenous antibody response.3

Anti-SARS-CoV-2 Monoclonal Antibodies That Received Emergency Use Authorizations From the Food and Drug Administration

Bamlanivimab (also known as LY-CoV555 and LY3819253) is a neutralizing monoclonal antibody that targets the RBD of the S protein of SARS-CoV-2. Etesevimab (also known as LY-CoV016 and LY3832479) is another neutralizing monoclonal antibody that binds to a different but overlapping epitope in the RBD of the SARS-CoV-2 S protein. Casirivimab (previously REGN10933) and imdevimab (previously REGN10987) are recombinant human monoclonal antibodies that bind to nonoverlapping epitopes of the S protein RBD of SARS-CoV-2.

Two combination products, bamlanivimab plus etesevimab and casirivimab plus imdevimab, are available through Food and Drug Administration (FDA) Emergency Use Authorizations (EUAs) for the treatment of mild to moderate COVID-19 in nonhospitalized patients with laboratory confirmed SARS-CoV-2 infection who are at high risk for progressing to severe disease and/or hospitalization. The issuance of an EUA does not constitute FDA approval. Because of an increasing number of reports of SARS-CoV-2 variants that are resistant to bamlanivimab alone, FDA has recently revoked the EUA for bamlanivimab, and the product will no longer be distributed in the United States.4

Recommendations

  • The COVID-19 Treatment Guidelines Panel (the Panel) recommends using one of the following anti-SARS-CoV-2 monoclonal antibody combinations (listed in alphabetical order) to treat outpatients with mild to moderate COVID-19 who are at high risk of clinical progression, as defined by the EUA criteria:
    • Bamlanivimab 700 mg plus etesevimab 1,400 mg (AIIa); or
    • Casirivimab 1,200 mg plus imdevimab 1,200 mg (AIIa).
  • Treatment should be started as soon as possible after the patient receives a positive result on a SARS-CoV-2 antigen or nucleic acid amplification test (NAAT) and within 10 days of symptom onset.
  • There are SARS-CoV-2 variants, particularly those that contain the mutation E484K (see below), that reduce the virus’ susceptibility to bamlanivimab and, to a lesser extent, casirivimab and etesevimab in vitro; however, the clinical impact of these mutations is not known.
  • In regions where SARS-CoV-2 variants with reduced in vitro susceptibility to bamlanivimab plus etesevimab are common, some Panel members would preferentially use casirivimab plus imdevimab while acknowledging that it is not known whether in vitro susceptibility data correlate with clinical outcomes.
  • The Panel recommends against the use of anti-SARS-CoV-2 monoclonal antibodies for patients who are hospitalized because of COVID-19, except in a clinical trial (AIIa). However, their use should be considered for persons with mild to moderate COVID-19 who are hospitalized for a reason other than COVID-19 but who otherwise meet the EUA criteria.

For additional information on the rationale for the Panel’s recommendations regarding anti-SARS-CoV-2 monoclonal antibodies for nonhospitalized patients with mild to moderate COVID-19, see Therapeutic Management of Patients with COVID-19.

SARS-CoV-2 Variants of Concern or Interest and Their Susceptibility to Anti-SARS-CoV-2 Monoclonal Antibodies

In laboratory studies, some SARS-CoV-2 variants of concern or interest that harbor certain mutations have markedly reduced susceptibility to bamlanivimab and may have lower sensitivity to etesevimab and casirivimab.5 However, the impact of these mutations on the clinical response to anti-SARS-CoV-2 monoclonal antibody combinations is uncertain, and the prevalence of these variants in different regions may vary. Of note:

  • The B.1.1.7 variant of concern, which is increasing in frequency in the United States, retains in vitro susceptibility to the anti-SARS-CoV-2 monoclonal antibodies that are currently available through EUAs.6,7
  • The B.1.351 variant of concern has been infrequently detected among SARS-CoV-2 samples sequenced in the United States to date. This variant includes the E484K mutation, which results in a marked reduction in in vitro susceptibility to bamlanivimab.8,9 In vitro studies suggest that bamlanivimab plus etesevimab has markedly reduced activity against the B.1.351 variant.6 In vitro studies also suggest that the K417N mutation, which is present in the B.1.351 variant along with the E484K mutation, reduces casirivimab activity, although the combination of casirivimab and imdevimab appears to retain activity.7
  • The P.1 variant of concern has been infrequently detected among SARS-CoV-2 samples sequenced in the United States to date. This variant includes the E484K mutation, which results in a marked reduction in in vitro susceptibility to bamlanivimab.6,10 In vitro studies suggest that bamlanivimab plus etesevimab also has markedly reduced activity against the P.1 variant.6,8,10 In vitro studies also suggest that the K417T mutation, which is present in the P.1 variant along with the E484K mutation, reduces casirivimab activity, although the combination of casirivimab and imdevimab appears to retain activity.7
  • The B.1.429/B.1.427 variants of concern (also called 20C/CAL.20C) that are circulating in parts of the United States, including California, Arizona, and Nevada, have the L452R mutation. This mutation is associated with a marked reduction in in vitro susceptibility to bamlanivimab. There appears to be a modest in vitro decrease in susceptibility to the combination of bamlanivimab and etesevimab, although the clinical implications of this finding are not known.6
  • The B.1.526 variant of interest is circulating in parts of the United States, such as New York. It commonly has the E484K mutation, which is associated with a marked reduction in in vitro susceptibility to bamlanivimab. There appears to also be reduced in vitro susceptibility to the combination of bamlanivimab and etesevimab, although the clinical implications of this finding are not known.6 In vitro studies suggest that the E484K mutation may reduce casirivimab activity, although the combination of casirivimab and imdevimab appears to retain activity.7

Ongoing population-based genomic surveillance of the types and frequencies of circulating SARS-CoV-2 variants, as well as studies on the susceptibility of different variants to available anti-SARS-CoV-2 monoclonal antibodies, will be important in defining the utility of specific monoclonal antibodies in the future.

Use of Anti-SARS-CoV-2 Monoclonal Antibodies in Patients Hospitalized for COVID-19

The FDA EUAs do not authorize the use of anti-SARS-CoV-2 monoclonal antibodies for patients who are hospitalized for COVID-19 or for the following patients:

  • Those who require oxygen therapy due to COVID-19; or
  • Those who are on chronic oxygen therapy due to an underlying non-COVID-19-related comorbidity and, because of COVID-19, require an increase in oxygen flow rate from baseline.

The FDA EUAs do permit the use of these monoclonal antibodies for patients who are hospitalized for an indication other than COVID-19 provided they have mild to moderate COVID-19 and are at high risk for progressing to severe disease and/or hospitalization.11,12

Anti-SARS-CoV-2 monoclonal antibodies may be available through expanded access programs for the treatment of immunocompromised patients who are hospitalized because of COVID-19. It is not yet known whether these antibodies provide clinical benefits in people with B-cell immunodeficiency or other immunodeficiencies.

Anti-SARS-CoV-2 monoclonal antibodies have not been shown to be beneficial in hospitalized patients with severe COVID-19.7,12 A substudy of A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients With COVID-19 (ACTIV-3) randomized patients hospitalized with COVID-19 to receive bamlanivimab 7,000 mg or placebo, each in addition to remdesivir. On October 26, 2020, following a prespecified interim futility analysis, enrollment into this study was stopped due to lack of clinical benefit.13 Among 314 hospitalized adults (163 in the bamlanivimab arm and 151 in the placebo arm), pulmonary outcomes were similar at Day 5 (OR of being in a more favorable category in the bamlanivimab arm than in the placebo arm 0.85; 95% CI, 0.56–1.29; P = 0.45). The time to hospital discharge was also similar in the two arms (rate ratio 0.97; 95% CI, 0.78–1.20).14

Clinical Trial Data

See Table 3a for information on the clinical trials evaluating the safety and efficacy of anti-SARS-CoV-2 monoclonal antibodies.

Monitoring

  • These anti-SARS-CoV-2 monoclonal antibodies are to be given as intravenous infusions and should only be administered in health care settings by qualified health care providers who have immediate access to medications to treat severe infusion reactions and to emergency medical services.
  • Patients should be monitored during the infusion and for at least 1 hour after the infusion is completed.
  • No dosage adjustments are required for body weight, renal impairment, or mild hepatic impairment.

Adverse Effects

  • In the Phase 2 Blocking Viral Attachment and Cell Entry with SARS-CoV-2 Neutralizing Antibodies (BLAZE-1) trial, the most common adverse events associated with bamlanivimab were nausea, diarrhea, dizziness, headache, pruritis, and vomiting. The safety profile of bamlanivimab at all three doses was reportedly like that of the placebo.
  • According to the EUA fact sheet for bamlanivimab plus etesevimab, the following adverse events were reported: nausea, dizziness, rash, pruritis, and pyrexia. In the Phase 3 BLAZE-1 study, 1% of the participants experienced hypersensitivity events, including infusion-related reactions, rash, and pruritis. All events resolved.
  • Hypersensitivity, including anaphylaxis and infusion reactions, may occur. According to the EUA for bamlanivimab, among >850 participants in ongoing trials who have received bamlanivimab, one anaphylactic reaction and one serious infusion-related reaction occurred, and both required treatment, which in one case included epinephrine.
  • According to the EUA fact sheet for casirivimab plus imdevimab, among the 533 participants who received casirivimab plus imdevimab in the R10933-10987-COV-2067 trial, one participant had an anaphylaxis reaction that required treatment with epinephrine, and four participants who received casirivimab 4,000 mg plus imdevimab 4,000 mg had an infusion reaction of grade 2 severity or higher, which, in two cases, resulted in permanent discontinuation of the infusion.

Drug-Drug Interactions

  • Drug-drug interactions are unlikely between bamlanivimab plus etesevimab or casirivimab plus imdevimab and medications that are renally excreted or that are cytochrome P450 substrates, inhibitors, or inducers.
  • Please see Table 3c for more information.

Vaccination

  • SARS-CoV-2 vaccination should be deferred for ≥90 days in people who have received anti-SARS-CoV-2 monoclonal antibodies. This is a precautionary measure, as the antibody treatment may interfere with vaccine-induced immune responses.15
  • For people who develop COVID-19 after receiving SARS-CoV-2 vaccination, prior vaccination should not affect treatment decisions, including the use of and timing of treatment with monoclonal antibodies.15

Considerations in Pregnancy

  • As immunoglobulin (Ig) G monoclonal antibodies, bamlanivimab plus etesevimab, casirivimab plus imdevimab, and bamlanivimab alone would be expected to cross the placenta. There are no available data on the use of these anti-SARS-CoV-2 monoclonal antibodies during pregnancy; however, IgG products are generally not withheld because of pregnancy when their use is indicated.
  • Anti-SARS-CoV-2 monoclonal antibodies should not be withheld from a pregnant individual with COVID-19 who has a condition that poses a high risk of progression to severe COVID-19, and the patient and provider determine that the potential benefit of the drug outweighs the potential risk (see the EUA criteria for the use of these products below).
  • Inclusion of pregnant people in clinical trials should be encouraged to inform decisions on whether to use anti-SARS-CoV-2 monoclonal antibody therapy in this population.

Considerations in Children

  • There are insufficient pediatric data to recommend either for or against the use of anti-SARS-CoV-2 monoclonal antibody products for children with COVID-19 who are not hospitalized but who have risk factors for severe disease. Based on adult studies, bamlanivimab plus etesevimab or casirivimab plus imdevimab may be considered for nonhospitalized children who meet EUA criteria, especially those who meet more than one criterion or are aged ≥16 years, on a case-by-case basis in consultation with a pediatric infectious disease specialist. Additional guidance on the use of anti-SARS-CoV-2 monoclonal antibodies for the treatment of COVID-19 in children is provided in a recent publication endorsed by the Pediatric Infectious Diseases Society.16
  • Most children with mild or moderate COVID-19, even those with risk factors specified in the EUAs for bamlanivimab plus etesevimab or casirivimab plus imdevimab, will not progress to more severe illness and will recover without specific therapy.
  • Risk factors for hospitalization have not been as clearly defined in children with COVID-19 as in adults with the disease, making it difficult to identify those children at the highest risk of hospitalization and those who would be likely to benefit from monoclonal antibody therapy.
  • Additional data on clinical outcomes in children who receive monoclonal antibodies for the treatment of COVID-19, including in those with specific risk factors, are needed.
  • Please see Special Considerations in Children for more information.

Clinical Trials

  • Health care providers are encouraged to discuss participation in anti-SARS-CoV-2 monoclonal antibody clinical trials with patients who have mild to moderate COVID-19.

Drug Availability

  • Bamlanivimab plus etesevimab and casirivimab plus imdevimab are available through FDA EUAs.17
  • Given the possibility of a limited supply of bamlanivimab plus etesevimab and casirivimab plus imdevimab, as well as challenges of distributing and administering the drugs, patients who are at highest risk for COVID-19 progression based on the EUA criteria should have priority access to the drugs.18,19
  • Efforts should be made to ensure that communities most affected by COVID-19 have equitable access to these monoclonal antibodies.

High-Risk Criteria in the Emergency Use Authorizations for Anti-SARS-CoV-2 Monoclonal Antibodies

The FDA EUAs for all available anti-SARS-CoV-2 monoclonal antibodies and combinations have the same criteria for use: they allow for the use of the monoclonal antibodies for the treatment of COVID-19 in nonhospitalized adults and children aged ≥12 years and weighing ≥40 kg who are at high risk for progressing to severe COVID-19 and/or hospitalization.

High-risk individuals as specified in the EUA are those who meet at least one of the following criteria:

  • Body mass index (BMI) ≥35
  • Chronic kidney disease
  • Diabetes mellitus
  • Immunocompromising condition
  • Currently receiving immunosuppressive treatment
  • Aged ≥65 years
  • Aged ≥55 years and have:
    • Cardiovascular disease, or
    • Hypertension, or
    • Chronic obstructive pulmonary disease or another chronic respiratory disease.
  • Aged 12 to 17 years and have:
    • BMI ≥85th percentile for their age and gender based on the Centers for Disease Control and Prevention growth charts; or
    • Sickle cell disease; or
    • Congenital or acquired heart disease; or
    • Neurodevelopmental disorders (e.g., cerebral palsy); or
    • A medical-related technological dependence that is not related to COVID-19 (e.g., tracheostomy, gastrostomy, positive pressure ventilation); or
    • Asthma or a reactive airway or other chronic respiratory disease that requires daily medication for control.
  1. Jiang S, Hillyer C, Du L. Neutralizing antibodies against SARS-CoV-2 and other human coronaviruses. Trends Immunol. 2020;41(5):355-359. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32249063.
  2. Wang Y, Zhang L, Sang L, et al. Kinetics of viral load and antibody response in relation to COVID-19 severity. J Clin Invest. 2020;130(10):5235-5244. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32634129.
  3. Weinreich DM, Sivapalasingam S, Norton T, et al. REGN-COV2, a neutralizing antibody cocktail, in outpatients with COVID-19. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33332778.
  4. Coronavirus (COVID-19) update: FDA revokes emergency use authorization for monoclonal antibody bamlanivimab. News release. Food and Drug Administration. 2021. Available at: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-revokes-emergency-use-authorization-monoclonal-antibody-bamlanivimab. Accessed April 19, 2021.
  5. Centers for Disease Control and Prevention. SARS-CoV-2 variant classifications and definitions. 2021. Available at: https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html. Accessed April 5, 2021.
  6. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of bamlanivimab and etesevimab. 2021. Available at: https://www.fda.gov/media/145802/download. Accessed February 17, 2021.
  7. Food and Drug Administration. Fact sheet for healthcare providers: emergency use authorization (EUA) of REGEN-COV (casirivimab and imdevimab). 2020. Available at: https://www.fda.gov/media/145611/download.
  8. Wang P, Liu L, Iketani S, et al. Increased resistance of SARS-CoV-2 variants B.I.315 and B.I.I.7 to antibody neutralization. bioRxiv. 2021;Preprint. Available at: https://www.biorxiv.org/content/10.1101/2021.01.25.428137v2.
  9. Wang P, Nair MS, Liu L, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33684923.
  10. Wang P, Wang M, Yu J, et al. Increased resistance of SARS-CoV-2 variant P.1 to antibody neutralization. bioRxiv. 2021;Preprint. Available at: https://www.biorxiv.org/content/10.1101/2021.03.01.433466v1.
  11. Food and Drug Administration. Frequently asked questions on the emergency use authorization of casirivimab + imdevimab. 2020. Available at: https://www.fda.gov/media/143894/download. Accessed January 20, 2021.
  12. Food and Drug Administration. Frequently asked questions on the emergency use authorization for bamlanivimab and etesevimab. 2021. Available at: https://www.fda.gov/media/145808/download. Accessed February 17, 2021.
  13. National Institute of Allergy and Infectious Diseases. Statement—NIH-sponsored ACTIV-3 trial closes LY-CoV555 sub-study. 2020. Available at: https://www.niaid.nih.gov/news-events/statement-nih-sponsored-activ-3-trial-closes-ly-cov555-sub-study.
  14. Activ-Tico Ly- CoV555 Study Group, Lundgren JD, Grund B, et al. A neutralizing monoclonal antibody for hospitalized patients with COVID-19. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33356051.
  15. Centers for Disease Control and Prevention. Interim clinical considerations for use of COVID-19 vaccines currently authorized in the United States. 2021. Available at: https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html. Accessed February 17, 2021.
  16. Wolf J, Abzug MJ, Wattier RL, et al. Initial guidance on use of monoclonal antibody therapy for treatment of COVID-19 in children and adolescents. J Pediatric Infect Dis Soc. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33388760.
  17. Public Health Emergency. Outpatient monoclonal antibody treatment for COVID-19 made available under emergency use authorization. March 24, 2021, update on COVID-19 variants and impact on bamlanivimab distribution. 2021. Available at: https://www.phe.gov/emergency/events/COVID19/investigation-MCM/Bamlanivimab/Pages/default.aspx. Accessed April 5, 2021.
  18. Kim L, Garg S, O'Halloran A, et al. Risk factors for intensive care unit admission and in-hospital mortality among hospitalized adults identified through the U.S. coronavirus disease 2019 (COVID-19)-associated hospitalization surveillance network (COVID-NET). Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32674114.
  19. Ko JY, Danielson ML, Town M, et al. Risk factors for COVID-19-associated hospitalization: COVID-19-associated hospitalization surveillance network and behavioral risk factor surveillance system. Clin Infect Dis. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32945846.